Macrocyclic RAS inhibitor

Abstract

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

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority to U.S. Application No. 63 / 351,146, filed on June 10, 2022, and U.S. Application No. 63 / 455,649, filed on March 30, 2023, the entire contents of each of which are incorporated herein by reference in their entirety.

Background Art

[0002] The overwhelming majority of small - molecule drugs act by binding to functionally important pockets on target proteins, thereby controlling the activity of the protein. For example, cholesterol - lowering agents 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 people 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 truth. 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 the above - described small - molecule drug discovery. Such targets are generally referred to as "undruggable." These undruggable targets include a vast and largely untapped reservoir of medically important human proteins. Therefore, there is much interest in discovering new molecular modalities capable of controlling the functions of such undruggable targets.

[0003] Ras proteins (K-Ras, H-Ras, and N-Ras) play an essential role in various human cancers and, therefore, have been well established in the literature as suitable targets for anticancer therapy. In fact, mutations in Ras proteins account for approximately 30% of all human cancers in the United States, and many of these are lethal. Dysregulation of Ras proteins due to mutant activation, overexpression, or upstream activation is common in human tumors, and mutant activation of Ras is frequently found in human cancers. For example, mutant activation of codon 12 in the Ras protein inhibits both the GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of Ras mutant proteins into the "on" (GTP-bound) state (Ras(ON)) and functioning by causing oncogenic MAPK signaling. In particular, Ras exhibits picomolar affinity for GTP and enables Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codon 13 of Ras (e.g., G13D) and at codon 61 (e.g., Q61K) are also causative of oncogenic activity in some cancers.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] In recent decades, despite extensive drug discovery efforts against Ras, drugs that directly target the "on" form of Ras have not yet been approved. Further efforts are needed to identify additional pharmaceuticals for cancers driven by various Ras mutations.

Means for Solving the Problems

[0006] Ras inhibitors are provided herein. These Ras inhibitors target Ras(ON), i.e., selectively bind to Ras(ON) or inhibit Ras(ON) (e.g., selective for the inactive form of Ras bound to GDP). The approach described herein requires the formation of a high-affinity three-component complex between two intracellular proteins that do not interact under normal physiological conditions with the synthetic ligand: the target protein of interest (e.g., Ras), and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophilin A). More specifically, in some embodiments, the inhibitors of Ras described herein drive the formation of a high-affinity tri-complex between the Ras protein and cyclophilin A (CYPA), a widely expressed cytosolic chaperone, thereby inducing a novel binding pocket in Ras. Without being bound by theory, one way in which the compounds of the invention and the complexes they form affect the inhibitory effect in Ras is thought by the inventors to be due to steric occlusion of the interaction site between Ras, which is required to propagate oncogenic signals, and downstream effector molecules such as RAF and PI3K.

[0007] Thus, in some embodiments, the present disclosure features a compound of structural formula Ia, or a pharmaceutically acceptable salt thereof:

[0008]

Chemical formula

[0009] (wherein the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(wherein C is bonded to -C(R 7 R 8 )-), -C(O)NH-CH(R 6 )-(wherein C is bonded to -C(R 7 R 8 )-), optionally substituted C1-C4 heteroalkylene, or 3-8 membered heteroarylene; swIp (switch I / P-loop) is an organic moiety that binds non-covalently to both the switch I binding pocket of the Ras protein and residues 12 or 13 of the P-loop (see, for example, Johnson et al., 292:12981-12993 (2017), which is incorporated herein by reference); X 1 is optionally substituted C1-C2 alkylene, NR, O, or S(O) n ; X 2 is O or NH; X 3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; Each R ’ is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N; Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N; Y 5is CH, CH2, or N; Y 6 is C(O), CH, CH2, or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3-14 membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; R 3 is absent or R 2 and R 3 combine with the atoms to which they are attached to form an optionally substituted 3-8 membered cycloalkyl or an optionally substituted 3-14 membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; R 7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached to form C=CR 7 ’R 8 ’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo; R 16 is hydrogen or C1-C3 alkyl); wherein, in some embodiments, i. the compound is

[0010]

Chemical formula

[0011]

Chemical formula

[0012] or

[0013]

Chemical formula

[0014] is not; or ii. when W is cyclopropyl, the compound is not a compound of formula X, and formula X is

[0015] [Chem.]

[0016] (wherein, R 1X is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2x is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2, or -NHS(O)2NH-).

[0017] In some embodiments, the present disclosure features a compound of structural formula Ib, or a pharmaceutically acceptable salt thereof:

[0018] [Chem.]

[0019] (wherein, the dotted line indicates 0, 1, 2, 3, or 4 non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene; B is absent, -NH-, -N(CH3)-, -O-, -CH(R 9 )-, or >C=CR 9 R 9’ (wherein carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(wherein C is bonded to -C(R 7 R 8 )-), -C(O)NH-CH(R 6 )-(wherein C is bonded to -C(R 7 R 8 )-), optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or is a linker; W is hydrogen, cyano, optionally substituted amino, optionally substituted amide, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 3- to 10-membered heteroaryl; Z is -C(O)- or -S(O)2-; X 1 is optionally substituted C1-C2 alkylene, NR, O, or S(O) n ; X 2 is O or NH; X 3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; Each R ’ is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 are independently C or N; Y 5 is CH, CH2, or N; Y 6 is C(O), CH, CH2, or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3-14 membered heterocycloalkyl; R 2is absent, or is hydrogen, C1-C6 alkyl optionally substituted, C2-C6 alkenyl optionally substituted, C2-C6 alkynyl optionally substituted, 3-6 membered cycloalkyl optionally substituted, 3-7 membered heterocycloalkyl optionally substituted, 6 membered aryl optionally substituted, or 5 or 6 membered heteroaryl optionally substituted; R 3 is absent, or R 2 and R 3 combine with the atom to which they are attached to form a 3-8 membered cycloalkyl optionally substituted or a 3-14 membered heterocycloalkyl optionally substituted; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or C1-C3 alkyl optionally substituted, or R 6 and R 7 combine with the carbon atom to which they are attached to form a 3-6 membered cycloalkyl optionally substituted or a 3-7 membered heterocycloalkyl optionally substituted; R 8 is hydrogen, halogen, hydroxy, cyano, C1-C3 alkoxy optionally substituted, C1-C3 alkyl optionally substituted, C2-C6 alkenyl optionally substituted, C2-C6 alkynyl optionally substituted, 3-8 membered cycloalkyl optionally substituted, 3-14 membered heterocycloalkyl optionally substituted, 5-10 membered heteroaryl optionally substituted, or 6-10 membered aryl optionally substituted, or R7 and R 8 combines with the carbon atom to which they are attached to form C=CR 7 ’R 8 ’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 9 and L combine with the atom to which they are attached to form optionally substituted 3-14 membered heterocycloalkyl; R 9’is hydrogen or optionally substituted C1-C6 alkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo; R 11 is hydrogen or C1-C3 alkyl; R 16 is hydrogen or C1-C3 alkyl); Here, in some embodiments: i. The compound is

[0020]

Chemical formula

[0021]

Chemical formula

[0022] or

[0023]

Chemical formula

[0024] isn't it? or ii. When W is cyclopropyl, the compound is not a compound of formula X, and formula X is

[0025]

Chemical formula

[0026] (wherein R 1Xis optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-15 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; R 2x is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2, or -NHS(O)2NH-).

[0027] There is also provided a pharmaceutical composition comprising a compound of formula Ia or formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. There is also provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, there is provided a method of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0029] There is further provided a method of 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.

[0030] It is specifically contemplated that any limitation discussed with respect to an embodiment of the present invention may apply to any other embodiment of the present invention. Further, any compound or composition of the present invention can be used in any method of the present invention, and any method of the present invention can be used to produce or utilize any compound or composition of the present invention.

[0031] Definitions and Chemical Terms In this application, unless the context clearly dictates otherwise: (i) the term "a" means "one or more"; (ii) the term "or" is used to mean "and / or" except when explicitly referring only to alternatives or when the alternatives are mutually exclusive, although both a definition that refers only to alternatives and "and / or" are supported in this disclosure; (iii) the terms "comprising" and "including" are understood to include the recited components or steps, whether presented by themselves or in conjunction with one or more additional components or steps; and (iv) when ranges are indicated, the endpoints are included.

[0032] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method used to determine the value. In certain embodiments, the term "about" refers to a range of values within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the recited value in either direction (greater than or less than), unless otherwise stated or otherwise apparent from the context (e.g., except when such a number exceeds 100% of the possible value).

[0033] As used herein, the term "adjacent" in the context of describing adjacent atoms refers to divalent atoms directly bonded by a covalent bond. As used herein, the term "compound of the invention" and like terms refer to compounds of formula Ia or formula Ib and their sub-formulas, as well as the compounds of Table 1, whether or not explicitly recited, and in addition, their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers, which are Ras inhibitors described herein.

[0034] The term "wild-type" refers to an entity having a "normal" state or structure or activity as seen in nature (in contrast to mutants, diseases, modified things, etc.). Those skilled in the art will understand that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0035] Those skilled in the art will understand that the specific compounds described herein can exist in one or more different isomeric (e.g., stereoisomeric, geometric isomeric, atropisomeric, tautomeric) forms, or in isotopic (e.g., one or more atoms such as hydrogen substituted with deuterium, where one or more atoms are substituted with different isotopes of the atom) forms. Unless otherwise specified or clear from the context, the structures described can be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0036] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers such as enantiomers and diastereomers are contemplated. Compounds of the disclosure containing an asymmetrically substituted carbon atom can be isolated in optically active form or in racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art and include, for example, resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers such as olefins, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. The Cis and trans geometric isomers in the compounds of the present disclosure are described and can be isolated as a mixture of isomers or in the form of separated isomers.

[0037] In some embodiments, one or more of the compounds described herein can exist in different tautomeric forms. As will be apparent from the context, references to such compounds include all such tautomeric forms unless expressly excluded. In some embodiments, tautomeric forms are obtained by the exchange of a single bond by an adjacent double bond and simultaneously the movement of a proton. In certain embodiments, tautomeric forms can be prototropic tautomers, which are protonation states of isomers having the same empirical formula and total charge as the reference form. Examples of moieties having prototropic tautomeric forms are keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole, in which a proton can occupy two or more positions of the heterocyclic system. In some embodiments, tautomeric forms are in equilibrium or can be stereochemically fixed to one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion.

[0038] Unless otherwise specified, structures shown in this specification also mean that they include compounds that differ only in the presence of one or more isotope-enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, etc., including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine. Isotope-labeled compounds (e.g., compounds labeled with 3 H and 14 C) may be useful in compound or substrate tissue distribution assays. Tritium labeling (i.e., 3 H), and carbon-14 (i.e., 14 C) isotopes may be useful due to the ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., 2 H), etc., can result in higher metabolic stability and, as a result, certain therapeutic advantages can be obtained (e.g., longer in vivo half-life or lower required dosage). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon. 15 O, 13 N, 11 C, and 18Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotope-labeled compounds is known to those skilled in the art. For example, isotope-labeled compounds can generally be prepared by following procedures similar to those disclosed for the compounds of the invention described herein, by replacing unlabeled reagents with labeled reagents.

[0039] As is known in the prior art, many chemical components can be employed in a variety of different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the 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 the form of hydrates or solvates.

[0040] Throughout various places in this specification, the substituents of the disclosed compounds are disclosed in groups or ranges. It is specifically intended that this disclosure includes each and every individual partial combination 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. Further, when a compound contains multiple positions where substituents are disclosed in groups or ranges, unless otherwise specified, this disclosure is intended to include individual compounds and groups of compounds (e.g., genera and subgenera) that include each and every individual partial combination of the individual members at each position.

[0041] The term "X optionally substituted" (e.g., "alkyl optionally substituted") is intended to be equivalent to "X, where X is optionally substituted" (e.g., "alkyl, where the alkyl is optionally substituted"). It is not intended to mean that the feature "X" (e.g., alkyl) itself is optional. As described herein, a particular compound of interest may contain one or more "optionally substituted" moieties. Generally, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when two or more positions of any given structure may be substituted with two or more substituents selected from a particular group, the substituents may be the same or different at all positions. For example, in the term "C1-C6 alkyl-C2-C9 heteroaryl optionally substituted", the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. Combinations of substituents contemplated by the present disclosure preferably result in the formation of stable or chemically suitable compounds. The term "stable", as used herein, refers to a compound that does not substantially change when subjected to the conditions that enable the production, detection, and in certain embodiments, the recovery, purification, and use for one or more of the purposes disclosed herein.

[0042] At a substitutable carbon atom of an "optionally substituted" group, suitable monovalent substituents are independently deuterium, halogen, -(CH2) 0~4 R ○ 、-(CH2) 0~4 OR ○ 、-O(CH2) 0~4 R ○ 、-O-(CH2) 0~4 C(O)OR ○ 、-(CH2)0~4 CH(OR ○ )2, -(CH2) 0~4 SR ○ 、R ○ which may be substituted with -(CH2) 0~4 Ph, R ○ which may be substituted with -(CH2) 0~4 O(CH2) 0~1 Ph,; R ○ which may be substituted with -CH=CHPh, R ○ which may be substituted with -(CH2) 0~4 O(CH2) 0~1 -pyridyl, and optionally (e.g., with methyl) substituted 4- to 11-membered saturated or unsaturated heterocycloalkyl (e.g., 4- to 8-membered saturated or unsaturated heterocycloalkyl (e.g., pyridyl)), 3- to 8-membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), -NO2, -CN, -N3, -(CH2) 0~4 N(R o )2, -(CH2) 0~4 N(R o )C(O)R o , -N(R o )C(S)R o , -(CH2) 0~4 N(R o )C(O)NR o 2, -N(R o )C(S)NR o , -(CH2) 0~4 N(R o )C(O)OR o , -N(R o )N(R o )C(O)R o , -N(R o )N(R o )C(O)NR o , -N(R o )N(R o )C(O)OR o , -(CH2) 0~4 C(O)R o , -C(S)R o , -(CH2) 0~4 C(O)OR o , -(CH2)0~4 -C(O)-N(R o )2, -(CH2) 0~4 -C(O)-N(R o )-S(O)2-R o , -C(NCN)NR o 2, -(CH2) 0~4 C(O)SR o , -(CH2) 0~4 C(O)OSiR o 3, -(CH2) 0~4 OC(O)R o , -OC(O)(CH2) 0~4 SR o , -SC(S)SR o , -(CH2) 0~4 SC(O)R o , -(CH2) 0~4 C(O)NR o , -C(S)NR o , -C(S)SR o , -(CH2) 0~4 OC(O)NR o , -C(O)N(OR o )R o , -C(O)C(O)R o , -C(O)CH2C(O)R o , -C(NOR o )R o , -(CH2) 0~4 SSR o , -(CH2) 0~4 S(O)2R o , -(CH2) 0~4 S(O)2OR o , -(CH2) 0~4 OS(O)2R o , -S(O)2NR o , -(CH2) 0~4 S(O)R o , -N(R o )S(O)2NR o , -N(R o )S(O)2R o , -N(OR o )R o , -C(NOR o )NR o , -C(NH)NR o , -P(O)2R o, -P(O)R o 2, -P(O)(OR o )2, -OP(O)R o 2, -OP(O)(OR o )2, -OP(O)(OR o )R o , -SiR o 3, -(C 1~4 linear or branched alkylene)O-N(R o )2, or -(C 1~4 linear or branched alkylene)C(O)O-N(R o )2 (wherein each R o may be substituted as defined below and is independently hydrogen, -C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2-(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, regardless of the above definition, two independently existing R ○ together with the intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl, monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and these may be substituted as defined below).

[0043] R o (or together with the intervening atom, a ring formed by two independent R o ) suitable monovalent substituents on are independently halogen, -(CH2) 0~2 R ● , -(haloR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2, -O(haloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● 、 -(C 1~4 (a linear or branched alkylene)C(O)OR ● , or -SSR ● (wherein each R ● is unsubstituted or, when preceded by "halo", substituted only by one or more halogens and independently is C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or selected from a 5- to 6-membered, saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur). Suitable divalent substituents on the saturated carbon atoms of R o include =O and =S.

[0044] Suitable divalent substituents on the saturated carbon atoms of a "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)) 2~3 O-, or -S(C(R * 2)) 2~3 S- (wherein each independent R * is hydrogen, C which can be substituted as defined below 1~6(selected from an aliphatic, or an unsubstituted, 5- to 6-membered, saturated ring, partially unsaturated ring, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur). Suitable divalent substituents bonded to an adjacent substitutable carbon of a "optionally substituted" group include -O(CR * 2) 2~3 O- (wherein each independent R * is hydrogen, C 1~6 aliphatic which can be substituted as defined below, or an unsubstituted, 5- to 6-membered, saturated ring, partially unsaturated ring, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0045] R * Suitable substituents on the aliphatic group of ● include halogen, -R ● , -(haloR ● ), -OH, -OR ● ), -CN, -C(O)OH, -C(O)OR ● ), -NH2, -NHR ● ), -NR ● 2, or -NO2 (wherein each R ● is unsubstituted or, when "halo" precedes, is substituted only by one or more halogens and independently is C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered, saturated ring, partially unsaturated ring, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0046] Suitable substituents on a substitutable nitrogen of a "optionally substituted" group include -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R †, -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † is mentioned (in the formula, each R † is independently hydrogen, C 1~6 aliphatic which can be substituted as defined below, or an unsubstituted, 3- to 6-membered, saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independently existing R † together with the intervening atom(s), form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0047] R † Suitable substituents on the aliphatic group of R ● are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2 (in the formula, each R 1~4 is unsubstituted or, when "halo" precedes, is substituted only by one or more halogens and is independently C 0~1 aliphatic, -CH2Ph, -O(CH2) † Ph, or a 5- to 6-membered, saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur). Suitable divalent substituents on the saturated carbon atom of R

[0048] As used herein, the term "acetyl" refers to the group -C(O)CH3. As used herein, the term "alkoxy" refers to -O-C1-C 20 an alkyl group, and an alkoxy group is bonded to the remainder of the compound through an oxygen atom.

[0049] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched, monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10, or 1 to 6) carbons. In some embodiments, the alkyl group is unbranched (i.e., straight-chain), and in some embodiments, the alkyl group is branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0050] As used herein, the term "alkylene" represents a saturated divalent hydrocarbon group derived from a straight-chain or branched, saturated hydrocarbon by removing two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, etc. "C x ~C y alkylene" represents 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-C 10 , C2-C 20 , C2-C6, C2-C 10 , or C2-C 20 alkylene). In some embodiments, alkylene can be further substituted with 1, 2, 3, or 4 substituents as defined herein.

[0051] As used herein, the term "alkenyl", unless otherwise specified, refers to a monovalent, straight-chain 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, exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl includes both cis and trans isomers. As used herein, the term "alkenylene", unless otherwise specified, refers to a divalent, straight-chain 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.

[0052] As used herein, the term "alkynyl" refers to a monovalent, straight-chain 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, exemplified by ethynyl and 1-propynyl.

[0053] As used herein, the term "alkynylsulfone" refers to a group having the structure

[0054]

Chemical formula

[0055] (wherein R is any chemically suitable substituent described herein). As used herein, the term "amino" refers to -N(R † )2, for example, -NH2 and -N(CH3)2.

[0056] As used herein, the term "aminoalkyl" refers to an alkyl moiety substituted by one or more amino moieties on one or more carbon atoms. As used herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acidic group (e.g., -CO2H or -SO3H), and the amino acid is attached to the parent molecular group by a side chain, an amino group, or an acid group (e.g., a 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, the amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid, in some embodiments, the amino acid is a D-amino acid, and in some embodiments, the amino acid is an L-amino acid. "Standard amino acids" means any of the 20 standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0057] As used herein, the term "aryl" represents a monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, and the ring to which the pendant group is attached is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. The aryl ring can be attached to its pendant group by any heteroatom or carbocyclic atom that results in a stable structure, and any of the ring atoms can be optionally substituted unless otherwise specified.

[0058] As used herein, the term "C0" represents a bond. For example, part of the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0059] As used herein, the terms "carbocyclic" and "carboscyclic" refer to a monovalent optionally substituted C3-C 12 monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, fused, or spirocyclic, all rings being formed of carbon atoms and at least one ring being non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carboscyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. The carbocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure, and any of the ring atoms may be optionally substituted unless otherwise specified.

[0060] As used herein, the term "carbonyl" represents a C(O) group that can also be represented as C=O. As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or the non-protonated corresponding group.

[0061] As used herein, the term "cyano" represents a -CN group. As used herein, the term "cycloalkyl" represents a monovalent saturated cyclic hydrocarbon group, which may be bridged, fused, or spirocyclic having 3-8 ring carbons unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0062] As used herein, the term "cycloalkenyl" represents a monovalent, non-aromatic, saturated cyclic hydrocarbon group, which may be cross-linked, fused, or spirocyclic having 3 to 8 ring carbons, and includes one or more carbon-carbon double bonds, unless otherwise specified.

[0063] As used herein, the term "diastereomer" means stereoisomers that are not mirror images of each other and cannot be superimposed on each other. As used herein, the term "enantiomer" means each individual optically active form of a compound of the invention having an optical purity or enantiomeric excess of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98% (measured by standard methods in the art).

[0064] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen is replaced by a halogen. As used herein, the term "haloalkyl" represents an alkyl moiety substituted with one or more identical or different halogen moieties on one or more carbon atoms.

[0065] As used herein, the term "halogen" represents 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 is replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom can appear in the middle or at the end of the radical. As used herein, the term "heteroalkylene" refers to a divalent, straight-chain or branched-chain alkylene group of 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons), unless otherwise specified, with at least one carbon atom replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom can appear in the middle or at the end of the radical.

