Indole derivatives as ras inhibitors for the treatment of cancer

Abstract

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

Description

[0001] Cross-reference of related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 078,802, filed September 15, 2020; U.S. Provisional Application No. 63 / 129,231, filed December 22, 2020; U.S. Provisional Application No. 63 / 184,412, filed May 5, 2021; and U.S. Provisional Application No. 63 / 192,775, filed May 25, 2021, the contents of which are hereby incorporated by reference in their entirety.

[0003] sequence list

[0004] This application contains a sequence list submitted electronically in ASCII format, which is hereby incorporated by full reference. The ASCII copy was created on September 14, 2021, named 51432-009WO5_Sequence_Listing_9_14_21_ST25, and is 1,189 bytes in size. Background Technology

[0005] Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of those proteins. For example, cholesterol-lowering drugs called statins bind to the active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. Indeed, the existence of many such drug / target interaction pairs may mislead one into believing that small molecule regulators targeting most (if not all) proteins can be discovered, thus justifying the amount of time, effort, and resources required. But this is far from the truth. Currently, it is estimated that only about 10% of all human proteins are suitable targets for small molecules. (Bojadzic and Buchwald, Curr Top Med Chem 18:674-699 (2019)). The remaining 90% are currently considered intractable or difficult to treat with the aforementioned small molecule drugs. These targets are often referred to as “undruggable.” These undruggable targets comprise a large and often unexplored reservoir of medically important human proteins. Therefore, there is great interest in discovering novel molecular modalities capable of modulating the function of such undruggable targets.

[0006] The literature has well established that Ras proteins (K-Ras, H-Ras, and N-Ras) play a crucial role in various human cancers and are therefore suitable targets for anticancer therapies. In fact, approximately 30% of all human cancers in the United States are caused by Ras protein mutations, many of which are fatal. Dysregulation of Ras proteins due to activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations of Ras are frequently found in human cancers. For example, an activating mutation at codon 12 in the Ras protein significantly biases the Ras mutant protein population towards the "on" (GTP-binding) state (Ras(ON)) by inhibiting the GTPase-activated protein (GAP)-dependent and inherent rate of GTP hydrolysis, thereby inducing oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, allowing it to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) in Ras also induce oncogenic activity in some cancers.

[0007] Despite extensive drug discovery efforts targeting Ras over the past decades, no drugs that directly target the "on" form of Ras have been approved. Further efforts are needed to discover other drugs for cancers driven by various Ras mutations. Summary of the Invention

[0008] This document provides Ras inhibitors. These Ras inhibitors target, i.e., selectively bind to or inhibit, Ras(ON) (e.g., selective relative to the inactive state of Ras bound to GDP). The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a cytoplasmic chaperone protein (presenting protein) (e.g., cyclophilin A) that is widely expressed in the cell. More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity triple complex between the Ras protein and the widely expressed cytoplasmic chaperone protein cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way the compounds of the present invention and the complexes they form exert an inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules such as RAF and PI3K required for the propagation of oncogenic signals.

[0009] Therefore, in some embodiments, this disclosure is characterized by a compound of structural formula Ia or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene.

[0012] Y is

[0013] W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3- to 10-membered heterocyclic alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0014] X 1 and X 4 Each can be independently CH2 or NH;

[0015] R 1 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 15-membered cycloalkyl group that is optionally substituted, a 3- to 6-membered cycloalkenyl group that is optionally substituted, a 3- to 6-membered heterocycloalkyl group that is optionally substituted, a 6- to 10-membered aryl group that is optionally substituted, or a 5- to 10-membered heteroaryl group that is optionally substituted.

[0016] R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and

[0017] R 10 It is hydrogen, hydroxyl, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments, R 10 It is hydrogen.

[0018] Also provided are pharmaceutical compositions comprising a compound of formula Ia or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0019] A method for treating cancer in a subject in need is also 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.

[0020] In some embodiments, a method is provided for treating a subject with Ras protein-related conditions, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0021] Another method for inhibiting Ras protein in cells is provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0022] Specifically, upon careful consideration, any limitations discussed regarding one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to manufacture or utilize any compound or composition of the invention.

[0023] Definitions and chemical terms

[0024] In this application, unless clearly indicated from the context, (i) the term “a (a)” means “one or more”; (ii) the term “or” is used to mean “and / or” unless explicitly indicated that the term refers to an alternative that is unique or that the alternatives are mutually exclusive, however, the definition supported by this disclosure refers to a unique alternative and “and / or”; (iii) the terms “comprising” and “including” should be understood to encompass the listed components or steps, whether presenting the components or steps alone or in combination with one or more additional components or steps; and (iv) when providing a scope, endpoints are included.

[0025] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the error of the means or method used to determine that value. In some embodiments, the term "about" refers to a range of values ​​in any direction (greater or less than) within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or lower percentages of the value, unless otherwise specified or otherwise apparent from the context (e.g., when the figure would exceed 100% of the possible value).

[0026] As used herein, in the context of describing adjacent atoms, the term "adjacent" refers to divalent atoms directly connected by covalent bonds.

[0027] As used herein, “compounds of the present invention” and similar terms, whether explicitly indicated or not, refer to the Ras inhibitors described herein, including compounds of formula Ia or Ib and their subforms, as well as compounds of Table 1a or Table 1b, and their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including transisomers), and tautomers.

[0028] The term "wildtype" refers to an entity that has the structure or activity seen in nature in a "normal" state or condition (as opposed to mutation, disease, alteration, etc.). Those skilled in the art will understand that wildtype genes and polypeptides often exist in many different forms (e.g., alleles).

[0029] 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, transisomers, tautomers) or isotopic forms (e.g., one or more atoms are substituted with different isotopes of that atom, such as hydrogen being substituted with deuterium). Unless otherwise indicated or clearly apparent from the context, the depicted structures are to be understood as representing any such isomeric or isotopic forms, individually or in combination.

[0030] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are covered. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as alkenes and C=N double bonds, may also be present in the compounds described herein, and all such stable isomers are covered in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure have been described and can be isolated in mixtures of isomers or in separate isomeric forms.

[0031] In some embodiments, one or more compounds described herein may exist in different tautomer forms. As will be clear from the context, unless explicitly excluded, references to the compounds encompass all such tautomer forms. In some embodiments, the tautomer form is obtained by the exchange of a single bond with an adjacent double bond, accompanied by proton migration. In some embodiments, the tautomer form may be a proton-transfer tautomer, which is an isomer protonated state having the same empirical formula and total charge as the reference form. Examples of portions having a proton-transfer tautomer form include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, amide-imine pairs, enamine-imine pairs, and cyclic forms in which the proton may occupy two or more positions in the heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-triazole, 2H-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, the tautomer form may be in equilibrium or spatially locked into one form through appropriate substitution. In some embodiments, the tautomer form is obtained by interconversion of acetals.

[0032] Unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Isotope-labeled compounds (e.g., labeled with...) 3 H and 14 Compounds of C can be used in the determination of the tissue distribution of compounds or substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are available because they are easy to prepare and detect. Alternatively, heavier isotopes, such as deuterium (i.e.,...), can be used. 2 H) substitution can provide certain therapeutic benefits due to enhanced metabolic stability (e.g., increased half-life in vivo or reduced dose requirement). In some embodiments, one or more hydrogen atoms are...2 H or 3 H substitution, or one or more carbon atoms being... 13 C or 14 Carbon-enriched carbon substitution. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to examine substrate acceptor 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 following a procedure similar to that disclosed for the compounds of the invention described herein, by replacing the unlabeled reagent with an isotopically labeled reagent.

[0033] As is known in the art, many chemical entities can exist in a variety of different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including any solid form. In some embodiments, the compounds described or depicted herein can be provided in hydrate or solvate form.

[0034] Throughout this specification, substituents of the compounds disclosed herein are disclosed in groups or ranges. Specifically, this disclosure is intended to include each individual combination of members of each of the groups and ranges. For example, the term "C1-C6 alkyl" specifically intends to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound comprises multiple positions, and where substituents are disclosed in groups or ranges at said positions, unless otherwise indicated, this disclosure is intended to cover the individual compounds and groups of compounds (e.g., subclasses of species) containing each individual combination of members at each position.

[0035] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl group is optionally substituted”). It is not intended that the characteristic “X” (e.g., alkyl) itself is optional. As described herein, some compounds of interest may contain one or more “optionally substituted” moieties. Generally, the term “substituted”, whether or not preceded by the term “optionally”, means that one or more hydrogens of the specified moiety are replaced by a suitable substituent, such as any of the substituents or groups described herein. Unless otherwise indicated, a “optionally substituted” group may have a suitable substituent at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. 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 combinations of substituents contemplated in this disclosure are preferably combinations of substituents that form stable or chemically viable compounds. As used herein, the term "stable" means that a compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0036] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group can independently be deuterium; halogen; -(CH2). 0-4 R o ;-(CH2) 0-4 OR o ;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ;-(CH2) 0-4 Ph, this group can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, this group can be R o Substitution; -CH=CHPh, this group can be replaced by R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl group, this group can be R oSubstitution; 4-11 membered saturated or unsaturated heterocyclic alkyl groups (e.g., 4-8 membered saturated or unsaturated heterocyclic alkyl groups (e.g., pyridyl)), which may optionally be substituted (e.g., substituted with methyl); 3-8 membered saturated or unsaturated cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2; -N(R) o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2; -N(R) o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 -C(O)-N(R o )2;-(CH2) 0-4 -C(O)-N(R o )-S(O)2-R o ;-C(NCN)NR o 2;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ;-(CH2) 0-4 SC(O)Ro ;-(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2;-C(S)SR o ;-(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR) o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR) o )R o ;-(CH2) 0- 4SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NOR) o )NR o 2;-C(NH)NR o 2; -P(O)2R o ;-P(O)R o 2; -P(O)(OR o )2;-OP(O)R o 2; -OP(O)(OR o )2;-OP(O)(OR o )R o ;-SiR o 3; -(C 1-4 (linear or branched alkylene)ON(R) o )2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R) o )2, where each R o It can be substituted and independently become hydrogen or -C as defined below. 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (5-6 membered heteroaryl ring), or 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, or despite the above definitions, two independently existing R o Together with the inserted atoms, they form 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0037] R o (or two independently existing R) o Suitable monovalent substituents on the ring formed with the inserted atom can independently be halogens, -(CH2). 0-2 R · -(halogenated R) · -(CH2) 0-2 OH, -(CH2) 0-2 OR · -(CH2) 0-2 CH(OR · 2. -O(halogenated R) · -CN, -N3, -(CH2) 0-2 C(O)R · -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · -(CH2) 0-2 SR · -(CH2) 0- 2SH、-(CH2) 0-2 NH2、-(CH2) 0-2 NHR · -(CH2) 0-2 NR · 2, -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · -(C 1-4 (straight-chain or branched alkylene)C(O)OR · or -SSR · , where each R · It is either unsubstituted or, in the case of a prefix "halogen group", substituted with one or more halogens, and independently selected from C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. R o Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0038] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2-3 S-, where R * It is selected from hydrogen each time it appears independently; C 1-6 An aliphatic group, which may be substituted as defined below; or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the adjacent substituted carbon of the "optionally substituted" group include: -O(CR * 2) 2- 3O-, where R * It is selected from hydrogen each time it appears independently; C 1-6 An aliphatic group, which may be substituted as defined below; or an unsubstituted 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0039] R * Suitable substituents on aliphatic groups include halogens, -R · -(halogenated R) · -OH, -OR · -O(halogenated R) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2 or -NO2, where each R · It is either unsubstituted or, if preceded by a "halogen group", substituted by only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0040] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include or Among them each Independently hydrogen; C 1-6 An aliphatic group, which may be substituted as defined below; an unsubstituted -OPh; or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur; or, despite the above definitions, two independently existing... Together with the inserted atoms, they form 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0041] Suitable substituents on the aliphatic group are independently halogens, -R · -(halogenated R) · -OH, -OR · -O(halogenated R) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2 or -NO2, where each R · It is either unsubstituted or, if preceded by a "halogen group", substituted by only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0042] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0043] As used herein, the term "alkoxy" refers to -O-Cl-C 20 Alkyl group, wherein the alkoxy group is attached to the rest of the compound via an oxygen atom.

