Indole derivatives as RAS inhibitors in cancer treatment

Abstract

The present invention provides a RAS inhibitor that selectively binds to or selectively inhibits Ras(ON). [Solution] A compound having the structure of formula Ia, or a pharmaceutically acceptable salt thereof. JPEG2026090276000524.jpg80170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. applications No. 63 / 078,802 filed on 15 September 2020; No. 63 / 129,231 filed on 22 December 2020; No. 63 / 184,412 filed on 5 May 2021; and No. 63 / 192,775 filed on 25 May 2021, all of which are incorporated herein by reference.

[0002] Sequence List This application includes a sequence listing submitted electronically in ASCII format, the entirety of which is incorporated herein by reference. A copy of the above ASCII file, created on 14 September 2021, is named 51432-009WO5_Sequence_Listing_9_14_21_ST25 and has a size of 1,189 bytes. [Background technology]

[0003] The vast majority of small molecule drugs act by binding to functionally important pockets on target proteins, thereby regulating the activity of those proteins. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrate. The fact that many such drug / target interaction pairs are known can be misleading to some extent, leading people to believe that, given a reasonable amount of time, effort, and resources, small molecule modulators can be discovered for most, if not all, proteins. This is far from the truth. Current estimates suggest that only about 10% of all human proteins are targetable by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18:674-699 (2019). The other 90% are currently considered refractory or refractory to the small molecule drug discovery described above. Such targets are commonly referred to as "andruggable." These undruggable targets comprise a vast and extensive underutilized reservoir of clinically important human proteins. Therefore, there is considerable interest in discovering novel molecular modalities capable of controlling the function of such undruggable targets.

[0004] The literature has well established that Ras proteins (K-Ras, H-Ras, and N-Ras) play essential roles in various human cancers and are therefore appropriate targets for anti-cancer therapies. In fact, mutations in the Ras protein account for approximately 30% of all human cancers in the United States, many of which are lethal. Dysregulation of the Ras protein due to mutation activation, overexpression, or upstream expression is common in human tumors, and mutation activation in Ras is frequently found in human cancers. For example, activation of a mutation at codon 12 in the Ras protein functions by inhibiting both the GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly distorting the population of Ras mutant proteins into an "on" (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. In particular, Ras exhibits picomolar affinity for GTP, allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations in codon 13 of Ras (e.g., G13D) and codon 61 (e.g., Q61K) also contribute to oncogenic activity in some cancers.

[0005] Despite extensive drug discovery efforts against Ras in recent decades, no drugs that directly target "on" Ras have yet been approved. Further efforts are needed to identify additional drugs for cancers driven by various Ras mutations. [Overview of the Initiative]

[0006] RAS inhibitors are provided herein. These Ras inhibitors target Ras(ON), i.e., selectively bind to or selectively inhibit Ras(ON) (e.g., more selective than the GDP-bound form of Ras, which is an inactive state). The approaches described herein require the formation of a high-affinity triplicate complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein (e.g., Ras) and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophyllin A). More specifically, in some embodiments, the Ras inhibitors described herein include a novel binding pocket cytosol in Ras, which drives the formation of a high-affinity triplicate complex between the Ras protein and the widely expressed cytosolic chaperone cyclophyllin A (CYPA). While not bound by theory, the inventors believe that one way in which the inhibitory effect on Ras is affected by the compounds and complexes of the present invention is the formation of steric occlusion at the interaction site between Ras and downstream effector molecules such as RAF and PI3K, which is necessary for the growth of oncogenic signals.

[0007] Therefore, in some embodiments, the present disclosure features a compound of structural formula Ia, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene.] Y is [ka] And, W is hydrogen, a C1-C4 alkyl group, an optionally substituted C1-C3 heteroalkyl group, an optionally substituted 3-10 member heterocycloalkyl group, an optionally substituted 3-10 member cycloalkyl group, an optionally substituted 6-10 member aryl group, or an optionally substituted 5-10 member heteroaryl group. X 1 and X 4 Each of these is independently either CH2 or NH, R 1 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-15 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, and R 10 [ is hydrogen, hydroxyl, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 heteroalkyl]. In some embodiments, R 10 It is hydrogen.

[0008] The present invention also provides pharmaceutical compositions comprising a compound of formula Ia, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] The present invention also provides a method for treating cancer in a subject requiring cancer treatment, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the present invention provides a method for treating a Ras protein-related disease in a subject requiring treatment for the Ras protein-related disease, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0011] A method for inhibiting the Ras protein in cells is provided, further comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0012] Any limitations discussed in relation to one embodiment of the present invention can be specifically conceived to apply to any other embodiment of the present invention. Furthermore, any compound or composition of the present invention can be used in any manner of the present invention, and any compound or composition of the present invention can be produced or utilized using any manner of the present invention.

[0013] Definitions and Chemical Terms In this application, unless otherwise clearly indicated by context, (i) the term “one (a)” means “one or more”; (ii) is used to mean “and / or” unless it is explicitly indicated that it means only alternative expressions or that such alternative expressions are mutually exclusive, however this disclosure supports the definitions that refer only to alternative expressions and to “and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or processes, whether presented by themselves or together with one or more additional components or processes; and (iv) where a scope is indicated, it includes endpoints.

[0014] As used herein, the term “approximately” is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value. In certain embodiments, unless otherwise stated or evident from the content (for example, if such a number may exceed 100% of the possible values), the term “approximately” refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% or less in either direction (above or below) the stated value.

[0015] As used herein, the term "adjacent" in the context of describing adjacent atoms means divalent atoms directly bonded by a covalent bond.

[0016] As used herein, “compounds of the present invention” and similar terms mean, whether expressly stated or not, the compounds of formula Ia or formula Ib and their subformulas, as well as the compounds of Table 1a or Table 1b, in addition to their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers, as described herein, and the Ras inhibitors described herein.

[0017] The term "wild-type" refers to an entity possessing a structure or activity found in nature in a "normal" state or context (as opposed to variants, diseases, or changes). Those skilled in the art will understand that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0018] Those skilled in the art will understand that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., hydrogen substituted with deuterium, in which one or more atoms are substituted with different isotopes of that atom). Unless otherwise specified or made clear from the context, the structures described may be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0019] The compounds described herein may be asymmetric (for example, having one or more stereocenters). Any stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active forms or as racemates. Methods for preparing optically active forms from optically active starting materials, such as by resolving racemic mixtures or by stereoselective methods, are known in the art. Many geometric isomers, such as olefins and C=N double bonds, can also be present in the compounds described herein, and all such stable isomers are considered in this invention. The cis and trans geometric isomers of the compounds of this disclosure are described and can be isolated as mixtures of isomers or as separated isomers.

[0020] In some embodiments, one or more of the compounds described herein can exist in different tautomeric forms. Unless explicitly excluded as apparent from the context, references to such compounds include all such tautomeric forms. In some embodiments, tautomeric forms result from the exchange of a single bond with an adjacent double bond and the movement of an attendant proton. In certain embodiments, tautomeric forms can be prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge as the reference form. Examples of moieties having prototropic tautomeric forms include ketone-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 a heterocyclic system. In some embodiments, tautomeric forms can be in equilibrium or can be stereochemically fixed in one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interchange.

[0021] Unless otherwise indicated, structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically 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 125Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. Isotope-labeled compounds (e.g., 3 H and 14 Compounds labeled with 1C can be useful in compound or substrate tissue partitioning assays. Tritium labeling (i.e., 3 H), and carbon 14 (i.e., 14 C) Isotopes can be useful due to their ease of preparation and detection. Furthermore, heavier isotopes, such as deuterium (i.e., 2 Substitution with H) etc. can lead to greater metabolic stability, which may result in certain therapeutic benefits (e.g., longer in vivo half-life or reduced dosage). In some embodiments, one or more hydrogen atoms are 2 H or 3 Replaced by H, or one or more carbon atoms 13 C or 14 It is replaced by carbon-enriched carbon. 15 O, 13 N, 11 C and 18 Positron-emitting isotopes such as fluorine are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents, following a procedure similar to the procedure disclosed for the compounds of the present invention as described herein.

[0022] As is known from the prior art, many chemical components can be used in various different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including any solid form. In some embodiments, the compounds described or explained herein can be provided or used in hydrate or solvate form.

[0023] In various parts of this specification, substituents of the compounds of this disclosure are disclosed in groups or ranges. This disclosure is specifically intended to include each individual partial combination of members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. Furthermore, where a compound includes multiple positions in which substituents are disclosed in groups or ranges, this disclosure is intended to cover individual compounds containing each and all individual element subcombinations at each position, as well as groups of compounds (e.g., genera and sub-genera), unless otherwise specified.

[0024] The term “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, where X is optionally substituted” (e.g., “alkyl, where the alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) itself is optional. Certain compounds of interest, as described herein, may contain one or more “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of a specified moiety are substituted by a preferred substituent, e.g., any substituent or group described herein, whether preceded by the term “optionally”. Unless otherwise specified, an “optionally substituted” group may have preferred substituents at each of its substituted positions, and if more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituents may be the same or different at all positions. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl”, the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The substituent combinations conceivable in this disclosure are preferably obtained by forming stable or chemically suitable compounds. The term “stable,” as used in the present invention, means a compound that remains substantially unchanged when subjected to conditions anticipating its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0025] Preferred monovalent substituents on the replaceable carbon atoms of the "optionally substituted" group are, independently, deuterium, halogen, -(CH2)O-4R°, -(CH2)O-4OR°, -O(CH2)O-4R°, -O-(CH2)O-4C(O)OR°, -(CH2)O-4CH(OR°)2, -(CH2)O-4SR°, -(CH2)O-4Ph[may be substituted with R°], -(CH2)O-4O(CH2)O-1Ph[may be substituted with R°], -CH=CHPh[may be substituted with R°], and -(CH2)O-4O(CH2)O-1-pyridyl[may be substituted with R°]. ], 4-11 member saturated or unsaturated heterocycloalkyls (e.g., 4-8 member saturated or unsaturated heterocycloalkyls (e.g., pyridyl)) which can be optionally substituted (e.g., with methyl), 3-8 member saturated or unsaturated cycloalkyls (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), -NO2, -CN, -N3, -(CH2)O-4N(R°)2, -(CH2)O-4N(R°)C(O) R°, -N(R°)C(S)R°, -(CH2)0-4N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2)0-4N(R°)C(O)OR°, -N(R°)N(R°)C(O)R °, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -C(S)R°, -(CH2)0-4C(O)OR°, -(CH2)0-4-C (O)-N(R°)2, -(CH2)0-4-C(O)-N(R°)-S(O)2-R°, -C(NCN)NR°2, -(CH2)0-4C(O)SR°, -(CH2)0-4C(O)OSiR°3, -( CH2)0-4OC(O)R°, -OC(O)(CH2)0-4SR°, -SC(S)SR°, -(CH2)0-4SC(O)R°, -(CH2)0-4C(O)NR°2, -C(S)NR°2, -C(S) SR°, -(CH2)0-4OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2)0-4SSR°, -(C H2)0-4S(O)2R°, -(CH2)0-4S(O)2OR°, -(CH2)0-4OS(O)2R°, -S(O)2NR°2, -(CH2)0-4S(O)R°, -N(R°)S(O)2NR°2,-N(R°)S(O)2R°, -N(OR°)R°, -C(NOR°)NR°2, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -P(O)(OR°)2, -OP(O)R°2, -OP(O)(OR°)2, -OP(O)(OR°)R°, -SiR°3, -(C1-4 linear or branched alkylene)ON(R°)2, or -(C1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° may be substituted as defined below, independently of hydrogen, -C1-6 aliphatic, -CH2Ph, -O(C H2)0-1Ph, -CH2- (a 5-6 member heteroaryl ring), or a 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independently existing R°s, together with the atom(s) between them, form a 3-12 member saturated, partially unsaturated, or monocyclic or bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0026] Suitable monovalent substituents on R° (or the ring formed by using two independently existing R° atoms together with the atoms in between) are, independently, halogens, -(CH2)O-2R ● ,-(HaroR ● ), -(CH2)O-2OH, -(CH2)O-2OR ● ,-(CH2)0-2CH(OR ● )2, -O(HaroR ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ● ,-(CH2)0-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● ,-(CH2)0-2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ●-(C1-4 linear or branched alkylene)C(O)OR ● , or -SSR ● It can be, and in the formula, each R ● The atoms are either unsubstituted or, where the prefix "halo" is located, substituted by only one or more halogens, and are independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents on the saturated carbon atom of R° include =O and =S.

[0027] Suitable divalent substituents on the saturated carbon atom of the "arbitrarily substituted" group are: =O, =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2))2-3O-, or -S(C(R * 2))2-3S- are listed, and in the formula, R exists independently in each case. * The group is selected from unsubstituted 5-6 membered, saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from hydrogen, C1-6 aliphatic which can be substituted as defined below, or nitrogen, oxygen, or sulfur. A preferred divalent substituent bonded to the vicinal substituteable carbon of the "optionally substituted" group is -O(CR * 2) A 2-3O- is an example, where each independently existing R* is selected from hydrogen, C1-6 aliphatic which can be substituted as defined below, or from unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] R * A suitable substituent on the aliphatic group is -R ● , (HaroR ●), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and in the formula, each R ● The ring is either unsubstituted, or, where it is preceded by "halo", substituted by only one or more halogens, and is independently a C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] A suitable substituent on the substituted nitrogen of the "optionally substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † The following are examples, where each R† is independently a saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from hydrogen, C1-6 aliphatic which can be substituted as defined below, unsubstituted -OPh, or nitrogen, oxygen, or sulfur, or two R independently existing, notwithstanding the above definition † These atoms, along with the atoms (or multiple atoms) interposed between them, form unsubstituted 3-12 member saturated, partially unsaturated, or aryl mono- or bicyclic rings containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ●, -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● is unsubstituted or, where "halo" precedes, is substituted only by one or more halogens and independently is C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, 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 atoms of R † include =O and =S.

[0031] As used herein, the term "acetyl" means the group -C(O)CH3.

[0032] As used herein, the term "alkoxy" means -O-C1-C 20 alkyl, and the alkoxy group is bonded to the remainder of the compound through an oxygen atom.

[0033] As used herein, the term "alkyl" means a saturated, straight-chain or branched-chain 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- and isopropyl, n-, sec-, iso and tert-butyl, and neopentyl.

[0034] As used herein, the term "alkylene" represents a saturated divalent hydrocarbon group derived from a straight-chain or branched-chain saturated hydrocarbon by removing two hydrogen atoms and is exemplified by methylene, ethylene, isopropylene, etc. The term "C x -C y"Alkylene" refers to an alkylene group having x to y carbon atoms. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C 10 , C2-C 20 , C2-C6, C2-C 10 , or C2-C 20 Alkylene). In some embodiments, the alkylene may be further substituted with one, two, three, or four substituents as defined herein.

[0035] As used herein, the term “alkenyl” means, unless otherwise specified, a monovalent linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds, exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyls include both cis and trans isomers. As used herein, the term “alkenylene” means, unless otherwise specified, a divalent linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds.

[0036] As used herein, the term "alkynyl" refers to a monovalent linear or branched group consisting of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbon atoms) containing a carbon-carbon triple bond, as exemplified by ethynyl and 1-propynyl.

[0037] As used herein, the term "alkynyl sulfone" means structure [ka] [wherein R is any chemically suitable substituent as described herein.] represents a group containing ]

[0038] As used herein, the term "amino" means -N(R† )2, for example, represents -NH2 and -N(CH3)2.

[0039] As used herein, the term "aminoalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more amino moieties.

[0040] As used herein, the term “amino acid” means a molecule having a side chain, an amino group, and an acidic group (e.g., -CO2H or -SO3H), and an amino acid is bonded to a parent molecule by a side chain, an amino group, or an acidic group (e.g., a side chain). As used herein, the term “amino acid” in its broadest sense means any compound or substance that can be incorporated into a polypeptide chain, for example, by the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid, in some embodiments, an amino acid is a D-amino acid, and in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” means any of the 20 standard L-amino acids commonly found in naturally occurring peptides. Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolicine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0041] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, wherein the ring bonded to the pendant group is aromatic. Examples of aryl groups include phenyl, naphthyl, phenantrenyl, and anthracenyl. The aryl ring may be bonded to its pendant group by any heteroatom or carbocyclic atom that results in a stable structure, and unless otherwise specified, any of the ring atoms may be substituted.

[0042] As used herein, the term "C0" represents a bond. For example, part of the term -N(C(O)-(C0-C5alkylene-H)- includes -N(C(O)-(C0alkylene-H)-, which is also represented by -N(C(O)-H)-.

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

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

[0045] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or the corresponding aprotonated group.

[0046] As used herein, the term "cyano" refers to the -CN group.

[0047] As used herein, the term "cycloalkyl" means a monovalent saturated cyclic hydrocarbon group, which may be crosslinked, condensed, or a spirocyclic group having 3 to 8 carbon atoms, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0048] As used herein, the term "cycloalkenyl" means a monovalent non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specified, may be crosslinked, condensed, or a spirocyclic group having 3 to 8 carbon atoms and containing one or more carbon-carbon double bonds.

[0049] As used herein, the term “diastereomer” means a stereoisomer that is not a mirror image of another and cannot be superimposed on another.

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

[0051] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen atom is substituted with a halogen.

[0052] As used herein, the term "haloalkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more identical or different halogen moieties.

[0053] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0054] As used herein, the term “heteroalkyl” refers to an “alkyl” group (as defined herein) in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may appear in the middle or at the ends of the radical.

[0055] As used herein, the term “heteroaryl” refers to a monovalent monocyclic or polycyclic cyclic structure containing at least one complete aromatic ring. That is, these contain 4n+2 π electrons within the monocyclic or polycyclic ring system and contain at least one ring heteroatom selected from N, O, or S within the aromatic ring. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term “heteroaryl” also includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings, such as a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindylol. The heteroaryl ring can be bonded to its pendant group at any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted unless otherwise specified. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0056] As used herein, the term "heterocycloalkyl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system, which may be bridged, condensed, or spirocyclic, in which at least one ring is non-aromatic, and the non-aromatic ring contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have 0 to 2 double bonds, and six- and seven-membered rings have 0 to 3 double bonds. Exemplary unsubstituted heterocycloalkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term "heterocycloalkyl" also refers to heterocyclic compounds having a bridged polycyclic structure in which one or more carbons or heteroatoms bridge two non-adjacent elements of a monocyclic ring, e.g., a quinuclidinyl group. The term "heterocycloalkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, pyridine ring, or pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthilidinyl. Heterocycloalkyl rings can be bonded to their pendant group at any ring atom that results in a stable structure, and any of the ring atoms can be substituted unless otherwise specified.

[0057] As used herein, the term "hydroxy" refers to the -OH group.

[0058] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more -OH moieties.

[0059] As used herein, “isomer” means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds and are therefore recognized to exist as stereoisomers, e.g., double bond isomers (i.e., geometric E / Z isomers), or diastereomers (e.g., enantiomers (i.e., (+) or (-), or cis / trans isomers)). In accordance with the present invention, the chemical structures described herein, and therefore the compounds of the present invention, are recognized to exist as all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereally pure), as well as enantiomers. This includes both isomers and stereoisomeric mixtures (e.g., racemic compounds). Enantiomers and stereoisomeric mixtures of the compounds of the present invention can usually be broken down into their constituent enantiomers or stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0060] As used herein, the term “stereoisomer” means all possible different isomeric and structural forms that a compound may have (for example, any compound of any formula described herein), in particular all possible stereochemical and structural isomeric forms of the basic molecular structure, including atropisomers, all diastereomers, enantiomers, or conformational isomers. Some of the compounds of the present invention may exist in different tautomers, all of which are included in the scope of the present invention.

[0061] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0062] As used herein, the term "thiocarbonyl" means a -C(S)- group.