[0066] As used herein, the term "heteroaryl" refers to a monovalent, monocyclic or polycyclic cyclic structure that contains at least one complete aromatic ring. That is, these contain 4n+2 π electrons within a monocyclic or polycyclic ring system and contain at least one ring heteroatom selected from N, O, or S within the aromatic ring. Exemplary unsubstituted heteroaryl groups 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 is fused to one or more aryl or carbocyclic rings, such as a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. The heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted unless otherwise specified. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0067] As used herein, the term "heterocycloalkyl" represents a monovalent, monocyclic, bicyclic, or polycyclic ring system, which may be bridged, fused, or spirocyclic, with at least one ring being non-aromatic, and the non-aromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has 0 to 2 double bonds, and the 6- and 7-membered rings have 0 to 3 double bonds. Exemplary unsubstituted heterocycloalkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term "heterocycloalkyl" also represents heterocyclic compounds having a bridged polycyclic structure in which one or more carbon or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as a quinuclidinyl group. The term "heterocycloalkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, pyridine ring, or pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthyridinyl. The heterocycloalkyl ring can be attached to its pendant group at any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted unless otherwise specified.

[0068] As used herein, the term "hydroxy" represents an -OH group. As used herein, the term "hydroxyalkyl" represents an alkyl moiety substituted by one or more -OH moieties on one or more carbon atoms.

[0069] As used herein, the term "isomer" means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the invention. The compounds of the invention can have one or more chiral centers or double bonds and, therefore, are recognized to exist as stereoisomers, such as double bond isomers (i.e., geometric E / Z isomers), or diastereomers (e.g., enantiomers (i.e., (+) or (-)), or cis / trans isomers). According to the invention, the chemical structures illustrated herein, i.e., the compounds of the invention, include both all corresponding stereoisomers, i.e., in stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure form) and mixtures of enantiomers and stereoisomers, e.g., racemic compounds. Mixtures of enantiomers and stereoisomers of the compounds of the invention can typically be resolved into the constituent enantiomers or stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0070] As used herein, the term "linker" refers to a divalent organic moiety that connects a first moiety (e.g., a macrocyclic moiety) to a second moiety (e.g., a crosslinking group). In some embodiments, the linker results in compounds capable of achieving an IC50 of 2 μM or less in the following examples and in the Ras-RAF disruption assay protocol provided herein.

[0071] The purpose of this biochemical assay is to measure the ability of a test compound to facilitate the formation of a ternary complex between a nucleotide-loaded Ras isoform and cyclophilin A, and the resulting ternary complex is BRAF RBDDisrupt the binding to the construct and inhibit Ras signaling via the RAF effector.

[0072] In assay buffer containing 25 mM HEPES (pH 7.3), 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, tagless cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variants), and GST-BRAF RBD are combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. The compounds are present in the plate wells as a 10-point 3-fold dilution series starting from a final concentration of 30 μM. After incubation at 25 °C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin is added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction is incubated for an additional 1.5 hours. The TR-FRET signal is read on a microplate reader (excitation 320 nm, fluorescence 665 / 615 nm). Compounds that promote the disruption of the Ras:RAF complex are identified as those that induce a decrease in the TR-FRET ratio relative to DMSO control wells.

[0073] In some embodiments, the linker contains 20 or fewer linear atoms. In some embodiments, the linker contains 15 or fewer linear atoms. In some embodiments, the linker contains 10 or fewer linear atoms. In some embodiments, the linker has a molecular weight of less than 500 g / mol. In some embodiments, the linker has a molecular weight of less than 400 g / mol. In some embodiments, the linker has a molecular weight of less than 300 g / mol. In some embodiments, the linker has a molecular weight of less than 200 g / mol. In some embodiments, the linker has a molecular weight of less than 100 g / mol. In some embodiments, the linker has a molecular weight of less than 50 g / mol.

[0074] As used herein, the term "stereoisomer" refers to all possible different isomeric forms and structural forms that a compound can have (e.g., a compound of any formula described herein), in particular, all possible stereochemical isomeric forms and structural isomeric forms of the basic molecular structure, including atropisomers, all diastereomers, enantiomers, or conformational isomers. Some compounds of the present invention can exist in different tautomeric forms, and all of the latter are included within the scope of the present invention.

[0075] As used herein, the term "sulfonyl" represents the -S(O)2- group. As used herein, the term "thiocarbonyl" refers to the -C(S)- group.

[0076] Those skilled in the art reading this disclosure will understand that the specific compounds described herein can be provided or utilized in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may relate to a particular form of the compound. In some embodiments, reference to a particular compound may relate to the compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound from a racemic mixture of the compound, a particular salt of a compound may be considered a different form from another salt form of the compound, a preparation containing one structural isomer ((Z) or (E)) of a double bond may be considered a different form from one containing the other structural isomer ((E) or (Z)) of the double bond, and a preparation in which one or more atoms are isotopes different from those present in a reference preparation may be considered a different form.

Mode for Carrying Out the Invention

[0077] Compound Ras inhibitors are provided herein. These Ras inhibitors target Ras(ON), i.e., selectively bind to Ras(ON) or inhibit Ras(ON) (e.g., are selective for Ras in the inactive state with GDP bound). As used herein, the term "RAS(ON) inhibitor" refers to an inhibitor that targets, i.e., selectively binds to or selectively inhibits, active-state RAS with GTP bound (e.g., is more selective than inactive-state RAS with GDP bound). Inhibition of active-state RAS with GTP bound includes, for example, inhibition of oncogenic signaling from active-state RAS with GTP bound. In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and selectively inhibits active-state RAS with GTP bound. In certain embodiments, the RAS(ON) inhibitor can also bind to or inhibit inactive-state RAS with GDP bound (e.g., with lower affinity or inhibition constant than active-state RAS with GTP bound). In some embodiments, the RAS(ON) inhibitor has a molecular weight of 800 - 1100 Da (including both ends). Thus, for example, the term "KRAS(ON) inhibitor" refers to any inhibitor that binds to KRAS at its GDP-bound "on" position. A "KRAS G12C (ON) inhibitor" is a KRAS inhibitor that selectively binds to or targets the G12C variant of KRAS. Non-limiting examples of RAS(ON) inhibitors (some of which are KRAS G12C (ON) inhibitors) are provided in WO2021091982, WO2021091967, WO2021091956, and WO2020132597.

[0078] As used herein, the term "RAS(OFF) inhibitor" refers to an inhibitor that targets, i.e., selectively binds to, or selectively inhibits, the inactive state of RAS bound to GDP, i.e., is more selective than the active state of RAS bound to GTP. Inhibition of the inactive state of RAS bound to GDP includes, for example, inhibiting the adaptation of RAS to its active conformation by isolating the inactive state by inhibiting the exchange of GDP for GTP. In certain embodiments, the RAS(OFF) inhibitor can also bind to, or inhibit, the active state of RAS bound to GTP (e.g., with a lower affinity or inhibition constant than the inactive state of RAS bound to GDP). In some embodiments, the RAS(OFF) inhibitor has a molecular weight of less than 700 Da. In some embodiments, the RAS(OFF) inhibitor has a molecular weight of less than 700 Da. Thus, for example, the term "KRAS(OFF) inhibitor" refers to any inhibitor that binds to KRAS at its GDP-bound "off" position. "KRAS G12C (OFF) inhibitor" is a KRAS inhibitor that selectively binds to or targets the G12C variant of KRAS. KRAS G12C (OFF) inhibitors are known in the art and non-limiting examples include adagrasib and sotorasib. Additional KRAS(OFF) inhibitors are provided herein.

[0079] The term "inhibitor" means a compound or agent (e.g., a peptide, an antibody) that prevents a biomolecule (e.g., a protein) from completing or initiating a reaction. An inhibitor can inhibit a reaction by competitive, uncompetitive, or non-competitive means.

[0080] The approaches described herein require the formation of a high-affinity three-component complex between two intracellular proteins that do not interact under normal physiological conditions with a synthetic ligand: a target protein of interest (e.g., Ras), and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophilin A). More specifically, in some embodiments, the inhibitors of Ras described herein drive the formation of a high-affinity tri-complex between the Ras protein and cyclophilin A (CYPA), a widely expressed cytosolic chaperone, thereby inducing a new binding pocket in Ras. Without being bound by theory, one way in which the compounds of the invention and the complexes they form affect the inhibitory effect on Ras is thought by the inventors to be due to steric occlusion of the interaction site between Ras, which is required to propagate oncogenic signals, and downstream effector molecules such as RAF.

[0081] Without being bound by theory, the inventors hypothesize that the non-covalent interactions of the compounds of the invention with Ras and chaperone proteins (e.g., cyclophilin A) may contribute to the inhibition of Ras activity. For example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bond interactions, and combinations thereof, may contribute to the ability of the compounds of the invention to form complexes and act as Ras inhibitors. Accordingly, various Ras proteins (e.g., wild-type Ras or Ras amp , or K-Ras, N-Ras, H-Ras, and their mutants at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, and others described herein, and combinations of Ras proteins) may be inhibited by the compounds of the invention.

[0082] Accordingly, compounds having the structure of formula Ia, or pharmaceutically acceptable salts thereof, are provided herein:

[0083]

Chemical formula

[0084] (wherein the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )(wherein C is bonded to -C(R 7 R 8 )-), -C(O)NH-CH(R 6 )(wherein C is bonded to -C(R 7 R 8 )-), optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; swIp (switch I / P-loop) is an organic moiety that non-covalently binds to both the switch I binding pocket of the Ras protein and residues 12 or 13 of the P-loop (see, for example, Johnson et al., 292:12981-12993 (2017), which is incorporated herein by reference); X 1 is optionally substituted C1-C2 alkylene, NR, O, or S(O) n ; X 2 is O or NH; X 3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R’ is independently H or C1-C4 alkyl optionally substituted; Y 1 is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 are independently C or N; Y 5 is CH, CH2, or N; Y 6 is C(O), CH, CH2, or N; R 1 is cyano, C1-C6 alkyl optionally substituted, C1-C6 heteroalkyl optionally substituted, 3-6 membered cycloalkyl optionally substituted, 3-6 membered cycloalkenyl optionally substituted, 3-6 membered heterocycloalkyl optionally substituted, 6-10 membered aryl optionally substituted, or 5-10 membered heteroaryl optionally substituted, or R 1 and R 2 combine with the atom to which they are attached to form a 3-14 membered heterocycloalkyl optionally substituted; R 2 is absent, hydrogen, C1-C6 alkyl optionally substituted, C2-C6 alkenyl optionally substituted, C2-C6 alkynyl optionally substituted, 3-6 membered cycloalkyl optionally substituted, 3-7 membered heterocycloalkyl optionally substituted, 6 membered aryl optionally substituted, 5 or 6 membered heteroaryl optionally substituted; R 3 is absent or R 2 and R 3 combine with the atom to which they are attached to form a 3-8 membered cycloalkyl optionally substituted or a 3-14 membered heterocycloalkyl optionally substituted; R 4is absent, or is hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 together with the carbon atom to which they are attached form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7 ’R 8 ’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or together with the carbon to which they are attached form carbonyl; R 7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo; R 16 is hydrogen or C1-C3 alkyl); wherein, in some embodiments, i. the compound is

[0085]

Chemical formula

[0086]

Chemical formula

[0087] or

[0088]

Chemical formula

[0089] is it not? or ii. When W is cyclopropyl, the compound is not a compound of formula X, where formula X is

[0090]

Chemical formula

[0091] (wherein R 1X is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-15 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; R 2x is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2, or -NHS(O)2NH-).

[0092] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Ib:

[0093]

Chemical formula

[0094] (wherein the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene; B is absent or -NH-, -N(CH3)-, -O-, -CH(R 9 )-, or >C=CR 9 R 9’ (wherein carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-), optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6 membered arylene, or 5-6 membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(wherein C is bonded to -C(R 7 R 8 )-), -C(O)NH-CH(R 6 )-(wherein C is bonded to -C(R 7 R 8 )-), optionally substituted C1-C4 heteroalkylene, or 3-8 membered heteroarylene; L is absent or is a linker; W is hydrogen, cyano, optionally substituted amino, optionally substituted amide, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3-11 membered heterocycloalkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 3-10 membered heteroaryl; Z is -C(O)- or -S(O)2-; X 1 is C1-C2 alkylene, NR, O, or S(O) optionally substituted n ; X 2 is O or NH; X 3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, C1-C4 alkyl optionally substituted, C2-C4 alkenyl optionally substituted, C2-C4 alkynyl optionally substituted, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R ’ is independently H or C1-C4 alkyl optionally substituted; Y 1 is C, CH, or N; Y 2 、Y 3 、Y 4 、and Y 7 are independently C or N; Y 5 is CH, CH2, or N; Y 6 is C(O), CH, CH2, or N; R 1 is cyano, C1-C6 alkyl optionally substituted, C1-C6 heteroalkyl optionally substituted, 3-6 membered cycloalkyl optionally substituted, 3-6 membered cycloalkenyl optionally substituted, 3-6 membered heterocycloalkyl optionally substituted, 6-10 membered aryl optionally substituted, or 5-10 membered heteroaryl optionally substituted, or R 1 and R 2 combine with the atom to which they are attached to form a 3-14 membered heterocycloalkyl optionally substituted; R 2is absent, or is hydrogen, C1-C6 alkyl optionally substituted, C2-C6 alkenyl optionally substituted, C2-C6 alkynyl optionally substituted, 3-6 membered cycloalkyl optionally substituted, 3-7 membered heterocycloalkyl optionally substituted, 6 membered aryl optionally substituted, or 5 or 6 membered heteroaryl optionally substituted; R 3 is absent, or R 2 and R 3 together with the atom to which they are attached form a 3-8 membered cycloalkyl optionally substituted or a 3-14 membered heterocycloalkyl optionally substituted; R 4 is absent, or is hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or C1-C3 alkyl optionally substituted, or R 6 and R 7 together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl optionally substituted or a 3-7 membered heterocycloalkyl optionally substituted; R 8 is hydrogen, halogen, hydroxy, cyano, C1-C3 alkoxy optionally substituted, C1-C3 alkyl optionally substituted, C2-C6 alkenyl optionally substituted, C2-C6 alkynyl optionally substituted, 3-8 membered cycloalkyl optionally substituted, 3-14 membered heterocycloalkyl optionally substituted, 5-10 membered heteroaryl optionally substituted, or 6-10 membered aryl optionally substituted, or R7 and R 8 combines with the carbon atom to which they are attached to form C=CR 7 ’R 8 ’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or in combination with the carbon to which they are attached, form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 9 and L combine with the atom to which they are attached to form optionally substituted 3-14 membered heterocycloalkyl; R 9’is hydrogen or optionally substituted C1-C6 alkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo; R 11 is hydrogen or C1-C3 alkyl; R 16 is hydrogen or C1-C3 alkyl); Here, in some embodiments: i. The compound is

[0095]

Chemical formula

[0096]

Chemical formula

[0097] or

[0098]

Chemical formula

[0099] isn't it? or ii. When W is cyclopropyl, the compound is not a compound of formula X, and formula X is

[0100]

Chemical formula

[0101] (wherein R 1Xis C1-C6 alkyl optionally substituted, C1-C6 heteroalkyl optionally substituted, 3-6 membered cycloalkyl optionally substituted, 3-6 membered cycloalkenyl optionally substituted, 3-15 membered heterocycloalkyl optionally substituted, 6-10 membered aryl optionally substituted, or 5-10 membered heteroaryl optionally substituted; R 2x is hydrogen, C1-C6 alkyl optionally substituted, C2-C6 alkenyl optionally substituted, C2-C6 alkynyl optionally substituted, 3-6 membered cycloalkyl optionally substituted, 3-7 membered heterocycloalkyl optionally substituted, 6 membered aryl optionally substituted, 5 or 6 membered heteroaryl optionally substituted; Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2, or -NHS(O)2NH-).

[0102] In some embodiments, Z is -C(O)-. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Ic:

[0103]

Chemical formula

[0104] (wherein Y 5 and Y 6 are independently CH or N; R 1is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; R 3 is absent, or R 2 and R 3 combine with the atoms to which they are attached to form an optionally substituted 3-8 membered cycloalkyl or an optionally substituted 3-14 membered heterocycloalkyl; R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl).

[0105] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula Id:

[0106]

Chemical formula

[0107] (wherein B is absent or -CH(R 9)-(wherein carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or R 2 and R 3 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl).

[0108] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Ie:

[0109]

Chemical formula

[0110] (wherein B is absent or -CH(R 9 )- (wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6 membered arylene, or 5-6 membered heteroarylene; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3-11 membered heterocycloalkyl, optionally substituted 3-8 membered cycloalkyl, or optionally substituted 3-8 membered heteroaryl; R 1is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; R 3 is absent or R 2 and R 3 combine with the atoms to which they are attached to form an optionally substituted 3-8 membered cycloalkyl or an optionally substituted 3-14 membered heterocycloalkyl; R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl).

[0111] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula If:

[0112]

Chemical formula

[0113] (wherein B is absent or -CH(R 9)-(wherein carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered hetero cycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3- to 11-membered hetero cycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered hetero cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl; R 8 is C1-C3 alkyl; R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered hetero cycloalkyl).

[0114] In some embodiments, R 1is a 5- to 10-membered heteroaryl, optionally substituted. In some embodiments, R 1 is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[0115] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula Ig:

[0116]

Chemical formula

[0117] (wherein B is absent or -CH(R 9 ))-(wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-), an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; W is hydrogen, an optionally substituted amino, an optionally substituted C1-C4 alkoxy, an optionally substituted C1-C4 hydroxyalkyl, an optionally substituted C1-C4 aminoalkyl, an optionally substituted C1-C4 haloalkyl, an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, an optionally substituted 3- to 11-membered heterocycloalkyl, an optionally substituted 3- to 8-membered cycloalkyl, or an optionally substituted 3- to 8-membered heteroaryl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl; R 8 is C1-C3 alkyl; R 9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; X e is N, CH, or CR 17 and; X f is N or CH; R 12 is optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 17 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl).

[0118] In some embodiments, R 7 is methyl. In some embodiments, R 8 is methyl. In some embodiments, A is optionally substituted C2-C4 alkylene. In some embodiments, A is optionally substituted C3 alkylene. In some embodiments, A is

[0119]

Chemical formula

[0120] and; In some embodiments, A is optionally substituted C2-C4 alkenylene. In some embodiments, A is optionally substituted C3 alkenylene. In some embodiments, A is optionally substituted C1-C4 heteroalkylene. In some embodiments, A is optionally substituted C2 heteroalkylene. In some embodiments, A is

[0121]

Chemical formula

[0122] as follows. In some embodiments, R 1 is

[0123]

Chemical formula

[0124] as follows. In some embodiments, R 1 is

[0125]

Chemical formula

[0126] as follows. In some embodiments, R 1 is

[0127]

Chemical formula

[0128] as follows (wherein Z 1 is N or CH, m is 1 or 2; R 18 、R 19 、R 20 、and R 21is, independently of each other, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R 18 and R 20 combine with the atom to which they are attached to form an optionally substituted 3-8 membered cycloalkyl or an optionally substituted 3-8 membered heterocycloalkyl, or R 20 and R 21 combine with the atom to which they are attached to form an optionally substituted 3-8 membered heterocycloalkyl, or R 19 and R 20 combine with the atom to which they are attached to form an optionally substituted 4-8 membered heterocycloalkyl).

[0129] In some embodiments, R 1 is

[0130]

Chemical formula

[0131] is. In some embodiments, R 1 is

[0132]

Chemical formula

[0133] is. In some embodiments, R 18 is methyl. In some embodiments, R 1 is

[0134]

Chem.

[0135] is. In some embodiments, B is -CHR 9 -. In some embodiments, R 9 is optionally substituted C1-C6 alkyl, or optionally substituted 3-6 membered cycloalkyl. In some embodiments, B is optionally substituted 6 membered arylene. In some embodiments, B is absent.

[0136] In some embodiments, the linker has the structure of formula II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula II (wherein A 1 is the bond between the linker and B; A 2 is the bond between W and the linker; B 1 , B 2 , B 3 , and B 4 are each independently optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NR N selected from; R Nis hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 cycloalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is optionally substituted C1-C 10 alkylene, optionally substituted C2-C 10 alkenylene, optionally substituted C2-C 10 alkynylene, optionally substituted 3- to 14-membered heterocycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C 10 polyethylene glycol, or optionally substituted C1-C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - is a chemical bond that attaches to -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 ).

[0137] In some embodiments, the linker is acyclic. In some embodiments, the linker has the structure of Formula IIa:

[0138]

Chemical formula

[0139] (wherein X a is absent or is N, R 14 is absent, hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C3 cycloalkyl; L 2 is absent, -C(O)-, -SO2-, optionally substituted C1-C4 alkylene, or optionally substituted C1-C4 heteroalkylene, X a , R 14 , or L 2 and at least one of them is present).

[0140] In some embodiments, the linker is a cyclic group or contains a cyclic group. In some embodiments, the linker has the structure of formula IIb:

[0141] [Chemical formula]

[0142] (wherein o is 0 or 1; X b is C(O) or SO2; R 15 is hydrogen or optionally substituted C1-C6 alkyl; Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L 3 is absent, -C(O)-, -SO2-, optionally substituted C1-C4 alkylene, or optionally substituted C1-C4 heteroalkylene).

[0143] In some embodiments, there is no linker. In some embodiments, W is hydrogen. In some embodiments, W is cyclopropyl optionally substituted, cyclobutyl optionally substituted, cyclopentyl optionally substituted, cyclohexyl optionally substituted, piperidine optionally substituted, piperazine optionally substituted, pyridine optionally substituted, or phenyl optionally substituted. In some embodiments, W is amino optionally substituted. In some embodiments, W is amide optionally substituted. In some embodiments, W is C1-C4 alkoxy optionally substituted. In some embodiments, W is C1-C4 alkyl optionally substituted. In some embodiments, W is C1-C4 hydroxyalkyl optionally substituted. In some embodiments, W is C1-C4 aminoalkyl optionally substituted. In some embodiments, W is C1-C4 haloalkyl optionally substituted. In some embodiments, W is C1-C4 guanidinoalkyl optionally substituted. In some embodiments, W is C0-C4 alkyl, 3-11 membered heterocycloalkyl optionally substituted. In some embodiments, W is 3-10 membered cycloalkyl optionally substituted. In some embodiments, W is 3-10 membered heteroaryl optionally substituted. In some embodiments, W is 6-10 membered aryl optionally substituted.