[0044] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms (e.g., 1 to 10 or 1 to 6). In some embodiments, the alkyl group is unbranched (i.e., linear); in some embodiments, the alkyl group is branched. Alkyl groups are, for example, but not limited to, methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0045] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight-chain or branched saturated hydrocarbon, and examples include methylene, ethylene, isopropylene, etc. The term "C" x-C y "Alkylene" indicates an alkylene having between x and y carbons. Indicative values ​​of x are 1, 2, 3, 4, 5, and 6, and indicative values ​​of y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C...). 10 C2-C 20 C2-C6, C2-C 10 Or C2-C 20 Alkylene). In some embodiments, the alkylene may be additionally substituted with 1, 2, 3 or 4 substituents as defined herein.

[0046] Unless otherwise specified, as used herein, the term "alkenyl" refers to a monovalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds, and examples are vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl groups include both cis and trans isomers. Unless otherwise specified, as used herein, the term "alkenylene" refers to a divalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0047] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched group containing 2 to 20 carbons (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) and examples thereof are ethynyl and 1-propynyl.

[0048] As used herein, the term "alkynyl sulfone" indicates a structure containing The group, wherein R is any chemically feasible substituent described herein.

[0049] As used herein, the term "amino" indicates For example, -NH2 and -N(CH3)2.

[0050] As used herein, the term "aminoalkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more amino moieties.

[0051] As described herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is linked to a parent molecule group via said side chain, amino group, or acid group (e.g., side chain). As used herein, the term "amino acid" in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by forming one or more peptide bonds. In some embodiments, the amino acid has the universal structure H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any one of the twenty standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxyl valine, isoleucine, leucine, lysine, methionine, valine, ornithine, phenylalanine, proline, pyrrolidone, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0052] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic system formed of carbon atoms, wherein the ring attached to a side group is an aromatic ring. Examples of aryl groups are phenyl, naphthyl, phenanthryl, and anthracene. An aromatic ring may be attached to its side group at any heteroatom or carbocyclic atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted.

[0053] As used herein, the term “C0” signifies a bond. For example, a portion of the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, which is also represented as -N(C(O)-H)-.

[0054] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to a monovalent, optionally substituted C3-C group. 12 A monocyclic, bicyclic, or tricyclic structure, which may be a bridging ring, a fused ring, or a spirocyclic ring, wherein all rings are formed of carbon atoms, and at least one ring is a non-aromatic ring. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, dihydroindenyl, decahydronaphthyl, etc. The carbocyclic ring may be attached to its side group at any ring atom that produces a stable structure, and unless otherwise specifically stated, any ring atom may optionally be substituted.

[0055] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0056] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH or C(O)OH, or its unprotonated counterpart.

[0057] As used herein, the term "cyano" refers to the -CN group.

[0058] As used herein, the term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon group, which, unless otherwise specified, can be a bridging ring, fused ring, or spiro ring having three to eight cyclic carbons, and examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0059] As used herein, the term "cycloalkenyl" means a monovalent, non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specified, can be a bridging ring, fused ring, or spiro ring having three to eight cyclic carbons and containing one or more carbon-carbon double bonds.

[0060] As used in this article, the term "diastereomer" means a stereoisomer that is not a mirror image of another and cannot be superimposed on another.

[0061] As used herein, the term "enantiomer" means each individual optically active form of the compound of the invention having at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98% optical purity or enantiomer excess (as determined by standard methods in the art).

[0062] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen atom is replaced by a halogen.

[0063] 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.

[0064] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0065] 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 be present in the middle or at the end of the group.

[0066] As used herein, the term "heteroaryl" refers to a monovalent, monocyclic, or polycyclic structure containing at least one fully aromatic ring: that is, it contains 4n+2 π electrons within the monocyclic or polycyclic system and contains at least one heteroatom selected from N, O, or S in the aromatic ring. An illustrative unsubstituted heteroaryl has 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups fused any of the aforementioned heteroaryl rings with one or more aromatic or carbocyclic rings, such as phenyl or cyclohexane rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. The heteroaryl ring can be attached to its side group at any ring atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted. In one embodiment, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents.

[0067] As used herein, the term "heterocyclic alkyl" means at least one ring is a non-aromatic ring, and wherein the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, in a monovalent, monocyclic, bicyclic, or polycyclic system, said ring system being a bridging ring, a fused ring, or a spirocyclic ring. Five-membered rings have zero to two double bonds, and six-membered and seven-membered rings have zero to three double bonds. Illustrative unsubstituted heterocyclic alkyl 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) carbons. The term "heterocyclic alkyl" also means a heterocyclic compound having a bridging polycyclic structure, wherein one or more carbons or heteroatoms bridge a non-adjacent member of a monocyclic ring, such as a quinine cycloyl group. The term "heterocyclic alkyl" includes bicyclic, tricyclic, and tetracyclic groups fused with any of the aforementioned heterocycles and one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as aryl, cyclohexane, cyclohexene, cyclopentane, cyclopentene, pyridine, or pyrrolidine rings. Examples of heterocyclic alkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridinyl, and decahydronaphthidyl. Heterocyclic alkyl rings may be attached to their side groups at any ring atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted.

[0068] As used herein, the term "hydroxyl group" refers to the -OH group.

[0069] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more -OH moieties.

[0070] As used herein, the term "isomer" means any tautomer, stereoisomer, transisomer, enantiomer, or diastereomer of any compound of the present invention. It should be understood that the compounds of the present invention may have one or more chiral centers or double bonds, and therefore exist in stereoisomeric form, such as double-bonded isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures described herein and therefore the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, as well as mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of this invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral 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 pure or enantiomerically pure intermediates, reagents, and catalysts via well-known asymmetric synthetic methods.

[0071] As used herein, the term "stereoisomer" refers to all possible different isomers and configurations that a compound (e.g., any compound of the formula described herein) may have, particularly all possible stereochemical and configurational isomers of the basic molecular structure, all diastereomers, enantiomers, or configurational isomers, including transisomers. Some compounds of the present invention may exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0072] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0073] As used herein, the term "thiocarbonyl" refers to the -C(S)- group.

[0074] Those skilled in the art will understand from this disclosure that certain compounds described herein may be provided or utilized in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, isomer forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a particular form of that compound. In some embodiments, reference to a particular compound may refer to that compound in any form. In some embodiments, for example, a formulation of a single stereoisomer of a compound may be considered a different form of the compound rather than a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt of the compound; a formulation of a configurational isomer ((Z) or (E)) containing a double bond may be considered a different form from a formulation of another configurational isomer ((E) or (Z)) containing the double bond; a formulation in which one or more isotopes differ from the isotopes present in a reference formulation may be considered a different form. Attached Figure Description

[0075] Figure 1A Compound A, which is a Ras inhibitor disclosed herein, is used in female BALB / c nude mice to demonstrate human pancreatic cancer HPAC KRAS. G12D / wt A graph showing the in vivo efficacy in a xenograft model. This figure displays the tumor volume (mm) in a mouse xenograft model. 3 The variation with the number of days after implantation. Mice were randomly assigned to treatment groups before administration of the test substance or mediator. Compound A was administered orally every other day.

[0076] Figure 1B This demonstrates compound A, the Ras inhibitor disclosed herein, obtained 72 hours after administration in BALB / c nude mice (6-8 weeks old, human non-small cell lung cancer (NSCLC) NCI-H441 KRAS). G12V / wt A graph showing dose-dependent exposure in blood and tumor samples from a xenograft model. Pharmacokinetics was analyzed based on the total concentration (nM) of compound A in tumors or blood up to 72 hours after a single oral dose of 10, 25, or 50 mg / kg. Tumor or blood samples were obtained from n = 3 animals at each time point.

[0077] Figure 1C This is a graph showing PK (10 mg / kg, po) and PD (dumps, 10 and 25 mg / kg, po) in untreated animals treated with a single dose of compound A, which is a Ras inhibitor disclosed herein.

[0078] Figure 1D This demonstrates compound A, as a Ras inhibitor disclosed herein, in the presence of heterozygous KRAS.G12V A graph illustrating the in vivo efficacy of the NCI-H441 CDX model. NCI-H441 cells were engrafted with 50% Matrigel. Animals were randomly assigned to groups and reached a mean tumor volume of approximately 155 mm. 3 Treatment was initiated at the appropriate time. Animals were administered 10 or 25 mg / kg orally once daily (orally qd) of compound A or a control for 32 days. All dose levels were well tolerated. n = 10 animals / group. ***p < 0.0001, determined by one-way ANOVA.

[0079] Figure 1E Compound A, as a KRAS(ON) inhibitor disclosed herein, is shown to have heterozygous KRAS. G12V The response at the end of the NCI-H441 CDX model. Tumors at the end of the NCI-H441 study are plotted as a percentage change in tumor volume compared to the volume at the start of treatment. R (regression) = number of regressions > 10% of the initial value. CR (complete response) = number of regressions > 80% of the initial value. Each animal is represented by an independent bar.

[0080] Figure 1F Animals treated with compound A, a KRAS(ON) inhibitor disclosed herein (in animals with heterozygous KRAS) are shown. G12V The percentage change in body weight (in the NCI-H441 CDX model) was measured twice weekly using a diameter-based method in NCI-H441 cell-derived xenografts. Body weight change was plotted as a percentage of the animal's initial body weight.