[0063] Those skilled in the art reading this disclosure will understand that certain compounds described herein may be provided or available in any of the following forms, such as salt form, protected form, prodrug form, ester form, isomer form (e.g., optical or structural isomer), isotopic form, etc. In some embodiments, reference to a particular compound may relate to a particular form of that compound. In some embodiments, reference to a particular compound may relate to the compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound from a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt form of the compound; a preparation containing a structural isomer of a double bond ((Z) or (E)) may be considered a different form from one containing other structural isomers of the double bond ((E) or (Z)); and a preparation in which one or more atoms are isotopes different from those present in the reference preparation may be considered a different form. [Brief explanation of the drawing]

[0064] [Figure 1A] This graph shows the in vivo efficacy of compound A, a Ras inhibitor disclosed herein, in a human pancreatic adenocarcinoma HPAC KRASG12D / wt xenograft model using female BALB / c nude mice. The graph shows tumor volume (mm3) and days post-transplant in the mouse xenograft model. Mice were randomized to the treatment group before administration of the test item or vehicle. Compound A was administered every other day by forced oral ingestion. [Figure 1B]This graph shows the dose-dependent exposure to compound A, a Ras inhibitor disclosed herein, in blood and tumor samples from BALB / c nude mice (6-8 weeks old, human non-small cell lung cancer (NSCLC) NCI-H441 KRASG12V / wt xenograft model) monitored over 72 hours post-administration. Pharmacokinetics were analyzed up to 72 hours based on the total concentration (nM) of compound A in tumors or blood after a single forced oral administration of 10, 25, or 50 mg / kg of compound A. Tumors or blood samples were taken from n=3 animals at each time point. [Figure 1C] This graph shows the PK (10 mg / kg, po) and PD (percentage of tumor DUSP compared to control, 10, and 25 mg / kg po) in naive animals treated with a single dose of compound A, a Ras inhibitor disclosed herein. [Figure 1D] This graph shows the in vivo efficacy of compound A, a Ras inhibitor disclosed herein, in an NCI-H441 CDX model including heterozygous KRASG12V. NCI-H441 cells were transplanted into 50% Matrigel. Animals were randomized and treatment was initiated with a mean tumor volume of approximately 155 mm3. Animals were administered compound A at 10 or 25 mg / kg po qd, or a control, for 32 days. All dose levels were tolerated. n=10 / group. ***P<0.0001 by one-way ANOVA. [Figure 1E] This shows the study-end response to compound A, a KRAS(ON) inhibitor disclosed herein, in NCI-H441 CDX models including heterozygous KRASG12V. Tumors at study-end in NCI-H441 are graphed as a percentage change in tumor volume compared to the volume at the start of treatment. R (regression) = number of regressions exceeding 10% from the initial stage. CR (complete remission) = number of regressions exceeding 80% from the initial stage. Each animal is represented as a separate bar. [Figure 1F]This shows the percentage change in body weight in animals treated with compound A, a KRAS(ON) inhibitor disclosed herein, in an NCI-H441 CDX model having heterozygous KRASG12V cells. Xenografts derived from NCI-H441 cells were measured twice a week by thickness measurement. Body weight change is graphed as a percentage of the animal's baseline body weight. [Figure 2A] This graph shows the in vivo efficacy of compound A, a KRAS(ON) inhibitor disclosed herein, in a human pancreatic Capan-2 CDX xenograft model containing heterozygous KRASG12V, using female BALB / c nude mice. The graph shows tumor volume (mm3) and days post-transplant in the mouse xenograft model. Capan-2 cells were infused into 50% Matrigel. Animals were randomized and treatment was initiated with a mean tumor volume of approximately 166 mm3. Animals were administered compound A at 10 mg / kg po qd or 25 mg / kg po q2d, or a control, for 28 days. All dose levels were tolerated. n=8 / group. **P=0.01, ***p<0.0001 by one-way ANOVA. [Figure 2B] This shows the response to compound A, a KRAS(ON) inhibitor disclosed herein, at the end of the study in a human pancreatic Capan-2 CDX xenograft model containing heterozygous KRASG12V. The Capan-2 tumor at the end of the study is graphed as the percentage change in tumor volume compared to the volume at the start of treatment. R (regression) = number of regressions exceeding 10% from the initial stage. Each animal is represented as a separate bar. [Figure 2C] This shows the percentage change in body weight in animals treated with compound A, a KRAS(ON) inhibitor disclosed herein, in a human pancreatic Capan-2 CDX xenograft model containing heterozygous KRASG12V. Capan-2 cell-derived xenografts were measured twice weekly by thickness measurement. Body weight change is graphed as a percentage of the animal's baseline body weight. [Figure 2D]This graph shows the in vivo efficacy of compound A, a KRAS(ON) inhibitor disclosed herein, in a human colorectal SW403 KRASG12V / wt xenograft model using female BALB / c nude mice. The graph shows tumor volume (mm3) and days post-transplant in the mouse xenograft model. SW403 cells were infused into 50% Matrigel. Animals were randomized and treatment was initiated with a mean tumor volume of approximately 171 mm3. Animals were administered compound A at 25 mg / kg po qd or 50 mg / kg po q2d, or a control, for 28 days. All dose levels were tolerated. n=8 / group. ***P<0.0001 by one-way ANOVA. [Figure 2E] This graph shows the response to compound A, a KRAS(ON) inhibitor disclosed herein, at the end of the study in a human colorectal SW403 KRASG12V / wt xenograft model. The SW403 tumor at the end of the study is graphed as the percentage change in tumor volume compared to the volume at the start of treatment. R (regression) = number of tumors with regression exceeding 10% from the initial stage. CR (complete remission) = number of tumors with regression exceeding 80% from the initial stage. Each animal is represented as a separate bar. [Figure 2F] This graph shows the percentage change in body weight in animals treated with compound A, a KRAS(ON) inhibitor disclosed herein, in a human colorectal SW403 KRASG12V / wt xenograft model. SW403 cell-derived xenografts were measured twice weekly by thickness measurement. Body weight change is graphed as a percentage of the animal's baseline body weight. [Figure 3A] This document shows the in vitro efficacy of compound A, a KRAS(ON) inhibitor disclosed herein, in multiple RAS-driven cancer cell lines. Each graph shows cell proliferation (%) relative to control and log M [compound A]. The in vitro cell proliferation inhibitory efficacy of Capan-1 (KRASG12V), NCI-H358 (KRASG12C), AsPC-1 (KRASG12D), HCT116 (KRASG13D), SK-MEL-30 (NRASQ61K), NCI-H1975 (EGFRT790M / L858R), and A375 (BRAFV600E) after 120 hours of exposure to compound A. [Figure 3B] This document shows the in vitro efficacy of compound B, a KRAS(ON) inhibitor disclosed herein, in multiple RAS-driven cancer cell lines. Each graph shows cell proliferation (%) relative to control and log M [compound B]. The in vitro cell proliferation inhibitory efficacy of Capan-1 (KRASG12V), NCI-H358 (KRASG12C), AsPC-1 (KRASG12D), HCT116 (KRASG13D), SK-MEL-30 (NRASQ61K), NCI-H1975 (EGFRT790M / L858R), and A375 (BRAFV600E) after 120 hours of exposure to compound B. [Figure 3C] This document demonstrates the in vitro efficacy of compound C, a KRAS(ON) inhibitor disclosed herein, in multiple RAS-driven cancer cell lines. Each graph shows cell proliferation (%) relative to control and log M [compound C]. The graphs also show the in vitro cell proliferation inhibitory efficacy of Capan-1 (KRASG12V), NCI-H358 (KRASG12C), AsPC-1 (KRASG12D), and A375 (BRAFV600E) after 120 hours of exposure to compound C. [Figure 4A] This report demonstrates the in vivo efficacy of compound A (25 mg / kg po qd), a KRAS(ON) inhibitor disclosed herein, in a human pancreatic adenocarcinoma HPAC KRASG12D / wt xenograft model using female BALB / c nude mice. The graphs show tumor volume (mm3) and post-transplant days in the mouse xenograft model. HPAC cells were transplanted into 50% Matrigel. Animals were randomized and treatment was initiated with a mean tumor volume of approximately 142 mm3. Animals were administered compound A at 25 mg / kg po qd or a control for 28 days. Dose levels were tolerable. n=9-10 / group. ***P<0.0001 by one-way ANOVA. [Figure 4B]This graph shows the response to compound A, a KRAS(ON) inhibitor disclosed herein, at the end of the study in a human pancreatic adenocarcinoma (HPAC) KRASG12D / wt xenograft model. The HPAC tumor at the end of the study is graphed as the percentage change in tumor volume compared to the volume at the start of treatment. CR (complete remission) = number of regressions exceeding 80% from the initial stage. Each animal is represented as a separate bar. [Figure 4C] This shows the percentage change in body weight in animals treated with compound A, a KRAS(ON) inhibitor disclosed herein, in a human pancreatic adenocarcinoma (HPAC) KRASG12D / wt xenograft model. HPAC cell-derived xenografts were measured twice weekly by thickness measurement. Body weight change is graphed as a percentage of the animal's baseline body weight. [Figure 4D] This report demonstrates the in vivo efficacy of compound A, a KRAS(ON) inhibitor disclosed herein, in a human colorectal GP2d KRASG12D / wt xenograft model using female BALB / c nude mice. The graphs show tumor volume (mm3) and days post-transplant in the mouse xenograft model. GP2d cells were transplanted into 50% Matrigel. Animals were randomized and treatment was initiated with a mean tumor volume of approximately 154 mm3. Animals were administered compound A at 25 mg / kg po qd or a control for 28 days. Dose levels were tolerable. n=10 / group. ***P<0.0001 by one-way ANOVA. [Figure 4E] This shows the response to compound A, a KRAS(ON) inhibitor disclosed herein, at the end of the study in a human colorectal GP2d KRASG12D / wt xenograft model. The tumor volume at the end of the GP2d study is graphed as the percentage change in tumor volume compared to the volume at the start of treatment. Each animal is represented as a separate bar. [Figure 4F] This shows the percentage change in body weight in animals treated with compound A, a KRAS(ON) inhibitor disclosed herein, in a human colorectal GP2d KRASG12D / wt xenograft model. GP2d cell-derived xenografts were measured twice a week by thickness measurement. Body weight change is graphed as a percentage of the animal's baseline body weight. [Figure 5A]This shows the in vitro efficacy of compound A, a KRAS(ON) inhibitor disclosed herein, against downregulatory immune checkpoint proteins in NCI-H358 KRASG12C cells. Figure 5A shows the cell surface expression of PD-L1, PVR, and CD73 on H358 cells after 48 hours of treatment with compound A in the presence of interferon-gamma (IFNγ), as measured by flow cytometry. Each graph shows the mean fluorescence intensity ((MFI), for each corresponding immune checkpoint protein) and log M [compound A]. [Figure 5B] This shows the in vitro efficacy of compound A, a KRAS(ON) inhibitor disclosed herein, against downregulatory immune checkpoint proteins in SW900 KRASG12C cells. Figure 5B shows the cell surface expression of PD-L1, PVR, and CD73 on SW900 cells after 48 hours of treatment with compound A in the presence of interferon-gamma (IFNγ), as measured by flow cytometry. Each graph shows the mean fluorescence intensity ((MFI), for each corresponding immune checkpoint protein) and log M [compound A]. [Figure 5C] This shows the in vitro efficacy of compound A, a KRAS(ON) inhibitor disclosed herein, against downregulatory immune checkpoint proteins in Capan-2 KRASG12C cells. Figure 5C shows the cell surface expression of PD-L1, PVR, and CD73 on Capan-2 cells after 48 hours of treatment with compound A in the presence of interferon-gamma (IFNγ), as measured by flow cytometry. Each graph shows the mean fluorescence intensity ((MFI), for each corresponding immune checkpoint protein) and log M [compound A]. [Figure 6]A and B show that compound A, a KRAS(ON) inhibitor disclosed herein, is active against RAS oncogene switching mutations observed in KRASG12C(OFF) resistance. Figure 6A is a heatmap showing the results of cellular RAS / RAF disruption assays for various KRAS mutations in the presence of different RAS inhibitors. Figure 6B shows the IC50 values ​​associated with each colored bar in the heatmap. [Figure 7A] Figures A-D show that compound A, a KRAS(ON) inhibitor disclosed herein, drives regression in a syngeneic KRASG12C tumor model in vivo and synergizes with anti-PD-1. eCT26(CRC, KRASG12C / G12C ABCB1- / -)I20 tumor growth in individual mice treated with vehicle and isotype (Figure 7A), anti-PD-1 (Figure 7B), compound A (Figure 7C), and compound A + anti-PD-1 (Figure 7D). [Figure 7B] Same as above. [Figure 7C] Same as above. [Figure 7D] Same as above. [Figure 8] This specification demonstrates that compound A, a KRAS(ON) inhibitor, is well-tolerated in vivo in combination with an anti-PD-1 agent in the eCT26(CRC,KRASG12C / G12C ABCB1- / -)I20 model. Body weight changes are graphed as a percentage of the animals' baseline body weight. [Figure 9]A, B, and C are KRAS(ON) inhibitors disclosed herein, demonstrating that compound A controls the immune tumor microenvironment in vivo through antitumor immunity. Flow cytometry immunophenotyping of eCT26 (CRC, KRASG12C / G12C ABCB1- / -)I20 tumors treated for 4 days with either a vehicle or compound A (25 mg / kg qd). Symbols indicate individual tumors. The mean starting tumor volume was approximately 188 mm3 in the vehicle group and approximately 586 mm3 in the compound A-treated group. Compound A monotherapy resulted in an increase in CD8+ T cells (Figure 9A). Compound A also resulted in a decrease in M2 macrophages (Figure 9B) and monocytic MDSCs (Figure 9C). Data are mean ± SD; two-sided Student's t-tests show *p<0.05, **p<0.01. [Figure 10A] This specification demonstrates that compound A, a KRAS(ON) inhibitor, exhibits significant antitumor activity in a human NSCLC KRASG12X tumor model in vivo. [Figure 10B] This specification demonstrates that compound A, a KRAS(ON) inhibitor, exhibits significant antitumor activity in vivo in PDAC. [Figure 11] This specification demonstrates that compound A, a KRAS(ON) inhibitor, extends the time to tumor doubling across multiple xenograft models. Log-rank trials (control vs. treated), p<0.0001. KRASG12X: n=154; other RAS and RAS pathway mutations: n=86; all RAS pathway MUTs included in both groups: n=240. Progression was defined as tumor doubling from baseline over 28 days. [Figure 12A] This study demonstrates that compounds A, B, and D, KRAS(ON) inhibitors disclosed herein, drive regression of KRASG12V tumors in vivo, as measured by mean tumor volume. n=6 / group. ***p<0.001. All treatments were well tolerated, as assessed by body weight. [Figure 12B]This study demonstrates that compounds A, B, and D, KRAS(ON) inhibitors disclosed herein, drive regression of KRASG12V tumors in vivo, as measured by percentage change in body weight. n=6 / group. ***p<0.001. All treatments were well tolerated, as assessed by body weight. [Figure 12C] This document demonstrates that compounds A, B, and D, KRAS(ON) inhibitors disclosed herein, drive regression of KRASG12V tumors in vivo, as measured by percentage change in tumor volume. n=6 / group. ***p<0.001. All treatments were well tolerated, as assessed by body weight. [Figure 13A] This specification presents PD results demonstrating that compounds A, B, and D, KRAS(ON) inhibitors disclosed herein, deeply and persistently inhibit RAS pathway signaling in vivo. Single-dose experiments. All doses were well tolerated. [Figure 13B] This specification presents pharmacokinetic (PK) results demonstrating that compounds A, B, and D, KRAS(ON) inhibitors disclosed herein, deeply and persistently inhibit RAS pathway signaling in vivo. Single-dose experiments. All doses were well tolerated. [Modes for carrying out the invention]

[0065] compound RAS inhibitors are provided herein. These Ras inhibitors target Ras(ON), i.e., selectively bind to Ras(ON) or selectively inhibit Ras(ON) (e.g., more selectively than the GDP-bound inactive state of Ras). As used herein, the term “RAS(ON) inhibitor” means an inhibitor that targets, i.e., selectively binds to or selectively inhibits the GTP-bound activated state of RAS (e.g., more selectively than the GDP-bound inactive state of RAS). Examples of inhibition of the GTP-bound activated state of RAS include inhibition of oncogenic signaling from the GTP-bound activated state of RAS. In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and selectively inhibits the GTP-bound activated state of RAS. In certain embodiments, the RAS(ON) inhibitor can also bind to or inhibit the GDP-bound inactive state of RAS (e.g., with lower affinity or inhibition constant than the GTP-bound activated state of RAS). In some embodiments, the RAS(ON) inhibitor has a molecular weight of 800-1100 Da (including both ends). Therefore, for example, the term "KRAS(ON) inhibitor" means any inhibitor that binds to KRAS at its GTP-binding "on" position. G12C A "(ON) inhibitor" is a KRAS inhibitor that selectively binds to or targets the G12C mutant of KRAS. G12C Non-limiting examples of (ON) inhibitors are described in WO2021091982, WO2021091967, WO2021091956, and WO2020132597.

[0066] As used herein, the term “RAS(OFF) inhibitor” means an inhibitor that targets, i.e., selectively binds to, or inhibits (e.g., selectively binds to, the GDP-bound inactive state of RAS) (e.g., selectively binds to, the GTP-bound active state of RAS). Inhibition of the GDP-bound inactive state of RAS includes, for example, inhibiting the exchange of GDP with GTP, thereby sequestering the inactive state and inhibiting the adaptation of RAS to its active conformation. In certain embodiments, the RAS(OFF) inhibitor can also bind to, or inhibit, the GTP-bound active state of RAS (e.g., with a lower affinity or inhibition constant than, for example, the GDP-bound inactive state of RAS). In some embodiments, the RAS(OFF) inhibitor has a molecular weight less than 700 Da. In some embodiments, the RAS(OFF) inhibitor has a molecular weight less than 700 Da. Therefore, for example, the term “KRAS(OFF) inhibitor” means any inhibitor that binds to KRAS in its GDP-bound “off” position. G12C An "(OFF) inhibitor" is a KRAS inhibitor that selectively binds to or targets the G12C mutant of KRAS. G12C (OFF) inhibitors are known in the art, and non-limiting examples include adaglacib and sotracib. Further KRAS(OFF) inhibitors are described herein.

[0067] The term "inhibitor" refers to a compound or agent (e.g., peptide, antibody) that prevents a biomolecule (e.g., protein) from completing or initiating a reaction. Inhibitors can inhibit reactions by competitive, non-competitive, or non-competitive means.

[0068] The approach described herein requires the formation of a high-affinity triplicate complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein (e.g., Ras) and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophyllin A). More specifically, in some embodiments, the Ras inhibitors described herein include a novel binding pocket cytosol in Ras, which drives the formation of a high-affinity triplicate complex between the Ras protein and the widely expressed cytosolic chaperone cyclophyllin A (CYPA). While not theoretically bound, the inventors believe that one way the inhibitory effect on Ras is affected by the compounds and complexes of the present invention is that steric occlusion is formed at the interaction site between Ras and downstream effector molecules such as RAFs, which is necessary for the growth of oncogenic signals.

[0069] While not bound by theory, the inventors hypothesize that non-covalent interactions of the compounds of the present invention with Ras and chaperone proteins (e.g., cyclophyllin A) may contribute to the inhibition of Ras activity. For example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, as well as combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as RAS inhibitors. Therefore, various Ras proteins may interact with the compounds of the present invention (e.g., wild-type Ras or Ras... amp Alternatively, inhibition may occur by K-Ras, N-Ras, H-Ras, and their variants at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, as well as others described herein, in addition to combinations of Ras proteins.

[0070] Therefore, compounds having the structure of formula Ia, or pharmaceutically acceptable salts thereof, are provided herein: [ka] [In the formula, A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene.] Y is [ka] And, W is hydrogen, a C1-C4 alkyl group, an optionally substituted C1-C3 heteroalkyl group, an optionally substituted 3-10 member heterocycloalkyl group, an optionally substituted 3-10 member cycloalkyl group, an optionally substituted 6-10 member aryl group, or an optionally substituted 5-10 member heteroaryl group. X 1 and X 4 Each of these is independently either CH2 or NH, R 1 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-15 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, and R 2 R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, and 10 [These are hydrogen, hydroxyl, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 heteroalkyl.]

[0071] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Ia-2: [ka] [In the formula, A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene.] Y is [ka] And, W is hydrogen, a C1-C4 alkyl group, an optionally substituted 3-10 member heterocycloalkyl group, an optionally substituted 3-10 member cycloalkyl group, an optionally substituted 6-10 member aryl group, or an optionally substituted 5-10 member heteroaryl group. R 1 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, and R 10 [ is a hydrogen- or optionally substituted C1-C6 heteroalkyl group]. In some embodiments, R 10 It is hydrogen.