[0144] In some embodiments, the compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or atropisomer thereof.

[0145] [Table 1-1]

[0146]

Table 1-2

[0147] In some embodiments, the compounds of the present invention have improved oral bioavailability (%F) compared to those known in the art. Methods for measuring oral bioavailability are known in the art, and one such method is provided below: Oral bioavailability can be determined in BALB / c mice. After intravenous (IV) bolus administration and forced oral (PO) administration of the test compound, approximately 30 μL of whole blood samples are collected at predetermined time points into tubes containing K2EDTA. The blood samples are centrifuged at 4600 rpm for about 5 minutes at 4 °C, and the plasma samples are stored at -80 °C prior to bioanalysis. The plasma samples are extracted by protein precipitation and analyzed by tandem mass spectrometry (LC MS / MS), for example, using an API 5500 system, by electrospray positive ionization method.

[0148] All PK parameters can be derived from plasma concentration data over time by non-compartmental analysis using WinNonlin. Bioavailability (F%, also %F) is estimated using the following formula:

[0149]

Equation

[0150] Generally, an F% (or %F) value greater than 30% is preferred, and a value greater than 50% is more preferred. In some embodiments, the compounds of the present invention are more selective for one or more specific Ras variants over other Ras variants or wild-type as compared to those known in the art. Methods for measuring such selectivity are known in the art, such as the Ras-Raf binding assay, and the protocol thereof is provided in the following examples. Thus, in some embodiments, the compounds of the present invention are selective for KRAS G12C over other Ras variants or wild-type. In some embodiments, the compounds of the present invention are selective for KRAS G12D over other Ras variants or wild-type. In some embodiments, the compounds of the present invention are selective for KRAS G12V over other Ras variants or wild-type. In some embodiments, the compounds of the present invention are selective for KRAS G12D over other Ras variants or wild-type. In some embodiments, the compounds of the present invention are selective for NRAS Q61K over other Ras variants or wild-type. In some embodiments, the compounds of the present invention are selective for KRAS G12D and KRAS G12V over other Ras variants and wild-type. The compounds of the present invention may also exhibit higher selectivity with respect to other RAS variants disclosed herein, or combinations thereof. In some embodiments, the compounds of the present invention exhibit an IC50 value of less than 30 nM against one or more of the Ras variants described herein in the above-described Ras-Raf binding assay.

[0151] In some embodiments, the compounds of the present invention are more potent for one or more specific Ras variants over other Ras variants or wild-type as compared to those known in the art. Methods for measuring such potency are known in the art, such as the pERK assay, and the protocol thereof is provided in the following examples. Thus, in some embodiments, the compounds of the present invention exhibit higher potency against KRAS G12D than those known in the art. In some embodiments, the compounds of the present invention are...G12V exhibits greater potency than those known in the art. In some embodiments, the compounds of the present invention are KRAS G12C exhibits greater potency than those known in the art. In some embodiments, the compounds of the present invention are KRAS G12D and KRAS G12V both exhibit greater potency than those known in the art. The compounds of the present invention may also exhibit greater potency against other RAS variants disclosed herein, or combinations thereof.

[0152] In some embodiments, the compounds of the present invention exhibit a greater detrimental effect on cell viability against one or more specific Ras variants compared to those known in the art, as compared to other Ras variants or the wild type. Methods for measuring cell viability are known in the art, such as the CellTiter-Glo® Cell Viability Assay, and its protocol is provided in the following examples. Thus, in some embodiments, the compounds of the present invention exhibit a greater decrease in cell viability against KRAS G12D compared to those known in the art. In some embodiments, the compounds of the present invention exhibit a greater decrease in cell viability against KRAS G12V compared to those known in the art. In some embodiments, the compounds of the present invention exhibit a greater decrease in cell viability against KRAS G12C compared to those known in the art. In some embodiments, the compounds of the present invention exhibit a greater decrease in cell viability against KRAS G12D and KRAS G12V both compared to those known in the art. The compounds of the present invention may also exhibit a greater decrease in cell viability compared to other RAS variants disclosed herein, or combinations thereof.

[0153] In some embodiments, the compounds of the present invention may exhibit high metabolic stability, permeability, or solubility, or combinations thereof, relative to those known in the art. Methods for measuring such properties are known in the art. In some embodiments, the compounds of the present invention may show improvement with respect to any of the following properties or combinations thereof, compared to those known in the art: selectivity, efficacy, cell viability, metabolic stability, permeability, or solubility.

[0154] In some embodiments, the compounds of the present invention are, for example, prodrugs for administration to cells or to a subject in need thereof, or act as such prodrugs. Also provided are pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0155] Also further provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The cancer can be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid cancer, myelodysplastic syndrome, or squamous cell lung cancer. In some embodiments, the cancer comprises a Ras mutation such as K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L, or combinations thereof. In some embodiments, the cancer comprises a Ras mutation such as N-Ras G12D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P, or combinations thereof. Other Ras mutations are described herein.

[0156] There is also provided a method for treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0157] There is also provided 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 present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L. The Ras protein can be, for example, N-Ras G12D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P. Other Ras proteins are described herein. The cell can be a cancer cell such as a pancreatic cancer cell, a colorectal cancer cell, a lung cancer (e.g., a non-small cell lung cancer cell), an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid cancer cell, a myelodysplastic syndrome cell, a melanoma cell, or a lung squamous cell carcinoma cell. Other cancer types are described herein. The cell can be in vivo or in vitro.

[0158] With respect to the compounds of the present invention, one stereoisomer can exhibit better inhibition than another stereoisomer. For example, one atropisomer can exhibit inhibition while another atropisomer may exhibit little or no inhibition.

[0159] In some embodiments, the methods or uses described herein further comprise administering an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, 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, a CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anti-cancer therapy is an SHP2 inhibitor. Other additional anti-cancer therapies are described herein.

[0160] Synthesis method The compounds described herein can be made from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes.

[0161] The compounds of the present invention can be prepared by methods known to those skilled in the art, such as those disclosed in WO2021 / 091956 and WO2022 / 060836, in combination with known synthetic organic chemistry techniques, the disclosures of each of which are incorporated herein by reference. For example, the compounds of the present invention can be synthesized using the methods shown in the following schemes, along with synthetic methods known in the field of synthetic organic chemistry or variations thereof that would be understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following schemes.

[0162] Scheme 1. General synthesis of macrocyclic esters

[0163]

Chemical formula

[0164] The general synthesis of the macrocyclic ester is outlined in Scheme 1. It can be prepared in four steps, starting from a suitably substituted indolyl boronic ester (1), protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol, and a suitably substituted boronic acid, involving palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation reactions.

[0165] (S)-2-Amino-3-(4-bromothiazol-2-yl)propanoic acid (2) can be coupled with methyl (S)-hexahydropyridazine-3-carboxylate to prepare methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (3).

[0166] Coupling of methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (3) and a suitably substituted indolyl boronic ester (1) in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps, gives a suitably protected macrocyclic intermediate (5), from which the final macrocyclic ester can be prepared. Deprotection and coupling with a suitably substituted carboxylic acid (or other coupling partner) gives the macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 6.

[0167] Furthermore, with respect to Scheme 1, the thiazole can be replaced with an alternative, optionally substituted 5- to 6-membered heteroarylene, or an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene (e.g., morpholino), or an optionally substituted 6-membered arylene (e.g., phenyl).

[0168] Scheme 2. Alternative general synthesis of the macrocyclic ester

[0169] [Chemistry]

[0170] Alternatively, the macrocycle can be prepared as described in Scheme 2. An appropriately substituted and protected indolyl boronic acid ester (7) can be coupled with (S)-2-amino-3-(4-bromothiazol-2-yl)propanoic acid in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. After coupling with methyl (S)-hexahydropyridazine-3-carboxylate, hydrolysis and macrolactonization can give the iodo intermediate (11). Subsequent palladium-mediated borylation and coupling with an appropriately substituted iodoaryl or iodoheteroaryl intermediate in the presence of a Pd catalyst can give an appropriately protected macrocyclic intermediate. Alkylation, deprotection, and coupling with an appropriately substituted carboxylic acid (or other coupling partner) can give the macrocyclic product. Additional deprotection or functionalization steps may be required to make the final compound 6.

[0171] Furthermore, with respect to Scheme 2, the thiazole can be replaced with an alternative, optionally substituted 5- to 6-membered heteroarylene, or an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene (e.g., morpholino), or an optionally substituted 6-membered arylene (e.g., phenyl).

[0172] The compounds in Table 1 of this specification were prepared using the methods disclosed herein or using the methods described herein in combination with the knowledge of those skilled in the art. Pharmaceutical Compositions and Methods of Use Pharmaceutical Compositions and Methods of Administration The compounds related to the present invention are Ras inhibitors and are useful for cancer treatment. Accordingly, one embodiment of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and in addition, a method for preparing such a composition using the compound of the present invention.

[0173] As used herein, the term "pharmaceutical composition" refers to a compound such as a compound of the present invention, or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient.

[0174] In some embodiments, the compound is present in the pharmaceutical composition in a unit dose appropriate for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition is formulated for administration in solid or liquid form, including oral administration, such as a drink (aqueous or non-aqueous solution or suspension), a tablet, such as a buccal, sublingual, and those targeted for systemic absorption, a bolus, a powder, a granule, a paste for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as a sterile solution or suspension, or as a sustained release formulation; topical application, such as a cream, an ointment, or a controlled release patch or spray applied to the skin, the lung, or the oral cavity; vaginal or rectal administration, such as in the form of a pessary, a cream, or a foam; sublingual administration; intraocular administration; transdermal administration; or nasal, pulmonary, and other mucosal surface administration.

[0175] As used herein, "pharmaceutically acceptable excipient" refers to any inert component (e.g., a vehicle capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory within the subject. Typical excipients include, for example, anti-adhesion agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coating agents, flavoring agents, fragrances, lubricants (flow promoters), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Excipients include, optionally substituted, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methyl cellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol, but are not limited thereto. Those skilled in the art are familiar with various agents and materials useful as excipients.For example, see, e.g., Ansel, et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0176] The compounds described herein can be provided or utilized in salt form, e.g., pharmaceutically acceptable salt form, whether or not explicitly described, unless explicitly stated to the contrary. As used herein, the term “pharmaceutically acceptable salt” refers to those salts of the compounds described herein that have no excessive toxicity, irritation, allergic response, etc., and are suitable for use in contact with the tissues of humans and other animals within the scope of sound medical judgment, having a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. 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 moiety with a suitable organic acid.

[0177] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts can be acid addition salts including inorganic or organic acids, or the salts can be prepared from inorganic or organic bases in the case of the acidic form of the compounds of the present invention. In some embodiments, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc. for forming basic salts are known in the art. Methods for preparing suitable salts are well established in the art.

[0178] 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, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-(optionally substituted) hydroxyethanesulfonate, 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.

[0179] 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. 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, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or insects. In some embodiments, the subject may be a transgenic animal, a genetically modified animal, or a clone.

[0180] As used herein, the term "dosage form" refers to physically discrete units of a compound (e.g., a compound of the present invention) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such an amount is an appropriate unit dose (or an entire fraction thereof) for administration according to a dosing regimen that has been measured to correlate with a desired or beneficial result when administered to a suitable population (i.e., using a therapeutic dosing regimen). One of ordinary skill in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms. As used herein, the term "dosing regimen" typically refers to a set of unit doses (typically two or more) administered individually to a subject, separated by periods of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosing regimen, which may have one or more doses. In some embodiments, the dosing regimen includes multiple doses, each separated from the others by the same length of time period. In some embodiments, the 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, the different doses within a dosing regimen are different amounts. In some embodiments, the dosing regimen includes a first dose at a first dosage, followed by one or more additional doses at a second dosage different from the first dosage. In some embodiments, the dosing regimen includes a first dose at a first dosage, followed by one or more additional doses at a second dosage the same as the first dosage. In some embodiments, the dosing regimen is correlated with a desired or beneficial result when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0181] "Therapeutic regimen" refers to a dosing regimen in which administration across a relevant population correlates with a desired or beneficial therapeutic result. The term "treatment" (and, additionally, "treating" or "treatment") in its broadest sense refers to any administration of a substance (e.g., a compound of the present invention) that partially or completely remits, alleviates, reduces, inhibits a particular disease, disorder, or condition, partially or completely delays the onset of a particular disease, disorder or condition, or partially or completely reduces the occurrence of one or more symptoms, features, or causes of a particular disease, disorder or condition. In some embodiments, such treatment can be administered to a subject that does not exhibit signs of the associated disease, disorder, or condition, or that exhibits only early signs of the disease, disorder, or condition. Alternatively, or in addition, in some embodiments, treatment can be administered to a subject that exhibits one or more established signs of the associated disease, disorder, or condition. In some embodiments, treatment can be in a subject diagnosed as suffering from the associated disease, disorder, or condition. In some embodiments, treatment can be in a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of progression of the associated disease, disorder, or condition.

[0182] The term "therapeutically effective amount" means an amount sufficient to treat a disease, disorder, or condition in a population suffering from or suspected of having the disease, disorder, or condition when administered according to 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. One of ordinary skill in the art will understand that the term "therapeutically effective amount" does not actually require that treatment success be achieved in a particular individual. Rather, a therapeutically effective amount can be an amount that produces a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. It is specifically understood that a particular subject can actually be "non-responsive" to a "therapeutically effective amount". In some embodiments, reference to a therapeutically effective amount can be reference to an amount measured in one or more specific tissues (e.g., tissues affected by the disease, disorder, or condition), or fluids (e.g., blood, saliva, serum, sweat, tears, urine). One of ordinary skill in the art will understand that in some embodiments, a therapeutically effective amount can be formulated or administered as a single dose. In some embodiments, a therapeutically effective amount can be formulated or administered in multiple doses, for example, as part of a dosing regimen.

[0183] For use in treating a subject, a compound of the invention, or a pharmaceutically acceptable salt thereof, can be formulated as a pharmaceutical or veterinary composition. Depending on the subject to be treated, the method of administration, and the type of treatment desired, e.g., prophylaxis, prevention, or treatment, the compound, or a pharmaceutically acceptable salt thereof, is formulated in a manner consistent with these parameters. A summary of such techniques is provided in Remington: The Science and Practice of Pharmacy, 21 stEdition, 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.

[0184] The compositions can each be prepared according to conventional mixing, granulating, or coating methods, and the pharmaceutical compositions of the present invention can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% (by weight or volume) of the compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, can be present in a total amount of from 1 to 95% by weight of the total weight of a composition such as a pharmaceutical composition.

[0185] The compositions can be provided in dosage forms suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, subcutaneous, topical, transdermal, sublingual, nasal, intravaginal, intravesical, intraurethral, intrathecal, epidural, transtympanic, or intraocular administration, or by injection, inhalation, or direct contact with the nasal, urogenital, reproductive, or oral mucosa. Thus, the pharmaceutical compositions can be, for example, in the form of tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels containing hydrogels, pastes, ointments, creams, plasters, medicated drinks, osmotic delivery devices, suppositories, enemas, injection solutions, implants, sprays, preparations suitable for iontophoresis delivery, or aerosols. The compositions can be formulated according to conventional pharmaceutical practice.

[0186] As used herein, the term "administer" refers to the administration of a composition (e.g., a compound or a formulation containing a compound as 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 intratracheal (including by tracheal instillation), intrabuccal, enteral, transcutaneous, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by endotracheal injection), transdermal, vaginal, or intravitreal administration.

[0187] Formulations can be prepared in a manner suitable for systemic administration or for local or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection), or may be prepared for transdermal, transmucosal, or oral administration. Formulations generally contain a diluent, and in addition may optionally contain adjuvants, buffers, preservatives, and the like. The compound, or a pharmaceutically acceptable salt thereof, may also be administered in liposomal compositions or as microemulsions.

[0188] For injection, the formulation may be prepared in conventional forms as a solution or suspension, or as a solid form suitable for solution or suspension in a liquid prior to injection, or as an emulsion. Suitable excipients include, for example, water, saline, dextrose, glycerol, and the like. Such compositions can also contain an amount of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, for example, sodium acetate, sorbitan monolaurate, and the like.

[0189] A variety of drug sustained release systems have also been devised. See, for example, U.S. Patent No. 5,624,677. For systemic administration, relatively non-invasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and nasal administration can also be mentioned. Oral administration is also suitable for the compounds of the present invention, or their pharmaceutically acceptable salts. Suitable forms include syrups, capsules, and tablets, as understood in the art.

[0190] Each compound described herein, or its pharmaceutically acceptable salt, can be formulated by various methods known in the art. For example, the first agent and the second agent of the combination therapy can be formulated together or individually. Other modalities of combination therapy are described herein.

[0191] Agents formulated individually or separately can be packaged together as a kit. Non-limiting examples include kits containing, for example, two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc., but are not limited thereto. The kit can include optional components useful for unit dose administration to a subject, such as a vial for reconstituting a powder form, a syringe for injection, a customized intravenous delivery system, an inhaler, etc. In addition, the unit dose kit can include instructions for use for the preparation or administration of the composition. The kit can be manufactured as a single-use unit dose for a particular subject, or as multiple uses for a particular subject (either at a fixed dose or as the efficacy of an individual compound, or its pharmaceutically acceptable salt, changes as the treatment progresses), or the kit can include multiple doses suitable for administration to multiple subjects ("bulk packaging"). The components of the kit can be assembled in a carton, blister pack, bottle, tube, etc.

[0192] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with pharmaceutically acceptable non-toxic excipients. These excipients can be, for example, inert diluents or fillers (such as sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (such as cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or arginine); binders (such as sucrose, glucose, sorbitol, acacia, arginine, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methyl cellulose, optionally substituted hydroxypropyl methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adhesives (such as magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be coloring agents, flavoring agents, plasticizers, wetting agents, buffering agents, etc.

[0193] Two or more compounds can be mixed or dispensed in tablets, capsules, or other vehicles. In one example, the first compound is contained inside the tablet and the second compound is present outside, with a substantial portion of the second compound being released before the release of the first compound.

[0194] Formulations for oral use may 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 is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules, and pellets can be prepared using the above-mentioned ingredients under tablets and capsules in a conventional manner, for example using a mixer, a fluidized bed apparatus, or a spray drying apparatus.

[0195] Dissolution or diffusion controlled release can be achieved by appropriate coating of tablets, capsules, pellets, or granules of the compound, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into an appropriate matrix. The controlled release coating can comprise one or more of the coating substances mentioned above, or shellac, beeswax, glyceryl wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-(optionally substituted) hydroxy methacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, or polyethylene glycol. In controlled release matrix formulations, matrix materials can also include, for example, hydrated methyl cellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, acrylic acid-methyl methacrylate methyl, polyvinyl chloride, polyethylene, or halogenated fluorocarbon.

[0196] The liquid forms in which the compounds of the present invention, or pharmaceutically acceptable salts thereof, and compositions can be incorporated for oral administration include aqueous solutions, preferably 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.

[0197] Generally, when administered to humans, the oral dosage of either the compounds of the present invention or pharmaceutically acceptable salts thereof is dependent on the nature of the compound and can be readily determined by those skilled in the art. The dosage can be, for example, about 0.001 mg to about 2000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 100 mg to about 1500 mg per day, about 500 mg to about 1500 mg per day, about 500 mg to about 2000 mg per day, or any range variables thereof. In some embodiments, the range of the daily dose for oral administration can be, for example, within about 0.001 mg to about 2000 mg per kg of human body weight, either as a single dose or divided doses. On the other hand, in some cases, it may be necessary to use dosages outside these limits.

[0198] In some embodiments, the pharmaceutical composition can further comprise an additional compound having anti-proliferative activity. Depending on the mode of administration, the compound, or a pharmaceutically acceptable salt thereof, is formulated into a suitable composition that enables easy delivery. Each compound of the combination therapy, or a pharmaceutically acceptable salt thereof, can be formulated by various methods known in the art. For example, the first agent and the second agent of the combination therapy can be formulated together or individually. Desirably, the first agent and the second agent are formulated together for simultaneous or substantially simultaneous administration of the agents.

[0199] 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, before, or after one or more other desired therapeutic agents or medical procedures. It will be understood that the particular combination of therapies (therapeutic agents or procedures) used in the combination regimen takes into account the suitability of the desired therapy or procedure and the desired therapeutic effect to be achieved. Further, it will be understood that the therapies used can achieve the desired effect for the same disorder or different effects (e.g., control of any adverse effects).

[0200] As described herein, the administration of each drug in combination therapy can independently be once to four times a day, over a period of one day to one year, and further, can even be over the lifetime of the subject. Chronic long-term administration may be indicated.

[0201] Method of Use In some embodiments, the present invention discloses a method of treating a disease or disorder characterized by ectopic Ras activity caused by a Ras variant. In some embodiments, the disease or disorder is cancer.

[0202] Accordingly, there is also provided a method for treating cancer in a subject in need thereof, the method comprising administering to the 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. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small intestine cancer, gastric 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. In some embodiments, the cancer is appendiceal cancer, endometrial cancer, or melanoma. There is also provided a method for treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the 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.