[0081] Figure 2A Compound A, which is a KRAS(ON) inhibitor disclosed herein, is used in female BALB / c nude mice with heterozygous KRAS. G12V A figure showing the in vivo efficacy of Capan-2CDX xenograft in a human pancreas model. This figure shows the tumor volume (mm) in a mouse xenograft model. 3 The changes occurred over the number of days post-implantation. Capan-2 cells were implanted with 50% Matrigel. Animals were randomly assigned to groups and the mean tumor volume reached approximately 166 mm. 3 Treatment was initiated at the appropriate time. Animals were administered compound A or control at 10 mg / kg po qd or 25 mg / kg po q2d for 28 days. All dose levels were tolerable. n = 8 animals / group. **p = 0.01, ***p < 0.0001, determined by one-way ANOVA.

[0082] Figure 2B Compound A, as a KRAS(ON) inhibitor disclosed herein, is shown to have heterozygous KRAS. G12VResponse at the end of the study in a human pancreas Capan-2 CDX xenograft model. Tumor at the end of the Capan-2 study is plotted as a percentage change in tumor volume compared to the volume at the start of treatment. R (regression) = regression rate > 10% of initial value. Each animal is represented by an independent bar.

[0083] Figure 2C Displayed with heterozygous KRAS G12V 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. Capan-2 cell-derived xenografts were measured twice weekly using a diaphragm method. Body weight change was plotted as a percentage of the animal's initial body weight.

[0084] Figure 2D Compound A, which is a KRAS(ON) inhibitor disclosed herein, is used in the human colon and rectum of female BALB / c nude mice to demonstrate SW403 KRAS. G12V / wt A graph showing the in vivo efficacy in a xenograft model. This figure displays the tumor volume (mm) in a mouse xenograft model. 3 The changes occurred over the number of days post-implantation. SW403 cells were implanted with 50% Matrigel. Animals were randomly assigned to groups and the mean tumor volume reached approximately 171 mm. 3 Treatment was initiated at the designated time. Animals were administered 25 mg / kg orally once daily or 50 mg / kg orally once daily twice daily (orally) of compound A or a control for 28 days. All dose levels were tolerable. n = 8 animals / group. ***p < 0.0001, determined by one-way ANOVA.

[0085] Figure 2E Compound A, as a KRAS(ON) inhibitor disclosed herein, was shown to be effective in human colon and rectum SW403 KRAS. G12V / wt Response at the end of the study in the xenograft model. Tumors at the end of the SW403 study are plotted as a percentage change in tumor volume compared to the initial volume at the start of treatment. R (regression) = number of regressions > 10% of initial. CR (complete response) = number of regressions > 80% of initial. Each animal is represented by an independent bar.

[0086] Figure 2F Displayed in human colon and rectum SW403 KRAS G12V / wt Percentage change in body weight in xenograft models treated with compound A, a KRAS(ON) inhibitor disclosed herein. SW403 cell-derived xenografts were measured twice weekly using a diaphragm method. Body weight change was plotted as a percentage of the animal's initial body weight.

[0087] Figure 3AThe in vivo efficacy of compound A, a KRAS(ON) inhibitor disclosed herein, in various RAS-driven cancer cell lines is demonstrated. Each figure shows the change in cell proliferation (% relative to control) with log M [compound A]. Regarding Capan-1 (KRAS) cells exposed to compound A for up to 120 hours... G12V ), NCI-H358 (KRAS) G12C AsPC-1 (KRAS) G12D HCT116 (KRAS) G13D ), SK-MEL-30 (NRAS) Q61K ), NCI-H1975 (EGFR T790M / L858R ) and A375 (BRAF) V600E The efficacy of cells in inhibiting cell proliferation in vitro.

[0088] Figure 3B The in vitro efficacy of compound B, a KRAS(ON) inhibitor disclosed herein, is demonstrated in various RAS-driven cancer cell lines. Each figure shows the change in cell proliferation (% relative to control) with log M [compound B]. Regarding Capan-1 (KRAS) cells exposed to compound B for up to 120 hours... G12V ), NCI-H358 (KRAS) G12C AsPC-1 (KRAS) G12D HCT116 (KRAS) G13D ), SK-MEL-30 (NRAS) Q61K ), NCI-H1975 (EGFR T790M / L858R ) and A375 (BRAF) V600E The efficacy of cells in inhibiting cell proliferation in vitro.

[0089] Figure 3C The in vitro efficacy of compound C, a KRAS(ON) inhibitor disclosed herein, is demonstrated in various RAS-driven cancer cell lines. Each figure shows the change in cell proliferation (% relative to control) with log M [compound C]. Regarding Capan-1 (KRAS) cells exposed to compound C for up to 120 hours... G12V ), NCI-H358 (KRAS) G12C AsPC-1 (KRAS) G12D ) and A375 (BRAF) V600E The efficacy of cells in inhibiting cell proliferation in vitro.

[0090] Figure 4ACompound A (25 mg / kg po qd), a KRAS(ON) inhibitor disclosed herein, was demonstrated in human pancreatic cancer HPAC KRAS in female BALB / c nude mice. G12D / wt In vivo efficacy in xenograft models. This figure shows the tumor volume (mm) in a mouse xenograft model. 3 The changes occurred over the number of days post-implantation. HPAC cells were implanted with 50% Matrigel. Animals were randomly assigned to groups and the mean tumor volume reached approximately 142 mm. 3 Treatment was initiated at the appropriate time. Animals were administered 25 mg / kg orally once daily (PO qd) of compound A or a control for 28 days. The dose level was well tolerated. n = 9–10 animals / group. ***p < 0.0001, determined by one-way ANOVA.

[0091] Figure 4B Compound A, as a KRAS(ON) inhibitor disclosed in this paper, is shown to be effective in human pancreatic cancer HPAC KRAS. G12D / wt Response at the end of the study in the xenograft model. Tumor at the end of the HPAC study is plotted as a percentage change in tumor volume compared to the initial volume at the start of treatment. CR (complete response) = regression rate > 80% of initial value. Each animal is represented by an individual bar.

[0092] Figure 4C Shown in human pancreatic cancer HPAC KRAS G12D / wt Percentage change in body weight in animals treated with compound A, a KRAS(ON) inhibitor disclosed herein, in a xenograft model. HPAC cell-derived xenografts were measured twice weekly using a diaphragm method. Body weight change was plotted as a percentage of the animal's initial body weight.

[0093] Figure 4D Compound A, which is a KRAS(ON) inhibitor disclosed herein, is shown in the human colon and rectum GP2d KRAS in female BALB / c nude mice. G12D / wt In vivo efficacy in xenograft models. This figure shows the tumor volume (mm) in a mouse xenograft model. 3 The changes occurred over the number of days post-implantation. GP2d cells were implanted with 50% Matrigel. Animals were randomly assigned to groups and the mean tumor volume reached approximately 154 mm. 3 Treatment was initiated at the appropriate time. Animals were administered 25 mg / kg orally once daily (PO qd) of compound A or a control for 28 days. The dose level was well tolerated. n = 10 animals / group. ***p < 0.0001, determined by one-way ANOVA.

[0094] Figure 4ECompound A, as a KRAS(ON) inhibitor disclosed herein, was shown to be effective in human colon and rectum GP2dKRAS. G12D / wt Response at the end of the study in the xenograft model. Tumor at the end of the GP2d study is plotted as a percentage change in tumor volume compared to the volume at the start of treatment. Each animal is represented by an independent bar.

[0095] Figure 4F Displayed in human colon and rectum GP2d KRAS G12D / wt Percentage change in body weight in xenograft models treated with compound A, a KRAS(ON) inhibitor disclosed herein. GP2d cell-derived xenografts were measured twice weekly using a caliper method. Body weight change was plotted as a percentage of the animal's initial body weight.

[0096] Figure 5A Compound A, which is a KRAS(ON) inhibitor disclosed herein, demonstrates in vitro downregulation of NCI-H358KRAS. G12C In vitro efficacy of immune checkpoint proteins in cells. Figure 5A The graph shows the cell surface expression levels of PD-L1, PVR, and CD73 in H358 cells after treatment with compound A for 48 hours in the presence of interferon-γ (IFNγ), as measured by flow cytometry. Each graph shows the mean fluorescence intensity ((MFI), for each corresponding immune checkpoint protein) as a function of log M[compound A].

[0097] Figure 5B Compound A, which is a KRAS(ON) inhibitor disclosed herein, downregulates SW900KRAS in vitro. G12C In vitro efficacy of immune checkpoint proteins in cells. Figure 5B The graph shows the cell surface expression levels of PD-L1, PVR, and CD73 in SW900 cells after treatment with compound A for 48 hours in the presence of interferon-γ (IFNγ), as measured by flow cytometry. Each graph shows the mean fluorescence intensity ((MFI), for each corresponding immune checkpoint protein) as a function of log M[compound A].

[0098] Figure 5C Compound A, which is a KRAS(ON) inhibitor disclosed herein, downregulates Capan-2KRAS in vitro. G12C In vitro efficacy of immune checkpoint proteins in cells. Figure 5CThe graph shows the cell surface expression levels of PD-L1, PVR, and CD73 in Capan-2 cells after treatment with compound A for 48 hours in the presence of interferon-γ (IFNγ), as measured by flow cytometry. Each graph shows the mean fluorescence intensity ((MFI), for each corresponding immune checkpoint protein) as a function of log M[compound A].

[0099] Figures 6A-6B This paper demonstrates compound A, a KRAS(ON) inhibitor disclosed herein, targeting KRAS... G12C The RAS oncogene conversion mutations observed in (OFF) resistance are active. Figure 6A This is a heatmap showing the results of RAS / RAF disruption assays for various KRAS mutations in cells under the presence of different RAS inhibitors. Figure 6B Displays the IC50 value associated with each colored bar in the heatmap.

[0100] Figures 7A-7D This demonstrates that compound A, as a KRAS(ON) inhibitor disclosed in this paper, drives syngeneic KRAS in vivo. G12C Tumor regression was observed in the tumor model and synergistically with anti-PD-1. In mice treated with the following methods, eCT26(CRC, KRAS) showed significant improvement. G12C / G12C ABCB1 - / - I20 tumor growth status: mediators and homologs ( Figure 7A Anti-PD-1 ( Figure 7B Compound A Figure 7C ); and compound A+ anti-PD-1 ( Figure 7D ).

[0101] Figure 8 The demonstration, in eCT26(CRC,KRAS) G12C / G12C ABCB1 - / - In the I20 model, the combination of compound A, a KRAS(ON) inhibitor disclosed in this paper, and anti-PD-1 was well tolerated in vivo. Body weight changes were plotted as a percentage of the animal's initial body weight.