[0072] In some embodiments, R 1 R is an optionally substituted 6-10 member aryl or an optionally substituted 5-10 member heteroaryl. In some embodiments, R 1This is an optionally substituted phenyl or an optionally substituted pyridine.

[0073] In some embodiments, A is an optionally substituted thiazole, an optionally substituted triazole, an optionally substituted morpholino, an optionally substituted piperidinyl, an optionally substituted pyridine, or an optionally substituted phenyl. In some embodiments, A is an optionally substituted thiazole, an optionally substituted triazole, an optionally substituted morpholino, or phenyl. In some embodiments, A is not an optionally substituted phenyl or benzimidazole. In some embodiments, A is not a hydroxyphenyl.

[0074] In some embodiments, Y is -NHC(O)- or -NHC(O)NH-.

[0075] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa: [ka] [In the formula, a is either 0 or 1].

[0076] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa-1: [ka] [In the formula, X 2 is N or CH, Each R 3This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0077] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa-2: [ka]

[0078] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa-3: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0079] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa-4: [ka]

[0080] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0081] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa-6: [ka]

[0082] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa-7: [ka]

[0083] In some embodiments (for example, either formula IIa-6 or IIa-7), R 6 It is methyl.

[0084] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIa-8 or formula IIa-9: [ka]

[0085] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa: [ka] [In the formula, a is either 0 or 1].

[0086] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa-1: [ka] [In the formula, X 2 is N or CH, Each R 3This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0087] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa-2: [ka]

[0088] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa-3: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0089] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa-4: [ka]

[0090] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0091] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa-6: [ka]

[0092] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa-7: [ka]

[0093] In some embodiments (for example, either formula IIIa-6 or IIIa-7), R 6 It is methyl.

[0094] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIIa-8 or formula IIIa-9: [ka]

[0095] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0096] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa-1: [ka] [In the formula, X 2 is N or CH, Each R 3This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0097] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa-2: [ka]

[0098] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa-3: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0099] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa-4: [ka]

[0100] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0101] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa-6: [ka]

[0102] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa-7: [ka]

[0103] In some embodiments (for example, either formula IVa-6 or IVa-7), R 6 It is methyl.

[0104] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IVa-8 or formula IVa-9: [ka]

[0105] In some embodiments (for example, any one of formulas IVa, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, or IVa-9), R 9 It is methyl.

[0106] In some embodiments, Y is -NHS(O)2- or -NHS(O)2NH-.

[0107] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Va: [ka] [In the formula, a is either 0 or 1].

[0108] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Va-1: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0109] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Va-2: [ka]

[0110] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Va-3: [ka] [In the formula, R 4 and R 5Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0111] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Va-4: [ka]

[0112] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Va-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0113] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIA: [ka] [In the formula, a is either 0 or 1].

[0114] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIa-1: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0115] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIa-2: [ka]

[0116] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIa-3: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0117] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIa-4: [ka]

[0118] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIa-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0119] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIa: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0120] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIa-1: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0121] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIa-2: [ka]

[0122] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIa-3: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0123] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIa-4: [ka]

[0124] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIa-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0125] In some embodiments (for example, any one of formulas VIIa, VIIa-1, VIIa-2, VIIa-3, VIIa-4, or VIIa-5), R 9 It is methyl.

[0126] In some embodiments, Y is -NHS(O)- or -NHS(O)NH-.

[0127] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIIa: [ka] [In the formula, a is either 0 or 1].

[0128] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIIa-1: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0129] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIIa-2: [ka]

[0130] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIIa-3: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0131] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIIa-4: [ka]

[0132] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula VIIIa-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0133] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IXa: [ka] [In the formula, a is either 0 or 1].

[0134] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IXa-1: [ka] [In the formula, X2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0135] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IXa-2: [ka]

[0136] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IXa-3: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0137] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IXa-4: [ka]

[0138] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IXa-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0139] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Xa: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0140] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Xa-1: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and n is an integer between 1 and 4.

[0141] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Xa-2: [ka]

[0142] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Xa-3: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0143] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Xa-4: [ka]

[0144] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula Xa-5: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0145] In some embodiments (for example, any one of formulas Xa, Xa-1, Xa-2, Xa-3, Xa-4, or Xa-5), R 9 It is methyl.

[0146] In some embodiments of any of the features described herein, a is 0. In some of the embodiments described above, a is 0.

[0147] In some embodiments of any of the features described herein, R 2 is an optionally substituted C1-C6 alkyl group. In some embodiments, R 2 The channel is selected from -CH2CH3 or -CH2CF3.

[0148] In some embodiments of any of the aspects described herein, W is a C1-C4 alkyl group. In some embodiments, W is [ka] That is the case.

[0149] In some embodiments of any of the embodiments described herein, W is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine, or optionally substituted phenyl.

[0150] In some embodiments of any of the models described herein, W is an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 3- to 10-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl.

[0151] In some embodiments of any of the aspects described herein, W is an optionally substituted 3- to 10-membered heterocycloalkyl group. In some embodiments, W is selected from the following or their stereoisomers: [ka] [ka] [ka] [ka] In some embodiments, W is selected from the following, or their stereoisomers: [ka]

[0152] In some embodiments of any of the aspects described herein, W is an optionally substituted 3- to 10-membered cycloalkyl group. In some embodiments, W is selected from the following or their stereoisomers: [ka] In some embodiments, W is selected from the following, or their stereoisomers: [ka]

[0153] In some embodiments of any of the aspects described herein, W is an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W is selected from the following or their stereoisomers: [ka]

[0154] In some embodiments of any of the embodiments described herein, W is an optionally substituted 6- to 10-membered aryl. In some embodiments, W is an optionally substituted phenyl.

[0155] In some embodiments of any of the embodiments described herein, W is an optionally substituted C1-C3 heteroalkyl. In some embodiments, W is selected from the following or their stereoisomers: [ka]

[0156] In some embodiments, the compounds of the present invention are selected from Table 1a, or are pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the present invention are selected from Table 1a, or are pharmaceutically acceptable salts or atropisomers thereof. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79 Table 1-80 Table 1-81 Table 1-82 Table 1-83

[0157] In some embodiments, the compounds of the present invention are selected from Table 1b, or are pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the present invention are selected from Table 1b, or are pharmaceutically acceptable salts or atropisomers thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 Table 2-48 Table 2-49 Table 2-50 Table 2-51 Table 2-52 Table 2-53 Table 2-54 [Table 2-55] [Table 2-56] [Table 2-57] [Table 2-58] [Table 2-59] [Table 2-60] [Table 2-61] [Table 2-62] [Table 2-63]

[0158] In some embodiments, the compound of the present invention is a compound selected from Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of the present invention is a compound selected from Table 2, or a pharmaceutically acceptable salt or atropisomer thereof.

[0159] In some embodiments, the compounds of the present invention are not compounds selected from Table 2. In some embodiments, the compounds of the present invention are not compounds selected from Table 2, or their pharmaceutically acceptable salts or stereoisomers. In some embodiments, the compounds of the present invention are not compounds selected from Table 2, or their pharmaceutically acceptable salts or atropisomers. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0160] In some embodiments, the compound of the present invention is a compound selected from Table 3 (e.g., C1-C20 or C1-C21), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0161] In some embodiments, the compounds of the present invention are not compounds selected from Table 3 (e.g., C1-C20 or C1-C21). In some embodiments, the compounds of the present invention are not compounds selected from Table 3 (e.g., C1-C20 or C1-C21), or their pharmaceutically acceptable salts or stereoisomers. In some embodiments, the compounds of the present invention are not compounds selected from Table 3 (e.g., C1-C20 or C1-C21), or their pharmaceutically acceptable salts or atropisomers. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7]

[0162] 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 shown below.

[0163] Oral bioavailability can be measured in BALB / c mice. After intravenous (IV) bolus and oral (PO) administration of the test compound, approximately 30 μL of whole blood sample was collected at predetermined time points and placed in a tube containing K2EDTA. The blood sample was centrifuged at 4600 rpm for approximately 5 minutes at 4°C, and the plasma sample was stored at -80°C before bioanalysis. The plasma sample was extracted by protein precipitation and analyzed by tandem mass spectrometry (LC MS / MS) using electrospray positive ionization, for example, on an API 5500 system.

[0164] All PK parameters can be derived from time-series plasma concentration data using non-compartmental analysis with WinNonlin. Bioavailability (both F% and %F) is estimated using the following equation:

number

[0165] AUC inf,PO This represents the area of ​​plasma concentration over time (0 to ∞) after PO administration.

[0166] AUC inf,IV This represents the area under the time course of plasma concentration (0 to ∞) after IV administration.

[0167] dose IV This is the total dose administered intravenously.

[0168] dose PO This is the total dose administered by PO.

[0169] Generally, an F% (or %F) value greater than 30% is preferred, and a value greater than 50% is more preferred.

[0170] In some embodiments, the compounds of the present invention are selective to one or more specific Ras variants than other Ras variants or wild types compared to those known in the art. Methods for measuring such selectivity, such as the Ras-Raf binding assay, which is provided in the following examples, are known in the art. Therefore, in some embodiments, the compounds of the present invention are selective to KRAS than other Ras variants or wild types. G12C It is selective for KRAS. In some embodiments, the compounds of the present invention are more selective for KRAS than other Ras variants or wild types. G12D It is selective for KRAS. In some embodiments, the compounds of the present invention are more selective for KRAS than other Ras variants or wild types. G12V It is selective for KRAS. In some embodiments, the compounds of the present invention are more selective for KRAS than other Ras variants or wild types. G12D It is selective for NRAS. In some embodiments, the compounds of the present invention are more selective for NRAS than other Ras variants or wild types. Q61K It is selective for KRAS. In some embodiments, the compounds of the present invention are more selective for KRAS than other Ras variants or wild types. G12D and KRAS G12V It is selective for. The compounds of the present invention may also exhibit greater selectivity for 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 for one or more Ras variants described herein in the Ras-Raf binding assay described above.

[0171] In some embodiments, the compounds of the present invention are potent against one or more specific Ras variants than other Ras variants or wild types compared to those known in the art. Methods for measuring such potency, such as the pERK assay, which is provided in the following examples, are known in the art. Therefore, in some embodiments, the compounds of the present invention are potent against KRAS variants than those known in the art. G12DIt exhibits greater efficacy against KRAS than those known in the art. In some embodiments, the compounds of the present invention are more effective against KRAS than those known in the art. G12V It exhibits greater efficacy against KRAS than those known in the art. In some embodiments, the compounds of the present invention are more effective against KRAS than those known in the art. G12C It exhibits greater efficacy against KRAS than those known in the art. In some embodiments, the compounds of the present invention are more effective against KRAS than those known in the art. G12D and KRAS G12V It exhibits greater efficacy against [specific target group]. The compounds of the present invention may also exhibit greater efficacy against other Ras variants disclosed herein, or combinations thereof.

[0172] In some embodiments, the compounds of the present invention exhibit a greater detrimental effect on cell viability to one or more specific Ras variants than other Ras variants or wild types, compared to those known in the art. Methods for measuring cell viability, such as the CellTiter-Glo® cell viability assay, which is provided in the following examples, are known in the art. Therefore, in some embodiments, the compounds of the present invention exhibit a greater detrimental effect on KRAS compared to those known in the art. G12D It shows a greater decrease in cell viability compared to KRAS. In some embodiments, the compounds of the present invention show a greater decrease in KRAS compared to those known in the art. G12V It shows a greater decrease in cell viability compared to KRAS. In some embodiments, the compounds of the present invention show a greater decrease in KRAS compared to those known in the art. G12C It shows a greater decrease in cell viability compared to KRAS. In some embodiments, the compounds of the present invention show a greater decrease in KRAS compared to those known in the art. G12D and KRAS G12V It exhibits a greater reduction in cell viability for both of these. The compounds of the present invention may also exhibit a greater reduction in cell viability for other Ras variants disclosed herein, or combinations thereof.

[0173] In some embodiments, the compounds of the present invention may exhibit greater metabolic stability, permeability, or solubility, or a combination thereof, than 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 improvements compared to those known in the art in any or a combination thereof of the following properties: selectivity, efficacy, cell viability, metabolic stability, permeability, or solubility.

[0174] In some embodiments, the compounds of the present invention are, or act as, prodrugs for administration to, for example, cells or other targets requiring administration.

[0175] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0176] A method for treating cancer in a subject requiring cancer treatment is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The cancer may be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid cancer, myelodysplastic syndrome, or small squamous cell carcinoma follicular carcinoma. In some embodiments, the cancer includes Ras mutations such as K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L, or combinations thereof. In some embodiments, the cancer includes Ras mutations 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.

[0177] A method for treating a Ras protein-related disorder in a subject requiring treatment for the disorder, further comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0178] A method for inhibiting Ras proteins in cells is provided, further comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L. The Ras protein may 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 cells may be cancer cells such as pancreatic cancer cells, colorectal cancer cells, lung cancer cells (e.g., non-small cell lung cancer cells), acute myeloid leukemia cells, multiple myeloma cells, thyroid cancer cells, myelodysplastic syndrome cells, melanoma cells, or small squamous cell carcinoma follicular carcinoma cells. Other types of cancer are described herein. The cells may be in vivo or in vitro.

[0179] With respect to the compounds of the present invention, one stereoisomer may exhibit better inhibition than another. For example, one atropisomer may exhibit inhibition, while other atropisomers may exhibit little to no inhibition.

[0180] In some embodiments, the methods or uses described herein further include administering an additional anticancer therapy. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are described herein.

[0181] Synthesis method The compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes.

[0182] The compounds of the present invention can be prepared by several methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods shown in the following scheme, along with synthetic methods known in the field of organic synthesis chemistry, or variations thereof as understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following scheme.

[0183] Scheme 1. General synthesis of macrocyclic esters [ka]

[0184] A general synthesis of macrocyclic esters is outlined in Scheme 1. A appropriately substituted indolylboronic acid ester (1) can be prepared in four steps, starting with a protected 3-(5-bromo-2-iodo-1H-indole-3-yl)-2,2-dimethylpropan-1-ol and an appropriately substituted boronic acid, and involving palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation.

[0185] (S)-2-amino-3-(4-bromothiazole-2-yl)propanoic acid (2) can be coupled with methyl(S)-hexahydropyridazine-3-carboxylate to prepare methyl-amino-3-(4-bromothiazole-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (3).

[0186] In the presence of a Pd catalyst, methyl-amino-3-(4-bromothiazole-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (3) is coupled with a suitably substituted indolylboronic acid ester (1), followed by hydrolysis and macrolactonization to produce the final macrocyclic ester and a suitably protected macrocyclic intermediate (5). Deprotection and coupling with a suitably substituted carboxylic acid (or other coupling partner) can yield the macrocyclic product. Additional deprotection or functionalization steps may be required to produce the final compound 6.

[0187] Furthermore, with respect to Scheme 1, thiazole can be replaced with an alternative, optionally substituted 5-6 member heteroarylene, or an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene (e.g., morpholino), or an optionally substituted 6 member arylene (e.g., phenyl).

[0188] Scheme 2. General synthesis of alternative macrocyclic esters. [ka]

[0189] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. A appropriately substituted and protected indolylboronic acid ester (7) can be coupled with (S)-2-amino-3-(4-bromothiazole-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 be followed to obtain an iodine intermediate (11). Subsequent palladium-mediated borylation and coupling with an appropriately substituted iodoaryl or iodoheteroaryl intermediate in the presence of a Pd catalyst can yield a appropriately protected macrocyclic intermediate. Alkylation, deprotection, and coupling with an appropriately substituted carboxylic acid (or other coupling partner) can yield the macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 6.

[0190] Furthermore, with respect to Scheme 2, thiazole can be replaced with an alternative, optionally substituted 5-6 member heteroarylene, or an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene (e.g., morpholino), or an optionally substituted 6 member arylene (e.g., phenyl).

[0191] The compounds in Table 1a or Table 1b of this Specified Method were prepared using the methods described herein, or by combining them with the knowledge of those skilled in the art and the methods disclosed herein.

[0192] Pharmaceutical composition and method of use Pharmaceutical composition and administration method The compounds related to the present invention are RAS inhibitors and are useful in cancer treatment. Accordingly, one embodiment of the present invention provides a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, as well as a method for preparing such a composition using the compound of the present invention.

[0193] In the present invention, the term "pharmaceutical composition" means a compound such as the compound of the present invention, or a pharmaceutically acceptable salt thereof, formulated with a pharmaceutically acceptable excipient.

[0194] In some embodiments, the compound is present in the pharmaceutical composition in a unit dose appropriate for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition can be specifically formulated for administration in solid or liquid form, including: oral administration, e.g., oral tablets (aqueous or non-aqueous or suspension), tablets, e.g., cheek, sublingual, and those targeted for intracellular absorption, pills, powders, granules, and pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection as a sterile solution or suspension, or as a sustained-release formulation; topical application, e.g., as a cream, ointment, or sustained-release patch, or as a spray applied to the skin, lungs, or oral cavity; e.g., as a pessary, cream, or foam suitable for vaginal or rectal, sublingual, intraocular, transdermal, or transnasal, lung, and other mucosal surfaces.

[0195] As used herein, “pharmaceutically acceptable excipient” means any inert component having properties that are toxic and non-inflammatory within the subject matter (e.g., a vehicle capable of suspending or dissolving an active compound). Typical excipients include, for example, anti-adhesives, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavorings, fragrances, lubricants (flow enhancers), preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Examples of excipients include, but are not limited to, optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with a wide variety of agents and materials useful as excipients. For example, for example, Ansel, et al., Ansel's See 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.

[0196] The compounds described herein may be provided or used in salt form, e.g., pharmaceutically acceptable salt form, whether or not expressly stated otherwise. As used herein, the term “pharmaceutically acceptable salt” means these salts of the compounds described herein that are suitable for use in contact with human and other animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., within the normal range of reasonable medical judgment, and that are balanced by a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PHStahl). The salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

[0197] The compounds of the present invention may have ionic groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts with inorganic or organic acids, or, in the case of the acidic form of the compounds of the present invention, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art for forming acid addition salts, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, or tartaric acid, and for forming basic salts, such as potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, and various amines. Methods for preparing suitable salts are well established in the art.

[0198] Typical acid addition salts include acetate, adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-(optionally substituted)hydroxylethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and valersates. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations (including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine).

[0199] As used herein, the term “subject” means any element in the animal kingdom. In some embodiments, “subject” means a human at any stage of development. In some embodiments, “subject” means a human patient. In some embodiments, “subject” means a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, or pigs). In some embodiments, subjects may be mammals, birds, reptiles, amphibians, fish, or insects, but are not limited to these. In some embodiments, subjects may be transgenic animals, genetically modified animals, or clones.

[0200] As used herein, the term “dosage form” means a physically distinct unit 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 a unit dose (or its entire fraction) appropriate for administration according to an administration regimen (i.e., using a therapeutic administration regimen) that has been measured to correlate with a desired or beneficial outcome when administered to the population in question. Those skilled 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 “administration regimen” means a set of unit doses (usually two or more) administered individually to a subject, usually divided into periods. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended administration regimen, which may have one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each separated from the others by time periods of the same length; in some embodiments, the dosing regimen comprises multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses within the dosing regimen are identical unit doses. In some embodiments, different doses within the dosing regimen are different amounts. In some embodiments, the dosing regimen comprises one or more further doses, a first dose at a first dose, followed by a second dose different from the first dose. In some embodiments, the dosing regimen comprises one or more further doses, a first dose at a first dose, followed by a second dose identical to the first dose. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered across a relevant population (i.e., it is a therapeutic dosing regimen).

[0201] A "treatment regimen" refers to a dosing regimen across relevant populations that correlates with a desired or beneficial therapeutic outcome.

[0202] The term “treatment” (and additionally, “to treat” or “to treat”) means, in its broadest sense, any administration of a substance (e.g., a compound of the present invention) that partially or completely remits, alleviates, reduces or inhibits a particular disease, disorder or condition; partially or completely delays the onset of a particular disease, disorder or condition; partially or completely reduces the severity of a particular disease, disorder or condition; or partially or completely reduces the occurrence of one or more symptoms, features, or causes of a particular disease, disorder or condition. In some embodiments, such treatment may be administered to subjects who show no signs of the related disease, disorder or condition, or to subjects who show only the initial signs of the disease, disorder or condition. Alternatively, or in addition, in some embodiments, such treatment may be administered to subjects showing established signs of one or more of the related diseases, disorders or conditions. In some embodiments, treatment may be administered to subjects diagnosed with suffering from the related disease, disorder or condition. In some embodiments, the treatment may be administered to subjects known to have one or more susceptibility factors that are statistically correlated with an increased risk of progression of the associated disease, disorder, or condition.