[0203] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds or salts, and the methods provided herein can be used for the treatment of a variety of cancers including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers treatable by the compounds or salts thereof, pharmaceutical compositions containing such compounds or salts, and the methods of the present invention include astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and tumor types such as thyroid cancer and sarcoma, but are not limited thereto. Other cancers include, for example, the following: cardiac cancer, such as non-epithelial malignant tumors (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer, such as bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal cancer, such as esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (epithelial malignant tumor, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, islet cell tumor, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); urogenital cancer, such as kidney cancer (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder cancer and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, non-epithelial malignant tumor), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, non-epithelial malignant tumor, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver cancer, such as liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract cancer, such as gallbladder cancer, ampulla cancer, cholangiocarcinoma; bone cancer, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;Nervous system cancers, such as cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), cancers of the meninges (meningioma, meningosarcoma, gliosis), brain cancers (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, neurofibromatosis type I, meningioma, glioma, sarcoma); gynecological cancers, such as cancers of the uterus (endometrial cancer, uterine cancer, endometrial cancer of the uterine body), cervix (cervical cancer, pre-tumor cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma), fallopian tube cancer (epithelial malignant tumor); hematological cancers, such as blood cancers (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia); myeloproliferative disorders (e.g., myelofibrosis and myeloproliferative tumors, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin cancers, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal cancers, such as neuroblastoma.;

[0204] In some embodiments, the Ras protein is wild-type. (Ras WT ). Thus, in some embodiments, the compounds of the invention are used in a method of treating a patient having a cancer that includes Ras WT (e.g., K-Ras WT , H-Ras WT , or N-Ras WT ). In some embodiments, the Ras protein is Ras amplified (e.g., K-Ras amp ). Thus, in some embodiments, the compounds of the invention are Ras amp (K-Ras amp , H-Ras amp , or N-Ras amp) It is used in the treatment method of a patient having cancer. In some embodiments, the cancer includes a Ras mutation such as the Ras mutations described herein. In some embodiments, the mutation is selected from the following: (a) The following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) The following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and (c) The following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof; Or any combination of the foregoing. In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the invention inhibit two or more Ras variants. For example, the compound may inhibit both K-Ras G12D and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12C and K-Ras G13C. In some embodiments, the compound may inhibit both K-Ras G12D and K-Ras G12V. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the mutation is selected from the group consisting of G12A, G12C, G12D, G12E, G12F, G12H, G12I, G12K, G12L, G12M, G12N, G12P, G12Q, G12R, G12S, G12T, G12V, G12W, and G12Y or combinations thereof of K-Ras, N-Ras, or H-Ras. In some embodiments, the mutation is selected from the group consisting of G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y or combinations thereof of K-Ras, N-Ras, or H-Ras. In some embodiments, the compound inhibits wild-type K-Ras, wild-type H-Ras, or wild-type N-Ras and optionally further inhibits mutant Ras proteins comprising the mutations described herein. In some embodiments, the cancer is non-small cell lung cancer and the Ras mutation comprises a K-Ras mutation such as K-Ras G12C. In some embodiments, the cancer is colorectal cancer and the Ras mutation comprises a K-Ras mutation such as K-Ras G12C. In some embodiments, the cancer is pancreatic cancer and the Ras mutation comprises an N-Ras mutation such as N-Ras G12D.In some embodiments, the cancer is non-small cell lung cancer and the Ras protein is K-Ras. amp It is.

[0205] Furthermore, in some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer comprises an N-Ras mutation selected from the group consisting of G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the invention inhibit two or more Ras variants. For example, the compound can inhibit both K-Ras G12C and K-Ras G13C. The compound can inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compound can inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the compound can inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compound can inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the invention inhibit Ras, in addition to one or more additional Ras mutations (e.g., K-, H-, or N-Ras WT inhibits (e.g., K-, H-, or N-Ras WT and, K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H-, or N-Ras WTand H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K-, H-, or N-Ras WT and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T). In some embodiments, the compounds of the invention, in addition to one or more additional Ras mutations, inhibit Ras amp (e.g., K-, H-, or N-Ras amp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H-, or N-Ras amp and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K-, H-, or N-Ras amp and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0206] Methods for detecting Ras mutations are known in the art. Such means include direct sequencing, as well as the use of high-sensitivity diagnostic assays (using CE-IVD marks) such as TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro, for example, as described in Domagala, et al., Pol J Pathol 3:145-164(2012), which is hereby incorporated by reference in its entirety, but are not limited thereto. See also, for example, WO2020 / 106640.

[0207] In some embodiments, the cancer is non-small cell lung cancer and the Ras mutation includes a K-Ras mutation such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is colorectal cancer and the Ras mutation includes a K-Ras mutation such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is pancreatic cancer and the Ras mutation includes a K-Ras mutation such as K-Ras G12D or K-Ras G12V. In some embodiments, the cancer is pancreatic cancer and the Ras mutation includes an N-Ras mutation such as N-Ras G12D. In some embodiments, the cancer is melanoma and the Ras mutation includes an N-Ras mutation such as N-Ras Q61R or N-Ras Q61K. In some embodiments, the cancer is non-small cell lung cancer and the Ras protein is K-Ras amp In any of the foregoing, if not otherwise specified, the compound may likewise inhibit Ras WT (e.g., K-, H-, or N-Ras WT ), or Ras amp (e.g., K-, H-, or N-Ras amp ).

[0208] In some embodiments, the cancer is a Ras mutation and STK11LOF comprises a KEAP1, EPHA5, or NF1 mutation, or a combination thereof. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation, an STK11 LOF mutation, and a KEAP1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and an STK11 LOF mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and an STK11 LOF mutation. In some embodiments, the cancer is a K-Ras G13C Ras mutation, and an STK11 LOF comprises a KEAP1, EPHA5, or NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and comprises a K-Ras G12C mutation. In any of the foregoing, the compound may similarly inhibit Ras WT (e.g., K-, H-, or N-Ras WT ), or Ras amp (e.g., K-, H-, or N-Ras amp ).

[0209] A method for inhibiting Ras protein within a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, is also provided. The compound or a pharmaceutically acceptable salt thereof can inhibit two or more types of Ras proteins within the cell. A method for inhibiting RAF-Ras binding, the method comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, is also provided. The cell can be a cancer cell. The cancer cell can be of any type of cancer described herein. The cell can be in vivo or in vitro.

[0210] Combination therapy The method of the present invention can include a compound of the present invention used alone or in combination with one or more additional therapies (e.g., non-drug therapies or therapeutic agents). The dosage of one or more additional therapies (e.g., non-drug therapies or therapeutic agents) can be reduced from the standard dosage administered alone. For example, the dosage can be determined empirically from drug combinations and permutations or can be estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0211] The compound of the present invention can be administered before, after, or simultaneously with such one or more additional therapies. When combined, the dosage of the compound of the present invention and the dosage of one or more additional therapies (e.g., non-drug therapies or therapeutic agents) provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The compound of the present invention and an additional therapy, such as an anti-cancer agent, can be administered together, such as in a single pharmaceutical composition, or separately, and when administered separately, can be administered simultaneously or sequentially. Such sequential administration can be at short or long intervals between administrations.

[0212] In some embodiments, the additional therapy is the administration of a side effect limiting agent (e.g., an agent intended to reduce the occurrence or severity of side effects of a treatment). For example, in some embodiments, the compounds of the present invention can also be used in combination with a therapeutic agent that treats nausea. Examples of drugs that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0213] In some embodiments, one or more additional therapies include non-drug therapies (e.g., surgery or radiation therapy). In some embodiments, one or more additional therapies include therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, one or more additional therapies include non-drug therapies (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, one or more additional therapies include two therapeutic agents. In still other embodiments, one or more additional therapies include three therapeutic agents. In some embodiments, one or more additional therapies include four or more therapeutic agents.

[0214] In this combination therapy section, all references to the drugs described, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers thereof, are incorporated by reference whether or not such are expressly described as such.

[0215] Non-drug therapy Examples of non-drug therapies include, but are not limited to, radiation therapy, cryotherapy, thermotherapy, surgery (e.g., surgical resection of tumor tissue), and T cell adoptive transfer (ACT) therapy.

[0216] In some embodiments, the compounds of the present invention can be used as adjuvant therapy after surgery. In some embodiments, the compounds of the present invention can be used as neoadjuvant therapy before surgery.

[0217] Radiation therapy can be used in a subject (e.g., a mammal (e.g., a human)) to inhibit abnormal cell growth or to treat a hyperproliferative disorder such as cancer. Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered by one or a combination of several methods, including, but not limited to, external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, total body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. This term is intended to include, without limitation, 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). Suitable radiation sources for use as cell modulating agents of the present invention include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, or other radionuclides that emit 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 I-125 or I-131, or the radioactive fluid can be generated using a suitable fluid slurry containing small particles of a solid radionuclide such as Au-198 or Y-90. Further, the radionuclide(s) can be embodied in a gel or radioactive microspheres.

[0218] In some embodiments, the compounds of the invention can render abnormal cells more sensitive to radiotherapy for the purpose of killing such cells or inhibiting their growth. Accordingly, the invention further relates to a method of radiosensitizing abnormal cells in a mammal to radiotherapy, the method comprising administering to the mammal an effective amount of a compound of the invention to radiosensitize the abnormal cells to radiotherapy. The amount of the compound in this method can be determined according to the means for ascertaining the effective amount of such compounds described herein. In some embodiments, the compounds of the invention can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0219] In some embodiments, the non-drug treatment is adoptive T cell transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR into T cells. Prior to the expansion and genetic modification of the T cells, the T cell source is obtained from a subject. T cells can be obtained from a number of sources including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from an infected site, peritoneal, pleural effusions, spleen tissue, and tumors. In certain embodiments of the invention, any number of T cell lines available in the art can be used. In some embodiments, the T cells are autologous T cells. Regardless of whether the T cells are genetically modified before or after to express the desired protein (e.g., CAR), the T cells can generally be activated and expanded using, for example, the methods described in U.S. Patent Nos. 6,352,694, 6,534,055, 6,905,680, 6,692,964, 5,858,358, 6,887,466, 6,905,681, 7,144,575, 7,067,318, 7,172,869, 7,232,566, 7,175,843, 7,572,631, 5,883,223, 6,905,874, 6,797,514, and 6,867,041.

[0220] Therapeutic agent The therapeutic agent can be a compound used in the treatment of cancer or a related symptom. For example, the therapeutic agent can be a steroid. Thus, in some embodiments, one or more additional therapies include steroids. Suitable steroids include, but are not limited to, 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, fluocinonide acetonide, fluocinonide, flucortin butyl, flucortolone, fluorometholone, fluprednolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halomethasone, hydrocortisone, loteprednol etabonate, madipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, sodium prednisolone phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0221] Further examples of therapeutic agents that can be used in combination therapy with the compounds of the present invention include the compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Applications Nos. WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0222] The therapeutic agent can be a biological agent (e.g., a cytokine such as an interleukin (e.g., interferon or IL-2)) used in the treatment of cancer or cancer-related symptoms. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof), that acts on a target to stimulate an anti-cancer response or antagonize an antigen important for cancer. Antibody-drug conjugates are also included.

[0223] The therapeutic agent can be a T cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-1 (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-L1 (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-L2 (e.g., a PD-L2 / Ig fusion protein) (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof (e.g., an inhibitory antibody or a small molecule inhibitor).In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody, such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol. (including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002).

[0224] The therapeutic agent can be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0225] The therapeutic agent can be an agent that treats cancer or a symptom associated therewith (e.g., a cytotoxic agent, a non-peptide small molecule, or another compound useful for treating cancer or a symptom associated therewith, collectively referred to as an "anticancer agent"). The anticancer agent can be, for example, a chemotherapeutic agent or a targeted therapeutic agent.

[0226] Anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthraquinone-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, adrenocortical steroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Further examples of anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, one or more additional therapies include two or more anticancer agents. The two or more anticancer agents can be used in combination or separately in cocktails that are administered. Suitable dosing regimens for combination anticancer agents are known in the art and are described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0227] Non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocone, meturedopa, and uredopa; ethyleneimine and methylamelamine including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (particularly bratasin and bratasinone); camptothecin (including the synthetic analog topotecan); bryostatin; calistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycin (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards such as chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, e.g., calicheamicin gamma1l and calicheamicin omega1l (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin, e.g., dynemicin A; bisphosphonates, e.g., clodronate; esperamicin;Neocarzinostatin chromophore and related chromoprotein-engineered antibiotics chromophore, actinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, calminomycin, cardinophyllin, chromomycin, daunorubicin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, for example, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, queramycin, rhodomycin, streptozocin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites, for example, methotrexate and 5-fluorouracil (5-FU); folic acid analogs, for example, denopterin, pteropterin, trimetrexate; purine analogs, for example, fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs, for example, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyridine, doxifluridine, enocitabine, floxuridine; androgens, for example, calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents, for example, aminoglutethimide, mitotane, trilostane; folic acid supplements, for example, folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; dexamethasone; diacontin; elfomithine; elliptinium acetate; epothilone, for example, epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, for example, maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone;Podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; lizoxine; schizophyllan; spirigermanium; tenuazonic acid; triaziquone; 2,2’,2’’-trichloroethylamine; trichothecenes, for example, T-2 toxin, verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gasitocin; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, for example, taxol (registered trademark) (paclitaxel), abraxane (registered trademark) (a Cremophor-free albumin-engineered nanoparticle formulation of paclitaxel), and taxotere (registered trademark) (docetaxel); chlorambucil; tamoxifen (Nolvadex (trademark)); raloxifene; aromatase inhibitor 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; LY117018; onapristone; toremifene (Fareston (registered trademark)); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar (registered trademark) gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, for example, cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine (registered trademark) (vinorelbine); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (for example, CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, for example, retinoic acid; esperamicin; capecitabine (for example, Xeloda (registered trademark)); and pharmaceutically acceptable salts of any of the foregoing.

[0228] Additional non-limiting examples of anti-cancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, abscisin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, albosidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthraquinone, anti-CD22 immunotoxin, anti-tumor agents (e.g., cell cycle non-specific anti-tumor agents, and other anti-tumor agents described herein), anti-tumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, bilicodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), caliculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, feruginol, foldecsin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, ranicodar, larotaxel, lenalidomide, lucanthone, lutetium texaphyrin, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, popo, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, talikodar, tegafur-uracil, temodal, tesetaxel, tris(2-chloroethyl)amine, troxacitabine, uramustine, vazimezan, vinflunine, ZD6126, and zosuquidar.

[0229] Additional non-limiting examples of anti-cancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase which metabolizes L-asparagine systemically and depletes cells that lack the ability to synthesize their own asparagine), antiplatelet agents, anti-proliferative / anti-mitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors such as abemaciclib, ribociclib, palbociclib;seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), temozolomide - dacarbazine (DTIC), anti - proliferative / anti - mitotic antimetabolites, e.g., folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2 - chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidin, suberoylanilide hydroxamic acid, vorinostat, LBH589, romidepsin, ACY - 1215, and panobinostat), mTOR inhibitors (e.g., bisphosphonates, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array520), DNA binders (e.g., Zalypsis (registered trademark)), PI3K inhibitors, e.g., PI3K delta inhibitors (e.g., GS - 1101 and TGR - 1202), PI3K delta and gamma inhibitors (e.g., CAL - 130), copanlisib, alpelisib, and idelalisib;Multi-target kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CSl (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), FTI (e.g., Zarnestra (trademark)), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists may be mentioned.;

[0230] In some embodiments, the anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine (registered trademark), sorafenib, or any analog or derivative variant of the foregoing.;

[0231] 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®), pyrimethamine, CP-654577, CP-724714, canertinib (CI1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, and JNJ-26483327.

[0232] In some embodiments, the anti-cancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0233] In some embodiments, the anti-cancer agent is an inhibitor of a member downstream of receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SHP3809, PF-07284892, or BBP-398, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof), SOS1 inhibitor (e.g., BI-1701963, BI-3406, SDR5, BAY-293, or RMC-5845, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof), Raf inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, AKT inhibitor, or mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor)). In some embodiments, the anti-cancer agent is JAB-3312.

[0234] In some embodiments, the anti-cancer agent is an SOS1 inhibitor. In some embodiments, the SOS1 inhibitor is selected from those disclosed in WO2021173524, WO2021130731, WO2021127429, WO2021092115, WO2021105960, WO2021074227, WO2020180768, WO2020180770, WO2020173935, WO2020146470, WO2019201848, WO2019122129, WO2018172250, and WO2018115380, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0235] In some embodiments, the anti-cancer agent is an additional Ras inhibitor or Ras vaccine, or another therapeutic modality designed to directly or indirectly reduce the oncogenic activity of Ras. In some embodiments, the anti-cancer agent is an additional Ras inhibitor. In some embodiments, the Ras inhibitor targets its activity or GTP-bound Ras. In some embodiments, the Ras inhibitor targets its inactivity or GDP-bound Ras. In some embodiments, the Ras inhibitor is, for example, an inhibitor of K-Ras G12C, such as AMG510 (sotorasib), MRTX1257, MRTX849 (adagrasib), JNJ-74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-3312, JAB-21000, JAB-21822, ERAS-3490, BI1823911, D-1553, D3S-001, HBI-2438, HS-10370, MK-1084, YL-15293, GFH925 (IBI351), RMC-6291, or GDC-6036, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is an inhibitor of K-Ras G12D, such as MRTX1133, MRTX282, JAB-22000, ERAS-4, HRS-4642, BI-2852, ASP3082, TH-Z827, TH-7835, or KD-8, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is a K-Ras G12V inhibitor, such as JAB-23000, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the KRAS(OFF) inhibitor is a pan-RAS(OFF) inhibitor. In certain embodiments, the pan-RAS(OFF) inhibitor is JAB-23400. In some embodiments, the Ras inhibitor is RMC-6236, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug,or a tautomer. In some embodiments, the Ras inhibitor is selected from the Ras(ON) inhibitors disclosed in the following WO2023060253, WO2022 / 060836, WO2022 / 235864, WO2022 / 235 / 870, WO2021091982, WO2021091967, WO2021091956, and WO2020132597, which are hereby incorporated by reference in their entirety, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. Other examples of Ras inhibitors that can be combined with the Ras inhibitors of the present invention are the following, which are hereby incorporated by reference in their entirety: WO2023287896, WO2023287730, WO2023284881, WO2023284730, WO2023284537, WO2023283933, WO2023283213, WO2023280280, WO2023280136, WO2023280026, WO2023278600, WO2023274383, WO2023327324, WO2023040989, WO2023039240, WO2023039020, WO2023036282, WO2023034290, WO2023030517, WO2023030495, WO2023030385, WO2023025116, WO2023020523, WO2023020521, WO2023020519, WO2023020518, WO2023020347, WO2023018812, WO2023018810, WO2023018809, WO2023018699, WO2023014979, WO2023014006, WO2023004102, WO2023003417, WO2023001141, WO2023001123, WO2022271658, WO2022269508, WO2022266167, WO2022266069, WO2022266015, WO2022265974, WO2022261154, WO2022261154, WO2022251576, WO2022251296, WO2022237815, WO2022232332, WO2022232331, WO2022232320, WO2022232318, WO2022223037,WO2022221739, WO2022221528, WO2022221386, WO2022216762 (for example, Compound 44 or Compound 66a), WO2022192794, WO2022192790, WO2022188729, WO2022187411, WO2022184178, WO2022173870, WO2022173678, WO2022135346, WO2022133731, WO2022133038, WO2022133345, WO2022132200, WO2022119748, WO2022109485, WO2022109487, WO2022066805, WO2022002102, WO2022002018, WO2021259331, WO2021257828, WO2021252339, WO2021248095, WO2021248090, WO2021248083, WO2021248082, WO2021248079, WO2021248055, WO2021245051, WO2021244603, WO2021239058, WO2021231526, WO2021228161, WO2021219090, WO2021219090, WO2021219072, WO2021218939, WO2021217019, WO2021216770, WO2021215545, WO2021215544, WO2021211864, WO2021190467, WO2021185233, WO2021180181, WO2021175199, WO2021173923, WO2021169990, WO2021169963, WO2021168193, WO2021158071, WO2021155716, WO2021152149, WO2021150613, WO2021147967, WO2021147965, WO2021143693, WO2021142252, WO2021141628, WO2021139748, WO2021139678, WO2021129824, WO2021129820, WO2021127404, WO2021126816, WO2021126799, WO2021124222, WO2021121371, WO2021121367, WO2021121330, WO2020050890, WO2020047192,Those provided in WO2020035031, WO2020028706, WO2019241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO2019150305, WO2019110751, WO2019099524, WO2019051291, WO2018218070, WO2018217651, WO2018218071, WO2018218069, WO2018206539, WO2018143315, WO2018140600, WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO2018068017, WO2018064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO2017058728, WO2017058902, WO2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO2014143659, and WO2013155223, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.,

[0236] In some embodiments, the therapeutic agent that can be combined with the compounds of the present invention is an inhibitor of the MAP kinase (MAPK) pathway (or "MAPK inhibitor"). Examples of MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, the MAPK inhibitor can be selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA119 / BAY86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (described in Roche, PLoS One.2014 Nov 25;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res.2011 Mar 1;17(5):989-1000). The MAPK inhibitor can be PLX8394, LXH254, GDC-5573, or LY3009120.

[0237] In some embodiments, the anti-cancer agent is an agent or inhibitor that interferes with the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway. Examples of PI3K / AKT inhibitors can include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, the PI3K / AKT inhibitor can be selected from one or more of NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0238] In some embodiments, the anti-cancer agent is an antagonist of PD-1 or PD-L1. In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies. In some embodiments, the therapeutic agent can be a pan-RTK inhibitor, such as afatinib.

[0239] Examples of IGF-1R inhibitors include linsitinib, or a pharmaceutically acceptable salt thereof. Examples of EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or certain antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment capable of partially or completely blocking EGFR activation by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999 (supra)), or Mab C225 (ATCC accession number HB-8508), or an antibody or antibody fragment having its binding specificity.

[0240] Examples of small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (Tykerb®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). Further non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and any pharmaceutically acceptable salts of such EGFR inhibitors: EP0520722; EP0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; EP0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642.Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0241] Examples of MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0242] Examples of PI3K inhibitors include, but are not limited to, wortmannin, 17-hydroxywortmannin analogs described in WO06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941, described in WO09 / 036082 and WO09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ235 or NVP-BEZ235, described in WO06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem), PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3’,2’:4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem), PIK75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem), PIK90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide) (available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-metha-(Z)-ylidene]-thiazolidine-2,4-dione) (available from Axon Medchem), TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyridinidin-4-one) (available from Axon Medchem), XL-765, and XL-147.Other PI3K inhibitors include demethoxybiridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0243] AKT inhibitors include Akt-1-1 (inhibiting Akt1) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); Akt-1-1,2 (inhibiting Akt1 and 2) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91: 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05 / 011700); indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134 (12 Suppl): 3493S-3498S); perifosine (e.g., interfering with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10 (15): 5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13: 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC154020; Yang et al., Cancer Res. 2004, 64: 4394-9), but are not limited thereto.