[0102] Figure 9A , 9B As demonstrated by 9C, compound A, a KRAS(ON) inhibitor disclosed herein, modulates the immunotumor microenvironment in vivo to favor antitumor immunity. eCT26 (CRC, KRAS) patients treated with a catalytic agent or 25 mg / kg qd of compound A for 4 days... G12C / G12C ABCB1 - / - I20 tumors underwent flow cytometry immunophenotyping analysis. Symbols indicate individual tumors. The mean initial tumor volume in the mediator group was approximately 188 mm². 3And in the compound A treatment group, it was approximately 586 mm. 3 Single-drug compound A induced an increase in CD8+ T cells. Figure 9A Compound A also affects M2 macrophages ( ). Figure 9B ) and MDSCs (monocytes) Figure 9C The data are the mean plus or minus SD; *p<0.05, **p<0.01, determined by a two-sided Student's t-test.

[0103] Figure 10A and 10B This demonstrates that compound A, as a KRAS(ON) inhibitor disclosed herein, is effective in human NSCLC ( Figure 10A ) or PDAC ( Figure 10B KRAS G12X It exhibits significant in vivo antitumor activity in tumor models.

[0104] Figure 11 Compound A, a KRAS(ON) inhibitor disclosed in this paper, prolonged tumor doubling time in various xenograft models. p < 0.0001, determined by log-rank test (controls vs. treatment). KRAS G12X n = 154; Other RAS and RAS pathway mutations: n = 86; All RAS pathways MUT The study included two groups: n = 240. Progression was defined as the doubling of the tumor relative to baseline within 28 days.

[0105] Figure 12A , 12B And 12C display, by average tumor volume ( Figure 12A ), percentage change in weight ( Figure 12B ) and percentage change in tumor volume ( Figure 12C As measured, compounds A, B, and D, which are KRAS(ON) inhibitors disclosed herein, drive KRAS in vivo. G12V Tumor regression. n = 6 animals / group. ***p < 0.001. All treatments were well tolerated as assessed by body weight.

[0106] Figure 13A and 13B Display PD( Figure 13A ) and PK ( Figure 13B The results demonstrate that compounds A, B, and D, as KRAS(ON) inhibitors disclosed herein, strongly and persistently inhibit RAS pathway signaling in vivo. Single-dose experiments; all doses were well tolerated. Detailed Implementation

[0107] compound

[0108] This document provides Ras inhibitors. These Ras inhibitors target, i.e., selectively bind to or inhibit Ras(ON) (e.g., selective relative to the inactive state of Ras's binding GDP). As used herein, the term "RAS(ON) inhibitor" refers to an inhibitor that targets, i.e., selectively binds to or inhibits the active state of RAS's binding GTP (e.g., selective relative to the inactive state of RAS's binding GDP). Inhibition of the active state of RAS's binding GTP includes, for example, inhibiting oncogenic signaling from the active state of RAS's binding GTP. In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the active state of RAS's binding GTP. In some embodiments, the RAS(ON) inhibitor may also bind to or inhibit the inactive state of RAS's binding GDP (e.g., with a lower affinity or inhibition constant than the active state of RAS's binding GTP). In some embodiments, the molecular weight of the RAS(ON) inhibitor is between 800 and 1100 Da, including the endpoints. Therefore, for example, the term "KRAS(ON) inhibitor" refers to any inhibitor that binds to KRAS at the "ON" position where GTP binds. G12C "(ON) inhibitors" are KRAS inhibitors that selectively bind to or target the G12C mutant form of KRAS. Non-limiting examples of KRAS(ON) inhibitors are provided in WO 2021091982, WO 2021091967, WO 2021091956 and WO2020132597, some of which are KRAS... G12C (ON) inhibitor.

[0109] As used herein, the term "RAS(OFF) inhibitor" refers to an inhibitor that targets, i.e., selectively binds to or inhibits the inactive state of RAS that binds GDP (e.g., is selective relative to the active state of RAS that binds GTP). Inhibiting the inactive state of RAS that binds GDP includes, for example, clamping the inactive state by inhibiting GDP exchange to GTP, thereby inhibiting RAS from presenting an active conformation. In some embodiments, the RAS(OFF) inhibitor may also bind to or inhibit the active state of RAS that binds GTP (e.g., has a lower affinity or inhibition constant than the inactive state of RAS that binds GDP). In some embodiments, the molecular weight of the RAS(OFF) inhibitor is less than 700 Da. In some embodiments, the molecular weight of the RAS(OFF) inhibitor is less than 700 Da. Thus, for example, the term "KRAS(OFF) inhibitor" refers to any inhibitor that binds to KRAS at the "OFF" position of its bound GDP. "KRAS" G12C"(OFF) inhibitors" are KRAS inhibitors that selectively bind to or target the G12C mutant form of KRAS. G12C (OFF) inhibitors are known in the art, and non-limiting examples include adagrasib and sotorasib. Additional KRAS (OFF) inhibitors are provided herein.

[0110] 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 through competitive, anti-competitive, or non-competitive means.

[0111] The method described herein requires the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a cytosolic chaperone protein (presenting protein) widely expressed in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described herein induce novel binding pockets in Ras by driving the formation of a high-affinity triple complex between the Ras protein and the widely expressed cytosolic chaperone protein cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way the compounds of the present invention and the complexes therein exert their inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules such as RAF required for the propagation of oncogenic signals.

[0112] Not bound by theory, the inventors hypothesize that the non-covalent interactions between the compounds of this invention and Ras and chaperone proteins (e.g., cyclic protein A) can facilitate the inhibition of Ras activity. For example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, and combinations thereof, can contribute to the ability of the compounds of this invention to form complexes and act as Ras inhibitors. Therefore, the compounds of this invention can inhibit various Ras proteins (e.g., wild-type Ras or Ras...). amp , or K-Ras, N-Ras, H-Ras and their mutants with mutations at positions 12, 13 and 61, such as G12C, G12D, G12V, G12S, G13C, G13D and Q61L, and other mutants described herein, in combination with Ras proteins).

[0113] Therefore, this article provides a compound having the structure of formula Ia or a pharmaceutically acceptable salt thereof:

[0114]

[0115] Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene.

[0116] Y is

[0117] W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3- to 10-membered heterocyclic alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0118] X 1 and X 4 Each can be independently CH2 or NH;

[0119] R 1 It is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and

[0120] R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 10 It is hydrogen, hydroxyl, optionally substituted C1-C3 alkyl or optionally substituted C1-C6 heteroalkyl.

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

[0122]

[0123] Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, or a substituted 5- to 6-membered heteroarylene.

[0124] Y is

[0125] W is hydrogen, C1-C4 alkyl, optionally substituted 3- to 10-membered heterocyclic alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0126] R 1 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, a 3- to 6-membered cycloalkenyl group that is optionally substituted, a 3- to 6-membered heterocycloalkyl group that is optionally substituted, a 6- to 10-membered aryl group that is optionally substituted, or a 5- to 10-membered heteroaryl group that is optionally substituted.

[0127] R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and

[0128] R 10 It is hydrogen or optionally a substituted C1-C6 heteroalkyl group. In some embodiments, R 10 It is hydrogen.

[0129] In some implementation schemes, R 1 It is a 6- to 10-membered aryl group optionally substituted or a 5- to 10-membered heteroaryl group optionally substituted. In some embodiments, R 1 It is either a phenyl group that has been optionally substituted or a pyridine group that has been optionally substituted.

[0130] In some embodiments, A is an optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, optionally substituted piperidinyl, optionally substituted pyridine, or optionally substituted phenyl. In some embodiments, A is an optionally substituted thiazole, optionally substituted triazole, 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.

[0131] In some implementations, Y is -NHC(O)- or -NHC(O)NH-.

[0132] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa:

[0133]

[0134] Where a is 0 or 1.

[0135] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa-1:

[0136]

[0137] Where X 2 It is N or CH;

[0138] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0139] n is an integer from 1 to 4.

[0140] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa-2:

[0141]

[0142] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa-3:

[0143]

[0144] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0145] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa-4:

[0146]

[0147] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa-5:

[0148]

[0149] Where X 3 It is N or CH;

[0150] m is 1 or 2;

[0151] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0152] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0153] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0154] R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is H. In some implementations, X 3 It is N, m is 1 and R 11 It is H.

[0155] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa-6:

[0156]

[0157] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa-7:

[0158]

[0159] In some implementations (e.g., implementations having any one of formula IIa-6 or IIa-7), R 6 It is a methyl group.

[0160] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa-8 or IIa-9:

[0161]

[0162] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa:

[0163]

[0164] Where a is 0 or 1.

[0165] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-1:

[0166]

[0167] Where X 2 It is N or CH;

[0168] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0169] n is an integer from 1 to 4.

[0170] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-2:

[0171]

[0172] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-3:

[0173]

[0174] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0175] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-4:

[0176]

[0177] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-5:

[0178]

[0179] Where X 3 It is N or CH;

[0180] m is 1 or 2;

[0181] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0182] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0183] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0184] R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1 and R 11 It is H.

[0185] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-6:

[0186]

[0187] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-7:

[0188]

[0189] In some implementations (e.g., implementations having any one of formula IIIa-6 or IIIa-7), R 6 It is a methyl group.

[0190] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-8 or IIIa-9:

[0191]

[0192] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa:

[0193]

[0194] Where R 9 It is an H or C1-C6 alkyl group; and

[0195] a is 0 or 1.

[0196] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-1:

[0197]

[0198] Where X 2 It is N or CH;

[0199] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0200] n is an integer from 1 to 4.

[0201] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-2:

[0202]

[0203] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-3:

[0204]

[0205] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0206] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-4:

[0207]

[0208] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-5:

[0209]

[0210] Where X 3 It is N or CH;

[0211] m is 1 or 2;

[0212] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0213] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0214] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0215] R7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It is H.

[0216] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-6:

[0217]

[0218] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-7:

[0219]

[0220] In some implementations (e.g., implementations having either formula IVa-6 or IVa-7), R 6 It is a methyl group.

[0221] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-8 or IVa-9:

[0222]

[0223] In some implementations (e.g., implementations having 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 a methyl group.

[0224] In some implementations, Y is -NHS(O)2- or -NHS(O)2NH-.

[0225] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Va:

[0226]

[0227] Where a is 0 or 1.

[0228] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Va-1:

[0229]

[0230] Where X 2 It is N or CH;

[0231] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0232] n is an integer from 1 to 4.

[0233] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Va-2:

[0234]

[0235] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Va-3:

[0236]

[0237] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0238] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Va-4:

[0239]

[0240] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Va-5:

[0241]

[0242] Where X 3 It is N or CH;

[0243] m is 1 or 2;

[0244] R 6R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0245] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0246] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0247] R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It is H.

[0248] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIa:

[0249]

[0250] Where a is 0 or 1.

[0251] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIa-1:

[0252]

[0253] Where X 2 It is N or CH;

[0254] Each R 3Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0255] n is an integer from 1 to 4.

[0256] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIa-2:

[0257]

[0258] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIa-3:

[0259]

[0260] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0261] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIa-4:

[0262]

[0263] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIa-5:

[0264]

[0265] Where X 3 It is N or CH;

[0266] m is 1 or 2;

[0267] R 6 R 7 R 8 and R 11Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0268] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0269] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0270] R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It is H.