[0203] The term “therapeutic dose” means a quantity sufficient to treat a disease, disorder, or condition when administered to a population suffering from or suspected of having a disease, disorder, or condition, according to a therapeutic administration regimen. In some embodiments, a therapeutic dose is a quantity that reduces the onset or severity of one or more symptoms of the disease, disorder, or condition, or delays the onset of one or more symptoms of the disease, disorder, or condition. Those skilled in the art will understand that the term “therapeutic dose” does not actually require that successful treatment be achieved in a particular individual. Rather, a therapeutic dose can be a quantity that, when administered to subjects requiring such treatment, produces a specific desired pharmacological response in a significant number of subjects. It is specifically understood that a particular subject may actually be “refractory” to the “therapeutic dose.” In some embodiments, a reference to a therapeutic dose may refer to a quantity measured in one or more specific tissues (e.g., tissues affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount can be formulated or administered as a single dose. In some embodiments, a therapeutically effective amount can be formulated or administered in multiple doses, for example, as part of an administration regimen.

[0204] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be formulated as pharmaceutical or veterinary compositions for use as a treatment for a target. Depending on the target to be treated, the method of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or treatment, the compounds, or pharmaceutically acceptable salts thereof, are formulated in a manner that matches these parameters. A summary of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21 stThis can be found in Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988–1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0205] Each composition can be prepared according to conventional mixing, granulation, or coating methods, and the pharmaceutical composition may contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% (by weight or by volume) of the compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein or a pharmaceutically acceptable salt thereof may be present in total in an amount of 1 to 95% of the total weight of the composition, such as the pharmaceutical composition.

[0206] The composition can be provided in dosage forms suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, transnasal, intravaginal, intravesical, intraurethral, ​​intrathecal, epidural, transaural, or intraocular administration, or for injection, inhalation, or direct contact with the nasal, genitourinary, reproductive, or oral mucosa. Accordingly, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, oral medications, infiltration delivery devices, suppositories, enemas, injections, implants, sprays, preparations suitable for iontophoresis delivery, or aerosols. The composition can be formulated according to conventional pharmaceutical regulations.

[0207] As used herein, the term “administration” means the administration of a composition (e.g., a compound, or a preparation containing a compound as described herein) to a subject or system. Administration to an animal subject (e.g., a human) may be by any suitable route. For example, in some embodiments, administration may be bronchial (including bronchial infusion), cheek, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, transnasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal infusion), transdermal, vaginal, or intravitreous.

[0208] Formulations can be prepared in a manner suitable for systemic administration or local or local administration. Systemic formulations may be designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection), or they may be prepared for transdermal, transmucosal, or oral administration. Formulations generally contain diluents, and optionally adjuvants, buffers, and preservatives. The compound, or a pharmaceutically acceptable salt thereof, may also be administered in a liposome composition or as a microemulsion.

[0209] For injection, formulations can be prepared in conventional forms, such as a solution or suspension, or as a solid suitable for solution or suspension in liquid before injection, or as an emulsion. Suitable excipients include, for example, water, saline, dextrose, and glycerol. Such compositions may also contain certain amounts of non-toxic auxiliary substances (e.g., wetting agents or emulsifiers), pH buffers, such as sodium acetate and sorbitan monolaurate.

[0210] Various sustained-release systems for pharmaceuticals have also been devised. See, for example, U.S. Patent No. 5,624,677.

[0211] Systemic administration can also be achieved through relatively non-invasive methods such as suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or pharmaceutically acceptable salts thereof. Preferred forms, as understood in the art, include syrups, capsules, and tablets.

[0212] Each compound described herein, or a pharmaceutically acceptable salt thereof, can be formulated in various ways known in the art. For example, the first and second agents of a combination therapy can be formulated together or individually. Other modalities of combination therapy are described herein.

[0213] Individually formulated or separately manufactured drugs can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing two pills, pills and powder, suppositories and liquid in a vial, or two topical creams. A kit may include any components that assist in administering a unit dose to a subject, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, or inhalers. In addition, a unit dose kit may include instructions for preparing or administering the composition. A kit may be manufactured as a single-use unit dose for a particular subject, or as a multi-use unit dose for a specific subject (where the efficacy of individual compounds or their pharmaceutically acceptable salts changes at a constant concentration or as treatment progresses), or a kit may contain multi-use doses (bulk packaging) suitable for administration to multiple subjects. The components of a kit can be assembled into cartons, blister packs, bottles, tubes, etc.

[0214] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with pharmaceutically acceptable, non-toxic excipients. These excipients may include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starch containing potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulators and disintegrants (e.g., cellulose derivatives containing microcrystalline cellulose, starch containing potato starch, croscarmellose sodium, alginate, or arginine); binders (e.g., sucrose, glucose, sorbitol, acacia, arginine, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, aluminum magnesium silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); as well as smoothers, lubricants, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavorings, plasticizers, wetting agents, and buffering agents.

[0215] Two or more compounds can be mixed or fractionated in a tablet, capsule, or other vehicle. In one example, the first compound is contained inside the tablet, the second compound is on the outside, and a substantial portion of the second compound is released before the first compound.

[0216] Formulations for oral use may be provided as chewable tablets, or as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or as flexible gelatin capsules in which the active ingredient can be mixed with water or an oil culture medium, e.g., peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets can be prepared using the above-mentioned components below tablets and capsules by conventional methods, for example, using a mixer, fluidized bed apparatus, or spray dryer.

[0217] Dissolution or diffusion-controlled release can be achieved by appropriate coatings for tablet, capsule, pellet, or granule formation of the compound, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into a suitable matrix. Sustained-release coatings may include the coating materials described above, or one or more of the following: shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate / butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-(optionally substituted) hydroxyl methacrylate, methacrylate hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate, or polyethylene glycol. In sustained-release matrix formulations, examples of matrix materials include hydrated methylcellulose, carnauba wax and stearyl alcohol, Carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0218] Liquid forms in which the compounds of the present invention, or pharmaceutically acceptable salts thereof, and compositions may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0219] In general, when administered to humans, the oral dose of any of the compounds of the present invention, or any pharmaceutically acceptable salt thereof, depends on the properties of the compound and can be quickly determined by those skilled in the art. The dose may be, for example, about 0.001 mg to about 2000 mg / day, about 1 mg to about 1000 mg / day, about 5 mg to about 500 mg / day, about 100 mg to about 1500 mg / day, about 500 mg to about 1500 mg / day, about 500 mg to about 2000 mg / day, or any range variable therefrom. In some embodiments, the daily dose range for oral administration may be, for example, a single dose or divided dose, within the range of about 0.001 mg to about 2000 mg per kg of human body weight. On the other hand, in some cases, it may be necessary to use doses other than those limited.

[0220] In some embodiments, the pharmaceutical composition may further contain additional compounds having antiproliferative activity. Depending on the method of administration, the compounds, or pharmaceutically acceptable salts thereof, are formulated into a suitable composition that allows for easy delivery. Each compound, or pharmaceutically acceptable salt thereof, of the combination therapy can be formulated in various ways known in the art. For example, the first and second agents of the combination therapy can be formulated together or individually. Preferably, the first and second agents are formulated together for simultaneous or near-simultaneous administration.

[0221] It will be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapy, that is, the compounds and pharmaceutical compositions can be formulated or administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures. In specific combinations of treatments (therapeutic agents or procedures) using combination regimens, the suitability of the desired therapeutic agent or procedure and the desired therapeutic effect to be achieved will be taken into consideration. Furthermore, it will be understood that the treatments used may achieve the desired effect for the same disease, or different effects (e.g., control of any adverse effects).

[0222] As described herein, each drug in combination therapy may be administered independently once to four times a day for a period of one to one year, and may also be administered throughout the patient's lifetime. Chronic, long-term administration may be indicated.

[0223] How to use In some embodiments, the present invention discloses methods for treating diseases or disorders characterized by ectopic Ras activity caused by Ras variants. In some embodiments, the disease or disorder is cancer.

[0224] Accordingly, the present invention also provides a method for treating cancer in a subject requiring treatment for cancer, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such compound or salt. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small intestine cancer, ampulla cancer, germ cell carcinoma, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophageal cancer, GI neuroendocrine cancer, ovarian cancer, sex cord-stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal cancer, endometrial cancer, or melanoma. The present invention also provides a method for treating Ras protein-related disorders in a subject requiring treatment for Ras protein-related disorders, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such compound or salt.

[0225] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds or salts, and the methods provided herein can be used to treat a wide variety of cancers, including, for example, lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers treatable by the compounds or salts thereof, pharmaceutical compositions containing such compounds or salts, and the methods of the present invention include, but are not limited to, astrocyte, breast, cervix, colorectal, uterine, esophageal, gastric, head and neck, hepatocyte, larynx, lung, pharyngeal, ovarian, prostate, and thyroid cancer and sarcoma. Other cancers include, for example: Cardiac malignancies, for example, non-epithelial malignancies (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung cancers, for example, bronchogenic carcinomas (squamous cell carcinomas, anaplastic small cell carcinomas, anaplastic large cell carcinomas, adenocarcinomas), alveolar (bronchial) carcinomas, bronchial adenomas, non-epithelial malignancies, lymphomas, chondrotoxic hamartomas, mesotheliomas; The gastrointestinal tract, for example, the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), the stomach (epithelial malignant tumor, lymphoma, leiomyosarcoma), the pancreas (ductal adenocarcinoma, islet cell tumor, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), and the large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); The urogenital organs, for example, the kidneys (adenocarcinoma, Wilms' tumor, (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, non-epithelial malignant tumor), testicles (seminal carcinoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, non-epithelial malignant tumor, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); Liver, for example, liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer, for example, gallbladder cancer, ampulla cancer, bile duct cancer; Bone, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system, for example, skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, non-epithelial malignant tumors); Gynecology, for example, the uterus (endometrial cancer, uterine cancer, endometrial cancer of the uterine body), the cervix (cervical cancer, pre-tumor cervical dysplasia), the ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), the vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma)), the fallopian tubes (epithelial malignant tumors); Hematological conditions, e.g., blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia), myeloproliferative disorders (e.g., myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic moles, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; and Adrenal glands, for example, neuroblastoma.

[0226] In some embodiments, the Ras protein is wild-type. (Ras WT Therefore, in some embodiments, the compounds of the present invention are Ras WT (For example, K-Ras WT H-Ras WT , or N-Ras WT It is used in treatment methods for patients with cancer including ). In some embodiments, the Ras protein is used for Ras amplification (e.g., K-Ras amp Therefore, in some embodiments, the compounds of the present invention are Ras amp (K-Ras amp H-Ras amp , or N-Ras amp It is used in methods for treating patients with cancer including ). In some embodiments, the cancer includes Ras mutations such as the Ras mutations described herein. In some embodiments, the mutations are selected from the following: (a) The following K-Ras variants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) The following H-Ras variants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and (c) The following N-Ras variants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof; Or any combination of the above. In some embodiments, the cancer includes a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer includes at least two Ras mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit two or more Ras 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 inhibits K-Ras G12D and K-Ras Both G12V can be inhibited. In some embodiments, the compound can 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 of K-Ras, N-Ras, or H-Ras, or combinations thereof. In some embodiments, the mutation is selected from the group consisting of G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y of K-Ras, N-Ras, or H-Ras, or combinations thereof. 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 containing the mutations described herein. 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. In some embodiments, the cancer is colorectal cancer, and the Ras mutation includes a K-Ras mutation such as K-Ras G12C. 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 non-small cell lung cancer, and the Ras protein is K-Ras amp That is the case.

[0227] Furthermore, in some embodiments, the cancer includes a K-Ras mutation selected from the group consisting of G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer includes an N-Ras mutation selected from the group consisting of G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer includes an H-Ras mutation selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer includes a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer contains at least two Ras mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit two or more Ras mutations. For example, the compound may inhibit both K-Ras G12C and K-Ras G13C. The compound may inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the present invention inhibit one or more additional Ras mutations in addition to Ras WT Inhibits (for example, K, H, or N-Ras) WT And, K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V;K, H, or N-Ras WTH-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Ras WT (and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T). In some embodiments, the compounds of the present invention are Ras in addition to one or more additional Ras mutations. amp Inhibits (for example, K, H, or N-Ras) amp And, K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V;K, H, or N-Ras amp H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Ras amp (and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0228] Methods for detecting Ras mutations are known in the art. Such methods include, but are not limited to, direct sequencing and the use of highly sensitive diagnostic assays (using the CE-IVD mark) including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro, which are incorporated herein by reference, for example. See also, for example, WO2020 / 106640.

[0229] In some embodiments, the cancer is non-small cell lung cancer, and the Ras mutation includes K-Ras mutations such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is colorectal cancer, and the Ras mutation includes K-Ras mutations such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation includes K-Ras mutations such as K-Ras G12D or K-Ras G12V. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation includes N-Ras mutations such as N-Ras G12D. In some embodiments, the cancer is melanoma, and the Ras mutation includes N-Ras mutations such as N-Ras Q61R or N-Ras Q61K. In some embodiments, the cancer is non-small cell lung cancer, and the Ras protein is K-Ras amp That is. Unless already specified, in any of the above, the compound is similarly Ras WT (For example, K-, H-, or N-Ras) WT ), or Ras amp (For example, K-, H-, or N-Ras) amp ) may be inhibited.

[0230] In some embodiments, cancer is caused by Ras mutations and STK11LOF This includes KEAP1, EPHA5, or NF1 mutations, or combinations thereof. In some embodiments, the cancer is non-small cell lung cancer and includes the K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and includes the K-Ras G12C mutation, STK11 LOF Mutations, including KEAP1 mutations. In some embodiments, the cancer is non-small cell lung cancer, and includes K-Ras G12C mutation and STK11 LOF The mutation is included. In some embodiments, the cancer is non-small cell lung cancer, and the K-Ras G12C mutation and STK11 LOF Includes mutations. In some embodiments, the cancer is a K-Ras G13C Ras mutation and STK11 LOF , comprising KEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and comprises the K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises the K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and comprises the K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises the K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and comprises the K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer and comprises the K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and comprises the K-Ras G12C mutation. In any of the above, the compound is similarly Ras WT (For example, K-, H-, or N-Ras) WT ), or Ras amp (For example, K-, H-, or N-Ras) amp ) may be inhibited.

[0231] A method for inhibiting the Ras protein within a cell is also provided, wherein the method comprises contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The compound or a pharmaceutically acceptable salt thereof can inhibit two or more Ras proteins within the cell. A method for inhibiting RAF-Ras binding is also provided, wherein the method comprises contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The cells may be cancer cells. The cancer cells may be of any type of cancer described herein. The cells may be in vivo or in vitro.

[0232] Combination therapy The methods of the present invention may include compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). The dosage of one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced from the standard dosage when administered alone. For example, the dosage may be determined empirically from the combination and permutation of drugs or estimated by isoborographic analysis (e.g., Black et al.). al., Neurology 65:S3-S6(2005)).

[0233] The compounds of the present invention may be administered before, after, or concurrently with one or more additional therapies. When combined, the dosage of the compounds of the present invention and the dosage of one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The compounds of the present invention and additional therapies, such as anticancer agents, may be administered together or separately in a single pharmaceutical composition, and if administered separately, they may be administered simultaneously or sequentially. Such sequential administration may have short or long intervals between doses.

[0234] In some embodiments, additional therapy involves the administration of side effect limiting agents (e.g., agents intended to reduce the occurrence or severity of side effects of the treatment). For example, in some embodiments, the compounds of the present invention may also be used in combination with therapeutic agents for treating nausea. Examples of agents that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0235] In some embodiments, one or more additional therapies include non-pharmacological treatment (e.g., surgery or radiotherapy). In some embodiments, one or more additional therapies include therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signaling inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, one or more additional therapies include non-pharmacological treatment (e.g., surgery or radiotherapy) and therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signaling inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, one or more additional therapies include two therapeutic agents. In yet another embodiment, one or more additional therapies include three therapeutic agents. In some embodiments, one or more additional therapies include four or more therapeutic agents.

[0236] In this chapter on combination therapies, all references for the listed drugs, or their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers, whether explicitly stated or not, are incorporated by reference.

[0237] Non-pharmacological therapy Examples of non-pharmacological treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0238] In some embodiments, the compounds of the present invention can be used as adjuvant therapy after surgery. In some embodiments, the compounds of the present invention can be used as preoperative adjuvant therapy before surgery.

[0239] Radiotherapy may be used in subjects (e.g., mammals (e.g., humans)) to inhibit abnormal cell proliferation or to treat hyperproliferative disorders such as cancer. Techniques for administering radiotherapy are known in the art. Radiotherapy can be administered by one or a combination of several methods, including, but not limited to, external beam therapy, internal radiotherapy, implantable radiation, stereotactic radiosurgery, total body radiotherapy, radiotherapy, and permanent or transient interstitial near-brightening therapy. As used herein, the term “near-brightening therapy” refers to radiotherapy delivered by spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radiation sources for use as cell modifiers in the present invention include both solids and liquids. In non-limiting examples, the radiation source may be radionuclides such as I-125, I-131, Yb-169, Ir-192 as solid sources, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material may also be a fluid prepared from any solution of the radionuclide(s), e.g., a solution of I-125 or I-131, or the radioactive fluid may be produced using a suitable fluid slurry containing small particles of a solid radionuclide such as Au-198 or Y-90. Furthermore, the radionuclide(s) may be embodied in gels or radioactive microspheres.

[0240] In some embodiments, the compounds of the present invention can make abnormal cells more sensitive to radiotherapy aimed at killing or inhibiting the proliferation of such cells. Therefore, the present invention further relates to a method for sensitizing abnormal cells in mammals to radiotherapy, the method comprising administering to a mammal an amount of the compound of the present invention effective in sensitizing the abnormal cells to radiotherapy. The amount of the compound in this method can be determined according to the means for determining an effective amount of such compound described herein. In some embodiments, the compounds of the present invention may be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0241] In some embodiments, the non-pharmacological treatment is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The T cell source is obtained from a subject before proliferation and genetic modification of the T cells. T cells can be obtained from several sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymic tissue, tissue from infection sites, ascites, pleural fluid, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Regardless of whether the T cells are genetically modified to express a desired protein (e.g., CAR), T cells are generally, for example, U.S. Patent Nos. 6,352,694, 6,534,055, 6,905,680, 6,692,964, 5,858,358, 6,887,466, 6,905,681, and It can be activated and propagated using the methods described in Nos. 7,144,575, 7,067,318, 7,172,869, 7,232,566, 7,175,843, 7,572,631, 5,883,223, 6,905,874, 6,797,514, and 6,867,041.

[0242] Therapeutic drugs The therapeutic agent may be a compound used to treat cancer or related conditions.

[0243] For example, the therapeutic agent may be a steroid. Therefore, in some embodiments, one or more additional therapies include a steroid. Preferred steroids include 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, crocortol, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, dexoxymethasone, dexamethasone, diflorasone, diflucortol, difprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortin butyl, flucortolone, fluorometholone, fluperolone acetate, flupredniden acetate, fluprednisolone, and flulandrenolide. Examples include, but are not limited to, fluticasone propionate, formocortal, halcinonide, halobetazole propionate, halomethasone, hydrocortisone, loteprednol etavonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, sodium prednisolone phosphate, prednisone, prednival, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexaacetonide, and their salts or derivatives.

[0244] Further examples of therapeutic agents that may be used in combination therapy with the compounds of the present invention include the compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, as well as International Patent Application No. WO0 Issues 1 / 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.

[0245] The therapeutic agent may be a biological agent used to treat cancer or related conditions (e.g., cytokines (e.g., interferons or interleukins such as IL-2)). In some embodiments, the biological agent is a biological agent of the immunoglobulin system, e.g., monoclonal antibodies (e.g., humanized antibodies, fully human antibodies, Fc fusion proteins, or functional fragments thereof) that inflict pain on a target to stimulate an anti-cancer response or antagonize antigens important to cancer. Antibody-drug conjugates are also included.