[0244] Examples of mTOR inhibitors include ATP-competitive mTORC1 / mTORC2 inhibitors such as PI-103, PP242, PP30; Torin1; FKBP12 potentiators; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives such as temsirolimus (Torisel®); everolimus (Afinitor®, WO94 / 09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs such as those disclosed in WO98 / 02441 and WO01 / 14387 such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolide)-rapamycin (also referred to as ABT578); 32-deoxorapamycin; 16-pentynilyloxy-32(S)-dihydrorapamycin; derivatives disclosed in WO05 / 005434; derivatives disclosed in 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 WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252), but are not limited thereto. In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO2018204416, WO2019212990, and WO2019212991), e.g., a structure

[0245] [Chemical formula]

[0246] It is RMC-5552 having Examples of BRAF inhibitors that can be used in combination with the compounds of the present invention include vemurafenib, dabrafenib, and encorafenib. BRAF can include class 3 BRAF mutations. In some embodiments, the class 3 BRAF mutation is one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0247] Examples of 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 conventional chemotherapy as well as targeted therapeutics including BCL-2 inhibitors such as ABT-263.

[0248] 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, maintenance of the cell cycle, 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 auto-inhibited conformation stabilized by a binding network involving residues from both the N-SH2 domain and the PTP domain. For example, stimulation by cytokines or growth factors acting through receptor tyrosine kinases (RTKs) results in the exposure of the catalytic site and the enzymatic activation of SHP2.

[0249] SHP2 is involved in signal transduction via the RAS mitogen-activated protein kinase (MAPK), JAK-STAT, or phosphoinositide 3-kinase-AKT pathways. Mutations in the PTPN11 gene and subsequent mutations in SHP2 have been identified in several human developmental disorders such as Noonan syndrome and Leopard syndrome, as well as in human cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancers. Some of these mutations destabilize the autoinhibited conformation of SHP2 and promote the autoactivation or enhanced growth factor-driven activation of SHP2. Therefore, SHP2 is a very attractive target for the development of novel therapies for the treatment of various diseases, including cancer. SHP2 inhibitors (e.g., RMC-4550 or SHP099) 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 cancers) in vitro. Therefore, combination therapy using SHP2 inhibitors and RAS pathway inhibitors can be a general strategy for preventing tumor resistance in a wide range of malignancies.

[0250] Non-limiting examples of such SHP2 inhibitors are known in the art and include: Chen et al., Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734, each of which is incorporated herein by reference; and PCT applications: WO2023282702, WO2023280283, WO2023280237, WO2023018155, WO2023011513, WO2022271966, WO2022271964, WO2022271911, WO2022259157, WO2022242767, WO2022241975, WO2022237676, WO2022237367, WO2022237178, WO2022235822, WO20222084008, WO2022135568, WO2021176072, WO2021171261, WO2021149817, WO2021148010, WO2021147879, WO2021143823, WO2021143701, WO2021143680, WO2021121397, WO2021119525, WO2021115286, WO2021110796, WO2021088945, WO2021073439, WO2021061706, WO2021061515, WO2021043077, WO2021033153, WO2021028362, WO2021033153, WO2021028362, WO2021018287, WO2020259679, WO2020249079, WO2020210384, WO2020201991, WO2020181283, WO2020177653, WO2020165734, WO2020165733, WO2020165732, WO2020156243, WO2020156242, WO2020108590, WO2020104635, WO2020094104, WO2020094018, WO2020081848, WO2020073949, WO2020073945, WO2020072656, WO2020065453,WO2020065452, WO2020063760, WO2020061103, WO2020061101, WO2020033828, WO2020033286, WO2020022323, WO2019233810, WO2019213318, WO2019183367, WO2019183364, WO2019182960, WO2019167000, WO2019165073, WO2019158019, WO2019152454, WO2019051469, WO2019051084, WO2018218133, WO2018172984, WO2018160731, WO2018136265, WO2018136264, WO2018130928, WO2018129402, WO2018081091, WO2018057884, WO2018013597, WO2017216706, WO2017211303, WO2017210134, WO2017156397, WO2017100279, WO2017079723, WO2017078499, WO2016203406, WO2016203405, WO2016203404, WO2016196591, WO2016191328, WO2015107495, WO2015107494, WO2015107493, WO2014176488, WO2014113584, CN115677661, CN115677660, CN115611869, CN115521305, CN115490697, CN115466273, CN115394612, CN115304613, CN115304612, CN115300513, CN115197225, CN114957162, CN114920759, CN114716448, CN114671879, CN114539223, CN114524772, CN114213417, CN114195799, CN114163457, CN113896710, CN113248521, CN113248449, CN113135924, CN113024508, CN112920131, CN112823796, CN112409334, CN112402385, CN112174935, 111848599, CN111704611, CN111393459, CN111265529,Those shown in CN110143949, CN108113848, US11179397, US20210085677, US10858359, US10934302, US10954243, US10988466, US11001561, US11033547, US11034705, or US11044675, or their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers are included.

[0251] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed-type irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, for example, a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor such as an inhibitor that targets a cysteine residue (C333) outside the active site of the phosphatase. In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155 having the following structure

[0252] [Chemical formula]

[0253] or its pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer. In some embodiments, the SHP2 inhibitor is RMC-4550 having the following structure

[0254] [Chemical formula]

[0255] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RMC-4630 having the following structure

[0256]

Chem.

[0257] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is JAB-3068 having the following structure

[0258]

Chem.

[0259] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is JAB-3312. In some embodiments, the SHP2 inhibitor is the following compound

[0260]

Chem.

[0261] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RLY-1971 having the following structure

[0262]

Chem.

[0263] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is ERAS-601, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is BBP-398, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is SH3809. In some embodiments, the SHP2 inhibitor is PF-07284892, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0264] In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, a HER2 inhibitor, an SHP2 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an SOS1 inhibitor, and a PD-L1 inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, an SHP2 inhibitor, and a PD-L1 inhibitor. See, for example, Hallin et al., Cancer Discovery, DOI:10.1158 / 2159-8290 (October 28,2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PD-L1 inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PD-L1 inhibitor and an SHP2 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer, and the treatment comprises administering the Ras inhibitor of the present invention in combination with a second or third therapeutic agent.

[0265] Examples of proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0266] Examples of immunotherapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAG1, and anti-OX40 agents.

[0267] Immunomodulatory imides (IMiDs) are a class of immunomodulatory drugs (drugs that regulate the immune response) that contain an imide group. Examples of the IMiD class include thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0268] Exemplary anti-PD-1 antibodies, and methods of using them, are described by Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 A1, and are additionally described elsewhere in this specification.

[0269] Examples of GITR agonists include GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent Nos. 6,111,090, 8,586,023, WO2010 / 003118, and WO2011 / 090754, or anti-GITR antibodies such as those described in U.S. Patent Nos. 7,025,962, EP1947183, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8,591,886, U.S. Patent No. 7,618,632, EP1866339, and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726, but are not limited thereto.

[0270] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-angiogenic agent. Anti-angiogenic agents include, without limitation, chemically synthesized compositions, antibodies, antigen-binding regions, radionuclides, as well as combinations and conjugates thereof, prepared in vitro. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally, act to inhibit or stimulate their target (e.g., activation or inhibition of a receptor or enzyme), thereby promoting cell death or arresting cell growth. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0271] An anti-angiogenic agent can be an MMP-2 (matrix-metalloproteinase 2) inhibitor, an MMP-9 (matrix-metalloproteinase 9) inhibitor, and a COX-II (cyclooxygenase 11) inhibitor. Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include celecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors have little or no activity to inhibit MMP-1. Those that selectively inhibit MMP-2 or AMP-9 are more preferred compared to other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO32-3555, and RS13-0830.

[0272] Additional exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., VEGF (e.g., bevacizumab), or antibodies or antigen-binding regions that specifically bind to their soluble VEGF receptors or ligand-binding regions), e.g., VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind thereto), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto), e.g., Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to them or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). Other anti-angiogenic agents include campus, IL-8, B-FGF, Tek antagonists (US2003 / 0162712, US6,413,932), anti-TWEAK agents (e.g., antibodies or antigen-binding regions that specifically bind, or soluble TWEAK receptor antagonists, see US6,727,225), ADAM disintegrin domains that antagonize the binding of integrin to its ligand (US2002 / 0042368), anti-eph receptor or anti-ephrin antibodies or antigen-binding regions that specifically bind (U.S. Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124, and their patent family members), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind), and antibodies or antigen-binding regions that specifically bind to the PDGF-BB ligand, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). Additional anti-angiogenic agents include SD-7784 (Pfizer, USA); siramesine (Merck KGaA, Germany, EPO0770622); pegaptanib octasodium (Gilead Sciences, USA);Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US5712291); Irormastat (Arriva, USA, US5892112); Emaxinib (Pfizer, USA, US5792783); Batabulinib (Novartis, Switzerland); 2-Methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anacortab Acetate (Alcon, USA); Alpha-D148Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands), DAC Anti-angiogenic Agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP0970070); ARGENT Technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen-E Fragment (BioActa, UK); Angiogenesis Inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Maspin (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP02233610); Platelet Factor 4 (RepliGen, USA, EP407122); Vascular Endothelial Growth Factor Antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis Inhibitor (SUGEN, USA); XL784 (Exelixis, USA); XL647 (Exelixis, USA);MAb, alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, USA); endostaurin hydrochloride (Lilly, USA); CEP7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC1 (Genoa Institute of Cancer Research, Italy); rBPI21 and BPI-derived angiogenesis inhibitor (XOMA, USA); PI88 (Progen, Australia); siramesine (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG292 (Telios, USA); endostatin (Boston Childrens Hospital, USA); ATN161 (Attenuon, USA); 2-methoxyestradiol (Boston Childrens Hospital, USA); ZD6474 (AstraZeneca, UK); ZD6126 (Angiogene Pharmaceuticals, UK); PPI2458 (Praecis, USA); AZD9935 (AstraZeneca, UK); AZD2171 (AstraZeneca, UK); batranib (pINN) (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthorrhizol (Yonsei University, South Korea); vaccine, gene-based, VEGF-2 (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX103 (University of California at San Diego, USA); PX478 (ProlX, USA);Metastatin (EntreMed, USA); Troponin I (Harvard University, USA); SU6668 (SUGEN, USA); OXI4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); Motuporamine C (British Columbia University, Canada); CDP791 (Celltech Group, UK); Actiprimod (pINN) (GlaxoSmithKline, UK); E7820 (Eisai, Japan); CYC381 (Harvard University, USA); AE941 (Aeterna, Canada); Vaccine, angiogenesis (EntreMed, USA); Urokinase plasminogen activator inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-alpha inhibitor (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); Angiostatin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, South Korea); GW2286 (GlaxoSmithKline, UK); EHT0101 (ExonHit, France); CP868596 (Pfizer, USA); CP564959 (OSI, USA); CP547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN633 (Kirin Brewery, Japan); Drug delivery system, intraocular, 2-methoxyestradiol; Anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitor; SU11248 (Pfizer, USA and SUGEN USA); ABT518 (Abbott, USA); YH16 (Yantai Rongchang, China);S-3APG (Boston Childrens 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); GFB116 (South Florida University, USA and Yale University, USA); CS706 (Sankyo, Japan); Combretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA) CV247 (Ivy Medical, UK); CKD732 (Chong Kun Dang, South Korea); Iloprost (Nippon Shinyaku, Japan); RG13577 (Aventis, France); WX360 (Wilex, Germany); Squaramine (Genaera, USA); RPI4610 (Sirna, USA); Heparanase inhibitor (InSight, Israel); KL3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland, and Schering AG, Germany); XMP300 (XOMA, USA); VGA1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA);Flk-1 (ImClone Systems, USA); TZ93 (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; n and Research Foundation, USA) may be mentioned.

[0273] Further examples of therapeutic agents that can be used in combination with the compounds of the present invention include agents that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor) (e.g., antibodies, antigen-binding regions, or soluble receptors), and antibodies or antigen-binding regions that specifically bind to its receptor, c-Met.

[0274] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an autophagy inhibitor. Examples of autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil (trademark)), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Also, antisense or siRNA that inhibits the expression of proteins, including but not limited to ATG5 (involved in autophagy), can be used. In some embodiments, one or more additional therapies include an autophagy inhibitor.

[0275] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-cancer agent. In some embodiments, one or more additional therapies include an anti-cancer agent. Non-limiting examples of anti-cancer agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ansamycin, ansestrim, argrabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, cermolukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dirazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab ozogamicin, combination of gimeracil / oteracil / tegafur, glycopyrronium, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alpha, interferon alpha, natural, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-Nl, interferon alpha-n3, interferon alpha con-1, interferon alpha, natural, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguane, irinotecan, ilsogladine,Ranelotide, LC9018 (Yakult), Leflunomide, Lenograstim, Sulfated Lentinan, Letrozole, Leukocyte Alpha Interferon, Leuprorelin, Levamisole + Fluorouracil, Rialoxazole, Lobaplatin, Lonidamine, Lovastatin, Masoprocol, Melarsoprol, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mismatch Double-Stranded RNA, Mitoguazone, Mitolactol, Mitoxantrone, Molgramostim, Nafarelin, Naloxone + Pentazocine, Nartograstim, Nedaplatin, Nilutamide, Noscapine, Novel Erythropoiesis-Stimulating Protein, NSC631570 Octreotide, Oprelvekin, Ostarine, Oxaliplatin, Paclitaxel, Pamidronic Acid, Pegaspargase, Peg Interferon Alpha-2b, Pentosan Polysulfate Sodium, Pentostatin, Picibanil, Pirarubicin, Rabbit Anti-Thymocyte Polyclonal Antibody, Polyethylene Glycol Interferon Alpha-2a, Porfimer Sodium, Raloxifene, Raltitrexed, Rasburicase, Rhenium Re186 Etidronate, RII Retinamid, Rituximab, Romurtide, Samarium (153Sm) Lexidronam, Sargramostim, Schizophyllan, Sobuzoxane, Sonermin, Strontium-89 Chloride, Suramin, Tasonermin, Tazarotene, Tegafur, Temoporfin, Temozolomide, Teniposide, Tetrachlorodecaoxide, Thalidomide, Timalphasin, Thyrotropin Alpha, Topotecan, Toremifene, Tositumomab-Iodine 131, Trastuzumab, Treosulfan, Tretinoin, Trilostane, Trimethoprim, Triptorelin, Tumor Necrosis Factor Alpha, Natural, Ubenimex, Bladder Cancer Vaccine, Maruyama Vaccine, Melanoma Lysate Vaccine, Valrubicin, Verteporfin, Vinorelbine, Viridin, Dinostatin Stimalamer, or Zoledronic Acid; Abarelix; AE941 (Aeterna), Ambamustine, Antisense Oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), Decitabine, Dexaminoglutethimide, Diacontin, EL532 (Elan), EM800 (Endorecherche), Eniluracil, Ethanidazole,Fenretinide, Filgrastim SD01 (Amgen), Fluvestrant, Galocitabine, Gastrin 17 Immunogen, HLA-B7 Gene Therapy (Vical), Granulocyte Macrophage Colony Stimulating Factor, Histamine Dihydrochloride, Ibritumomab Tiuxetan, Ilomastat, IM862 (Cytran), Interleukin-2, Iproxifene, LDI200 (Milkhaus), Relizumab, Rituximab, 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, Noratraxate, P30 Protein, Pegvisomant, Pemetrexed, Porfiromycin, Prinomastat, RL0903 (Shire), Rubitecan, Satraplatin, Sodium Phenylacetate, Sparfloxacin, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), Tetrathiomolybdate, Taliblastine, Thrombopoietin, Tin Ethyl Ethiopurpurin, Tirapazamine, Cancer Vaccine (Biomira), Melanoma Vaccine (New York University), Melanoma Vaccine (Sloan Kettering Institute), Melanoma Tumor Lysate Vaccine (New York Medical College), Viral Melanoma Cell Lysate Vaccine (Royal Newcastle Hospital), or Valspodar.

[0276] Additional examples of therapeutic agents that can be used in combination with the compounds of the present invention include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilimumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP224; adalimumab (Humira®); ado-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); certolizumab pegol (Cimzia®); daclizumab (Zenapax®); daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); gemtuzumab ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®);Ranibizumab (Lucentis (registered trademark)); Raxibacumab (Abthrax (registered trademark)); Tocilizumab (Actemra (registered trademark)); Tositumomab; Tositumomab-I-131; Tositumomab and Tositumomab-I-131 (Bexxar (registered trademark)); Ustekinumab (Stelara (registered trademark)); AMG102; AMG386; AMG479; AMG655; AMG706; AMG745; and AMG951.

[0277] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the disclosure are co-administered with other therapies as described herein. When used in combination therapy, the compounds described herein can be administered simultaneously with or separately from the second drug. This combined administration can include co-administration of the two drugs in the same dosage form, co-administration in separate dosage forms, and separate administrations. That is, either the compounds described herein and the agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, either the compounds of the invention and the therapies described herein can be administered simultaneously, and both drugs are present in separate formulations. In another alternative, the compounds of the disclosure can be administered, followed by administration of any of the therapies described herein, and vice versa. In some embodiments of separate dosing protocols, either the compounds of the invention and the therapies described herein are administered minutes apart, or hours apart, or days apart.

[0278] In some embodiments of any of the methods described herein, the first therapy (e.g., a compound of the invention) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent may be administered immediately before or after, or up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours before or after, or up to 1 - 7, 1 - 14, 1 - 21, or 1 - 30 days before or after the one or more additional therapies.

[0279] The invention also features a kit comprising (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the invention), and (b) a package inserted with instructions for practicing any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the invention), (b) one or more additional therapies (e.g., non - drug therapy or therapeutic agents), and (c) a package inserted with instructions for practicing any of the methods described herein.

[0280] One aspect of the invention further relates to combining separate pharmaceutical compositions in the form of a kit, for the purpose of contemplating the treatment of a disease or a symptom associated therewith by a combination of pharmaceutically active compounds that can be administered separately. The kit may comprise two separate pharmaceutical compositions, namely a compound of the invention and one or more additional therapies. The kit may include a container for containing 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 may be provided with 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), at different dosing intervals, or when the dosing of the individual components of the combination is desired by a prescribing healthcare provider.

Example

[0281] The present disclosure is further illustrated by the following examples and synthesis examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to impose any limitation on the scope of the present disclosure. It should be further understood that various other embodiments, modifications, and equivalents thereof that may be suggested to those skilled in the art without departing from the spirit of the present disclosure or the scope of the appended claims may be utilized.

[0282] Chemical synthesis The definitions used in the following examples and elsewhere in this specification are as follows.

[0283]

Table 2

[0284] Instrument Mass spectrometry data collection was performed using a Shimadzu LCMS-2020, Agilent 1260LC-6120 / 6125MSD, Shimadzu LCMS-2010EV, or Waters Acquity UPLC equipped with either a QDa detector or an SQ detector 2. The sample was injected into the C18 reversed phase in the liquid phase. An acetonitrile gradient was used to elute the compound from the column and supply it to the mass spectrometer. Initial data analysis was performed using either Agilent ChemStation, Shimadzu LabSolutions, or Waters MassLynx. NMR data was collected using either a Bruker AVANCE III HD 400MHz, Bruker Ascend 500MHz instrument, or a Varian 400MHz, and the raw data was analyzed using either TopSpin or Mestrelab Mnova.

[0285] Example 1. Synthesis of Compounds The compounds in Table 1 and their synthetic intermediates can be prepared by those skilled in the art of synthetic organic chemistry, for example, by combining the experimental procedures and known techniques detailed in the Examples sections of WO2021 / 091956 and WO2022 / 060836, which are incorporated herein by reference in their entirety. Additional synthetic preparations are provided below.

[0286] Example C: (1S,2S)-N-((7 3 S,9S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3,3-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-5-oxa-1(3,5)-indolo-7(3,1)-pyridazinacyclotridecaphane-9-yl)-2-methylcyclopropane-1-carboxamide

[0287]

Chemical Structure

[0288] Step 1. To a stirred solution of methyl (S)-hexahydropyridazine-3-carboxylate (1.47 g, 4.36 mmol) and NMM (43.6 mmol) in 20 mL of DCM, (S)-2-((tert-butoxycarbonyl)amino)hex-5-enoic acid (1 g, 4.36 mmol) and EDCI (1.67 g, 8.72 mmol) / HOBT (0.87 mmol) were added portionwise at 0 °C under an air atmosphere. The resulting mixture was stirred at 25 °C for 2 h under an air atmosphere. The resulting mixture was washed with H2O (3 × 20 mL). The aqueous layer was extracted with DCM (3 × 20 mL). The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC to give methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)hex-5-enoyl)hexahydropyridazine-3-carboxylate (782 mg, 50.44%) as a yellow oil. LCMS (ESI): m / z [M+H] + C 17 H 30 Theoretical value for C17H26N3O5 356.2; measured value 356.0. Step 2. To a stirred solution / mixture of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)hex-5-enoyl)hexahydropyridazine-3-carboxylate (500 mg) and DCM (10 mL), TFA (10 mL) was added at room temperature. The resulting mixture was concentrated under reduced pressure and used in the next step without further purification.

[0289] Step 3. To a stirred solution of methyl (S)-1-((S)-2-aminohex-5-enoyl)hexahydropyridazine-3-carboxylate (500 mg, 1.96 mmol) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (196.06 mg, 1.96 mmol) in 10 mL of DCM, HATU (744.62 mg, 1.96 mmol) and DIPEA (2531.02 mg, 19.56 mmol) were added at room temperature. The resulting mixture was washed with H2O (3 × 100 mL). The residue was purified by silica gel column chromatography to give methyl (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (500 mg, 75.67%) as a white solid.