[0271] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIa:

[0272]

[0273] Where R 9 It is an H or C1-C6 alkyl group; and

[0274] a is 0 or 1.

[0275] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIa-1:

[0276]

[0277] Where X 2 It is N or CH;

[0278] Each R 3Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0279] n is an integer from 1 to 4.

[0280] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIa-2:

[0281]

[0282] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIa-3:

[0283]

[0284] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0285] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIa-4:

[0286]

[0287] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIa-5:

[0288]

[0289] Where X 3 It is N or CH;

[0290] m is 1 or 2;

[0291] R 6 R 7 R 8 and R 11Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0292] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0293] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0294] R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It is H.

[0295] In some implementations (e.g., implementations having any one of formulas VIIa, VIIa-1, VIIa-2, VIIa-3, VIIa-4, or VIIa-5), R 9 It is a methyl group.

[0296] In some implementations, Y is -NHS(O)- or -NHS(O)NH-.

[0297] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIIa:

[0298]

[0299] Where a is 0 or 1.

[0300] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIIa-1:

[0301]

[0302] Where X 2 It is N or CH;

[0303] Each R 3Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0304] n is an integer from 1 to 4.

[0305] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIIa-2:

[0306]

[0307]

[0308] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIIa-3:

[0309]

[0310] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0311] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIIa-4:

[0312]

[0313] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIIa-5:

[0314]

[0315] Where X 3 It is N or CH;

[0316] m is 1 or 2;

[0317] R 6 R7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0318] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0319] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0320] R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It is H.

[0321] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa:

[0322]

[0323] Where a is 0 or 1.

[0324] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa-1:

[0325]

[0326] Where X 2 It is N or CH;

[0327] Each R 3Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0328] n is an integer from 1 to 4.

[0329] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa-2:

[0330]

[0331] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa-3:

[0332]

[0333] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0334] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa-4:

[0335]

[0336] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa-5:

[0337]

[0338] Where X 3 It is N or CH;

[0339] m is 1 or 2;

[0340] R 6 R 7 R 8 and R 11Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0341] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0342] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0343] R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It is H.

[0344] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Xa:

[0345]

[0346] Where R 9 It is an H or C1-C6 alkyl group; and

[0347] a is 0 or 1.

[0348] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Xa-1:

[0349]

[0350] Where X 2 It is N or CH;

[0351] Each R 3Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0352] n is an integer from 1 to 4.

[0353] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Xa-2:

[0354]

[0355]

[0356] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Xa-3:

[0357]

[0358] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0359] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Xa-4:

[0360]

[0361]

[0362] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Xa-5:

[0363]

[0364] Where X 3 It is N or CH;

[0365] m is 1 or 2;

[0366] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0367] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0368] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0369] R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It is H.

[0370] In some implementations (e.g., implementations having any one of formulas Xa, Xa-1, Xa-2, Xa-3, Xa-4, or Xa-5), R 9 It is a methyl group.

[0371] In some embodiments of any aspect described herein, a is 0. In some embodiments of any of the foregoing, a is 0.

[0372] In some implementations of any aspect described herein, R 2 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 2 Selected from -CH2CH3 or -CH2CF3.

[0373] In some embodiments described herein, W is a C1-C4 alkyl group. In some embodiments, W is:

[0374]

[0375] In some embodiments of any aspect 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.

[0376] In some embodiments of any aspect described herein, W is a substituted 3- to 10-membered heterocyclic alkyl, a substituted 3- to 10-membered cycloalkyl, a substituted 6- to 10-membered aryl, or a substituted 5- to 10-membered heteroaryl.

[0377] In some embodiments described herein, W is optionally a substituted 3- to 10-membered heterocyclic alkyl group. In some embodiments, W is selected from the following or their stereoisomers:

[0378]

[0379]

[0380] In some implementations, W is selected from the following or its stereoisomers:

[0381]

[0382] In some embodiments described herein, W is optionally a substituted 3- to 10-membered cycloalkyl group. In some embodiments, W is selected from the following or their stereoisomers:

[0383] In some implementations, W is selected from the following or its stereoisomers:

[0384]

[0385] In some embodiments of any aspect described herein, W is optionally a substituted 5- to 10-membered heteroaryl group. In some embodiments, W is selected from the following or their stereoisomers:

[0386]

[0387] In some embodiments of any aspect described herein, W is an optionally substituted 6- to 10-membered aryl group. In some embodiments, W is an optionally substituted phenyl group.

[0388] In some embodiments described herein, W is an optionally substituted C1-C3 heteroalkyl group. In some embodiments, W is selected from the following or their stereoisomers:

[0389]

[0390] In some embodiments, the compounds of the present invention are selected from Table 1a or their pharmaceutically acceptable salts or stereoisomers. In some embodiments, the compounds of the present invention are selected from Table 1a or their pharmaceutically acceptable salts or transisomers.

[0391] Table 1a: Some compounds of the present invention

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459] It should be noted that bonds in some compounds are shown as straight lines or wedges. In some cases, the relative stereochemistry of the stereoisomers has been determined; in others, the absolute stereochemistry has been determined. All stereoisomers of the compounds in the table above are covered in this invention. In certain embodiments, the transisomers of the compounds in the table above are covered. Any compound shown in parentheses indicates that the compound is a diastereomer, and the absolute stereochemistry of such diastereomers may be unknown.

[0460] In some embodiments, the compounds of the present invention are selected from the compounds in Table 1b or their pharmaceutically acceptable salts or stereoisomers. In some embodiments, the compounds of the present invention are selected from the compounds in Table 1b or their pharmaceutically acceptable salts or transisomers.

[0461] Table 1b: Some compounds of the present invention

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517] It should be noted that bonds in some compounds are shown as straight lines or wedges. In some cases, the relative stereochemistry of the stereoisomers has been determined; in others, the absolute stereochemistry has been determined. All stereoisomers of the compounds in the table above are covered in this invention. In certain embodiments, the transisomers of the compounds in the table above are covered. Any compound shown in parentheses indicates that the compound is a diastereomer, and the absolute stereochemistry of such diastereomers may be unknown.

[0518] In some embodiments, the compounds of the present invention are selected from the compounds in Table 2 or their pharmaceutically acceptable salts or stereoisomers.

[0519] In some embodiments, the compounds of the present invention are not selected from the compounds in Table 2. In some embodiments, the compounds of the present invention are not selected from the compounds in Table 2 or their pharmaceutically acceptable salts or stereoisomers. In some embodiments, the compounds of the present invention are not selected from the compounds in Table 2 or their pharmaceutically acceptable salts or transisomers.

[0520] Table 2: Some Compounds

[0521]

[0522]

[0523]

[0524]

[0525]

[0526] In some embodiments, the compounds of the present invention are selected from the compounds in Table 3 (e.g., C1-C20 or C1-C21) or their pharmaceutically acceptable salts or stereoisomers.

[0527] In some embodiments, the compounds of the present invention are not selected from the compounds in Table 3 (e.g., C1-C20 or C1-C21). In some embodiments, the compounds of the present invention are not selected from the compounds in 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 selected from the compounds in Table 3 (e.g., C1-C20 or C1-C21) or their pharmaceutically acceptable salts or transisomers.

[0528] Table 3: Some Compounds

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535] In some embodiments, the compounds of the present invention have improved oral bioavailability (%F) compared to compounds known in the art. Methods for measuring oral bioavailability are known in the art, and one such method is provided below:

[0536] Oral bioavailability was determined in BALB / c mice. Following intravenous (IV) bolus and oral (PO) administration of the test compound, approximately 30 μL of whole blood samples were collected at specified time points into tubes containing K₂EDTA. Blood samples were centrifuged at 4600 rpm for approximately 5 minutes at 4°C, and plasma samples were stored at -80°C for bioanalysis. Protein samples were extracted by protein precipitation and analyzed by tandem mass spectrometry (LC MS / MS) using electrospray ionization on a system such as the API 5500.

[0537] All PK parameters were obtained using non-compartmental analysis with WinNonlin from plasma concentration data over time. Bioavailability (F%, also expressed as %F) was estimated using the following formula:

[0538]

[0539] AUC inf,PO The area under the plasma concentration curve from time zero to indefinite time after PO administration.

[0540] AUC inf,IV The area under the plasma concentration curve from time zero to IV administration over an infinite period of time.

[0541] Dose IV This is the total dose administered via IV.

[0542] Dose PO It is the total dose of PO administered.

[0543] Generally, it is preferred that the F% (or %F) value is greater than 30%, and more preferably greater than 50%.

[0544] In some embodiments, the compounds of the present invention are selective for one or more specific Ras mutants relative to other Ras mutants or wild-type, compared to compounds known in the art. Methods for measuring such selectivity are known in the art, such as Ras-Raf binding assays, as provided in the following examples. Therefore, in some embodiments, the compounds of the present invention are selective for KRAS relative to other Ras mutants or relative to wild-type. G12C It is selective. In some embodiments, the compounds of the present invention are selective for KRAS compared to other Ras mutants or compared to wild type. G12D It is selective. In some embodiments, the compounds of the present invention are selective for KRAS compared to other Ras mutants or compared to wild type. G12V It is selective. In some embodiments, the compounds of the present invention are selective for KRAS compared to other Ras mutants or compared to wild type. G12DIt is selective. In some embodiments, the compounds of the present invention are more effective against NRAS than other Ras mutants or compared to the wild type. Q61K It is selective. In some embodiments, the compounds of the present invention are more selective for KRAS than other Ras mutants and wild-type. G12D and KRAS G12V The compounds of this invention exhibit selectivity. They may also show high selectivity for other RAS mutants or combinations thereof disclosed herein. In some embodiments, the compounds of this invention exhibit IC50 values ​​of less than 30 nm for one or more Ras mutants described herein in the above Ras-Raf binding assay.

[0545] In some embodiments, the compounds of the present invention are more potent against one or more specific Ras mutants than against other Ras mutants or wild-types compared to compounds known in the art. Methods for measuring such potency are known in the art, such as the pERK assay, which is the protocol provided in the following examples. Therefore, in some embodiments, the compounds of the present invention are effective against KRAS... G12D The compounds exhibit higher potency than those known in the art. In some embodiments, the compounds of the present invention are effective against KRAS. G12V The compounds exhibit higher potency than those known in the art. In some embodiments, the compounds of the present invention are effective against KRAS. G12C The compounds exhibit higher potency than those known in the art. In some embodiments, the compounds of the present invention are effective against KRAS. G12D and KRAS G12V The compounds exhibit higher potency than compounds known in the art. The compounds of this invention may also exhibit high potency against other RAS mutants or combinations thereof disclosed herein.