[0246] The therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is a drug such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is a drug such as an antibody that interacts with a ligand for a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion protein) (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibody, e.g., avelumab, durvalumab, atezolizumab, pizilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or Preusser, M. et al. Checkpoint inhibitors disclosed in al. (2015) Nat. Rev. Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirirumab, IPH2101, 1-7F9, and KW-6002.

[0247] The therapeutic agent may be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (ethigirimab).

[0248] Therapeutic agents may be drugs that treat cancer or related conditions (e.g., cytotoxic agents, non-peptide small molecules, or other compounds useful in treating cancer or related conditions, collectively referred to as “anticancer agents”). Anticancer agents may be, for example, chemotherapeutic agents or targeted therapy agents.

[0249] Anticancer agents include mitotic inhibitors, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyrotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum-coordinated complexes, anthracendione-substituted ureas, methylhydrazine derivatives, corticosteroids, progestins, estrogens, antiestrogens, androgens, and gonadotropin-releasing hormone analogs. Further anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, one or more additional therapies comprise two or more anticancer agents. Two or more anticancer drugs can be used in a cocktail, either administered in combination or individually. Preferred administration regimens for combination anticancer drugs are known in the art and are described, for example, in Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a(1999) and Douillard et al., Lancet 355(9209):1041-1047(2000).

[0250] Other non-exclusive examples of anticancer drugs include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents, e.g., thiotepa and cyclophosphamide; alkyl sulfonates, e.g., busulfan, improsulfan, and pigosulfan; aziridines, e.g., be Nzodopa, carbocone, metsuredopa, and uredopa; ethyleneimines and methylamelamines, e.g., altoretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bratacin and bratacinone); camptothecin (e.g., synthetic analog topotecan); briostatin; callistatin; CC-1065 (e.g., its adzeresin, karzeresin, and Beizelesin synthetic analogs); cryptophycin (specifically, cryptophycin 1 and cryptophycin 8); dorastatin; duocalmycin (e.g., synthetic analogs KW-2189 and CB1-TM1); eryuterobin; pancratistatin; sarcodictiin A; spongistatin; nitrogen mustard, e.g., chlorambucil, chlornafadin, colophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine Minoxide hydrochloride, melphalan, nobenbitin, fenestrine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, e.g., camulstine, chlorozotosine, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, e.g., engine antibiotics (e.g., calicheamicin, e.g., calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins such as dynemicin A; bisphosphonates such as clodronate; esperamicin;Neocardinostatin chromophore and related pigment protein enediin antibiotic chromophore, acrasinomycin, actinomycin, autoramycin, azaserin, bleomycin, kactinomycin, calicheamicin, carabicin, kaminomycin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detrubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino - Doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin C and other mitomycins, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, pteropterin, and trimethrexate; f Purine analogs such as rudarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid infusions such as fluphosphate; acegraton; aldofamide glycoside; aminolevulinic acid Acids; Enyluracil; Amsacrine; Bestrabusil; Bisanthren; Edatrexate; Defofamine; Demecolsin; Diadiquan; Elfomithine; Erliptinium acetate; Epotilon B and other Epotilons; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Mytansinoids such as Ronidynin, Mytansin and Ansamitosin; Mitoguazone; Mitoxantrone; Mopidamole; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid;2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS Natural Products, Eugene, OR); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic Acid; Triadicone; 2,2',2''-Trichlorotriethylamine; Trichothecenes such as T-2 toxin, Veraculine A, Loridine A, and Anguidine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxoids, e.g., Taxol® (paclitaxel), Abraxane® (chromophore-free, albumin-modified nanoparticle formulation of paclitaxel), and Taxotere® (doxetaxel); Chlorambucil; Tamoxifen (Nolvadex®); Raloxifene; Aromatase inhibitory 4(5)-imidazole; 4-hydroxytamoxifen; Trioxyfen; Keoxyfen; LY 117018; Onapristone; Toremifene (Fareston®); Flutamide, Niltamide, Bicalutamide, Leuprolide, Goserelin; Chlorambucil; Gemzar® Gemcitabine; 6-Thiogunine; Mercaptopurine; Platinum analogs such as cisplatin, oxaliplatin, and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Navelbine® (Vinorelbine); Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitors RFS Examples include difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicin; capecitabine (e.g., Xeloda®); and any pharmaceutically acceptable salt of any of the above.

[0251] Non-exclusive examples of additional anticancer drugs include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, Avisin, avagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfarazine, arbocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracendione, anti-CD22 immunotoxin, antitumor drugs (e.g., cell cycle nonspecific antitumor drugs, and other antitumor drugs described herein), antitumor herbs, apadiquon, atiprimod, azathioprine, berotecan, bendamustine, and BIBW. 2992, Bilicodal, Brostarisin, Briostatin, Butionine sulfoximine, CBV (chemotherapy), Calyculine, Dichloroacetate, Discordamorid, Elsamitolu, Enocitabine, Eribulin, Exatecan, Exislind, Ferginol, Forodesine, Phosfestrol, ICE chemotherapy regimen, IT-101, Imexone, Imiquimod, Indocarbazole, Ilofluben, Lanikidal, Lalotaxel, Lenalidomide, Lucanton, Lulutotecan, Maphosfamide, Mitozolomide, Examples include napoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, reximod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swainsonin, talaporfin, talikidal, tegafur-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, bajimezan, vinflunin, ZD6126, and zoskidal.

[0252] Further non-exclusive examples of anticancer drugs include vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophilotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin), mitomycin, and enzymes (e.g., enzymes that systemically metabolize L-asparagine and combine it with its own asparagine). L-asparaginase, which eliminates cells that lack the ability to function, antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., mechloretamine, cyclophosphamide and its analogs, melphalan, and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors such as abemaciclib, ribociclib, and palbociclib), sericiclib, UCN-01, P1446A-05 Antiproliferative / antimitotic metabolites and related inhibitors (e.g., PD-0332991, Dynacyclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and its analogues, as well as streptozocin), trazeneth-dacarbadinine (DTIC), folic acid analogues, pyrimidine analogues (e.g., fluorouracil, floxuridine, and cytarabine), purine analogues, etc.) For example, mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum-coordinate complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apisidan, suberoylanilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistocertib, temsirolimus, everolimus, ridafololimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array520), DNA binding agents (e.g., Zalypsis®), PI3K inhibitors such as PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and hormone agonists such as leutinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38)), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Za Examples include natural products such as rnestra (trademark), anti-CD138 (e.g., BT062), Torcl / 2-specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0253] In some embodiments, the anticancer agent is selected from mechloretamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or derivative variant of the foregoing.

[0254] In some embodiments, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies, e.g., trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors, e.g., gefitinib (Iressa®), erlotinib (Tarceva®), pyritinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.

[0255] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib, brigatinib, entrectinib, ensartinib (X-396), lorlatinib, ASP3026, CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0256] In some embodiments, the anticancer agent is an inhibitor of a downstream member of the receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitors (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, or BBP-398, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer), S These include OS1 inhibitors (e.g., BI-1701963, BI-3406, SDR5, BAY-293, or RMC-5845, or their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers), Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors, or mTOR inhibitors (e.g., mTORC1 inhibitors or mTORC2 inhibitors). In some embodiments, the anticancer agent is JAB-3312.

[0257] In some embodiments, the anticancer 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 from pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers thereof.

[0258] In some embodiments, the anticancer agent is a further Ras inhibitor or Ras vaccine, or another treatment designed to directly or indirectly reduce the oncogenic activity of Ras. In some embodiments, the anticancer agent is a further Ras inhibitor. In some embodiments, the Ras inhibitor targets active or GTP-bound Ras. In some embodiments, the Ras inhibitor targets inactive or GDP-bound Ras. In some embodiments, the Ras inhibitor is, for example, an inhibitor of K-Ras G12C, such as AMG 510 (sotrasib), MRTX1257, MRTX849 (adaglasib), JNJ-74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21000, RMC-6291, or an inhibitor of GDC-6036, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is a K-Ras G12D inhibitor, e.g., MRTX1133 or JAB-22000, 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, e.g., JAB-23000, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is RMC-6236, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is selected from the Ras(ON) inhibitors disclosed in WO2021091982, WO2021091967, WO2021091956, and WO2020132597, which are incorporated herein by reference in their entirety, or from their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers. Other examples of RAS inhibitors that can be combined with the Ras inhibitors of the present invention are shown below, and these include:All of these are incorporated herein by reference: WO2021173923, WO2021169990, WO2021169963, WO2021168193, WO2021158071, WO2021155716, WO2021152149, WO2021150613, WO2021147967, WO2021147965, WO2021143693, WO2021142252, WO2021141628, WO2021139748, WO2021139678, WO2021129824, WO2021129820, WO20 21127404, WO2021126816, WO2021126799, WO2021124222, WO2021121371, WO2021121367, WO2021121330, WO2020050890, WO2020047192, WO2020035031 , WO2020028706, WO2019241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO20191 50305, WO2019110751, WO2019099524, WO2019051291, WO2018218070, WO2018217651, WO2018218071, WO2018218069, WO2018206539, WO2018143315, WO 2018140600, WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO2018068017, WO20180645 10, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO2017058728, WO2017058902, WO2017058792, WO201 7058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO2014143659,and WO2013155223, or its pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers.

[0259] In some embodiments, therapeutic agents that can be combined with the compounds of the present invention are inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"). Examples of MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, MAPK inhibitors include trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132, vemurafenib, pimacertib, TAK733, RO4987655 (CH4987655), CI-1040, PD-0325901, CH5126766, MAP855, AZD6244, refametinib (RDEA 119 / BAY 86-9766), GDC-0973 / XL581, AZD8330 (ARRY-424704 / ARRY-704), RO5126766 (Roche, PLoS One. 2014 Nov). One or more of the following may be selected (as described in 25;9(11)) and GSK1120212 (or JTP-74057, as described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). MAPK inhibitors may be PLX8394, LXH254, GDC-5573, or LY3009120.

[0260] In some embodiments, the anticancer agent is a disruptor or inhibitor of the RAS-RAF-ERK, PI3K-AKT-TOR, or PI3K-AKT signaling pathway. Examples of PI3K / AKT inhibitors include, but are not limited to, one or more PI3K / AKT inhibitors listed in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP-BEZ235, BGT226, XL765 / SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, and GSK2126458.

[0261] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0262] In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0263] IGF-1R inhibitors include lincitinib or its pharmaceutically acceptable salts.

[0264] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zaltumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its native ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br.J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor may be a monoclonal antibody Mab E7.6.3 (Yang, 1999 above), or Mab C225 (ATCC accession number HB-8508), or an antibody or antibody fragment having binding specificity thereto.

[0265] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8, and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). Further examples of the limited scope of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and any pharmaceutically acceptable salts of such EGFR inhibitors: EP0520722;EP0566226;WO96 / 33980;U.S. Patent No. 5,747,498;WO96 / 30347;EP0787772;WO97 / 30034;WO97 / 30044;WO97 / 38994;WO97 / 49688;EP837063;WO98 / 02434;WO97 / 38983;WO95 / 19774;WO95 / 19970;WO97 / 13771;WO98 / 02437;WO9 8 / 02438;WO97 / 32881;DE19629652;WO98 / 33798;WO97 / 32880;WO97 / 32880;EP68202 7;WO97 / 02266;WO97 / 27199;WO98 / 07726;WO97 / 34895;WO96 / 31510;WO98 / 14449;WO 98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and O92 / 20642.Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin.Ther. Patents 1998, 8(12):1599-1625. In some embodiments, EGFR inhibitors are ERBB inhibitors. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0266] MEK inhibitors include, but are not limited to, pimacertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a class I MEK1 mutation selected from D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0267] PI3K inhibitors include wartmannin, 17-hydroxywartmannin analog described in WO06 / 044453, 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazine-1-yl]methyl]thieno[3,2-d]pyrimidine-4-yl]morpholine (also known as pictilisib or GDC-0941, described in WO09 / 036082 and WO09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]quinoline-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ) Also known as 235 and described in WO06 / 122806), (S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido[3',2':4,5]fl[3,2-d]pyrimidine-2-yl]phenol hydrochloride (available from Axon Medchem), PIK 75(2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridine-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem), PIK 90(N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem), AS-252424(5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidined-2,4-dione (Axon Examples include, but are not limited to, TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrinidine-4-one (available from Axon Medchem), XL-765, and XL-147.Other PI3K inhibitors include demethoxypyridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0268] Examples of AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al., Biochem.J.2005,385(Pt.2):399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al., Biochem.J.2005,385(Pt.2):399-408); API-59CJ-Ome (e.g., Jin et al., Br.J.Cancer 2004,91:1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05 / 011700); indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li J Nutr.2004,134(12)). Examples include, but are not limited to, Suppl):3493S-3498S); Perifosine (e.g., interfering with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):5242-52); Phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and trisirivine (TCN or API-2 or NCI discriminant: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0269] mTOR inhibitors include ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, e.g., temsirolimus (Torisel®); everolimus (Afinitor®, WO94 / 09010); ridafololimus (also known as deforolimus or AP23573); rapalogs, e.g., those disclosed in WO98 / 02441 and WO01 / 14387, e.g., AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolite)-rapamycin (also referred to as ABT578); 32-deoxo Rapamycin; 16-pentinyloxy-32(S)-dihydrolapanisin; derivatives disclosed in WO05 / 005434; U.S. Patents 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, as well as WO94 / 090101, WO92 / 051 Examples include, but are not limited to, derivatives disclosed in 79, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018 / 204416, as well as phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a disteric inhibitor having the following structure (see, for example, WO2018 / 204416, WO2019 / 212990, and WO2019 / 212991), e.g., RMC-5552. [ka]

[0270] Examples of BRAF inhibitors that can be used in combination with the compounds of the present invention include vemurafenib, dabrafenib, and encorafenib. BRAF may include class 3 BRAF mutations. In some embodiments, class 3 BRAF mutations are selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0271] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. The myeloid cell leukemia-1 (MCL-1) protein is one of the major anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression, as well as resistance to targeted therapies, including BCL-2 inhibitors such as ABT-263, as well as to conventional chemotherapy.

[0272] In some embodiments, additional therapeutic agents are SHP2 inhibitors. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which contributes to multiple cellular functions, including proliferation, differentiation, maintenance of the cell cycle, and migration. SHP2 has two N-terminal Src homology domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains regulate the intracellular localization and functional regulation of SHP2. The molecule exists in an inactive, self-inhibitory conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. For example, stimulation by cytokines or growth factors acting via receptor tyrosine kinases (RTKs) leads to exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0273] SHP2 is involved in signaling via the RAS mitogen-activated protein kinase (MAPK), JAK-STAT, or phosphoinositol 3-kinase-AKT pathways. Mutations in the PTPN11 gene and subsequent SHP2 mutations have been identified in several human developmental disorders, including Noonan syndrome and Leopard syndrome, as well as in human cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, and colon cancer. Some of these mutations destabilize the autoinhibitory conformation of SHP2, promoting SHP2 autoactivation or enhanced growth factor-driven activation. Therefore, SHP2 is a very attractive target for the development of novel therapies for the treatment of various diseases, including cancer. SHP2 inhibitors (e.g., RMC-4550 or SHP099) combined with RAS pathway inhibitors (e.g., MEK inhibitors) have been shown to inhibit the growth of several cancer cell lines (e.g., pancreatic cancer, lung cancer, ovarian cancer, and breast cancer) in vitro. Therefore, combination therapy using SHP2 inhibitors and RAS pathway inhibitors can be a common strategy for preventing tumor resistance in a wide range of malignancies.

[0274] Such non-limiting examples of SHP2 inhibitors are known in the art, including Chen et al., Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al. al., Oncotarget, 2017, 8, 113734; and PCT applications: WO2021149817, WO2021148010, WO2021147879, WO2021143823, WO2021143701, WO2021143680, WO2021121397, WO2021119525, WO2021115286, WO2021110796, WO2021088945, WO2021073439, WO2021061706, WO20 21061515, WO2021043077, WO2021033153, WO2021028362, WO2021033153, WO2021028362, WO2021018287, WO2020259679, WO202 0249079, WO2020210384, WO2020201991, WO2020181283, WO2020177653, WO2020165734, WO2020165733, WO2020165732, WO20201 56243, WO2020156242, WO2020108590, WO2020104635, WO2020094104, WO2020094018, WO2020081848, WO2020073949, WO202007 3945, WO2020072656, WO2020065453, WO2020065452, WO2020063760, WO2020061103, WO2020061101, WO2020033828, WO20200332 86, WO2020022323, WO2019233810, WO2019213318, WO2019183367, WO2019183364, WO2019182960, WO2019167000, WO201916507 3, 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, WO201619132 8. Examples include WO2015107495, WO2015107494, WO2015107493, WO2014176488, WO2014113584, US20210085677, US10858359, US10934302, US10954243, US10988466, US11001561, US11033547, US11034705, or US11044675, or their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers.

[0275] 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. [ka] Alternatively, it may be a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0276] In some embodiments, the SHP2 inhibitor is RMC-4550 having the following structure, [ka] Alternatively, it may be a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0277] In some embodiments, the SHP2 inhibitor is RMC-4630 having the following structure, [ka] Alternatively, it may be a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0278] In some embodiments, the SHP2 inhibitor is JAB-3068 having the following structure. [ka] Alternatively, it may be a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0279] In some embodiments, the SHP2 inhibitor is JAB-3312. In some embodiments, the SHP2 inhibitor is the following compound [ka] Alternatively, it may be a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0280] In some embodiments, the SHP2 inhibitor is RLY-1971 having the following structure. [ka] Alternatively, it may be a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0281] 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.

[0282] In some embodiments, additional therapeutic agents are selected from the group consisting of MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors. See, for example, Hallin et al., Cancer Discovery, DOI:10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a 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.

[0283] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0284] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically modified T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAG1, and anti-OX40 agents.

[0285] Immunomodulators (IMiDs) are a class of immunomodulatory drugs (drugs that modulate the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0286] Exemplary anti-PD-1 antibodies and their uses are described in Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 A1), and further described elsewhere in this specification.

[0287] GITR agonists include GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent No. 6,111,090, No. 8,586,023, WO2010 / 003118, and WO2011 / 090754, or, for example, U.S. Patent No. 7,025,962, EP1947183, U.S. Patent No. 7,812,135, No. 8,388,967, No. 8,591, Examples of anti-GITR antibodies include, but are not limited to, those described in No. 886, No. 7,618,632, EP1866339, and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0288] Another example of a therapeutic agent that may be used in combination with the compounds of the present invention is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions, antibodies, antigen-binding domains, radionuclides, and combinations and conjugates thereof, which are synthetically prepared in vitro. Anti-angiogenic agents may be agonists, antagonists, allosteric modulators, toxins, or, more generally, may act to inhibit or stimulate their targets (e.g., by activating or inhibiting receptors or enzymes), thereby promoting cell death or halting cell proliferation. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0289] Anti-angiogenic agents may include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limited examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include arecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, and WO99 / 5288. As described in 9, WO99 / 29667, WO99 / 007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US2009 / 0012085, and U.S. Patents 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those with little or no activity to inhibit MMP-1. More preferred are those that selectively inhibit MMP-2 or AMP-9 compared to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS13-0830.