[0290] Step 4. To a stirred solution of methyl (3S)-1-[(2S)-2-{[(1S,2S)-2-methylcyclopropyl]formamido}hex-5-enoyl]-1,2-diazinan-3-carboxylate (500 mg, 1.48 mmol) in THF (10 mL) and H2O (10 mL), LiOH (177.43 mg, 7.41 mmol) was added at room temperature. The mixture was acidified to pH 5 with 1 M HCl (aqueous solution). The aqueous layer was extracted with DCM (3 × 100 mL). The organic mixture was concentrated under reduced pressure to give 420 mg of a crude product, which was used directly without further purification. LCMS (ESI): m / z [M+H] + C 16 H 26 Theoretical value for C17H25N3O4 324.2; measured value 324.3. Step 5. To a stirred solution of (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylic acid (320 mg, 0.99 mmol) and (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (537.85 mg, 0.99 mmol) in 10 mL of DCM, DCC (408.32 mg, 1.98 mmol) and DMAP (24.18 mg, 0.20 mmol) were added at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (720 mg, 85.71%) as a white solid. LCMS (ESI): m / z [M+H] + C 44 H 63 Theoretical value for CBrN7O5 848.4; Measured value 848.5. Step 6. To a stirred solution of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (640 mg, 0.75 mmol) in toluene (9 mL), dioxane (3 mL), and H2O (3 mL) were added K3PO4 (400 mg, 1.88 mmol) and Pd(dppf)Cl2 (122 mg, 0.15 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(1-ethyl-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-vinyl-1H-indol-3-yl)-2,2-dimethylpropyl (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (500 mg, 83.31%) as a white solid. LCMS (ESI): m / z [M+H] + C 46 H 66 Theoretical value for C H N7O5 796.5; measured value 796.5. Step 7. To a stirred solution of 3-(1-ethyl-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-vinyl-1H-indol-3-yl)-2,2-dimethylpropyl (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (800 mg, 1.01 mmol) and titanium tetraisopropoxide (142.81 mg, 0.50 mmol) in 100 mL of DCM was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.17 g, 0.20 mmol) portionwise at 25 °C under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (1S,2S)-N-((7 3 S,9S,E)-11-ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3,3-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-5-oxa-1(3,5)-indela-7(3,1)-pyridazinacyclotridecafuran-12-en-9-yl)-2-methylcyclopropane-1-carboxamide (17 mg, 2.17%) as a white solid. LCMS (ESI): m / z [M+H] + C 44 H 62 N7O5 calcd 768.5; found 768.5. Step 8. (1S,2S)-N-((7 3 S,9S,E)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3,3-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6-Hexahydro-1 1 To a solution of (1S,2S)-N-((7 3 S,9S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3,3-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-5-oxa-1(3,5)-indol-7(3,1)-pyridazinacyclotridecafuran-9-yl)-2-methylcyclopropane-1-carboxamide (260 mg, 0.13 mmol) in a pressure tank, Pd(OH)2 / C (20%, 0.26 g) was added. The mixture was hydrogenated at room temperature for 1 h under H2 at 30 psi, filtered through a sand core funnel, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1S,2S)-N-((7 + C 44 H 64 N7O5 theoretical value 770.5; measured value 770.6. 11H NMR (300 MHz, DMSO-d6) δ 8.51 - 8.43 (d, 1H), 8.01 - 7.93 (m, 1H), 7.43 - 7.34 (m, 1H), 7.28 (s, 1H), 7.24 - 7.18 (m, 1H), 7.03 - 6.95 (m, 1H), 5.48 - 5.38 (m, 1H), 5.34 - 5.23 (m, 1H), 4.40 - 4.28 (m, 1H), 4.16 - 3.97 (m, 2H), 3.95 - 3.81 (m, 1H), 3.71 - 3.47(m, 3H), 3.28 - 3.21 (m, 4H), 3.00 - 2.79 (m, 4H), 2.66 - 2.58 (m, 1H), 2.48 - 2.43 (m, 4H), 2.28 - 2.21 (m, 4H), 1.92 - 1.76 (m, 3H), 1.69 - 1.41 (m, 7H), 1.40 - 1.32 (m, 5H), 1.18 - 1.06 (m, 3H), 1.04 - 0.95 (m, 4H), 0.88 - 0.72 (m, 4H), (s, 4H), 0.57 (s, 3H), 0.47 - 0.36 (m, 1H). Synthesis of (1S,2R)-2-(3-(3-((tert-butyldiphenylsilyl9)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-((RS)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)cyclopropylmethanesulfonate

[0291]

Chemical Structure

[0292] Step 1. To a stirred solution of 3-(5-bromo-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropan-1-ol (15 g, 33.7 mmol) in DCM (150 mL) and DMF (30 mL) were added imidazole (6.88 g, 101.1 mmol) and TBDPSCl (13.89 g, 50.5 mmol) at 20 °C. The resulting solution was stirred at 60 °C for 2 h. The solution was diluted with DCM (300 mL) and H2O (300 mL). The layers were separated and the organic layer was washed with H2O (100 mL×3), brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to give 5-bromo-3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indole (19.8 g, 81% yield) as a colorless oil. LCMS (ESI): m / z [M+H] + C 39 H 47 Theoretical value for C, H, BrN2O2Si 683.3; measured value 683.2. Step 2. A solution of pinacol vinyl boronate (10.4 g, 67.5 mmol), 5-bromo-3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indole (42 g, 61.4 mmol), DIPEA (15.87 g, 122.8 mmol), Pd2(dba)3 (5.62 g, 6.1 mmol), and P(t-Bu)3HBF4 (3.56 g, 12.2 mmol) in dehydrated toluene (320 mL) was stirred at 95 °C for 2 h under an N2 atmosphere. The solution was cooled and the precipitate was filtered off. The filtrate was evaporated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to give 3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-[(1E)-prop-1-en-1-yl]indole (37 g, 84% yield) as a greenish semi-oil. LCMS (ESI): m / z [M+H] + C 47 H 61 Theoretical value for CBN2O4Si 757.5; Measured value 757.5. Step 3. A stir bar was placed in a 100 mL round-bottom flask that had been dried by heating. ZnEt2 (1 M solution in hexane, 39.8 mL, 39.8 mmol) and DCM (160 mL) were placed in the vessel. CH2I2 (21.3 g, 79.5 mmol) was added dropwise to the reaction mixture via syringe at -5 °C. The resulting mixture was stirred at -5 °C for 1 hour, then 3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]indole (12 g, 15.9 mmol) was added dropwise to the flask as a solution in DCM (30 mL). The reaction mixture was warmed to 20 °C and stirred vigorously for 16 hours. The reaction mixture was then quenched with saturated NH4Cl (aqueous solution), extracted with DCM (50 × 2 mL), and washed with brine (50 × 2 mL). The organic phase was collected, dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography to give 3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]indole (10 g, 77% yield) as a pale yellow semi-solid. LCMS (ESI): m / z [M+H] + C 48 Theoretical value for C63H63BN2O4Si 771.5; measured value 771.4. Step 4. To a solution of 3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]indole (12 g, 15.6 mmol) in THF (120 mL) and NaOH (12 mL) was added 30% H2O2 (6 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 and extracted with EtOAc (20 × 3 mL), washed with brine (30 mL × 2). The organic phase was collected, dried over Na2SO4 and then concentrated to give a residue. The residue was purified by silica gel column chromatography to give (1S,2R)-2-(3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl)cyclopropan-1-ol (10 g, 92% yield) as a pale green semi-solid. LCMS (ESI): m / z [M+H] + C 42 H 52 Theoretical value for N2O3Si 661.4; measured value 661.3. To a solution of (1S,2R)-2-(3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl)cyclopropan-1-ol (7.2 g, 10.9 mmol, 1.0 eq) in DCM (72 mL) were added Et3N (2.21 g, 21.8 mmol) and DMAP (0.27 g, 2.18 mmol). Then methanesulfonyl chloride (1.86 g, 16.4 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at 20 °C for 1 h. The mixture was quenched with saturated NaHCO3 (aqueous solution), extracted with DCM (50×2 mL), and washed with brine (50×2 mL). The organic phase was collected, dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography to give (1S,2R)-2-(3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-((RS)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)cyclopropylmethanesulfonate (a 2:1 diastereomer mixture, ratio 1:1.6, 6.8 g, 80% yield) as a pale green semi-solid. LCMS (ESI): m / z [M+H] + C 43 H 54 Theoretical value for N2O5SSi 739.4; measured value 739.3. Example A7: (1SR,2RS,3SR)-N-((2 1 RS,2 2 SR,7 3 RS,5RS)-1 2 -(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1Synthesis of H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecaphane-5-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0293]

Chem.

[0294] Step 1. To a solution of tert-butyl N-[(3S)-2-oxooxetan-3-yl]carbamate (20 g, 0.107 mol) in MeCN (100 mL) was added N,1-dimethylaniline (13 g, 0.11 mol) at 20 °C. The resulting solution was stirred at 20 °C for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (R)-3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (25 g, 65% yield) as a pale yellow solid. LCMS (ESI): m / z [M+H] + C 16 H 25 The theoretical value of C15H22N2O4 is 309.2; the measured value is 309.2. Step 2. To a stirred solution of rac-(R)-3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (29 g, 0.09 mol) in MeOH (70 mL) and toluene (210 mL) was added (trimethylsilyl)diazomethane (21 g, 0.19 mol) at 20 °C. The resulting solution was stirred at 20 °C for 2 h. After quenching with H2O (20 mL), it was concentrated to dryness to give a residue. The residue was diluted with EtOAc (800 mL) and H2O (100 mL). The organic layer was washed with H2O (100 mL × 3), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give methyl (R)-3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoate (23 g, 72% yield) as a pale yellow oil. LCMS (ESI): m / z [M+H]+ C 16 H 25 The theoretical value of N2O4 is 323.2; the measured value is 323.3. Step 3. To a solution of rac-methyl (R)-3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoate (7.1 g, 0.02 mol) in MeOH (50 mL) was added Pd / C (1 g, 14 wt%) at 20 °C. The resulting solution was stirred at 20 °C for 16 h under a H2 atmosphere (1 atm). The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude desired product methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(methylamino)propanoate (4 g, purity >90%) as a pale yellow oil. This crude product was used in the next step without further purification.

[0295] Step 4. Cs2CO3 (3.81 g, 0.012 mol) was added to a stirred solution of (3-{4-[5-(3-{3-[(tert-butyldimethylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-5-[(1S,2R)-2-(methanesulfonyloxy)cyclopropyl]indol-2-yl)-6-[(1S)-1-methoxyethyl]pyridin-3-yl]piperazin-1-yl}phenyl)methyl formate (3.28 g, 0.004 mol) and rac-methyl (R)-3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoate (4.55 g, 0.02 mol) in MeCN (5 mL) at 20 °C. The resulting solution was stirred at 80 °C for 3 days under a N2 atmosphere. The solution was diluted with EtOAc (600 mL) and H2O (100 mL). The organic layer was washed with H2O (50 mL × 3), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give the desired product benzyl 4-(5-(5-((1RS,2SR)-2-(((RS)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)(methyl)amino)cyclopropyl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-((RS)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (1.8 g, purity 50%) as a pale yellow solid. LCMS (ESI): m / z [M+H] + C 54 H 80 Theoretical value for C54H80N6O8Si 969.6; Measured value 969.4. Step 5. To a stirred solution of benzyl 4-(5-(5-((1RS,2SR)-2-(((RS)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)(methyl)amino)cyclopropyl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-((RS)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (1.7 g, 0.002 mol) in THF (18 mL) and H2O (6 mL) was added LiOH (0.09 g, 0.004 mol) at 20 °C and the resulting solution was stirred for 2 h. The pH was adjusted to 7 with 1 N HCl at 5 °C, concentrated, and the residue was dissolved in DCM (200 mL), washed with H2O (20 mL) and brine (50 mL), dried over Na2SO4 and concentrated to give (RS)-3-(((1SR,2RS)-2-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.7 g, 50% purity) as a grey foam, which was used directly in the next step without further purification.

[0296] Step 6. To a stirred solution of (RS)-3-(((1SR,2RS)-2-(2-(5-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.9 g, 1.67 mmol) and methyl (3S)-1,2-diazinane-3-carboxylate dihydrochloride (363 mg, 1.67 mmol) in DCM (16 mL) was added DIPEA (1.08 g, 8.37 mmol), followed by T3P (1.28 g, 2.01 mmol) at 5 °C and the mixture was stirred for 1 h. The solution was diluted with DCM (300 mL) and H2O (50 mL). The organic layer was washed with H2O (30 mL × 3), brine (30 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give the desired product methyl (S)-1-((RS)-3-(((1SR,2RS)-2-(2-(5-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (two diastereomers were separated, V-0173-03-P1; 590 mg, yield 30%; V-0173-03-P2: 470 mg, yield 23%) as a pale yellow solid. LCMS (ESI): m / z [M+H] + C 59 H 88 Theoretical value for C8H11N8O9Si 1081.6; Measured value 541.4 [M / 2+H] + To a stirred solution of methyl (S)-1-((RS)-3-(((1SR,2RS)-2-(2-(5-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (300 mg, 0.28 mmol) in MeOH (3 mL) was added NH4F (410 mg, 11.2 mmol) at 20 °C. The resulting solution was stirred at 60 °C for 48 h. The solution was concentrated under reduced pressure to give a residue, which was diluted with EtOAc (40 mL) and H2O (20 mL). The organic layer was washed with H2O (20 mL × 3), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give methyl (3S)-1-[(2S)-2-{[tert-butyl(formyl)-$l^{3}-oxydanyl]amino}-3-{[(1R,2S)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl](methyl)amino}propanoyl]-1,2-diazinane-3-carboxylate (200 mg, purity 70%) as a pale green semi-oil. The crude product was used in the next step without further purification.

[0297] Step 8. To a stirred solution of methyl (S)-1-((RS)-3-(((1SR,2RS)-2-(2-(5-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (300 mg, 0.31 mmol), HOBT (424.3 mg, 3.1 mmol), and DIPEA (1.62 g, 12.4 mmol) in DCM (30 mL) was added EDCI (1.81 g, 9.3 mmol). The reaction mixture was stirred at 35 °C for 5 h. The mixture was quenched with H2O (60 mL) and the resulting mixture was extracted with DCM (50 mL × 3). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give benzyl 4-(5-((2 1 RS,2 2 SR,7 3 S,5RS)-5-((tert-butoxycarbonyl)amino)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indela-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafan-12-yl)-6-((RS)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (50 mg, yield 16%) as a pale yellow semi-solid. LCMS (ESI): m / z [M+H] + C 52 H 70 N8O8 calcd 935.5; found 936.1. Step 9. To a solution of benzyl 4-(5-((2 1 RS,2 2 SR,7 3(S,5RS)-5-((tert-Butoxycarbonyl)amino)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecaphane-12-yl)-6-((RS)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (120 mg, 0.13 mmol) in a solution, Pd / C (50% w / w, 60 mg) was added. Then, under a H2 atmosphere (1 atm), the reaction mixture was stirred at 20 °C for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl ((2 1 RS,2 2 SR,7 3 S,5RS)-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecaphane-5-yl)carbamate (90 mg, purity 70%) was obtained as a pale yellow solid. This was used directly in the next step without further purification.

[0298] Step 10. Stirred at 20 °C i tert-Butyl ((2 1 RS,2 2 SR,7 3 S,5RS)-1 1 -ethyl-1 2-(2-((RS)-1-Methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafan-5-yl)carbamate (45 mg, 0.06 mmol), (1-ethoxycyclopropoxy)trimethylsilane (586 mg, 3.37 mmol) in a solution, AcOH (5.1 mg, 0.08 mmol) and sodium cyanoborohydride (14.1 mg, 0.24 mmol) were added. The reaction mixture was stirred at 60 °C for 3 hours. The mixture was diluted in EtOAc (20 mL) and washed with H2O (10 mL × 2) and brine (20 mL). The organic phase was recovered, dried over Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by silica gel chromatography to give tert-butyl ((2 1 RS,2 2 SR,7 3 S,5RS)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafan-5-yl)carbamate (20 mg, yield 38%) was obtained as a pale green semi-solid. LCMS (ESI): m / z [M+H] + C 47 H 68 N8O6 theoretical value 841.5; measured value 841.2. Step 11. To a solution of tert-butyl ((2 1 RS,2 2 SR,7 3 S,5RS)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafuran-5-yl)carbamate (20 mg, 0.02 mmol) in DCM (0.5 mL) was added TFA (0.2 mL) at 20 °C, and then the reaction mixture was stirred for 1 h. The mixture was concentrated until dry (2 1 RS,2 2 SR,7 3 S,5RS)-5-amino-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1- -ethyl-3,11,11-trimethyl-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafuran-6,8-dione (20 mg TFA salt, purity 90%) was obtained as a pale green oil. This was used directly in the next step without further purification.

[0299] Step 12. In DMF (0.5 mL) stirred at 0 °C of (2 1 RS,2 2 SR,7 3(S,5RS)-5-Amino-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1- -ethyl-3,11,11-trimethyl-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafuran-6,8-dione (6.2 mg, 0.06 mmol) in a solution, HATU (15.4 mg, 0.05 mmol) and DIPEA (34.9 mg, 0.30 mmol) were added dropwise. The reaction mixture was stirred at 0 °C for 0.5 h. The mixture was diluted in EtOAc (30 mL) and washed with H2O (20 mL × 2) and brine (20 mL). The organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to give (1SR,2RS,3SR)-N-((2 1 RS,2 2 SR,7 3 RS,5RS)-1 2 -(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafuran-5-yl)-2,3-dimethylcyclopropane-1-carboxamide (5.0 mg, yield 21%) was obtained as a white solid. LCMS (ESI): m / z [M+H] + C 48 H 68 The theoretical value of N8O5 is 837.5; the measured value is 837.5. 11H NMR (400 MHz, CD3OD) δ 8.40 (d, J = 2.8, 1H), 7.95 (s, 1H), 7.37 - 7.30 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.67 - 6.63 (m, 1H), 6.31 - 6.24 (m, 1H), 5.66 - 5.62 (m, 1H), 4.48 (d, J = 13.2 Hz, 1H), 4.19 - 4.12 (m, 2H), 4.06 - 3.88 (m, 3H), 3.77 - 3.75 (m, 1H), 3.48 - 3.40 (m, 1H), 3.28 - 3.08 (m, 6H), 2.93 - 2.70 (m, 8H), 2.60 - 2.53 (m, 1H), 2.35 (s, 3H), 2.19 - 2.15 (m, 1H), 1.93 - 1.90 (m, 1H), 1.75 - 1.60 (m, 3H), 1.40 (d, J = 6.4 Hz, 3H), 1.30 - 1.19 (m, 4H), 1.16 - 0.99 (m, 10H), 0.81 (s, 3H), 0.66 (s, 3H), 0.56 - 0.45 (m, 4H). Example A6: (1r,2R,3S)-N-((2 1 R,2 2 R,7 3 S,5S)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-9-oxa-1(5,3)-indola-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafuran-5-yl)-2,3-dimethylcyclopropane-1-carboxamide synthesis

[0300]