[0546] In some embodiments, the compounds of the present invention exhibit a higher detrimental effect on cell viability against one or more specific Ras mutants compared to other Ras mutants or wild-type compounds, compared to compounds known in the art. Methods for measuring cell viability are known in the art, such as... Cell viability assay, which is performed according to the protocol provided in the following examples. Therefore, in some embodiments, the compounds of the present invention are targeted at KRAS compared to compounds known in the art. G12D This results in a significant reduction in cell viability. In some embodiments, the compounds of the present invention target KRAS compared to compounds known in the art. G12V This results in a significant reduction in cell viability. In some embodiments, the compounds of the present invention target KRAS compared to compounds known in the art. G12CThis results in a significant reduction in cell viability. In some embodiments, the compounds of the present invention target KRAS compared to compounds known in the art. G12D and KRAS G12V The compounds of this invention also exhibit a significant reduction in cell viability against other RAS mutants or combinations thereof disclosed herein.

[0547] In some embodiments, the compounds of the present invention may exhibit higher metabolic stability, permeability, or solubility, or combinations thereof, compared to compounds known in the art. Methods for measuring such properties are known in the art. In some embodiments, the compounds of the present invention may exhibit improvements in any one or a combination of the following properties compared to compounds known in the art: selectivity, potency, cell viability, metabolic stability, permeability, or solubility.

[0548] In some embodiments, the compounds of the present invention are or are used as prodrugs, for example for administration to cells or to subjects in need.

[0549] Pharmaceutical compositions are also provided, the pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0550] A method of treating a subject with cancer is also 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 adenocarcinoma, myelodysplastic syndrome, or squamous cell lung cancer. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L, or a combination thereof. In some implementations, the cancer contains 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 also described herein.

[0551] Another method is provided for treating Ras protein-related conditions in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0552] Another method for inhibiting Ras proteins in cells is provided, 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 can be, for example, N-Ras G12D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P. Other Ras proteins are also 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 adenocarcinoma cells, myelodysplastic syndrome cells, myeloma cells, or squamous cell lung cancer cells. Other cancer types are also described herein. The cells may be in vivo or in vitro.

[0553] For the compounds of the present invention, the inhibitory effect exhibited by one stereoisomer may be superior to that of another stereoisomer. For example, one transisomer may exhibit inhibitory effect, while another transisomer may exhibit very little or no inhibitory effect.

[0554] In some embodiments, the methods or uses described herein further include administering additional anticancer therapies. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, EGFR inhibitor, second Ras inhibitor, SHP2 inhibitor, SOS1 inhibitor, Raf inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, AKT inhibitor, mTORC1 inhibitor, BRAF inhibitor, PD-L1 inhibitor, PD-1 inhibitor, CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are also described herein.

[0555] Synthesis method

[0556] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0557] The compounds of the present invention can be prepared by a variety of methods well known to those skilled in organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described in the following embodiments, as well as synthetic methods known in synthetic organic chemistry or modifications thereof as understood by those skilled in the art. These methods include, but are not limited to, those described in the following embodiments.

[0558] Scheme 1. General Synthetic Methods for Macrocyclic Esters

[0559]

[0560] Scheme 1 outlines the general synthetic method for macrocyclic esters. Appropriately substituted indolylboronic esters (1) can be prepared in four steps using protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boronic acids as starting materials, including palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation.

[0561] Methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (3) can be prepared by coupling (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid (2) with methyl (S)-hexahydropyridazine-3-carboxylate.

[0562] The final macrocyclic ester can be prepared by coupling methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (3) with a suitably substituted indoleboronic ester (1) in the presence of a Pd catalyst, followed by hydrolysis and macrocyclic lactone conversion steps to produce a suitably protected macrocyclic intermediate (5). Deprotection and coupling with a suitably substituted carboxylic acid (or other coupling complex) yields the macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 6.

[0563] Additionally, for Scheme 1, thiazole may be replaced by alternatively substituted 5- to 6-membered heterocyclic alkyl or substituted 3- to 6-membered cycloalkyl, substituted 3- to 6-membered heterocyclic alkyl (e.g., morpholino) or substituted 6-membered aryl (e.g., phenyl).

[0564] Option 2. Substitutes for general synthetic methods of macrocyclic esters

[0565]

[0566] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. Appropriately substituted and protected indoleboronic esters (7) are coupled with (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Coupling with methyl (S)-hexahydropyridazine-3-carboxylate, followed by hydrolysis and macrocyclic lactone formation, yields an iodine intermediate (11). Subsequent palladium-mediated borylation and coupling with an appropriately substituted iodoaryl or iodohearyl intermediate in the presence of a Pd catalyst yields a appropriately protected macrocyclic intermediate. Alkylation, deprotection, and coupling with an appropriately substituted carboxylic acid (or other coupling complex) produce the macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 6.

[0567] Additionally, for scheme 2, thiazole may be alternatively replaced by a substituted 5- to 6-membered heterocyclic alkyl group or a substituted 3- to 6-membered cycloalkyl group, a substituted 3- to 6-membered heterocyclic alkyl group (e.g., morpholino), or a substituted 6-membered aryl group (e.g., phenyl).

[0568] The compounds listed in Table 1a or Table 1b herein were prepared using the methods disclosed herein or by combining the methods described herein with the knowledge of those skilled in the art.

[0569] Pharmaceutical Compositions and Methods of Use

[0570] Pharmaceutical Compositions and Administration

[0571] The compounds involved in this invention are Ras inhibitors and can be used to treat cancer. Therefore, one embodiment of this invention provides pharmaceutical compositions comprising the compounds of this invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, and methods for preparing such compositions using the compounds of this invention.

[0572] As used herein, the term "pharmaceutical composition" refers to a compound formulated with a pharmaceutically acceptable excipient, such as the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, the compound is present in the pharmaceutical composition in a unit dose suitable for administration in a treatment regimen, the compound showing a statistically significant likelihood of achieving the intended therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for administration by: oral administration, such as liquids (aqueous or non-aqueous solutions or suspensions), tablets (e.g., intended for buccal, sublingual, and systemic absorption), pills, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; surface administration, such as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or mouth; intravaginal or rectal administration, such as pessaries, creams, or foams; sublingual administration; ocular administration; transdermal administration; or nasal, pulmonary, and other mucosal surfaces.

[0574] As used herein, “pharmaceuticalally acceptable excipient” means any inactive ingredient (e.g., a medium that suspends or dissolves an active compound) that is non-toxic and non-inflammatory in the body of a subject. Typical excipients include, for example: anti-adhesion agents, antioxidants, adhesives, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavoring agents, fragrances, flow enhancers, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, croscarmellose, citric acid, croscarmellose, cysteine, ethyl cellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn starch), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. A variety of reagents and materials are well known to those skilled in the art to be used as excipients. See, for example, Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0575] Unless explicitly stated otherwise, the compounds described herein, whether explicitly stated or not, may be provided or used in salt form, for example, in pharmaceutically acceptable salt form. As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound described herein that, to the extent of reasonable medical judgment, is suitable for use in contact with human tissues without excessive toxicity, irritation, anaphylactic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (edited by P.H. Stahl and C. G. Germuth), Wiley-VCH, 2008. The salt may be prepared in situ during the final isolation and purification of the compounds described herein, or isolated by reacting a free basic group with a suitable organic acid.

[0576] The compounds of the present invention may have ionizable groups, thereby enabling their preparation into pharmaceutically acceptable salt forms. The salt may be an acid addition salt involving an inorganic or organic acid, or, if the compound of the present invention is in acid form, the salt may be prepared from an inorganic or organic base. In some embodiments, the compound is prepared or used in a pharmaceutically acceptable salt form, which is prepared as an addition product of a pharmaceutically acceptable acid or base. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid, for forming acid addition salts; and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc., for forming base salts. Methods for preparing suitable salts are recognized in the art.

[0577] Representative acid addition salts include acetates, adipates, alginates, ascorbic acid salts, aspartate salts, benzenesulfonates, benzoates, hydrogen sulfates, borates, butyrates, camphorates, camphor sulfonates, citrates, cyclopentanepropionates, disaccharides, dodecyl sulfates, ethanesulfonates, transbutenedioates, glucono-heptahydrates, glyceryl phosphates, hemisulfates, heptahydrates, hexanoates, hydrobromates, hydrochlorides, hydroiodates, and 2-optionally substituted hydroxy-ethanesulfonates. Salts, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, dihydroxynaphthalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, undecanoates, valerates, and similar salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts and similar salts, 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.

[0578] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, "subject" refers to a human being at any developmental stage. In some embodiments, "subject" refers to a human patient. In some embodiments, "subject" refers to a non-human animal. In some embodiments, a non-human animal is a mammal (e.g., rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, or pig). In some embodiments, a subject includes, but is not limited to, mammals, birds, reptiles, amphibians, fish, or insects. In some embodiments, a subject may be a transgenic animal, a genetically engineered animal, or a clone.

[0579] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (e.g., the compound of the present invention) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, the amount is an amount (or a portion thereof) of a unit dose suitable for administration according to a dosing regimen that is determined to be associated with a desired or beneficial outcome when administered to a relevant population (i.e., according to a therapeutic dosing regimen). 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 the administration of multiple dosage forms. As used herein, the term "dosing regimen" refers to a set of unit doses (typically more than one unit dose) administered individually to a subject, said unit doses typically spaced at intervals of time. In some embodiments, a given therapeutic compound (e.g., the compound of the present invention) has a recommended dosing regimen that may involve one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each of which is spaced at equal intervals of time; in some embodiments, the dosing regimen comprises multiple doses and at least two distinct time intervals separating the individual doses. In some embodiments, all doses within the dosing regimen are amounts of the same unit dose. In some embodiments, the different doses within a dosing regimen are different amounts. In some embodiments, the dosing regimen includes a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose different from the first dose. In some embodiments, the dosing regimen includes a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose identical to the first dose. In some embodiments, the dosing regimen is associated with desired or beneficial outcomes when administered to a relevant population (i.e., a therapeutic dosing regimen).

[0580] "Treatment regimen" refers to a dosage regimen in which a patient is administered a treatment to a population in relation to the desired or beneficial therapeutic outcome.

[0581] The term "treatment" ("treatment / treat / treating") in its broadest sense refers to any application of a substance (such as the compounds of the present invention) that partially or completely relieves, improves, reduces, or inhibits one or more symptoms, features, or causes of a particular disease, condition, or disorder; delays its onset; reduces its severity; or decreases its occurrence. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, condition, or disorder, or to a subject who exhibits only early signs of the disease, condition, or disorder. Alternatively or additionally, in some embodiments, treatment may be administered to a subject exhibiting one or more defined signs of the relevant disease, condition, or disorder. In some embodiments, treatment may be used on a subject diagnosed with the relevant disease, condition, or disorder. In some embodiments, treatment may be used on a subject known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, condition, or disorder.