[0290] Further exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., VEGF (e.g., bevacizumab), or antibodies or antigen-binding regions that specifically bind to their soluble VEGF receptors or ligand-binding regions), e.g., VEGF-TRAP®, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to them), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them), e.g., Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to them or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them). Other anti-angiogenic agents include Canas, IL-8, B-FGF, Tek antagonists (US2003 / 0162712, US6,413,932), anti-Tweak agents (e.g., antibodies or antigen-binding domains that specifically bind, or soluble Tweak receptor antagonists, see US6,727,225), ADAM distointegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), and anti-eph receptors or anti-ephrin antibodies or antigen-binding domains that specifically bind. Examples include (U.S. Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124, and their respective patent family members), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to them), as well as antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them). Additional anti-angiogenic agents include SD-7784 (Pfizer, USA) and silentide (Merck). KGaA (Germany, EPO0770622), pegaptanib octa sodium (Gilead Sciences, USA), alpha-statin (BioActa, UK), M-PGA (Celgene, USA, US5712291), ilostat (Arriva, USA, US5892112), emaxanib (Pfizer, USA, US5792783), batalanib (Novartis, Switzerland), 2-methoxyestradiol (EntreMed, USA), TLC ELL-12 (Elan, Ireland), anecoltab acetate (Alcon, USA), alpha-D148 Mab (Amgen, USA), CEP-7055 (Cephalon, USA), antiviral Mab (Crucell, Netherlands), DAC anti-angiogenic agent (ConjuChem, Canada), Angiocidin (InKine Pharmaceutical, USA), KM-2550 (Kyowa Hakko, Japan), SU-0879 (Pfizer, USA), CGP-79787 (Novartis, Switzerland, EP0970070), ARGENT technology (Ariad, USA), YIGSR-Stealth (Johnson & Johnson, USA), Fibrinogen-E fragment (BioActa, UK), Angiogenesis inhibitor (Trigen, UK), TBC-1635 (Encysive Pharmaceuticals, USA), SC-236 (Pfizer, USA), ABT-567 (Abbott, USA), Metastatin (EntreMed, USA), Maspin (Sosei, Japan), 2-Methoxyestradiol (Oncology Sciences Corporation, USA), ER-68203-00 (IV AX, USA), BeneFin (Lane Labs, USA), Tz-93 (Tsumura, Japan), TAN-1120 (Takeda, Japan), FR-111142 (Fujisawa, Japan, JP02233610), Platelet Factor IV (RepliGen, USA, EP407122), Vascular Endothelial Growth Factor Antagonist (Borean, Denmark), Bevacizumab (pINN) (Genentech, USA), Angiogenesis Inhibitor (SUGEN, USA), XL 784 (Exelixis, USA), XL 647 (Exelixis, USA), MAb, Alpha-5 Beta-3 Integrin, Second Generation (Applied Molecular Evolution, USA and MedImmune, USA), Enzastaurin Hydrochloride (Lilly, USA), CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France), BC 1 (Genoa Institute of Cancer Research, Italy), rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA), PI 88 (Progen, Australia), Silendide (Merck KGaA, Germany, Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA), AVE 8062 (Ajinomoto, Japan), AS 1404 (Cancer Research Laboratory, New Zealand), SG 292 (Telios, USA), Endostatin (Boston Children's Hospital, USA), ATN 161 (Attenuon, USA), 2-Methoxyestradiol (Boston Children's Hospital, USA), ZD 6474 (AstraZeneca, UK), ZD 6126 (Angiogene Pharmaceuticals, UK), PPI 2458 (Praecis, USA), AZD 9935 (AstraZeneca, UK), AZD 2171 (AstraZeneca, UK), vatalanib (pINN) (Novartis, Switzerland and Schering AG,Germany), tissue factor pathway inhibitor (EntreMed, USA), pegaptanib (Pinn) (Gilead Sciences, USA), xantrizole (Yonsei University, South Korea), vaccine, gene-based VEGF-2 (Scripps Clinic and Research Foundation, USA), SPV5.2 (Supratek, Canada), SDX 103 (University of California at San Diego, USA), PX 478 (ProlX, USA), metastatin (EntreMed, USA), troponin I (Harvard University, USA), SU 6668 (SUGEN, USA), OXI 4503 (OXiGENE, USA), o-guanidine (Dimensional Pharmaceuticals, USA), motupolamine C (British Columbia University, Canada), CDP 791 (Celltech) Group, UK), atiprimod (pINN) (GlaxoSmithKline, UK), E 7820 (Eisai, Japan), CYC 381 (Harvard University, USA), AE 941 (Aeterna, Canada), vaccines, angiogenic agents (EntreMed, USA), urokinase plasminogen activator inhibitors (Dendreon, USA), ogluphanide (pINN) (Melmotte, USA), HIF-alfa inhibitors (Xenova, UK), CEP 5214 (Cephalon, USA), BAY RES 2622 (Bayer, Germany), angiocidin (InKine, USA), A6 (Angstrom, USA), KR 31372 (Korea Research Institute of Chemical Technology, South Korea), GW 2286 (GlaxoSmithKline, UK), EHT 0101 (ExonHit, France), CP, 868596 (Pfizer, USA), CP 564959 (OSI, USA), CP 547632 (Pfizer, USA), 786034 (GlaxoSmithKline, UK), KRN 633 (Kirin Brewery, Japan), drug delivery system, intraocular, 2-methoxyestradiol, Anguinex (Maastricht University, Netherlands and Minnesota University, USA), ABT 510 (Abbott, USA), AAL 993 (Novartis, Switzerland), VEGI (ProteomTech, USA), tumor necrosis factor-alpha inhibitor, SU 11248 (Pfizer, USA and SUGEN, USA), ABT 518 (Abbott, USA), YH16 (Yantai Rongchang, China), S-3APG (Boston Children's Hospital, USA and EntreMed, USA), MAb, KDR (ImClone Systems, USA), MAb, alpha 5 beta (Protein Design, USA), KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA), GFB 116 (South Florida University, USA and Yale University, USA), CS 706 (Sankyo, Japan), Combretastatin A4 prodrug (Arizona State University, USA), Chondroitinase AC (IBEX, Canada), BAY RES 2690 (Bayer, Germany), AGM 1470 (Harvard University, USA, Takeda, Japan and TAP, USA), AG 13925 (Agouron, USA), Tetrathiomolybdate (University of Michigan, USA), GCS 100 (Wayne State University, USA), CV 247 (Ivy Medical, UK), CKD 732 (Chong Kun Dang, South Korea), Ilsogladine (Nippon Shinyaku, Japan), RG 13577 (Aventis, France), WX 360 (Wilex, Germany), Squalamine (Genaera, USA), RPI 4610 (Sirna, USA), Heparanase Inhibitor (InSight, Israel), KL 3106 (Kolon, South Korea), Honokiol (Emory University, USA), ZK CDK (Schering AG, Germany), ZK Angio (Schering AG, Germany), ZK 229561 (Novartis, Switzerland and Schering AG, Germany), XMP 300 (XOMA, USA), VGA 1102 (Taisho, Japan), VE-cadherin-2 antagonist (ImClone Systems, USA), vasostatin (National Institutes of Health, USA), Flk-1 (ImClone Systems, USA), TZ 93 (Tsumura, Japan), tamstatin (Beth Israel Hospital, USA), truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA), Tie-2 ligand (Regeneron, USA), and thrombo Spongin 1 inhibitors (Allegheny Health, Education and The Research Foundation (USA) is one example.

[0291] Further examples of therapeutic agents that may be used in combination with the compounds of the present invention include agents that specifically bind to and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor) (e.g., antibodies, antigen-binding domains, or soluble receptors), as well as antibodies or antigen-binding domains that specifically bind to the receptor c-Met.

[0292] Another example of therapeutic agents that may be used in combination with the compounds of the present invention is autophagy inhibitors. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil®), bafilomycin A1, 5-amino-4-imidazole carboxamidriboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Furthermore, antisense or siRNAs that inhibit the expression of proteins, including but not limited to ATG5 (which is involved in autophagy), may also be used. In some embodiments, one or more additional therapies include autophagy inhibitors.

[0293] Another example of a therapeutic agent that may be used in combination with the compounds of the present invention is an antineoplastic agent. In some embodiments, one or more additional therapies include an antineoplastic agent. Non-limiting examples of antineoplastic agents include acemannan, acralubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amiphostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, algravin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, bromodeoxyuridine, capecitabine, cermoloukin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, and DA 3030 (Dong-A), daclizumab, denileukin difutox, deslorerin, dexrazoxane, dilazep, docetaxel, docosanol, doxelcalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, ederfosine, edrecolomab eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exislind, fadrozol, filgrastim, finasteride, fludarabine phosphate, formestan, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination Combined, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin (imiquimod), interferon alpha, interferon alpha, natural type, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-NI, interferon alpha-n3, interferon alpha-con-1, interferon alpha, natural type, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural type interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguan, irinotecan, ilsoglazine,Lanreotide, LC9018 (Yakult), Leflunomide, Lenograstim, Lentinan sulfate, Letrozole, Leukocyte alpha interferon, Leuprorelin, Levamizole + Fluorouracil, Rialozol, Lovaplatin, Ronidamin, Lovastatin, Masopropyl, Melalsoprole, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mispaired double-stranded RNA, Mitoguazone, Mitractol, Mitoxantrone, Morglamostim, Nafarelin, Naloxone + Pentazocine, Naltograstim, Neda Platin, nilutamide, noscapine, novel erythropoiesis-promoting protein, NSC631570 octreotide, oprelbequin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspar gauze, pegylated interferon alpha-2b, pentosan, sodium polysulfate, pentostatin, picibanil, pirarubicin, rabbit anti-thymocyte polyclonal antibody, polyethylene glycol interferon alpha-2a, porfimer sodium, raloxifene, larcitrexed, rasbrine bodyment (rasbu riembodiment), etidronate rhenium Re186, RII retinamide, rituximab, romultide, samarium (153Sm) lexidonam, salglamostim, schizophyllan, sobuzoxane, sonelmin, strontium-89 chloride, suramin, tasonelmin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfacin, thyroid-stimulating hormone alpha, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, treosulfan, Tretinoin, trilostane, trimethrexate, triptorelin, tumor necrosis factor alpha, natural type, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma solubilizing solution vaccine, barrubicin, verteporfin, vinorelbine, bilirulysine, dinostatin stimalamer or zoledronic acid; Abarelix; AE941 (Aeterna), ambamustin, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), decitabine, dexaaminoglutethimide, diazicon, EL532 (Elan),EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, gallocitabine, gastrin-17 immunogene, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxyfen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine-131MAb (Techniclone), polymorphoemic mucin-yttrium-90MAb (Antisoma), marimast, menogalil, mitumomab, motexafine, gadolinium, MX6 (Galderma), nelarabine, noratexed, P30 protein, pegvisomant, pemetrexed, porphyromycin, prinomast, RL0903 (Shire), rubitecan, satoraplatin, sodium phenylacetate, sparphosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, saliblastin, thrombopoietin, tin ethylethiopurine, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering (Institute), melanoma tumor breakdown product vaccine (New York Medical College), viral melanoma cell solubilization vaccine (Royal, Examples include Newcastle Hospital, or Valspodal.

[0294] Additional examples of therapeutic agents that may be used in combination with the compounds of the present invention include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; Atasicept; CP-870893; Lucatumumab; Dasetuzumab; Muromonab-CD3; Ipirumumab; MEDI4736 (Imfinzi (registered trademark)); MSB0010718C; AMP 224; Adalimumab (Humira®); Adtrastuzumab emtansine (Kadcyla®); Aflibercept (Eylea®); Alemtuzumab (Campath®); Basiliximab (Simulect®); Belimumab (Benlysta®); Basiliximab (Simulect®); Belimumab (Benlysta®); Brentuximab vedotin (Adcetris®); Canakinumab (Ilaris®); Certolizumab pegol (Cimzia®); Daclizumab (Zenapax®); Daratumumab (Darzale x(registered trademark)); denosumab (Prolia(registered trademark)); eculizumab (Soliris(registered trademark)); efalizumab (Raptiva(registered trademark)); gemtuzumab ozogamicin (Mylotarg(registered trademark)); golimumab (Simponi(registered trademark)); ibritumomab tiuxetan (Zevalin(registered trademark)); infliximab (Remicade(registered trademark)); motabizumab (Numax(registered trademark)); natalizumab (Tysabri(registered trademark)); obinutuzumab (Gazyva(registered trademark)); ofatumumab (Arzerra(registered trademark)); omalizumab (Xolair(registered trademark)); palivizumab (Synagis(registered trademark));Pertuzumab (Perjeta®); Pertuzumab (Perjeta®); Ranibizumab (Lucentis®); Laxibakumab (Abthrax®); Tocilizumab (Actemra®); Tositumomab; Tositumomab-i-131; Tositumomab and Tositumomab-i-131 (Bexxar®); Ustekinumab (Stelara®); AMG 102; AMG; Examples include the 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0295] The compounds described herein can be used in combination with other agents disclosed herein or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, one or more compounds of this disclosure are administered concurrently with other therapies, such as those described herein. When used in combination therapy, the compounds described herein may be administered concurrently with or separately from a second agent. This combined administration may include concurrent administration of the two agents in the same dosage form, concurrent administration in separate dosage forms, and separate administration. That is, the compounds described herein and any agents described herein may be formulated together in the same dosage form and administered concurrently. Alternatively, the compounds of the present invention and any therapy described herein may be administered concurrently, with both agents existing in separate formulations. In another alternative, the compounds of this disclosure may be administered, followed by any therapy described herein, and vice versa. In some embodiments of separate administration protocols, the compounds of the present invention and any therapy described herein are administered at intervals of several minutes, several hours, or several days.

[0296] In some embodiments of any of the methods described herein, the first therapy (e.g., the compound of the present invention) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent is administered immediately before or after one or more additional therapies, or up to 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after.

[0297] The present invention also features a kit comprising (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the present invention), and (b) a package containing instructions for carrying out any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the present invention), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a package containing instructions for carrying out any of the methods described herein.

[0298] One aspect of the present invention, intending to treat a disease or associated symptoms using a combination of pharmaceutically active compounds that can be administered separately, further relates to combining separate pharmaceutical compositions in the form of a kit. The kit may comprise two separate pharmaceutical compositions, i.e., the compounds of the present invention, and one or more additional therapies. The kit may comprise containers for housing the separate compositions, such as divided bottles or divided foil packets. Examples of additional containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for using the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing healthcare professional.

[0299] Numbered embodiments [1] Compounds having the structure of formula Ia, or pharmaceutically acceptable salts thereof: [ka] [In the formula, A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene.] Y is [ka] And, W is hydrogen, a C1-C4 alkyl group, an optionally substituted C1-C3 heteroalkyl group, an optionally substituted 3-10 member heterocycloalkyl group, an optionally substituted 3-10 member cycloalkyl group, an optionally substituted 6-10 member aryl group, or an optionally substituted 5-10 member heteroaryl group. X 1 and X 4 Each of these is independently either CH2 or NH, R 1 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-15 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, and R10 [These are hydrogen, hydroxyl, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 heteroalkyl.]

[0300] [2]R 1 The compounds described in paragraph [1], or pharmaceutically acceptable salts thereof, wherein the compound is an optionally substituted 6- to 10-membered aryl or an optionally substituted 5- to 10-membered heteroaryl.

[0301] [3]R 1 The compounds described in paragraph [2], or pharmaceutically acceptable salts thereof, wherein the compound is optionally substituted with phenyl or optionally substituted with pyridine.

[0302] [4] A is any compound described in any one of paragraphs [1] to [3], or a pharmaceutically acceptable salt thereof, wherein A is any optionally substituted thiazole, any optionally substituted triazole, any optionally substituted morpholino, any optionally substituted piperidinyl, any optionally substituted pyridine, or any optionally substituted phenyl.

[0303] [5] A is not an optionally substituted phenyl or benzimidazole, the compounds described in any one of paragraphs [1] to [3], or a pharmaceutically acceptable salt thereof.

[0304] [6] The compounds described in paragraph 5, wherein A is not hydroxyphenyl, or any pharmaceutically acceptable salt thereof.

[0305] [7] A compound described in any one of paragraphs [1] to [6], or a pharmaceutically acceptable salt thereof, wherein the compound is not one of the compounds in Table 2.

[0306] [8] A compound described in any one of paragraphs [1] to [7], or a pharmaceutically acceptable salt thereof, which is not a compound in Table 3.

[0307] [9] A compound described in any one of paragraphs [1] to [8], or a pharmaceutically acceptable salt thereof, wherein Y is -NHC(O)- or -NHC(O)NH-.

[0308]

[10] Compounds having the structure of formula IIa, as described in paragraph [9], or pharmaceutically acceptable salts thereof: [ka] [In the formula, a is either 0 or 1].

[11] Compounds described in paragraph

[10] having the structure of formula II-1a, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0309]

[12] Compounds described in paragraph

[11] having the structure of formula IIa-2, or pharmaceutically acceptable salts thereof: [ka]

[0310]

[13] Compounds described in paragraph

[12] having the structure of formula IIa-3, or pharmaceutically acceptable salts thereof: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0311]

[14] Compounds described in paragraph

[13] having the structure of formula IIa-4, or pharmaceutically acceptable salts thereof: [ka]

[0312]

[15] Compounds described in paragraph

[14] having the structure of formula IIa-5, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0313]

[16] Compounds described in paragraph

[15] having the structure of formula IIa-6, or pharmaceutically acceptable salts thereof: [ka]

[0314]

[17] Compounds described in paragraph

[15] having the structure of formula IIa-7, or pharmaceutically acceptable salts thereof: [ka]

[0315]

[18] R 6 The compounds described in paragraph

[16] or

[17] , wherein is methyl.

[0316]

[19] Compounds described in paragraph

[15] having the structure of formula IIa-8 or formula IIa-9, or pharmaceutically acceptable salts thereof: [ka]

[0317]

[20] Compounds having the structure of formula IIIa, as described in paragraph [9], or pharmaceutically acceptable salts thereof: [ka] [In the formula, a is either 0 or 1].

[0318]

[21] Compounds described in paragraph

[20] having the structure of formula IIIa-1, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0319]

[22] Compounds described in paragraph

[21] having the structure of formula IIIa-2, or pharmaceutically acceptable salts thereof: [ka]

[0320]

[23]

[22] Compounds described in paragraph

[22] having the structure of formula IIIa-3, or pharmaceutically acceptable salts thereof: [ka] [In the formula, R 4 and R 5Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0321]

[24] Compounds described in paragraph

[23] having the structure of formula IIIa-4, or pharmaceutically acceptable salts thereof: [ka]

[0322]

[25] Compounds described in paragraph

[24] having the structure of formula IIIa-5, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0323]

[26] Compounds described in paragraph

[25] having the structure of formula IIIa-6, or pharmaceutically acceptable salts thereof: [ka]

[0324]

[27] Compounds described in paragraph

[25] having the structure of formula IIIa-7, or pharmaceutically acceptable salts thereof: [ka]

[0325]

[28] R 6 The compounds described in paragraph

[26] or

[27] , wherein is methyl.

[0326]

[29] Compounds described in paragraph

[25] having the structure of formula IIIa-8 or formula IIIa-9, or pharmaceutically acceptable salts thereof: [ka]

[0327]

[30] Compounds described in paragraph [9] having the structure of formula IVa, or pharmaceutically acceptable salts thereof: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0328]

[31] Compounds described in paragraph

[30] having the structure of formula IVa-1, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0329]

[32] Compounds described in paragraph

[31] having the structure of formula IVa-2, or pharmaceutically acceptable salts thereof: [ka]

[0330]

[33] A compound having the structure of formula IVa-3, as described in paragraph

[32] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0331]

[34] Compounds described in paragraph

[33] having the structure of formula IVa-4, or pharmaceutically acceptable salts thereof: [ka]

[0332]

[35] A compound having the structure of formula IVa-5, as described in paragraph

[34] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0333]

[36] A compound having the structure of formula IVa-6, as described in paragraph

[35] , or a pharmaceutically acceptable salt thereof: [ka]

[0334]

[37] A compound having the structure of formula IVa-7, as described in paragraph

[35] , or a pharmaceutically acceptable salt thereof: [ka]

[0335]

[38] R 6 The compounds described in paragraph

[36] or

[37] , wherein is methyl.

[0336]

[39] Compounds described in paragraph

[35] having the structure of formula IVa-8 or formula IVa-9, or pharmaceutically acceptable salts thereof: [ka]

[0337]

[40] R 9 A compound described in any one of paragraphs

[30] to

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

[0338]

[41] A compound described in any one of paragraphs [1] to [8], or a pharmaceutically acceptable salt thereof, wherein Y is -NHS(O)2- or -NHS(O)2NH-.

[0339]

[42] Compounds described in paragraph

[41] having the structure of formula Va, or pharmaceutically acceptable salts thereof: [ka] [In the formula, a is either 0 or 1].

[43] Compounds described in paragraph

[42] having the structure of formula Va-1, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0340]

[44] Compounds described in paragraph

[43] having the structure of formula Va-2, or pharmaceutically acceptable salts thereof: [ka]

[0341]

[45] Compounds described in paragraph

[44] having the structure of formula Va-3, or pharmaceutically acceptable salts thereof: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0342]

[46] Compounds described in paragraph

[45] having the structure of formula Va-4, or pharmaceutically acceptable salts thereof: [ka]

[0343]

[47] Compounds described in paragraph

[46] having the structure of formula Va-5, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0344]

[48] ​​Compounds described in paragraph

[41] having the structure of formula VIa, or pharmaceutically acceptable salts thereof: [ka] [In the formula, a is either 0 or 1].