Chemical Structure

[0301] Step 1. To a solution of 3-(5-bromo-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropyl acetate (10 g, 0.014 mol) and methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}hexa-5-enoate (10.2 g, 0.042 mol) in MeCN (100 mL) were added tri-o-tolylphosphine (3.4 g, 0.011 mol), Et3N (4.25 g, 0.042 mol), and Pd(OAc)2 (1.9 g, 0.008 mol) at 20 °C. The solution was stirred at 90 °C for 16 h under N2. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give a crude product, which was purified by silica gel chromatography to give methyl (2S,5E)-6-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}-2-{[(tert-butoxy)carbonyl]amino}hexa-5-enoate (10 g, yield 75%) as a pale yellow solid. LCMS (ESI): m / z [M+H] + C 49 H 65 Theoretical value for C55H71N5O9 868.5; measured value 868.5. To a solution of Et2Zn (92 mL, 92 mmol) in DCM (160 mL) was added TFA (10.5 g, 92 mmol) at 0 °C. The solution was stirred at 0 °C under N2 for 1 hour. To this solution was added CH2I2 (24.6 g, 92 mmol) at 0 °C, and the solution was stirred for 1 hour. To this solution was added methyl (2S,5E)-6-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}-2-{[(tert-butoxy)carbonyl]amino}hex-5-enoate (8 g, 9.2 mmol) at 0 °C. The solution was stirred at 20 °C under N2 for 14 hours. The mixture was quenched with saturated NaHCO3 and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated to give the crude product, which was purified by silica gel chromatography to give methyl (2S)-4-[(1R,2R)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}cyclopropyl]-2-aminobutanoate (5.4 g, yield 59%) as a pale yellow solid. LCMS (ESI): m / z [M+H] + C 45 H 59 Theoretical value for C55H73N5O7 782.4; measured value 782.3. Step 3. To a solution of methyl (2S)-4-[(1R,2R)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}cyclopropyl]-2-aminobutanoate (5.5 g, 7 mmol) and NaHCO3 (2.9 g, 35 mmol) in THF / H2O (1:1, 60 mL) was added (Boc)2O (4.58 g, 21 mmol) at 20 °C and the mixture was stirred for 1 h. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated to give the crude product, which was purified by silica gel chromatography to give methyl (2S)-4-[(1R,2R)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}cyclopropyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate (5.4 g, 61% yield) as a yellow solid. LCMS (ESI): m / z [M+H] + C 50 H 67 Theoretical value for C55H82N5O9 882.5; measured value 882.4. Step 4. To a solution of methyl (2S)-4-[(1R,2R)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}cyclopropyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate (5.3 g, 0.006 mol) in THF / H2O (5:1, 60 mL) was added LiOH (2.16 g, 0.09 mol) at 20 °C. The solution was stirred at 20 °C for 16 h. The mixture was quenched with 1 M HCl and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoic acid (5.7 g, a mixture of two isomers from LCMS, purity 70%) as a yellow solid. LCMS (ESI): m / z [M+H] + C 47 H 63 Theoretical value for C45H55N5O8 826.4; found 826.4. Step 5. To a solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoic acid (5.5 g, 6.7 mmol) and methyl (3S)-1,2-diazinane-3-carboxylate (1.9 g, 13.4 mmol) in DMF (55 mL) were added DIPEA (25.98 g, 0.2 mol) and HATU (3.8 g, 0.01 mol) at 0 °C, and the mixture was stirred for 1 h. The mixture was quenched with H2O (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated to give the crude product, which was purified by silica gel chromatography to give methyl (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoyl]-1,2-diazinane-3-carboxylate (5 g, yield 58%) as a yellow solid. LCMS (ESI): m / z [M+H] + C 53 H 73 Theoretical value for C49H67N7O9 is 952.6; measured value is 952.4. Step 6. To a solution of methyl (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoyl]-1,2-diazinane-3-carboxylate (2.5 g, 2.6 mmol) in THF / H2O (3:1, 24 mL) was added LiOH (0.19 g, 7.8 mmol) at 20 °C. The solution was stirred at 20 °C for 1 h. The mixture was adjusted to pH 7 with 1 N HCl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give (3S)-1-[(2S,3R)-2-{[(1R,2R,3S)-2,3-dimethylcyclopropyl]formamide}-3-ethoxy-3-[(3R)-1-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}pyrrolidin-3-yl]propanoyl]-1,2-diazinane-3-carboxylic acid (2.5 g, purity 70%) as a yellow solid. LCMS (ESI): m / z [M+H] + C 52 H 71 Theoretical value for C49H70N7O9 is 938.5; measured value is 938.4. Step 7. To a solution of (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoyl]-1,2-diazinane-3-carboxylic acid (2.5 g, 2.7 mmol) in DCM (250 mL) were added DIPEA (10.47 g, 81 mmol), HOBt (3.65 g, 27 mmol), and EDCI (15.5 g, 81 mmol) at 20 °C. The solution was stirred at 45 °C for 16 h under N2. The reaction mixture was purified by preparative HPLC to give benzyl 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-((tert-butoxycarbonyl)amino)-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-1(5,3)-indolazepino-7(1,3)-pyridazino-2(1,2)-cyclopropanacyclododecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (120 mg, yield 4.8%) as a white solid. LCMS (ESI): m / z [M+H] + C 52 H 69 N7O8 calcd 920.5; found 920.5. Step 8. To a solution of benzyl 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-((tert-butoxycarbonyl)amino)-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,74 ,7 5 ,7 6 -Hexahydro-1 1 H-9-oxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (80 mg, 0.087 mmol) in a solution, TFA (1 mL) was added at 20 °C and stirred for 1 hour. The mixture was quenched with saturated NaHCO3 and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated, and benzyl 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-amino-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-9-oxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecaphane-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (116 mg, purity > 90%) was obtained as a white solid. LCMS (ESI): m / z [M+H] + C 47 H 61 The theoretical value of C17H24N7O6 is 820.5; the measured value is 820.4. Step 9. Benzyl 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-amino-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1H-9-oxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecan-1 2 -(yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (96 mg, 0.12 mmol) and (1R,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (27 mg, 0.23 mmol) in a solution, DIPEA (151 mg, 1.17 mmol) and HATU (66 mg, 0.17 mmol) were added at 0 °C and stirred for 1 hour. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated under reduced pressure to obtain a crude material, which was purified by preparative TLC to give benzyl 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamide)-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecan-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (80 mg, yield 67%) was obtained as a white solid. LCMS (ESI): m / z [M+H] + C 53 H 69 The theoretical value of N7O7 is 916.5; the measured value is 916.4. Step 10. Benzyl 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamide)-1 1-Ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecaphane-1 2 -yl-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.076 mmol) and paraformaldehyde (3.2 mg, 0.107 mmol) in a solution, Pd / C (23.2 mg, 50% w / w) was added at 20 °C. The solution was stirred at 20 °C under H2 (1 atm) for 16 hours. The mixture was filtered and the filtrate was concentrated to obtain a crude product, which was purified by preparative TLC to give (1r,2R,3S)-N-((2 1 R,2 2 R,7 3 S,5S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-9-oxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecaphane-5-yl)-2,3-dimethylcyclopropane-1-carboxamide (40.5 mg, yield 64%) was obtained as a white solid. LCMS (ESI): m / z [M+H] + C 46 H65N7O5 theoretical value 796.5; measured value 796.4. 11H NMR (400 MHz, MeOD) δ 8.44 (d, J = 2.7 Hz, 1H), 7.50 (s, 1H), 7.38 (d, J = 2.8 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 5.71 (d, J = 7.2 Hz, 1H), 4.43 (s, 1H), 4.08 - 3.97 (m, 3H), 3.86 - 3.69 (m, 3H), 3.36 (d, J = 4.3 Hz, 4H), 3.24 (d, J = 14.2 Hz, 1H), 2.98 (s, 3H), 2.88 (s, 1H), 2.70 (t, J = 4.7 Hz, 4H), 2.41 (s, 3H), 2.09 (t, J = 15.0 Hz, 2H), 1.98 (d, J = 11.8 Hz, 1H), 1.90 (dd, J = 11.4, 7.3 Hz, 3H), 1.66 (dd, J = 23.0, 8.7 Hz, 2H), 1.52 - 1.45 (m, 1H), 1.42 (d, J = 6.3 Hz, 3H), 1.32 (d, J = 7.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 5H), 1.08 (dd, J = 9.0, 4.2 Hz, 8H), 0.92 (s, 3H), 0.68 - 0.62 (m, 4H), 0.51 (dt, J = 8.5, 4.4 Hz, 1H). Example A5: (1SR,2RS,3SR)-N-((2 1 RS,2 2 SR,7 3 RS,5RS)-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1Synthesis of H-3,9-dioxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecaphane-5-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0302]

Chem.

[0303] Step 1. Pd(OAc)2 (3.07 g, 13.6 mmol) and 1,10-phenanthroline (2.47 g, 13.6 mmol) were added to a stirred flask containing an ethyl vinyl ether / DCM (375:225 mL) solution at 20 °C. After stirring for 30 minutes under a N2 atmosphere, methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-hydroxypropanoate (60 g, 273.7 mmol) was added to the solution, and the resulting reaction mixture was stirred at 20 °C for 4 days. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography to give methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(vinyloxy)propanoate (30 g, yield 43%) as a colorless oil. LCMS (ESI): m / z [M+H] + C 11 H 19 Theoretical value of C + ; A solution of 3-(5-bromo-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropyl acetate (5.0 g, 10.26 mmol), methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(vinyloxy)propanoate (6.29 g, 25.65 mmol), Pd(OAc)2 (1.38 g, 6.2 mmol), tri-o-tolylphosphine (2.5 g, 8.21 mmol), and Et3N (3.12 g, 30.78 mmol) in MeCN (50 mL) under N2 at step 2 was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give methyl (2S)-3-{[(E)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}ethenyl]oxy}-2-{[(tert-butoxy)carbonyl]amino}propanoate (0.9 g, 14% yield) as a greenish semi-oil. LCMS (ESI): m / z [M+H] + C 36 H 49 Theoretical value for C40H51N3O8 652.4; Measured value 652.4. Step 3. ZnEt2 (1 M solution in hexanes, 11.1 mL, 11.1 mmol) and DCM (13 mL) were added to a 100 mL round-bottom flask containing the flame-dried stir bar. CH2I2 (5.91 g, 22.1 mmol) was added dropwise via syringe to the reaction mixture at -10 °C, and the reaction was stirred for 1 hour. Then, methyl (2S)-3-{[(E)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}ethenyl]oxy}-2-{[(tert-butoxy)carbonyl)amino}propanoate (900 mg, 1.38 mmol) was added dropwise to the flask as a solution in DCM (5 mL). The reaction mixture was warmed to 20 °C and stirred vigorously for 11 hours. The reaction mixture was then concentrated to give a residue. The residue was dissolved in EtOAc (50 mL) and washed with H2O (50 mL x 2). The organic phase was collected, dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC to give methyl (2S)-3-[(1R,2S)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}cyclopropoxy]-2-{[(tert-butoxy)carbonyl]amino}propanoate (400 mg, 51% yield) as a yellow semi-solid. LCMS (ESI): m / z [M+H] + C 32 H 43 Theoretical value for C H N3O6 566.3; Measured value 566.3. To a solution of methyl (2S)-3-[(1R,2S)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}cyclopropoxy]-2-aminopropanoate (0.73 g, 1.3 mmol) and (Boc)2O (850 mg, 3.9 mmol) in THF (15 mL) and H2O (5 mL) was added NaHCO3 (330 mg, 3.9 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and EtOAc (20 mL), the organic phase was separated and dried over Na2SO4. The solvent was removed under reduced pressure to afford methyl (2S)-3-[(1R,2S)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}cyclopropoxy]-2-{[(tert-butoxy)carbonyl]amino}propanoate (0.9 g) as a green semi-solid. This was used directly in the next step without further purification.

[0304] Step 5. To a solution of methyl (2S)-3-[(1R,2S)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}cyclopropoxy]-2-{[(tert-butoxy)carbonyl]amino}propanoate (0.9 g, 1.57 mmol) in THF (10 mL) and H2O (2 mL) was added LiOH (0.16 g, 6.75 mmol), and then the reaction mixture was stirred at 20 °C for 12 h. The mixture was poured into H2O (20 mL). 1N HCl was added to the mixture to pH 7, and the resulting mixture was extracted with EtOAc (20 mL × 3). The organic phases were collected, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropoxy]propanoic acid (0.85 g, yield 90%). LCMS (ESI): m / z [M+H] + C 34 H 47 Theoretical value for C32H45N3O7 is 610.3; measured value is 610.4. A solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropoxy]propanoic acid (700 mg, 1.15 mmol), methyl (3S)-1,2-diazinane-3-carboxylate (248.3 mg, 1.72 mmol) and DIPEA (445 mg, 3.44 mmol) in DCM (7 mL) was treated with T3P (1.46 g, 2.30 mmol) at 0 °C, and then the reaction mixture was stirred at 0 °C for 1 h. The mixture was quenched with H2O (50 mL), and the resulting mixture was extracted with DCM (50 ml × 3). The organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give methyl (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropoxy]propanoyl]-1,2-diazinane-3-carboxylate (0.45 g, 48% yield) as a pale green solid. LCMS (ESI): m / z [M+H] + C 40 H 57 Theoretical value for C42H55N5O8 736.4; found 736.4. Step 7. To a solution of methyl (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropoxy]propanoyl]-1,2-diazinane-3-carboxylate (450 mg, 0.61 mmol) in THF (4.5 mL) and H2O (0.9 mL) was added LiOH (73 mg, 3.1 mmol), and then the reaction mixture was stirred at 0 °C for 2 h. The mixture was poured into H2O (50 mL). 1N HCl was added to the mixture to pH 7, and the resulting mixture was extracted with EtOAc (50 mL × 3). The organic phases were collected, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropoxy]propanoyl]-1,2-diazinane-3-carboxylic acid (440 mg, 90% yield) as a green semi-oil. LCMS (ESI): m / z [M+H] + C 39 H 55 Theoretical for C38H51N5O8 722.4; found 722.4. Step 8. To a stirred solution of (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropoxy]propanoyl]-1,2-diazinane-3-carboxylic acid (450 mg, 0.62 mmol), HOBT (842 mg, 6.2 mmol), and DIPEA (3.22 g, 24.9 mmol) in DCM (45 mL) was added EDCI (3.59 g, 18.6 mmol), and then the reaction mixture was stirred at 20 °C for 12 h. The mixture was quenched with H2O (60 mL), and the resulting mixture was extracted with DCM (50 mL × 3). The organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give tert-butyl ((2 1 RS,2 2 SR,7 3 RS,5RS)-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-3,9-dioxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafuran-5-yl)carbamate (180 mg, yield 37%) as a pale yellow semi-solid. LCMS (ESI): m / z [M+H] + C 39 H 53 Theoretical value for C H N5O7 704.3; measured value 704.4. Step 9. To a solution of methyl (3S)-1-[(2S,3R)-2-{[(1R,2R,3S)-2,3-dimethylcyclopropyl]formamide}-3-ethoxy-3-[3-({1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}oxy)cyclobutyl]propanoyl]-1,2-diazinane-3-carboxylate (180 mg, 0.26 mmol) in DCM (10 mL) was added ZnBr2 (1.15 g, 5.11 mmol), and the reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with DCM (10 mL) and H2O (10 mL). The organic phase was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (2 1 RS,2 2 SR,7 3 RS,5RS)-5-amino-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-3,9-dioxa-1(5,3)-indolazepino-7(1,3)-pyridazino-2(1,2)-cyclopropanacyclododecane-6,8-dione (170 mg, purity 90%) as a pale green solid. LCMS (ESI): m / z [M+H] + C 34 H 45 N5O5 calculated 604.3; found 604.3. Step 10. To (2 1 RS,2 2 SR,7 3 RS,5RS)-5-amino-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-7 1 ,7 2,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-3,9-dioxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafan-6,8-dione (170 mg, 0.28 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (63 mg, 0.56 mmol) solution, HATU (129.3 mg, 0.34 mmol) and DIPEA (361 mg, 2.8 mmol) were added dropwise. The reaction mixture was stirred at 0 °C for 0.5 h. The mixture was diluted in EtOAc (30 mL) and washed with water (20 mL × 2) and brine (20 mL). The organic phase was recovered, dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by silica gel chromatography to give (1SR,2RS,3SR)-N-((2 1 RS,2 2 SR,7 3 RS,5RS)-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -hexahydro-1 1 H-3,9-dioxa-1(5,3)-indol-7(1,3)-pyridazina-2(1,2)-cyclopropanacyclododecafan-5-yl)-2,3-dimethylcyclopropane-1-carboxamide (5.8 mg, yield 2.6%) was obtained as a white solid. LCMS (ESI): m / z [M+H] + C 40 H 53 The theoretical value of N5O6 is 700.3; the measured value is 700.4. 11H NMR (400 MHz, CD3OD) δ 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 7.88 - 7.86 (m, 1H), 7.71 (s, 1H), 7.52 (dd, J = 8.0, 4.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.70 (dd, J = 7.6, 5.6 Hz, 1H), 4.47 (d, J = 12.4 Hz, 1H), 4.47 (q, J = 6.0 Hz, 1H), 4.14 - 4.02 (m, 2H), 3.95 - 3.89 (m, 1H), 3.84 - 3.80 (m, 2H), 3.72 - 3.67 (m, 1H), 3.59 - 3.56 (m, 1H), 3.36 - 3.33 (m, 1H), 3.14 (s, 3H), 2.99 - 2.96 (m, 1H), 2.86 - 2.80 (m, 1H), 2.51 - 2.48 (m, 1H), 2.28 - 2.21 (m, 2H), 1.98 - 1.93 (m, 1H), 1.81 - 1.64 (m, 2H), 1.45 (d, J = 6.0 Hz, 3H), 1.32 - 1.29 (m, 2H), 1.23 - 1.18 (m, 2H), 1.13 - 1.04 (m, 10H), 0.72 - 0.71 (m, 6H). In vitro and in vivo experiments: The following assays may be performed to evaluate various properties of the compounds of the present invention. Compounds A1 - A6 herein show (i) pERK (Capan-1, K-Ras G12V) IC50 of less than 8 μM, (ii) MOA (G13C) IC50 of less than 30 μM, or (iii) both (i) and (ii).

[0305] Potency assay: pERK The purpose of this assay was to measure the ability of test compounds to inhibit K-Ras intracellularly. Activated K-Ras induces an increase in phosphorylation of ERK (pERK) at threonine 202 and tyrosine 204. This procedure measures the decrease in cellular pERK in response to test compounds. The procedure described below is applicable to K-Ras G12C in NCI-H358 cells.

[0306] Note: This protocol can be performed by substituting other cell lines and can be used to evaluate the properties of inhibitors of other RAS variants, including, for example, AsPC-1 (K-Ras G12D), Capan-1 (K-Ras G12V), NCI-H1355 (K-Ras G13C), Hs766T (K-Ras Q61H), NCI-H2347, or KU-19-19 (N-Ras Q61R), or SK-MEL-30 (N-Ras Q61K).

[0307] NCI-H358 cells were grown and maintained using the medium and procedures recommended by ATCC. One day prior to compound addition, cells were seeded into 384-well cell culture plates (40 μL / well) and grown overnight in an incubator at 37 °C and 5% CO2. Test compounds were prepared in 10-fold serial dilutions in 10 mM DMSO. On the day of the assay, 40 nl of the test compounds were added to each well of the cell culture plates using an Echo 550 liquid handler (LabCyte®). The concentrations of the test compounds were tested in duplicate. After compound addition, the plates were shaken at 300 rpm for 15 seconds, centrifuged, and the cells were incubated at 37 °C and 5% CO2 for 4 hours. After incubation, the medium was removed and the cells were washed once with phosphate-buffered saline.

[0308] In some experiments, the pERK levels of the cells were determined using the AlphaLISA SureFire Ultra p-ERK1 / 2 assay kit (PerkinElmer). The cells were lysed in 25 μL of lysis buffer and shaken at room temperature at 600 RPM. The lysate (10 μl) was transferred to a 384-well Opti-plate (PerkinElmer), and 5 μL of acceptor mix was added. After incubation in the dark for 2 hours, 5 μl of donor mix was added, the plate was sealed, and incubated at room temperature for 2 hours. The signal was read on an Envision plate reader (PerkinElmer) using standard AlphaLISA settings. The analysis of the raw data was performed in any of the following ways. a) In Excel (Microsoft) and Prism (GraphPad), the signal was plotted against the logarithm of 10 of the compound concentration, and the IC 50 was determined by fitting a four-parameter sigmoid concentration-response model. Or b) Using Genedata Screener (Genedata), the normalized signal was plotted against the logarithm of 10 of the compound concentration, and the IC50 was determined by fitting a four-parameter sigmoid concentration-response model.

[0309] In other experiments, cellular pERK was determined by In-Cell Western. After compound treatment, cells were washed twice with 200 μL of tris-buffered saline (TBS) and fixed for 15 minutes with 150 μl of 4% paraformaldehyde in TBS. Fixed cells were washed four times for 5 minutes each with TBS containing 0.1% Triton X-100 (TBST), then blocked for 60 minutes at room temperature with 100 μl of Odyssey blocking buffer (LI-COR). The primary antibody (pERK, CST-4730, Cell Signaling Technology) was diluted 1:200 in blocking buffer, 50 μl was added to each well, and incubated overnight at 4 °C. Cells were washed four times for 5 minutes each with TBST. The secondary antibody (IR-800CW rabbit, LI-COR, diluted 1:800) and DNA stain DRAQ5 (LI-COR, diluted 1:2000) were added and incubated for 1 - 2 hours at room temperature. Cells were washed four times for 5 minutes each with TBST. Plates were scanned on a Li-COR Odyssey CLx Imager. Analysis of raw data was performed with Excel (Microsoft) and Prism (GraphPad), signals were plotted against the logarithm of the compound concentration, and the IC 50 was determined by fitting a four-parameter sigmoid concentration-response model.

[0310] Disruption of the interaction between the compounds of the present invention and K-Ras with the B-Raf Ras-binding domain (BRAF RBD ), also known as the MOA assay Note - The following protocol describes the procedure for monitoring the disruption of K-Ras G12C (GMP-PNP) binding to BRAF by the compounds of the present invention. This protocol can also be performed with other Ras proteins or nucleotides substituted. RBD

[0311] ​The purpose of this biochemical assay was to measure the ability of a test compound to facilitate the formation of a ternary complex between a nucleotide-loaded K-Ras isoform and cyclophilin A. The resulting ternary complex disrupts the binding to the BRAF RBD construct and inhibits K-Ras signaling via the RAF effector. Data were reported as IC50 values.

[0312] In assay buffer containing 25 mM HEPES (pH 7.3), 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, untagged cyclophilin A, His6-K-RasGMPPNP, and GST-BRAF RBD were combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. Compounds were present in the plate wells as a 10-point 3-fold dilution series starting at a final concentration of 30 μM. After incubation at 25 °C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for an additional 1.5 hours. The TR-FRET signal was read on a microplate reader (excitation 320 nm, fluorescence 665 / 615 nm). Compounds that promoted the disruption of the K-Ras:RAF complex were identified as those that induced a decrease in the TR-FRET ratio relative to DMSO control wells.

[0313] Determination of cell viability in RAS mutant cancer cell lines Protocol: CellTiter-Glo® Cell Viability Assay Note - The following protocol describes the procedure for monitoring the cell viability of KRAS mutant cancer cell lines in response to the compounds of the present invention. Other RAS isoforms can be used, but the number of cells seeded will vary depending on the cell line used.

[0314] The purpose of this cell assay is to determine the effect of a test compound on the growth of three human cancer cell lines (NCI-H358 (KRAS G12C), AsPC-1 (KRAS G12D), Capan-1 (KRAS G12V)) over a 5-day treatment period by quantifying the amount of ATP present at the endpoint using the CellTiter-Glo® 2.0 reagent (Promega).

[0315] Cells are seeded at 250 cells / well in 40 μl of growth medium in a 384-well assay plate and incubated overnight at 37 °C in a humidified atmosphere with 5% CO2. On the day of the assay, the test compound is prepared in a 9-fold serial dilution in 1 mM or 10 mM high-concentration DMSO as needed. The test compound (40 nl) is directly dispensed into each well of the cell culture plate using an Echo550 liquid handler (LabCyte®). The plate is shaken at 300 rpm for 15 seconds, centrifuged, and incubated at 37 °C with 5% CO2 in a humidified atmosphere for 5 days. On day 5, the assay plate and its contents are equilibrated to room temperature for approximately 30 minutes. CellTiter-Glo® 2.0 reagent (25 μl) is added, and the plate contents are mixed on an orbital shaker for 2 minutes and then incubated at room temperature for 10 minutes. Luminescence is measured using a PerkinElmer Enspire. The data are normalized as follows: (signal of sample / average DMSO) × 100. The data are fitted using a 4-parameter logistic fit.