[0582] The term "therapeuticly effective amount" means an amount sufficient to treat a disease, condition, or disorder when administered according to a therapeutic dosing regimen to a population suffering from or susceptible to that disease, condition, or disorder. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity of one or more symptoms of the disease, condition, or disorder, or delays its onset. Those skilled in the art will understand that the term "therapeuticly effective amount" does not actually require achieving the desired successful treatment in a particular individual. In fact, a therapeutically effective amount can be an amount that provides a specific desired pharmacological response in a substantial number of subjects when administered to a patient requiring said treatment. It is particularly important to understand that a particular subject may actually be "therapeuticly effective amount" "refractory." In some embodiments, the referred therapeutically effective amount may refer to an amount measured in one or more specific tissues (e.g., tissues affected by the disease, condition, or disorder) 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 may be formulated as a single dose or administered in a single dose. In some implementations, the therapeutically effective dose may be formulated as multiple doses, for example, as part of a dosing regimen, or administered in multiple doses.

[0583] For use as a treatment for subjects, the compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the desired type of treatment, such as prevention, control, or treatment, the compounds or pharmaceutically acceptable salts thereof are formulated in accordance with the parameters described herein. An overview of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0584] The compositions can be prepared according to commonly used mixing, granulation, or coating methods, and the pharmaceutical compositions of the present invention may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the compounds of the present invention or pharmaceutically acceptable salts thereof. In some embodiments, the amount of the compounds described herein or pharmaceutically acceptable salts thereof may be, by weight, 1-95% of the total amount of the pharmaceutical composition.

[0585] The composition may be provided in dosage forms suitable for administration such as intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intracystic, intraurethral, ​​intrathecal, epidural, ocular, or by injection, inhalation, or direct contact with the nasal, genitourinary, genital, or oral mucosa. Therefore, 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, solutions, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoresis delivery, or aerosols. The composition may be formulated according to common pharmaceutical practices.

[0586] As used herein, the term "administration" means administering a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system. Administration to animal subjects (e.g., to humans) can be performed via any suitable route. For example, in some embodiments, administration can be via bronchial (including bronchial infusion), buccal, intestinal, intradermal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, mucosal, nasal, oral, rectal, subcutaneous, sublingual, surface, tracheal (including intratracheal infusion), percutaneous, vaginal, or vitreous administration.

[0587] Formulations can be prepared for systemic or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous) or those prepared for transdermal, transmucosal, or oral administration. Formulations will generally include diluents and, in some cases, adjuvants, buffers, preservatives, etc. Compounds or pharmaceutically acceptable salts thereof may also be administered as liposome compositions or as microemulsions.

[0588] For injection, formulations can be prepared in commonly used forms, such as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in emulsion forms. Suitable excipients include, for example, water, saline, dextrose, glycerol, etc. These compositions may also contain a certain amount of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, etc.

[0589] Various sustained-release drug delivery systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0590] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. It will be understood in the art that suitable forms include syrups, capsules, and tablets.

[0591] Each compound described herein, or its pharmaceutically acceptable salt, can be formulated in a variety of ways known in the art. For example, the first and second agents in a combination therapy can be formulated together or separately. Other modalities of combination therapy are also described herein.

[0592] Individually or separately formulated pharmaceutical preparations may be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, suppositories, or liquids in vials, two topical creams, etc. The kit may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstitution of the powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit dose kit may contain instructions for the preparation and administration of the composition. The kit may be manufactured as a single-use unit dose for one subject, for multiple uses for a specific subject (constant dose, or in which the potency of individual compounds or their pharmaceutically acceptable salts may vary with treatment progression); or the kit may contain multiple doses suitable for administration to multiple subjects (“integral package”). The kit components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0593] Formulations for oral use include tablets containing a mixture of an active ingredient and a non-toxic, pharmaceutically acceptable excipient. The excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0594] Two or more compounds may be mixed together in tablets, capsules or other media, or they may be separated. In one example, the first compound is contained on the inside of the tablet, while the second compound is on the outside, thereby allowing the majority of the second compound to be released before the first compound is released.

[0595] Formulations for oral use may also be provided as chewable tablets or as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or as soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets may be prepared using the ingredients mentioned above for tablets and capsules, in a conventional manner, using, for example, a mixer, a fluid bed apparatus, or a spray dryer.

[0596] Controlled release through dissolution or diffusion can be achieved by appropriately coating the compound with tablets, capsules, pellets, or granules, or by incorporating the compound or a pharmaceutically acceptable salt thereof into a suitable matrix. Controlled release coatings may include one or more of the coating substances mentioned above, such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogels, 1,3-butanediol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene or halogenated fluorocarbons.

[0597] Liquid forms of compounds or pharmaceutically acceptable salts and compositions thereof that can be incorporated into the present invention 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 mediators.

[0598] Generally, when administered to humans, the oral dose of any compound of the present invention or a pharmaceutically acceptable salt thereof will depend on the nature of the compound and can be readily determined by those skilled in the art. The dose can be, for example, from about 0.001 mg to about 2000 mg daily, from about 1 mg to about 1000 mg daily, from about 5 mg to about 500 mg daily, from about 100 mg to about 1500 mg daily, from about 500 mg to about 1500 mg daily, from about 500 mg to about 2000 mg daily, or any range derived therefrom. In some embodiments, the daily dose for oral administration may, for example, be in the range of from about 0.001 mg to about 2000 mg per kilogram of human body weight, administered in a single dose or divided doses. On the other hand, in some cases, doses outside the stated limits may be necessary.

[0599] In some embodiments, the pharmaceutical composition may additionally contain an additional compound having antiproliferative activity. Depending on the administration regimen, the compound or a pharmaceutically acceptable salt thereof will be formulated to suit the composition for delivery. Each compound or a pharmaceutically acceptable salt thereof in the combination therapy may be formulated in a variety of ways known in the art. For example, the first and second agents in the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for simultaneous or near-simultaneous administration of these agents.

[0600] It should be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated together with one or more other desired therapeutic agents or medical procedures, or administered concurrently with, before, or after the administration of such one or more other desired therapeutic agents or medical procedures. The specific combination of the therapies (therapeutic agents or procedures) used in the combination regimen should take into account the compatibility of the desired therapeutic agent or procedure with the desired therapeutic effect to be achieved. It should also be understood that the therapies used may achieve the desired effect for the same condition, or they may achieve different effects (e.g., controlling any adverse effects).

[0601] As described in this article, the individual drugs in the combination therapy can be administered independently, once to four times daily, for one day to one year, and even for the subject's lifetime. Chronic / long-term administration is also applicable.

[0602] How to use

[0603] In some embodiments, the present invention discloses a method for treating a disease or condition characterized by abnormal Ras activity caused by a Ras mutant. In some embodiments, the disease or condition is cancer.

[0604] Therefore, a method for treating cancer in a subject of need is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary site, endometrial cancer, esophageal and gastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal cancer, endometrial cancer, or melanoma. A method for treating Ras protein-related conditions in a subject of need is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0605] In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compounds of the present invention or their salts, pharmaceutical compositions comprising such compounds or salts, and methods include, but are not limited to, the following tumor types: astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral cavity, ovarian, prostate, and thyroid cancers and sarcomas. Other cancers include, for example:

[0606] Heart-related sarcomas, such as: angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma;

[0607] Lung cancer, for example: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

[0608] Gastrointestinal tract, such as: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet tumor, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0609] Urogenital tract, such as: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminomatous sarcoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma);

[0610] The liver, for example: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0611] Bile duct cancer, such as gallbladder cancer, ampullary cancer, and bile duct cancer;

[0612] Skeletal tumors, such as: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrogenic osteoid), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor;

[0613] Nervous system, such as: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma;

[0614] Gynecological conditions, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, cervical precancerous dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer);

[0615] Hematopoietic system, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders (such as myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodyplasia syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0616] Skin conditions, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and

[0617] Adrenal glands, for example: neuroblastoma.

[0618] In some implementations, the Ras protein is wild-type (Ras WT Therefore, in some embodiments, the compounds of the present invention are used to treat patients with Ras WT (e.g. K-Ras) WT H-Ras WT or N-RasWT In methods for treating cancer patients, Ras protein is amplified (e.g., K-Ras) in some implementations. amp Therefore, in some embodiments, the compounds of the present invention are used to treat patients with Ras amp (K-Ras amp H-Ras amp or N-Ras amp In methods for treating patients with cancer. In some embodiments, the cancer contains a Ras mutation, such as the Ras mutation described herein. In some embodiments, the mutation is selected from:

[0619] (a) The following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations thereof;

[0620] (b) The following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R, and combinations thereof;

[0621] (c) The following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof;

[0622] Or a combination of any of the foregoing. In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit multiple Ras mutations. For example, the compounds may inhibit both K-RasG12D and K-RasG12C. In some embodiments, the compounds may inhibit both K-RasG12V and K-RasG12C. In some embodiments, the compounds may inhibit both K-RasG12C and K-RasG13C. In some embodiments, the compounds may inhibit both K-RasG12D and K-RasG12V. In some embodiments, the compound can inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the mutations in K-Ras, N-Ras, or H-Ras are selected from the group consisting of: G12A, G12C, G12D, G12E, G12F, G12H, G12I, G12K, G12L, G12M, G12N, G12P, G12Q, G12R, G12S, G12T, G12V, G12W, and G12Y, or combinations thereof. In some embodiments, the mutations in K-Ras, N-Ras, or H-Ras are selected from the group consisting of: G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y, or combinations thereof. In some embodiments, the compound inhibits wild-type K-Ras, wild-type H-Ras, or wild-type N-Ras, and optionally also inhibits mutant Ras protein 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 .

[0623] Additionally, in some embodiments, the cancer contains K-Ras mutations selected from the group consisting of: G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer contains N-Ras mutations selected from the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer contains H-Ras mutations selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer contains Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit multiple Ras mutants. For example, the compounds may inhibit both K-Ras G12C and K-Ras G13C. The compounds may inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compounds may inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the compounds may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compounds may inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the present invention inhibit Ras WT and one or more additional Ras mutations (e.g., K-, H-, or N-Ras). WT and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K-, H- or N-Ras WT and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K-, H- or N-Ras WTAnd 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 inhibit Ras amp and one or more additional Ras mutations (e.g., K-, H-, or N-Ras). amp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K-, H- or N-Ras amp and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K-, H- or N-Ras amp and N-RasQ61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T).

[0624] Methods for detecting Ras mutations are known in the art. These methods include, but are not limited to, direct sequencing and the use of highly sensitive diagnostic assays (using CE-IVD markers), such as those described in Domagala et al., Pol J Pathol 3:145-164 (2012), which are incorporated herein by full reference, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreenPyro. See also, for example, WO 2020 / 106640.