[0345]

[49] Compounds described in paragraph

[48] having the structure of formula VIa-1, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0346]

[50] Compounds described in paragraph

[49] having the structure of formula VIa-2, or pharmaceutically acceptable salts thereof: [ka]

[0347]

[51] A compound having the structure of formula VIa-3, as described in paragraph

[50] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0348]

[52] Compounds described in paragraph

[51] having the structure of formula VIa-4, or pharmaceutically acceptable salts thereof: [ka]

[0349]

[53] Compounds described in paragraph

[52] having the structure of formula VIa-5, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0350]

[54] Compounds described in paragraph

[41] having the structure of formula VIIa, or pharmaceutically acceptable salts thereof: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0351]

[55] Compounds described in paragraph

[54] having the structure of formula VIIa-1, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0352]

[56] A compound having the structure of formula VIIa-2, as described in paragraph

[55] , or a pharmaceutically acceptable salt thereof: [ka]

[0353]

[57] A compound having the structure of formula VIIa-3, as described in paragraph

[56] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0354]

[58] Compounds described in paragraph

[57] having the structure of formula VIIa-4, or pharmaceutically acceptable salts thereof: [ka]

[0355]

[59] Compounds described in paragraph

[58] having the structure of formula VIIa-5, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0356]

[60] R 9 A compound described in any one of paragraphs

[54] to

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

[0357]

[61] A compound described in any one of paragraphs [1] to [8], or a pharmaceutically acceptable salt thereof, wherein Y is -NHS(O)- or -NHS(O)NH-.

[0358]

[62] Compounds described in paragraph

[61] having the structure of formula VIIIa, or pharmaceutically acceptable salts thereof: [ka] [In the formula, a is either 0 or 1].

[0359]

[63] Compounds described in paragraph

[62] having the structure of formula VIIIa-1, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0360]

[64] Compounds described in paragraph

[63] having the structure of formula VIIIa-2, or pharmaceutically acceptable salts thereof: [ka]

[0361]

[65] A compound having the structure of formula VIIIa-3, as described in paragraph

[64] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0362]

[66] Compounds described in paragraph

[65] having the structure of formula VIIIa-4, or pharmaceutically acceptable salts thereof: [ka]

[0363]

[67] Compounds described in paragraph

[66] having the structure of formula VIIIa-5, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0364]

[68] Compounds described in paragraph

[61] having the structure of formula IXa, or pharmaceutically acceptable salts thereof: [ka] [In the formula, a is either 0 or 1].

[0365]

[69] Compounds described in paragraph

[68] having the structure of formula IXa-1, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0366]

[70] Compounds described in paragraph

[69] having the structure of formula IXa-2, or pharmaceutically acceptable salts thereof: [ka]

[0367]

[71] A compound having the structure of formula IXa-3, as described in paragraph

[70] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0368]

[72] A compound having the structure of formula IXa-4, as described in paragraph

[71] , or a pharmaceutically acceptable salt thereof: [ka]

[0369]

[73] A compound having the structure of formula IXa-5, as described in paragraph

[72] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0370]

[74] Compounds described in paragraph

[61] having the structure of formula Xa, or pharmaceutically acceptable salts thereof: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0371]

[75] Compounds described in paragraph

[74] having the structure of formula Xa-1, or pharmaceutically acceptable salts thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0372]

[76] A compound having the structure of formula Xa-2, as described in paragraph

[75] , or a pharmaceutically acceptable salt thereof: [ka]

[0373]

[77] A compound having the structure of formula Xa-3, as described in paragraph

[76] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls.

[0374]

[78] Compounds described in paragraph

[77] having the structure of formula Xa-4, or pharmaceutically acceptable salts thereof: [ka]

[0375]

[79] A compound having the structure of formula Xa-5, as described in paragraph

[78] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0376]

[80] R 9 A compound described in any one of paragraphs

[74] to

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

[0377]

[81] A compound described in any one of paragraphs

[10] -

[40] ,

[42] -

[60] , or

[62] -

[80] , or a pharmaceutically acceptable salt thereof, wherein a is 0.

[0378]

[82] A compound described in any one of paragraphs

[10] -

[40] ,

[42] -

[60] , or

[62] -

[80] , wherein a is 1, or a pharmaceutically acceptable salt thereof.

[0379]

[83] R 2 The compounds described in any one of paragraphs [1] to

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

[0380]

[84] R 2However, the compounds described in paragraph

[83] , selected from -CH2CH3 or -CH2CF3, or pharmaceutically acceptable salts thereof.

[0381]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is a C1-C4 alkyl group.

[0382]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine, or optionally substituted phenyl.

[0383]

[87] A compound according to any one of paragraphs [1] to

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 3- to 10-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl.

[0384]

[88] A compound according to any one of paragraphs [1] to

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 10-membered heterocycloalkyl group.

[0385]

[89] W is one of the compounds described in paragraph

[88] , or a pharmaceutically acceptable salt thereof, selected from the following or their stereoisomers: [ka] [ka] [ka] [ka]

[0386]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 10-membered cycloalkyl group.

[0387]

[91] W is one of the compounds described in paragraph

[90] , or a pharmaceutically acceptable salt thereof, selected from the following or their stereoisomers: [ka]

[0388]

[92] A compound according to any one of paragraphs [1] to

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 5- to 10-membered heteroaryl.

[0389]

[93] W is one of the compounds described in paragraph

[92] , or a pharmaceutically acceptable salt thereof, selected from the following, or their stereoisomers: [ka]

[0390]

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

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

[0391]

[95] The compounds described in paragraph

[94] , or pharmaceutically acceptable salts thereof, wherein W is optionally substituted phenyl.

[0392]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted C1-C3 heteroalkyl.

[0393]

[97] W is one of the compounds described in paragraph

[96] , or a pharmaceutically acceptable salt thereof, selected from the following or their stereoisomers: [ka]

[0394]

[98] W is a compound described in paragraph

[85] , or a pharmaceutically acceptable salt thereof, selected from the following: [ka]

[0395]

[99] Compounds listed in Table 1a, or pharmaceutically acceptable salts thereof.

[0396]

[0100] Compounds listed in Table 1b, or pharmaceutically acceptable salts thereof.

[0397]

[0101] Compounds having the structure of formula Ib, or pharmaceutically acceptable salts thereof: [ka] [In the formula, A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene.] Y is [ka] And, W is hydrogen, a C1-C4 alkyl, an optionally substituted C1-C3 heteroalkyl, an optionally substituted 3-10 member heterocycloalkyl, an optionally substituted 3-10 member cycloalkyl, an optionally substituted 6-10 member aryl, or an optionally substituted 5-10 member heteroaryl, or W is -R 14 C(=O)R15 [In the formula, R 14 R is a cycloalkyl group with 3 to 10 members. 15 This is selected from optionally substituted 3-10 member cycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. X 1 and X 4 Each of these is independently CH2, CH(CH3), or NH. R 1 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-15 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, and optionally substituted 5 or 6 member heteroaryl. R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, and R 12 and R 13 Each is independently selected from F or CH3, or R 12 and R 13 These combine with the atoms they bond to to form a three-membered cycloalkyl group.

[0398]

[0102] R 1 The compounds described in paragraph

[0101] , or pharmaceutically acceptable salts thereof, wherein the compound is an optionally substituted 6-10 membered aryl or an optionally substituted 5-10 membered heteroaryl.

[0399]

[0103] R 1 The compounds described in paragraph

[0102] , or pharmaceutically acceptable salts thereof, wherein the compound is optionally substituted with phenyl or optionally substituted with pyridine.

[0400]

[0104] A compound according to any one of paragraphs

[0101] to

[0103] , or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, optionally substituted piperidinyl, optionally substituted pyridine, or optionally substituted phenyl.

[0401]

[0105] A is not an optionally substituted phenyl or benzimidazole, the compound described in any one of paragraphs

[0101] to

[0103] , or a pharmaceutically acceptable salt thereof.

[0402]

[0106] A compound described in paragraph

[0105] , wherein A is not hydroxyphenyl, or a pharmaceutically acceptable salt thereof.

[0403]

[0107] A compound described in any one of paragraphs

[0101] to

[0106] , or a pharmaceutically acceptable salt thereof, which is not a compound in Table 2.

[0404]

[0108] A compound described in any one of paragraphs

[0101] to

[0107] , which is not a compound in Table 3, or a pharmaceutically acceptable salt thereof.

[0405]

[0109] A compound described in any one of paragraphs

[0101] to

[0108] , or a pharmaceutically acceptable salt thereof, wherein Y is -NHC(O)- or -NHC(O)NH-.

[0406]

[0110] A compound having the structure of formula IIb, as described in paragraph

[0109] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, a is either 0 or 1].

[0407]

[0111] A compound having the structure of formula IIb-1, as described in paragraph

[0110] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0408]

[0112] A compound having the structure of formula IIb-2, as described in paragraph

[0111] , or a pharmaceutically acceptable salt thereof: [ka]

[0409]

[0113] A compound having the structure of formula IIb-3, as described in paragraph

[0112] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0410] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIb-3, where W is an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 3- to 10-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl, or W is -R 14 C(=O)R 15 [In the formula, R 14 R is a cycloalkyl group with 3 to 10 members. 15 R is selected from optionally substituted 3-10 member cycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. 2 R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, 4 and R 5Each is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and R 10 This is a hydrogen atom, a hydroxyl atom, an optionally substituted C1-C6 alkoxy, an optionally substituted C1-C3 alkyl, an optionally substituted C1-C6 heteroalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl.

[0411]

[0114] A compound having the structure of formula IIb-4, as described in paragraph

[0113] , or a pharmaceutically acceptable salt thereof: [ka]

[0412] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula IIb-4, where W is an optionally substituted 3-10 member heterocycloalkyl, an optionally substituted 3-10 member cycloalkyl, an optionally substituted 6-10 member aryl, or an optionally substituted 5-10 member heteroaryl, or W is -R 14 C(=O)R 15 [In the formula, R 14 R is a cycloalkyl group with 3 to 10 members. 15 R is selected from optionally substituted 3-10 member cycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. 2R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, 5 is selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls, and R 10 This is a hydrogen atom, a hydroxyl atom, an optionally substituted C1-C6 alkoxy, an optionally substituted C1-C3 alkyl, an optionally substituted C1-C6 heteroalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl.

[0413]

[0115] A compound having the structure of formula IIb-5, as described in paragraph

[0114] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0414]

[0116] A compound having the structure of formula IIb-6, as described in paragraph

[0115] , or a pharmaceutically acceptable salt thereof: [ka]

[0415]

[0117] A compound having the structure of formula IIb-7, as described in paragraph

[0115] , or a pharmaceutically acceptable salt thereof: [ka]

[0416]

[0118] R 6 The compounds described in paragraph

[0116] or

[0117] , wherein the compound is methyl.

[0417]

[0119] Compounds described in paragraph

[0115] having the structure of formula IIb-8 or formula IIb-9, or pharmaceutically acceptable salts thereof: [ka]

[0418]

[0120] A compound having the structure of formula IIIb, as described in paragraph

[0109] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, a is either 0 or 1].

[0419]

[0121] A compound having the structure of formula IIIb-1, as described in paragraph

[0120] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0420]

[0122] A compound having the structure of formula IIIb-2, as described in paragraph

[0121] , or a pharmaceutically acceptable salt thereof: [ka]

[0421]

[0123] A compound having the structure of formula IIIb-3, as described in paragraph

[0122] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0422]

[0124] A compound having the structure of formula IIIb-4, as described in paragraph

[0123] , or a pharmaceutically acceptable salt thereof: [ka]

[0423]

[0125] A compound having the structure of formula IIIb-5, as described in paragraph

[0124] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0424]

[0126] A compound having the structure of formula IIIb-6, as described in paragraph

[0125] , or a pharmaceutically acceptable salt thereof: [ka]

[0425]

[0127] A compound having the structure of formula IIIb-7, as described in paragraph

[0125] , or a pharmaceutically acceptable salt thereof: [ka]

[0426]

[0128] R 6 The compounds described in paragraph

[0126] or

[0127] , wherein the compound is methyl.

[0427]

[0129] A compound described in paragraph

[0125] having the structure of formula IIIb-8 or formula IIIb-9, or a pharmaceutically acceptable salt thereof: [ka]

[0428]

[0130] A compound having the structure of formula IVb, as described in paragraph

[0109] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0429]

[0131] A compound having the structure of formula IVb-1, as described in paragraph

[0130] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0430]

[0132] A compound having the structure of formula IVb-2, as described in paragraph

[0131] , or a pharmaceutically acceptable salt thereof: [ka]

[0431]

[0133] A compound having the structure of formula IVb-3, as described in paragraph

[0132] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0432]

[0134] A compound having the structure of formula IVb-4, as described in paragraph

[0133] , or a pharmaceutically acceptable salt thereof: [ka]

[0433]

[0135] A compound having the structure of formula IVb-5, as described in paragraph

[0134] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0434]

[0136] A compound having the structure of formula IVb-6, as described in paragraph

[0135] , or a pharmaceutically acceptable salt thereof: [ka]

[0435]

[0137] A compound having the structure of formula IVb-7, as described in paragraph

[0135] , or a pharmaceutically acceptable salt thereof: [ka]

[0436]

[0138] R 6 The compounds described in paragraph

[0136] or

[0137] , wherein the compound is methyl.

[0437]

[0139] Compounds described in paragraph

[0135] having the structure of formula IVb-8 or formula IVb-9, or pharmaceutically acceptable salts thereof: [ka]

[0438]

[0140] R 9 A compound described in any one of paragraphs

[0130] to

[0139] , wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

[0439]

[0141] A compound described in any one of paragraphs

[0101] to

[0108] , or a pharmaceutically acceptable salt thereof, wherein Y is -NHS(O)2- or -NHS(O)2NH-.

[0440]

[0142] A compound having the structure of formula Vb, as described in paragraph

[0141] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, a is either 0 or 1].

[0441]

[0143] A compound having the structure of formula Vb-1, as described in paragraph

[0142] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0442]

[0144] A compound having the structure of formula Vb-2, as described in paragraph

[0143] , or a pharmaceutically acceptable salt thereof: [ka]

[0443]

[0145] A compound having the structure of formula Vb-3, as described in paragraph

[0144] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0444]

[0146] A compound having the structure of formula Vb-4, as described in paragraph

[0145] , or a pharmaceutically acceptable salt thereof: [ka]

[0445]

[0147] A compound having the structure of formula Vb-5, as described in paragraph

[0146] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0446]

[0148] A compound having the structure of formula VIb, as described in paragraph

[0141] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, a is either 0 or 1].

[0447]

[0149] A compound having the structure of formula VIb-1, as described in paragraph

[0148] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0448]

[0150] A compound having the structure of formula VIb-2, as described in paragraph

[0149] , or a pharmaceutically acceptable salt thereof: [ka]

[0449]

[0151] A compound having the structure of formula VIb-3, as described in paragraph

[0150] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0450]

[0152] A compound having the structure of formula VIb-4, as described in paragraph

[0151] , or a pharmaceutically acceptable salt thereof: [ka]

[0451]

[0153] A compound having the structure of formula VIb-5, as described in paragraph

[0152] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0452]

[0154] A compound having the structure of formula VIIb, as described in paragraph

[0141] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0155] A compound having the structure of formula VIIb-1, as described in paragraph

[0154] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0453]

[0156] A compound having the structure of formula VIIb-2, as described in paragraph

[0155] , or a pharmaceutically acceptable salt thereof: [ka]

[0454]

[0157] A compound having the structure of formula VIIb-3, as described in paragraph

[0156] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0455]

[0158] A compound having the structure of formula VIIb-4, as described in paragraph

[0157] , or a pharmaceutically acceptable salt thereof: [ka]

[0456]

[0159] A compound having the structure of formula VIIb-5, as described in paragraph

[0158] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0457]

[0160] R 9 A compound described in any one of paragraphs

[0154] to

[0159] , wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

[0458]

[0161] A compound described in any one of paragraphs

[0101] to

[0108] , or a pharmaceutically acceptable salt thereof, wherein Y is -NHS(O)- or -NHS(O)NH-.

[0459]

[0162] A compound having the structure of formula VIIIb, as described in paragraph

[0161] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, a is either 0 or 1].

[0460]

[0163] A compound having the structure of formula VIIIb-1, as described in paragraph

[0162] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0461]

[0164] A compound having the structure of formula VIIIb-2, as described in paragraph

[0163] , or a pharmaceutically acceptable salt thereof: [ka]

[0462]

[0165] A compound having the structure of formula VIIIb-3, as described in paragraph

[0164] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0463]

[0166] A compound having the structure of formula VIIIb-4, as described in paragraph

[0165] , or a pharmaceutically acceptable salt thereof: [ka]

[0464]

[0167] A compound having the structure of formula VIIIb-5, as described in paragraph

[0166] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0465]

[0168] A compound having the structure of formula IXb, as described in paragraph

[0161] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, a is either 0 or 1].

[0466]

[0169] A compound having the structure of formula IXb-1, as described in paragraph

[0168] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3 This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0467]

[0170] A compound having the structure of formula IXb-2, as described in paragraph

[0169] , or a pharmaceutically acceptable salt thereof: [ka]

[0468]

[0171] A compound having the structure of formula IXb-3, as described in paragraph

[0170] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0469]

[0172] A compound having the structure of formula IXb-4, as described in paragraph

[0171] , or a pharmaceutically acceptable salt thereof: [ka]

[0470]

[0173] A compound having the structure of formula IXb-5, as described in paragraph

[0172] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0471]

[0174] A compound having the structure of formula Xb, as described in paragraph

[0161] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is either 0 or 1.

[0472]

[0175] A compound having the structure of formula Xb-1, as described in paragraph

[0174] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 2 is N or CH, Each R 3This is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls, and n is an integer between 1 and 4.

[0473]

[0176] A compound having the structure of formula Xb-2, as described in paragraph

[0175] , or a pharmaceutically acceptable salt thereof: [ka]

[0474]

[0177] A compound having the structure of formula Xb-3, as described in paragraph

[0176] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 4 and R 5 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-11 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. In some embodiments, R 4 and R 5 It is not hydrogen.

[0475]

[0178] A compound having the structure of formula Xb-4, as described in paragraph

[0177] , or a pharmaceutically acceptable salt thereof: [ka]

[0476]

[0179] A compound having the structure of formula Xb-5, as described in paragraph

[0178] , or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 3 is N or CH, m is either 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These combine with the atoms they bond to to form optionally substituted 3-8 member cycloalkyl groups, or optionally substituted 3-8 member heterocycloalkyl groups, or R 7 and R 8 These combine with the atoms they bond to to form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 7 and R 11 These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0477]

[0180] R 9 A compound described in any one of paragraphs

[0174] to

[0179] , wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

[0478]

[0181] A compound described in any one of paragraphs

[0110] to

[0140] ,

[0142] to

[0160] , or

[0162] to

[0180] , wherein a is 0, or a pharmaceutically acceptable salt thereof.

[0479]

[0182] A compound described in any one of paragraphs

[0110] to

[0140] ,

[0142] to

[0160] , or

[0162] to

[0180] , wherein a is 1, or a pharmaceutically acceptable salt thereof.

[0480]

[0183] R 2 The compounds described in any one of paragraphs

[0101] to

[0182] , or pharmaceutically acceptable salts thereof, wherein the C1-C6 alkyl group is optionally substituted.

[0481]

[0184] R 2 However, the compounds described in paragraph

[0183] , selected from -CH2CH3 or -CH2CF3, or a pharmaceutically acceptable salt thereof.

[0482]

[0185] R 10 A compound described in any one of paragraphs

[0101] to

[0184] , wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0483]

[0186] R 10 The compounds described in any one of paragraphs

[0101] to

[0184] , which are hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or pharmaceutically acceptable salts thereof.

[0484]

[0187] R 10 The compounds described in paragraph

[0186] , or pharmaceutically acceptable salts thereof, which are optionally substituted ethoxy compounds.

[0485]

[0188] R 10 However, the following compounds, or their stereoisomers, selected from the compounds described in paragraph

[0186] , or their pharmaceutically acceptable salts: [ka]

[0486]

[0189] A compound described in any one of paragraphs

[0101] to

[0188] , wherein W is a C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

[0487]

[0190] A compound according to any one of paragraphs

[0101] to

[0188] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine, or optionally substituted phenyl.