[0316] Although the invention has been described in connection with its specific embodiments, the invention is capable of further modification, and this application is generally intended to cover any variations, uses, or adaptations of the invention that fall within the known or customary practice of the art to which the invention pertains and that include such departures from the present disclosure as may be made within the essential features set forth herein.

[0317] All publications, patents, and patent applications are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety herein.

Claims

1. A compound having the structure of formula Ia, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds; A is C which is optionally substituted ２ ~C ４ alkylene, C which is optionally substituted １ ~C ４ heteroalkylene, or C which is optionally substituted ２ ~C ４ is alkenylene; G is optionally substituted C １ ~C ４ alkylene, optionally substituted C １ ~C ４ alkenylene, optionally substituted C １ ~C ４ heteroalkylene, -C(O)O-CH(R ６ )(wherein C is bonded to -C(R ７ R ８ ), -C(O)NH-CH(R ６ )(wherein C is bonded to -C(R ７ R ８ ), optionally substituted C １ ~C ４ heteroalkylene, or 3- to 8-membered heteroarylene; swIp (switch I / P-loop) is an organic moiety that non-covalently binds to both the switch I binding pocket of the Ras protein and residues 12 or 13 of the P-loop; X １ is optionally substituted C １ ~C ２ alkylene, NR, O, or S(O) ｎ wherein; X ２ is O or NH; X ３ is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C １ -C ４ alkyl, optionally substituted C ２ -C ４ alkenyl, optionally substituted C ２ -C ４ alkynyl, C(O)R', C(O)OR', C(O)N(R') ２ , S(O)R', S(O) ２ R', or S(O) ２ N(R') ２ wherein; Each R ’ is independently H or C １ to C ４ alkyl which is optionally substituted; Y １ is C, CH, or N; Y ２ 、 Y ３ 、 Y ４ 、 and Y ７ is independently C or N; Y ５ is CH, CH ２ or N; Y ６ is C(O), CH, CH ２ , or N; R １ is cyano, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R １ and R ２ combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R ２ is absent, hydrogen, optionally substituted C １ -C ６ -C ２ -C ６ -alkenyl, optionally substituted C ２ -C ６ -alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R ３ Does not exist, or R ２ and R ３ combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R ４ is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R ５ is C optionally substituted with hydrogen or halogen １ to C ４ alkyl, cyano, hydroxy, or C １ to C ４ alkoxy, cyclopropyl, or cyclobutyl; R ６ is hydrogen or methyl; R ７ is hydrogen, halogen, or optionally substituted C １ to C ３ alkyl, or R ６ and R ７ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R ８ is hydrogen, halogen, hydroxy, cyano, optionally substituted C １ -C ３ -alkoxy, optionally substituted C １ -C ３ -alkyl, optionally substituted C ２ -C ６ -alkenyl, optionally substituted C ２ -C ６ -alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R ７ and R ８ combine with the carbon atom to which they are attached to form C═CR ７ ’R ８ ’; C═N(OH), C═N(O—C １ ~C ３ alkyl), C═O, C═S, C═NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R ７ａ and R ８ａ each independently is hydrogen, halo, C １ to C ３ alkyl, optionally substituted, or combines with the carbon to which they are attached to form a carbonyl; R ７’ is hydrogen, halogen, or optionally substituted C １ to C ３ alkyl; R ８’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C １ to C ３ alkoxy, optionally substituted C １ to C ３ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R ７’ and R ８’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R １０ is hydrogen, halo, hydroxy, C １ to C ３ alkoxy, or C １ to C ３ alkyl; R １０ａ is hydrogen or a halo; R １６ is hydrogen or C １ to C ３ alkyl); and wherein, i. the compound is 【Chemical Formula 2】 【Chemical Formula 3】 or 【Chemical Formula 4】 not, or ii. when W is cyclopropyl, the compound is not a compound of formula X, and formula X is 【Chemical Formula 5】 (wherein, R １Ｘ is optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R ２ｘ is hydrogen, optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; Y is -NHC(O)-, -NHCONH-, -NHCONCH ３ ３ -, -NHCOO-, -NHSO-, -NHSONH-, -NHSO ２ ２ , or -NHSO ２ ２ NH-), said compound, or a pharmaceutically acceptable salt thereof.

2. A compound having the structure of formula Ib, or a pharmaceutically acceptable salt thereof: 【Chemical Formula 6】 (In the formula, the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds; A is C which is optionally substituted ２ ~C ４ alkylene, C which is optionally substituted １ ~C ４ heteroalkylene, or C which is optionally substituted ２ ~C ４ and is alkenylene; B is absent, -NH-, -N(CH ３ ), -, -O-, -CH(R ９ ), or >C=CR ９ R ９’ (wherein carbon is bonded to the carbonyl carbon of -N(R １１ )C(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C １ ~C ４ alkylene, optionally substituted C １ ~C ４ alkenylene, optionally substituted C １ ~C ４ heteroalkylene, -C(O)O-CH(R ６ )(wherein C is bonded to -C(R ７ R ８ ), -C(O)NH-CH(R ６ )(wherein C is bonded to -C(R ７ R ８ ), optionally substituted C １ ~C ４ heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or is a linker; W is hydrogen, cyano, optionally substituted amino, optionally substituted amide, optionally substituted C １ -C ４ -alkoxy, optionally substituted C １ -C ４ -hydroxyalkyl, optionally substituted C １ -C ４ -aminoalkyl, optionally substituted C １ -C ４ -haloalkyl, optionally substituted C １ -C ４ -alkyl, optionally substituted C １ -C ４ -guanidinoalkyl, C ０ -C ４ -alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 3- to 10-membered heteroaryl; Z is -C(O)-, or -S(O)- ２ -; X １ is optionally substituted C １ to C ２ alkylene, NR, O, or S(O) ｎ and; X ２ is O or NH; X ３ is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C １ -C ４ -alkyl, optionally substituted C ２ -C ４ -alkenyl, optionally substituted C ２ -C ４ -alkynyl, C(O)R', C(O)OR', C(O)N(R') ２ , S(O)R', S(O) ２ R', or S(O) ２ N(R') ２ ; Each R ’ is independently H or optionally substituted C １ to C ４ alkyl; Y １ is C, CH, or N; Y ２ 、 Y ３ 、 Y ４ 、 and Y ７ is independently C or N; Y ５ is CH, CH ２ , or N; Y ６ is C(O), CH, CH ２ , or N; R １ is cyano, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R １ and R ２ combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R ２ is either absent, or hydrogen, optionally substituted C １ -C ６ -C ２ -alkyl, optionally substituted C ６ -C ２ -C ６ -alkenyl, optionally substituted C ３ -C ２ -alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R ３ is either absent, or R ２ and R ３ combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R ４ is absent, or is hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R ５ is C optionally substituted with hydrogen or halogen １ ~C ４ alkyl, cyano, hydroxy, or C １ ~C ４ alkoxy, cyclopropyl, or cyclobutyl; R ６ is hydrogen or methyl; R ７ is hydrogen, halogen, or optionally substituted C １ -C ３ -alkyl, or R ６ and R ７ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R ８ is hydrogen, halogen, hydroxy, cyano, optionally substituted C １ to C ３ alkoxy, optionally substituted C １ to C ３ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R ７ and R ８ combine with the carbon atom to which they are attached to form C═CR ７ ′R ８ ′; C═N(OH), C═N(O—C １ ~C ３ alkyl), C═O, C═S, C═NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R ７ａ and R ８ａ are each independently hydrogen, halo, optionally substituted C １ to C ３ alkyl, or they combine with the carbon to which they are attached to form a carbonyl; R ７’ is hydrogen, halogen, or optionally substituted C １ to C ３ alkyl; R ８’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C １ to C ３ alkoxy, optionally substituted C １ to C ３ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R ７’ and R ８’ combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R ９ is hydrogen, F, optionally substituted C １ -C ６ -C １ -alkyl, optionally substituted C ６ -C-heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R ９ R and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R ９’ is hydrogen or optionally substituted C １ -C ６ -alkyl; R １０ is hydrogen, halo, hydroxy, C １ to C ３ alkoxy, or C １ to C ３ alkyl; R １０ａ is hydrogen or a halo; R １１ is hydrogen or C １ to C ３ alkyl; R １６ is hydrogen or C １ to C ３ alkyl), and; wherein, i. the compound is 【Chemical Formula 7】 [Chemical Formula 8] or 【Chemical Formula 9】 not, or ii. when W is cyclopropyl, the compound is not a compound of formula X, and formula X is 【Chemical 10】 (wherein, R １Ｘ is optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R ２ｘ is hydrogen, optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Y is -NHC(O)-, -NH C(O)NH-, -NH C(O)NCH ３ -, -NH C(O)O-, -NH S(O)-, -NH S(O)NH-, -NH S(O) ２ , or -NH S(O) ２ NH-), the compound, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)-.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Ic: 【Chemical 11】 (wherein Y ５ and Y ６ are independently CH or N; R １ is cyano, optionally substituted C １ ~C ６ alkyl, optionally substituted C １ ~C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R ２ is hydrogen, optionally substituted C １ -C ６ -C ２ -alkyl, optionally substituted C ６ -C ３ -alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R ３ is absent, or R ２ and R ３ combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R ９ is C optionally substituted with １ -C ６ alkyl, C optionally substituted with １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R １０ is hydrogen, hydroxy, C １ to C ３ alkoxy, or C １ to C ３ alkyl).

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Id: 【Chemical Formula 12】 (wherein B is absent or -CH(R ９ ) - (wherein carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered hetero cycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; W is hydrogen, an optionally substituted amino, an optionally substituted C １ -C ４ alkoxy, an optionally substituted C １ -C ４ hydroxyalkyl, an optionally substituted C １ -C ４ aminoalkyl, an optionally substituted C １ -C ４ haloalkyl, an optionally substituted C １ -C ４ alkyl, an optionally substituted C １ -C ４ guanidinoalkyl, C ０ -C ４ alkyl, an optionally substituted 3- to 11-membered heterocycloalkyl, an optionally substituted 3- to 8-membered cycloalkyl, or an optionally substituted 3- to 8-membered heteroaryl; Y ５ and Y ６ are each independently CH or N; R １ is cyano, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R ２ is hydrogen, C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R ３ is absent, or R ２ and R ３ combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R ９ is optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R １０ is hydrogen, hydroxy, C １ -C ３ -alkoxy, or C １ -C ３ -alkyl).

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Ie: 【Chemical 13】 (wherein B is absent or -CH(R ９ )-(wherein carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; W is hydrogen, an optionally substituted amino, an optionally substituted C １ -C ４ alkoxy, an optionally substituted C １ -C ４ hydroxyalkyl, an optionally substituted C １ -C ４ aminoalkyl, an optionally substituted C １ -C ４ haloalkyl, an optionally substituted C １ -C ４ alkyl, an optionally substituted C １ -C ４ guanidinoalkyl, C ０ -C ４ alkyl, an optionally substituted 3- to 11-membered heterocycloalkyl, an optionally substituted 3- to 8-membered cycloalkyl, or an optionally substituted 3- to 8-membered heteroaryl; R １ is cyano, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R ２ is hydrogen, optionally substituted C １ -C ６ -C ２ -alkyl, optionally substituted C ６ -C ３ -alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R ３ is absent, or R ２ and R ３ combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R ９ is optionally substituted C １ to C ６ alkyl, optionally substituted C １ to C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R １０ is hydrogen, hydroxy, C １ to C ３ alkoxy, or C １ to C ３ alkyl).

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula If: 【Chemical Formula 14】 (wherein B is absent or -CH(R ９ )-(wherein carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; W is hydrogen, optionally substituted amino, optionally substituted C １ -C ４ -alkoxy, optionally substituted C １ -C ４ -hydroxyalkyl, optionally substituted C １ -C ４ -aminoalkyl, optionally substituted C １ -C ４ -haloalkyl, optionally substituted C １ -C ４ -alkyl, optionally substituted C １ -C ４ -guanidinoalkyl, C ０ -C ４ -alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R １ is cyano, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R ２ is C １ to C ６ alkyl or 3- to 6-membered cycloalkyl; R ７ is C １ to C ３ alkyl; R ８ is C １ to C ３ alkyl; R ９ is C optionally substituted with １ to C ６ alkyl, C optionally substituted with １ to C ６ heteroalkyl, 3- to 6-membered cycloalkyl optionally substituted, or 3- to 7-membered heterocycloalkyl optionally substituted).

8. R １ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is a 5- to 10-membered heteroaryl optionally substituted.

9. R １ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Ig: 【Chemical Formula 15】 (wherein B is absent or -CH(R ９ )-(wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; W is hydrogen, an optionally substituted amino, an optionally substituted C １ -C ４ alkoxy, an optionally substituted C １ -C ４ hydroxyalkyl, an optionally substituted C １ -C ４ aminoalkyl, an optionally substituted C １ -C ４ haloalkyl, an optionally substituted C １ -C ４ alkyl, an optionally substituted C １ -C ４ guanidinoalkyl, C ０ -C ４ alkyl, an optionally substituted 3- to 11-membered heterocycloalkyl, an optionally substituted 3- to 8-membered cycloalkyl, or an optionally substituted 3- to 8-membered heteroaryl; R ２ is C １ to C ６ alkyl or 3- to 6-membered cycloalkyl; R ７ is C １ to C ３ alkyl; R ８ is C １ to C ３ alkyl; R ９ is C optionally substituted with １ -C ６ alkyl, C optionally substituted with １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; X ｅ is N, CH, or CR １７ ; X ｆ is N or CH; R １２ is optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ heteroalkyl; R １７ is optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl).

11. R ７ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

12. R ８ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

13. A is C which is optionally substituted ２ ~C ４ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is alkylene

14. A is C which is optionally substituted ３ The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein A is alkylene

15. A is 【Chemical 16】 The compound according to claim 14, or a pharmaceutically acceptable salt thereof.

16. A is C which is optionally substituted ２ ~C ４ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is alkenylene

17. A is C which is optionally substituted ３ The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein A is alkenylene

18. A is optionally substituted C １ ~C ４ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is a heteroalkylene

19. A is C which is optionally substituted ２ The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein A is a heteroalkylene

20. A is 【Chemical 17】 The compound according to claim 19, or a pharmaceutically acceptable salt thereof.

21. R １ is 【Chemical 18】 The compound according to any one of claims 10 to 20, or a pharmaceutically acceptable salt thereof.

22. R １ is 【Chemical Formula 19】 The compound according to claim 21, or a pharmaceutically acceptable salt thereof.

23. R １ is 【Chemical 20】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof: (wherein, Z １ is N or CH, m is 1 or 2; R １８ 、 R １９ 、 R ２０ 、 and R ２１ are each independently hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R １８ and R ２０ combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl, or R ２０ and R ２１ combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl or R １９ and R ２０ are combined with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl).

24. R １ is 【Chemical 21】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

25. R １ is 【Chemical 22】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

26. R １８ The compound according to claim 24 or 25, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

27. R １ is 【Chemical 23】 The compound according to claim 22, or a pharmaceutically acceptable salt thereof.

28. B is -CHR ９ The compound according to any one of claims 2 to 27, or a pharmaceutically acceptable salt thereof, wherein B is -

29. R ９ is C optionally substituted １ ~C ６ alkyl, or 3- to 6-membered cycloalkyl optionally substituted, the compound according to claim 28, or a pharmaceutically acceptable salt thereof.

30. The compound according to any one of claims 2 to 27, or a pharmaceutically acceptable salt thereof, wherein B is an optionally substituted 6-membered arylene;

31. The compound according to any one of claims 2 to 27, or a pharmaceutically acceptable salt thereof, wherein B is absent;

32. The compound according to any one of claims 2 to 31, or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of formula II: A １ - (B １ ) ｆ - (C １ ) ｇ - (B ２ ) ｈ - (D １ ) - (B ３ ) ｉ - (C ２ ) ｊ - (B ４ ) ｋ - A ２ Formula II (wherein, A １ is a bond between the linker and B; A ２ is a bond between W and the linker; B １ , B ２ , B ３ , and B ４ are each independently optionally substituted C １ to C ２ alkylene, optionally substituted C １ to C ３ heteroalkylene, O, S, and NR Ｎ selected from; R Ｎ is hydrogen, optionally substituted C １ to C ４ alkyl, optionally substituted C １ to C ３ cycloalkyl, optionally substituted C ２ to C ４ alkenyl, optionally substituted C ２ to C ４ alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C １ to C ７ heteroalkyl; C １ and C ２ are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D １ is optionally substituted C １ to C １０ alkylene, optionally substituted C ２ to C １０ alkenylene, optionally substituted C ２ to C １０ alkynylene, optionally substituted 3- to 14-membered heterocycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C ２ to C １０ Polyethylene glycol, or optionally substituted C １ ~C １０ heteroalkylene, or A １ -(B １ ) ｆ -(C １ ) ｇ -(B ２ ) ｈ - is a chemical bond that attaches to -(B ３ ) ｉ -(C ２ ) ｊ -(B ４ ) ｋ -A ２ ).

33. The compound according to any one of claims 2 to 32, or a pharmaceutically acceptable salt thereof, wherein the linker is acyclic;

34. The compound according to claim 33, or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of formula IIa: 【Chemical 24】 (wherein, X ａ is absent or is N, R １４ is absent, hydrogen, optionally substituted C １ ~C ６ Alkyl or optionally substituted C １ ~C ３ is cycloalkyl; L ２ is absent, -C(O)-, -SO ２ -, optionally substituted C １ ~C ４ alkylene, or optionally substituted C １ ~C ４ heteroalkylene, and X ａ , R １４ , or L ２ (where at least one of them exists).

35. The compound according to any one of claims 2 to 32, or a pharmaceutically acceptable salt thereof, wherein the linker is a cyclic group or contains a cyclic group;

36. The compound according to any one of claims 2 to 32 or 31, or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of formula IIb: 【Chemical 25】 (wherein o is 0 or 1; X ｂ is C(O) or SO ２ ; R １５ is hydrogen or C １ to C ６ alkyl which is optionally substituted; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L ３ is absent, -C(O)-, -SO ２ -, optionally substituted C １ ~C ４ alkylene, or optionally substituted C １ ~C ４ heteroalkylene).

37. The compound according to any one of claims 2 to 31, or a pharmaceutically acceptable salt thereof, wherein the linker is absent;

38. The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is hydrogen;

39. The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is cyclopropyl optionally substituted, cyclobutyl optionally substituted, cyclopentyl optionally substituted, cyclohexyl optionally substituted, piperidine optionally substituted, piperazine optionally substituted, pyridine optionally substituted, or phenyl optionally substituted.

40. The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is amino optionally substituted.

41. The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is amide optionally substituted.

42. W is optionally substituted C １ ~C ４ The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is an alkoxy group.

43. W is optionally substituted C １ ~C ４ The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is alkyl.

44. W is C which is optionally substituted １ ~C ４ The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is a hydroxyalkyl

45. W is optionally substituted C １ - C ４ The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, which is aminoalkyl.

46. W is C optionally substituted with １ ~C ４ The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

47. W is optionally substituted C １ ~C ４ The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, which is guanidinoalkyl.

48. W is C ０ -C ４ alkyl, or optionally substituted 3- to 11-membered heterocycloalkyl, the compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof.

49. The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is a 3- to 10-membered cycloalkyl optionally substituted.

50. The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is a 3- to 10-membered heteroaryl optionally substituted.

51. The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein W is a 6- to 10-membered aryl optionally substituted.

52. The compound described in Table 1, or a pharmaceutically acceptable salt thereof.

53. A pharmaceutical composition comprising the compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

54. 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 the compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 53.

55. The method according to claim 54, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, or uterine cancer.

56. The method according to claim 55, wherein the cancer comprises a Ras mutation.

57. The method according to claim 56, wherein the Ras mutation is at position 12, 13, or 61.

58. The method according to claim 56 or 57, wherein the Ras mutation is at position 12.

59. The method according to claim 57, wherein the Ras mutation is at a position selected from the group consisting of G12C, G12D, G12V, G12R, G13C, G13D, and Q61K, or a combination thereof.

60. The method according to claim 59, wherein the Ras mutation is at a position selected from the group consisting of G12D, G12V, and G12R, or a combination thereof.

61. The method according to claim 60, wherein the Ras mutation is at a position selected from the group consisting of G12D, and G12V, or a combination thereof.

62. The method according to any one of claims 54 to 61, wherein the cancer is pancreatic cancer.

63. The method according to any one of claims 54 to 61, wherein the cancer is lung cancer.

64. The method according to any one of claims 54 to 61, wherein the cancer is colorectal cancer.

65. A method for treating a Ras protein-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 53.

66. A method for inhibiting a Ras protein in a cell, comprising contacting the cell with an effective amount of the compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 53.

67. The method according to claim 66, wherein two or more Ras proteins are inhibited in the cell.

68. The method according to claim 66 or 67, wherein the cell is a cancer cell.

69. The method according to claim 68, wherein the cancer cell is a pancreatic cancer cell.

70. The method according to claim 68, wherein the cancer cell is a lung cancer cell.

71. The method according to claim 68, wherein the cancer cell is a colorectal cancer cell.

72. The method according to any one of claims 56 to 71, wherein the Ras protein is KRAS.

73. The method or use according to any one of claims 54 to 72, wherein the method further comprises administering an additional anti-cancer therapy.

74. The method according to claim 73, wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, an SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

75. The method according to claim 73 or 74, wherein the additional anti-cancer therapy is an SHP2 inhibitor.

76. The method according to claim 73 or 74, wherein the additional anti-cancer therapy comprises an SHP2 inhibitor and a PD-L1 inhibitor.

77. The method according to claim 73 or 74, wherein the additional anti-cancer therapy comprises a second Ras inhibitor and a PD-L1 inhibitor.

78. wherein the second Ras inhibitor is a KRAS Ｇ１２Ｃ inhibitor, the method according to claim 74 or 75.

79. wherein the second Ras inhibitor is a KRAS Ｇ１２Ｃ (ON) inhibitor, the method according to claim 78.

80. wherein the second Ras inhibitor is a KRAS Ｇ１２Ｃ (OFF) inhibitor, the method according to claim 78.

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