[0488]

[0191] A compound according to any one of paragraphs

[0101] to

[0188] , wherein W is an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 3- to 10-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[0489]

[0192] A compound according to any one of paragraphs

[0101] to

[0188] , wherein W is an optionally substituted 3- to 10-membered heterocycloalkyl group, or a pharmaceutically acceptable salt thereof.

[0490]

[0193] W is one of the following compounds, or selected from their stereoisomers, as described in paragraph

[0192] , or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka] [ka]

[0491]

[0194] A compound according to any one of paragraphs

[0101] to

[0188] , wherein W is an optionally substituted 3- to 10-membered cycloalkyl group, or a pharmaceutically acceptable salt thereof.

[0492]

[0195] W is one of the following, or selected from their stereoisomers, one of the compounds described in paragraph

[0194] , or a pharmaceutically acceptable salt thereof: [ka] [ka]

[0493]

[0196] A compound according to any one of paragraphs

[0101] to

[0188] , wherein W is an optionally substituted 5- to 10-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[0494]

[0197] W is one of the following compounds, or selected from their stereoisomers, as described in paragraph

[0196] , or a pharmaceutically acceptable salt thereof: [ka]

[0495]

[0198] A compound according to any one of paragraphs

[0101] to

[0188] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 6- to 10-membered aryl.

[0496]

[0199] The compounds described in paragraph

[0198] , or pharmaceutically acceptable salts thereof, wherein W is optionally substituted phenyl.

[0497] The compound according to any one of paragraphs

[0101] to

[0188] , wherein W is optionally substituted C1-C3 heteroalkyl, or a pharmaceutically acceptable salt thereof.

[0498] The compound according to paragraph

[0200] , wherein W is selected from the following or stereoisomers thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula]

[0499] The compound according to paragraph

[0189] , wherein W is selected from the following, or a pharmaceutically acceptable salt thereof: [Chemical formula]

[0500]

[0203] W is -R 14 C(=O)R 15 [wherein, R 14 is 3- to 10-membered cycloalkyl, and R 15 is selected from optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.], the compound according to any one of paragraphs

[0101] to

[0188] , or a pharm...

Claims

1. Compounds having the structure of formula Ia, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 [In the formula, A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, or an optionally substituted C] ２ -C ４ Alkylene, or optionally substituted C ２ -C ４ It is alkenylene, Y is, 【Chemistry 2】 And, W is hydrogen, C １ -C ４ Alkyl, optionally substituted C １ -C ３ Heteroalkyl, optionally substituted 3-10 member heterocycloalkyl, optionally substituted 3-10 member cycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, X １ and X ４ are each independently CH ２ or NH, R １ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-15 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ 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, and R １０ C is a hydrogen atom, a hydroxyl atom, or an optionally substituted C atom. １ -C ３ Alkyl or optionally substituted C １ -C ６ It is heteroalkyl.

2. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted with a 6-10 member aryl group, or optionally substituted with a 5-10 member heteroaryl group.

3. R １ The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted with phenyl or optionally substituted with pyridine.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, optionally substituted piperidinyl, optionally substituted pyridine, or optionally substituted phenyl.

5. A is not an optionally substituted phenyl or benzimidazole, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, wherein A is not hydroxyphenyl, or a pharmaceutically acceptable salt thereof.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is not one of the compounds listed in Table 2.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is not one of the compounds listed in Table 3.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y is -NHC(O)- or -NHC(O)NH-.

10. A compound according to claim 9 having the structure of formula IIa, or a pharmaceutically acceptable salt thereof: 【Transformation 3】 [In the formula, a is either 0 or 1].

11. A compound according to claim 10 having the structure of formula II-1a, or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 [In the formula, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

12. A compound according to claim 11 having the structure of formula IIa-2, or a pharmaceutically acceptable salt thereof: 【Transformation 5】

13. A compound according to claim 12 having the structure of formula IIa-3, or a pharmaceutically acceptable salt thereof: 【Transformation 6】 [In the formula, R ４ and R ５ These are, independently, halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls.

14. A compound according to claim 13 having the structure of formula IIa-4, or a pharmaceutically acceptable salt thereof: 【Transformation 7】

15. A compound according to claim 14 having the structure of formula IIa-5, or a pharmaceutically acceptable salt thereof: 【Transformation 8】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

16. A compound according to claim 15 having the structure of formula IIa-6, or a pharmaceutically acceptable salt thereof: 【Chemistry 9】

17. A compound according to claim 15 having the structure of formula IIa-7, or a pharmaceutically acceptable salt thereof: 【Chemistry 10】

18. R ６ The compound according to claim 16 or 17, wherein is methyl.

19. A compound according to claim 15 having the structure of formula IIa-8 or formula IIa-9, or a pharmaceutically acceptable salt thereof: 【Chemistry 11】

20. A compound according to claim 9 having the structure of formula IIIa, or a pharmaceutically acceptable salt thereof: 【Chemistry 12】 [In the formula, a is either 0 or 1].

21. A compound according to claim 20 having the structure of formula IIIa-1, or a pharmaceutically acceptable salt thereof: 【Chemistry 13】 [In the formula, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

22. A compound according to claim 21 having the structure of formula IIIa-2, or a pharmaceutically acceptable salt thereof: 【Chemistry 14】

23. A compound according to claim 22 having the structure of formula IIIa-3, or a pharmaceutically acceptable salt thereof: 【Chemistry 15】 [In the formula, R ４ and R ５ These are, independently, halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls.

24. A compound according to claim 23 having the structure of formula IIIa-4, or a pharmaceutically acceptable salt thereof: 【Chemistry 16】

25. A compound according to claim 24 having the structure of formula IIIa-5, or a pharmaceutically acceptable salt thereof: 【Chemistry 17】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

26. A compound according to claim 25 having the structure of formula IIIa-6, or a pharmaceutically acceptable salt thereof: [Chemistry 18]

27. A compound according to claim 25 having the structure of formula IIIa-7, or a pharmaceutically acceptable salt thereof: 【Chemistry 19】

28. R ６ The compound according to claim 26 or 27, wherein is methyl.

29. A compound according to claim 25 having the structure of formula IIIa-8 or formula IIIa-9, or a pharmaceutically acceptable salt thereof: 【Chemistry 20】

30. A compound according to claim 9 having the structure of formula IVa, or a pharmaceutically acceptable salt thereof: 【Chemistry 21】 [In the formula, R ９ is H or C １ -C ６ It is alkyl, and a is either 0 or 1.

31. A compound according to claim 30 having the structure of formula IVa-1, or a pharmaceutically acceptable salt thereof: 【Chemistry 22】 [where, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

32. A compound according to claim 31 having the structure of formula IVa-2, or a pharmaceutically acceptable salt thereof: 【Chemistry 23】

33. A compound according to claim 32 having the structure of formula IVa-3, or a pharmaceutically acceptable salt thereof: 【Chemistry 24】 [wherein, R ４ and R ５ are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, 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 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl].

34. A compound according to claim 33 having the structure of formula IVa-4, or a pharmaceutically acceptable salt thereof: 【Chemistry 25】

35. A compound according to claim 34 having the structure of formula IVa-5, or a pharmaceutically acceptable salt thereof: 【Chemistry 26】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

36. A compound according to claim 35 having the structure of formula IVa-6, or a pharmaceutically acceptable salt thereof: 【Chemistry 27】

37. A compound according to claim 35 having the structure of formula IVa-7, or a pharmaceutically acceptable salt thereof: 【Chemistry 28】

38. R ６ The compound according to claim 36 or 37, wherein is methyl.

39. A compound according to claim 35 having the structure of formula IVa-8 or formula IVa-9, or a pharmaceutically acceptable salt thereof: 【Chemistry 29】

40. R ９ A compound according to any one of claims 30 to 39, wherein is methyl, or a pharmaceutically acceptable salt thereof.

41. Y is -NHS(O) ２ - or -NHS(O) ２ A compound according to any one of claims 1 to 8, which is NH-, or a pharmaceutically acceptable salt thereof.

42. A compound according to claim 41 having the structure of formula Va, or a pharmaceutically acceptable salt thereof: 【Transformation 30】 [In the formula, a is either 0 or 1].

43. A compound according to claim 42 having the structure of formula Va-1, or a pharmaceutically acceptable salt thereof: 【Chemistry 31】 [In the formula, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

44. A compound according to claim 43 having the structure of formula Va-2, or a pharmaceutically acceptable salt thereof: 【Chemistry 32】

45. A compound according to claim 44 having the structure of formula Va-3, or a pharmaceutically acceptable salt thereof: 【Transformation 33】 [In the formula, R ４ and R ５ These are, independently, halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls.

46. A compound according to claim 45 having the structure of formula Va-4, or a pharmaceutically acceptable salt thereof: 【Transformation 34】

47. A compound according to claim 46 having the structure of formula Va-5, or a pharmaceutically acceptable salt thereof: 【Chemistry 35】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

48. A compound according to claim 41 having the structure of formula VIa, or a pharmaceutically acceptable salt thereof: 【Transformation 36】 [In the formula, a is either 0 or 1].

49. A compound according to claim 48 having the structure of formula VIa-1, or a pharmaceutically acceptable salt thereof: 【Chemistry 37】 [In the formula, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

50. A compound according to claim 49 having the structure of formula VIa-2, or a pharmaceutically acceptable salt thereof: 【Transformation 38】

51. A compound according to claim 50 having the structure of formula VIa-3, or a pharmaceutically acceptable salt thereof: 【Chemistry 39】 [In the formula, R ４ and R ５ These are, independently, halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls.

52. A compound according to claim 51 having the structure of formula VIa-4, or a pharmaceutically acceptable salt thereof: 【Chemistry 40】

53. A compound according to claim 52 having the structure of formula VIa-5, or a pharmaceutically acceptable salt thereof: 【Chemistry 41】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

54. A compound according to claim 41 having the structure of formula VIIa, or a pharmaceutically acceptable salt thereof: 【Chemistry 42】 [In the formula, R ９ is H or C １ -C ６ It is alkyl, and a is either 0 or 1.

55. A compound according to claim 54 having the structure of formula VIIa-1, or a pharmaceutically acceptable salt thereof: 【Chemistry 43】 [In the formula, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

56. A compound according to claim 55 having the structure of formula VIIa-2, or a pharmaceutically acceptable salt thereof: 【Chemistry 44】

57. A compound according to claim 56 having the structure of formula VIIa-3, or a pharmaceutically acceptable salt thereof: 【Chemistry 45】 [In the formula, R ４ and R ５ These are, independently, halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls.

58. A compound according to claim 57 having the structure of formula VIIa-4, or a pharmaceutically acceptable salt thereof: 【Chemistry 46】

59. A compound according to claim 58 having the structure of formula VIIa-5, or a pharmaceutically acceptable salt thereof: 【Chemistry 47】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

60. R ９ A compound according to any one of claims 54 to 59, wherein is methyl, or a pharmaceutically acceptable salt thereof.

61. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y is -NHS(O)- or -NHS(O)NH-.

62. A compound according to claim 61 having the structure of formula VIIIa, or a pharmaceutically acceptable salt thereof: 【Chemistry 48】 [In the formula, a is either 0 or 1].

63. A compound according to claim 62 having the structure of formula VIIIa-1, or a pharmaceutically acceptable salt thereof: 【Chemistry 49】 [In the formula, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

64. A compound according to claim 63 having the structure of formula VIIIa-2, or a pharmaceutically acceptable salt thereof: [Transformation 50]

65. A compound according to claim 64 having the structure of formula VIIIa-3, or a pharmaceutically acceptable salt thereof: 【Chemistry 51】 [In the formula, R ４ and R ５ These are, independently, halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls.

66. A compound according to claim 65 having the structure of formula VIIIa-4, or a pharmaceutically acceptable salt thereof: 【Chemistry 52】

67. A compound according to claim 66 having the structure of formula VIIIa-5, or a pharmaceutically acceptable salt thereof: 【Chemistry 53】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

68. A compound according to claim 61 having the structure of formula IXa, or a pharmaceutically acceptable salt thereof: 【Chemistry 54】 [In the formula, a is either 0 or 1].

69. A compound according to claim 68 having the structure of formula IXa-1, or a pharmaceutically acceptable salt thereof: 【Transformation 55】 [In the formula, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

70. A compound according to claim 69 having the structure of formula IXa-2, or a pharmaceutically acceptable salt thereof: 【Transformation 56】

71. A compound according to claim 70 having the structure of formula IXa-3, or a pharmaceutically acceptable salt thereof: 【Chemistry 57】 [In the formula, R ４ and R ５ These are, independently, halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls.

72. A compound according to claim 71 having the structure of formula IXa-4, or a pharmaceutically acceptable salt thereof: 【Transformation 58】

73. A compound according to claim 72 having the structure of formula IXa-5, or a pharmaceutically acceptable salt thereof: 【Chemistry 59】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

74. A compound according to claim 61 having the structure of formula Xa, or a pharmaceutically acceptable salt thereof: 【Transformation 60】 [In the formula, R ９ is H or C １ -C ６ It is alkyl, and a is either 0 or 1.

75. A compound according to claim 74 having the structure of formula Xa-1, or a pharmaceutically acceptable salt thereof: 【Chemistry 61】 [In the formula, X ２ is N or CH, Each R ３ This includes halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group independently selected from a heteroalkyl group, an optionally substituted 3-6 membered cycloalkyl group, an optionally substituted 3-6 membered cycloalkenyl group, an optionally substituted 3-11 membered heterocycloalkyl group, an optionally substituted 6-10 membered aryl group, or an optionally substituted 5-10 membered heteroaryl group, and n is an integer between 1 and 4.

76. A compound according to claim 75 having the structure of formula Xa-2, or a pharmaceutically acceptable salt thereof: 【Transformation 62】

77. A compound according to claim 76 having the structure of formula Xa-3, or a pharmaceutically acceptable salt thereof: 【Transformation 63】 [In the formula, R ４ and R ５ These are, independently, halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-11 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls.

78. A compound according to claim 77 having the structure of formula Xa-4, or a pharmaceutically acceptable salt thereof: 【Chemistry 64】

79. A compound according to claim 78 having the structure of formula Xa-5, or a pharmaceutically acceptable salt thereof: 【Transformation 65】 [In the formula, X ３ is N or CH, m is either 1 or 2. R ６ , R ７ , R ８ , and R １１ Each of these is independently of hydrogen and optionally substituted C. １ -C ６ Alkyl, optionally substituted C １ -C ６ Selected from heteroalkyls, optionally substituted 3- to 6-membered cycloalkyls, optionally substituted 3- to 6-membered cycloalkenyls, optionally substituted 3- to 6-membered heterocycloalkyls, optionally substituted 6- to 10-membered aryls, or optionally substituted 5- to 10-membered heteroaryls, or R ６ and R ７ These combine with the atoms they bond to to form optionally substituted 3- to 8-membered cycloalkyl groups, or optionally substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R ８ These combine with the atoms they bond to to form arbitrarily substituted 3- to 8-membered heterocycloalkyl groups, or R ７ and R １１ These combine with the atoms they bond to to form optionally substituted 4- to 8-membered heterocycloalkyl groups.

80. R ９ A compound according to any one of claims 74 to 79, wherein is methyl, or a pharmaceutically acceptable salt thereof.

81. A compound according to any one of claims 10 to 40, 42 to 60, or 62 to 80, wherein a is 0, or a pharmaceutically acceptable salt thereof.

82. A compound according to any one of claims 10 to 40, 42 to 60, or 62 to 80, wherein a is 1, or a pharmaceutically acceptable salt thereof.

83. R ２ However, C is arbitrarily substituted. １ -C ６ A compound according to any one of claims 1 to 82, which is alkyl, or a pharmaceutically acceptable salt thereof.

84. R ２ However, -CH ２ CH ３ or -CH ２ CF ３ A compound according to claim 83, or a pharmaceutically acceptable salt thereof, selected from the above.

85. W is C １ -C ４ A compound according to any one of claims 1 to 84, which is alkyl, or a pharmaceutically acceptable salt thereof.

86. A compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine, or optionally substituted phenyl.

87. The compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 3- to 10-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl.

88. The compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 10-membered heterocycloalkyl group.

89. The compound according to claim 88, or a pharmaceutically acceptable salt thereof, wherein W is selected from the following, or their stereoisomers: 【Chemistry 66-1】 【Chemistry 66-2】 【Chemistry 66-3】 【Chemistry 66-4】

90. The compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 10-membered cycloalkyl group.

91. W is selected from the following, or stereoisomers thereof, the compound according to claim 90, or a pharmaceutically acceptable salt thereof: 【Transformation 67】

92. The compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 5 to 10-membered heteroaryl.

93. The compound according to claim 92, or a pharmaceutically acceptable salt thereof, wherein W is selected from the following, or their stereoisomers: 【Transformation 68】

94. The compound according to any one of claims 1 to 84, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 6- to 10-membered aryl group.

95. The compound according to claim 94, or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted phenyl.

96. W is arbitrarily replaced by C １ -C ３ A compound according to any one of claims 1 to 84, which is a heteroalkyl compound, or a pharmaceutically acceptable salt thereof.

97. The compound according to claim 96, or a pharmaceutically acceptable salt thereof, wherein W is selected from the following, or their stereoisomers: 【Transformation 69】

98. W is selected from the following compounds, or pharmaceutically acceptable salts thereof, according to claim 85: 【Transformation 70】

99. Compounds listed in Table 1a, or pharmaceutically acceptable salts thereof.

100. A pharmaceutical composition comprising a compound according to any one of claims 1 to 99, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

101. A method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 99, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 100.

102. The method according to claim 101, wherein the cancer includes a Ras mutation.

103. The method according to claim 102, wherein the Ras mutation is located at position 12, 13, or 61.

104. The method according to claim 102 or 103, wherein the Ras mutation is located at position 12.

105. The method according to claim 103, wherein the Ras mutation is located at a position selected from the group consisting of G12C, G12D, G12V, G12R, G13C, G13D, and Q61K, or combinations thereof.

106. The method according to claim 105, wherein the Ras mutation is located at a position selected from the group consisting of G12D, G12V, and G12R, or a combination thereof.

107. The method according to claim 106, wherein the Ras mutation is located at a position selected from the group consisting of G12D and G12V, or a combination thereof.

108. The method according to any one of claims 101 to 107, wherein the cancer is pancreatic cancer.

109. The method according to any one of claims 101 to 107, wherein the cancer is lung cancer.

110. The method according to any one of claims 101 to 107, wherein the cancer is colorectal cancer.

111. A method for treating a Ras protein-related disorder in a subject requiring treatment for the disorder, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 99, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 100.

112. A method for inhibiting Ras protein within a cell, the method comprising contacting the cell with a therapeutically effective amount of a compound according to any one of claims 1 to 99, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 100.

113. The method according to claim 112, wherein two or more types of Ras proteins are inhibited within the cell.

114. The method according to claim 112 or 113, wherein the cells are cancer cells.

115. The method according to claim 114, wherein the cancer cells are pancreatic cancer cells.

116. The method according to claim 114, wherein the cancer cells are lung cancer cells.

117. The method according to claim 114, wherein the cancer cells are colorectal cancer cells.

118. The method according to any one of claims 101 to 117, wherein the Ras protein is KRAS.

119. The method or use according to any one of claims 101 to 118, further comprising administering an additional anti-cancer treatment.

120. The method according to claim 119, wherein the additional anticancer treatment is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

121. The method according to claim 119 or 120, wherein the additional anti-cancer treatment is an SHP2 inhibitor.

122. The method according to claim 119 or 120, wherein the additional anticancer treatment comprises an SHP2 inhibitor and a PD-L1 inhibitor.

123. The method according to claim 119 or 120, wherein the additional treatment comprises a second Ras inhibitor and a PD-L1 inhibitor.

124. The second Ras inhibitor is KRAS Ｇ１２Ｃ The method according to claim 120 or 123, wherein the method is an inhibitor.

125. The second Ras inhibitor is KRAS Ｇ１２Ｃ The method according to claim 123 or 124, wherein the (ON) inhibitor is used.

126. The second Ras inhibitor is KRAS Ｇ１２Ｃ The method according to claim 123 or 124, wherein the (OFF) inhibitor is used.

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