[0625] In some embodiments, the cancer is non-small cell lung cancer, and the Ras mutation includes a K-Ras mutation, such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is colorectal cancer, and the Ras mutation includes a K-Ras mutation, such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation includes a K-Ras mutation, such as K-Ras G12D or K-Ras G12V. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation includes an N-Ras mutation, such as N-Ras G12D. In some embodiments, the cancer is melanoma, and the Ras mutation includes an N-Ras mutation, such as N-Ras Q61R or N-Ras Q61K. In some embodiments, the cancer is non-small cell lung cancer, and the Ras protein is K-Ras. amp In any of the foregoing, unless otherwise specified, the compound may also inhibit Ras. WT (e.g., K-, H-, or N-Ras) WT ) or Ras amp (e.g., K-, H-, or N-Ras) amp ).

[0626] In some implementations, the cancer includes Ras mutations and STK11. LOF KEAP1, EPHA5, or NF1 mutations, or combinations thereof. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12C mutation, STK11 mutation, or STK11 mutation. LOF Mutations and KEAP1 mutations. In some implementations, the cancer is non-small cell lung cancer and contains K-Ras G12C and STK11 mutations. LOF Mutations. In some implementations, the cancer is non-small cell lung cancer and contains K-Ras G12C and STK11 mutations. LOF Mutations. In some implementations, the cancer includes K-Ras G13C Ras mutations as well as STK11 mutations. LOFKEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and contains a K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and contains a K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and contains a K-Ras G12C mutation. In any of the foregoing embodiments, the compound may also inhibit Ras WT (e.g., K-, H-, or N-Ras) WT ) or Ras amp (e.g., K-, H-, or N-Ras) amp ).

[0627] A method for inhibiting Ras protein in cells is also provided, comprising 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 multiple types of Ras protein in cells. A method for inhibiting RAF-Ras binding is also provided, comprising 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 belong to any type of cancer described herein. The cells may be in vivo or in vitro.

[0628] Combination therapy

[0629] The methods of the present invention may include the compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). When administered alone, the dose of one or more of the additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced relative to a standard dose. For example, the dose may be determined empirically based on the combination and arrangement of drugs or inferred by isoradiometric analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0630] The compounds of the present invention may be administered before, after, or simultaneously with one or more of the additional therapies. When combined, the dose of the compounds of the present invention provides a therapeutic effect (e.g., synergistic or additive therapeutic effect) in conjunction with the dose of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). The compounds of the present invention and additional therapies, such as anticancer agents, may be administered together, for example, as a single pharmaceutical composition, or separately, and when administered separately, the administration may occur simultaneously or sequentially. Such sequential administration may be close in time or distant in time.

[0631] In some embodiments, the additional therapy is the administration of a side effect limiter (e.g., an agent intended to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of the present invention may also be used in combination with a therapeutic agent 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.

[0632] In some embodiments, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies include therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, the one or more additional therapies include two therapeutic agents. In still other embodiments, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0633] In this section on combination therapies, all references are incorporated by way of citation for the pharmaceutical agents described, or for their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers, whether or not so explicitly stated.

[0634] Non-drug therapy

[0635] Examples of non-pharmacological treatments include, but are not limited to, radiotherapy, cryotherapy, hyperthermia, surgery (e.g., surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0636] In some embodiments, the compounds of the present invention can be used as postoperative adjuvant therapy. In some embodiments, the compounds of the present invention can be used as preoperative neoadjuvant therapy.

[0637] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative conditions, such as cancer, in subjects (e.g., mammals, such as humans). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implantation radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and sustained or transient proximal therapy. As used herein, the term "proximal therapy" refers to radiation therapy delivered by inserting a radioactive material into or near a space defined by a tumor or other proliferative tissue disease site within the body. This term is intended, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu). Suitable radiation sources used as cell conditioning agents of the present invention include solids and liquids. As a non-limiting example, the radioactive source can be a radioactive nucleus, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radioactive nuclei that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from a solution of any radioactive nucleus, such as a solution of I-125 or I-131, or the radioactive fluid can be prepared using a slurry containing small particles of a suitable fluid, such as Au-198 or Y-90. Furthermore, the radioactive nucleus can be embedded in a gel or radioactive microspheres.

[0638] In some embodiments, the compounds of the present invention can sensitize abnormal cells to radiotherapy, thereby killing or inhibiting the growth of such cells. Therefore, the present invention further relates to a method for sensitizing abnormal cells in a mammal to radiotherapy, the method comprising administering to the mammal a quantity of the compounds of the present invention, the quantity of which effectively sensitizes the abnormal cells to radiotherapy. The amount of the compound in this method may be determined according to the manner used to determine the effective amount of such compounds described herein. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0639] In some embodiments, the non-pharmacological treatment is adoptive T-cell transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may 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 source of the T cells is obtained from the subject before the T cells are expanded and genetically modified. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of the invention, a variety of T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Before or after T cell genes are modified to express the desired protein (e.g., CAR), the T cells can generally be activated and expanded using methods described, for example, in the following U.S. patents: 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0640] Therapeutic agents

[0641] Therapeutic agents can be compounds used to treat cancer or its related symptoms.

[0642] For example, the therapeutic agent may be a steroid. Therefore, in some embodiments, the one or more additional therapies include steroids. Suitable steroids may include, but are not limited to, acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, and cortisol. sone, cortivazol, deflazacort, desonide, deoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortinbutyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasolPropionate, halometasone, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, 25-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone Triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0643] Other examples of therapeutic agents that can be used in combination therapies with the compounds of the present invention include compounds described in the following patents: U.S. Patents 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and others. International patent applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089 and WO00 / 02871.

[0644] Therapeutic agents can be biological agents (e.g., cytokines such as interferon or leukocyte-stimulating factors such as IL-2) used to treat cancer or related symptoms. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that activates a target to stimulate an anticancer response or antagonizes an antigen important for cancer. Antibody-drug conjugates are also included.

[0645] 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, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L2 inhibitor or antagonist (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) (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 antibodies such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or... Checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0646] Therapeutic agents can be anti-TIGIT antibodies, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0647] Therapeutic agents can be drugs used to treat cancer or related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapy agents or targeted therapy agents.

[0648] Anticancer agents include mitosis inhibitors, insertional 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, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted urea, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, the one or more additional therapies comprise two or more anticancer agents. The two or more anticancer agents may be used in a mixture for combined or separate administration. Suitable dosing regimens for combined anticancer agents are known in the art and are described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0649] Other non-limiting examples of anticancer agents include (Imatinib Mesylate); (carfilzomib); (bortezomib); Casodex (bicalutamide); Gefitinib; alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; azacyclopropanes, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and tris(hydroxymethylmelamine); polyacetyl (especially bullatacin and bullatacinone); camptothecin (including its synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adoxin). Synthetic analogs of zelesin, carzelesin, and bizelesin; cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189, and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, and mechlorethamine hydrochloride. Oxylide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicin, calicheamicin γll and calicheamicin ωll (see, for example, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophores. Chromophore and related chromophores, including alkenyne antibiotic chromophores, aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, and chromomycins. Actinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyano-morpholino-doxorubicin, 2-pyrrolinyl-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (e.g., mitomycin C), mycophenolic acid (Acid), nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU);Folic acid analogs, such as denopterin, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-thioazolidinyl pyrimidine, carmofur, cytarabine, doxifluridine, enocitabine, and fluxuridine; and androgens, such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergics, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate); epothilone, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;Losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; Polysaccharide complexes (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonicacid; triaziquone; 2,2',2”-trichlorotriethylamine; trichothecene, such as T-2 toxin, verracurin A, roridin A. A) and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipebroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, for example (paclitaxel) (A nanoparticle formulation of paclitaxel without polyoxyethylene hydrogenated castor oil and albumin-engineered paclitaxel) and (Docetaxel); Chloranbucil; Tamoxifen (Nolvadex) TM ); raloxifene; aromatase inhibitory 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene Flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamicins; capecitabine (e.g.) ), and pharmaceutically acceptable salts of any of the above.

[0650] Additional, non-restricted examples of anticancer agents include trastuzumab. Bevacizumab Cetuximab Rituximab ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, demethoxygeldanamycin, alpharadin, alvocidib, thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antitumor drugs (e.g., cell cycle nonspecific antitumor agents and other antitumor agents described herein), antitumor herbs, apaziquone, atipremod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoxidesulfoximine), CBV (chemotherapy), calyculin, dichloroacetic acid, discormolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, lanicoquerone (l) aniquidar), larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, naproxen, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A) Sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, 2-chloroethylamine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0651] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vincristine, vinorelbine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin / actinomycin D, donomycin, and idarubicin), anthracycline, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and removes cells that cannot synthesize asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., methylmuscarin, cyclophosphamide and analogues, melphalan, and chlorambucil), ethyleneimine, and methylmelamine (e.g., hexamethyl melamine). amines and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors, such as abemaciclib, ribociclib, palbociclib, seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues),And streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites (e.g., folic acid analogs), pyrimidine analogs (e.g., fluorouracil, azuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, amylglutathione, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroamic acid), etc. acid), vorinostat, LBH 589, romidepsin, ACY-1215 and panobinostat, mTOR inhibitors (e.g. vistusertib, temsirolimus, everolimus, ridaforolimus and sirolimus), KSP (Eg5) inhibitors (e.g. Array 520), DNA binding agents (e.g., PI3K inhibitors, such as PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), PI3Kδ and γ inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multi-kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogens) and hormone agonists, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), and telomerase inhibitors (e.g., GRN inhibitors). 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), PI3K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra) TM Anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targets (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.

[0652] In some implementation schemes, the anticancer agent is selected from methicillin, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, etc. Sorafenib or any of the aforementioned analogues or derivative variants.

[0653] In some implementations, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies, such as trastuzumab. and pertuzumab Small molecule tyrosine kinase inhibitors, such as gefitinib Erlotinib Pilitinib, CP-654577, CP-724714, Canertinib (CI 1033), HKI-272, Lapatinib (GW-572016); ), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543 and JNJ-26483327.

[0654] In some implementations, 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.

[0655] In some implementations, the anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., an SHP2 inhibitor, such as 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 thereof). SOS1 inhibitors (e.g., BI-1701963, BI-3406, SDR5, BAY-293, or RMC-5845, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers thereof), 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.

[0656] In some embodiments, the anticancer agent is an SOS1 inhibitor. In some embodiments, the SOS1 inhibitor is selected from those disclosed in WO2021173524, WO 2021130731, WO 2021127429, WO 2021092115, WO 2021105960, WO2021074227, WO 2020180768, WO 2020180770, WO 2020173935, WO 2020146470, WO2019201848, WO 2019122129, WO 2018172250 and WO 2018115380, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs or tautomers thereof.

[0657] In some embodiments, the anticancer agent is an additional Ras inhibitor or a Ras vaccine, or another therapeutic agent designed to directly or indirectly reduce the carcinogenic activity of Ras. In some embodiments, the anticancer agent is an additional Ras inhibitor. In some embodiments, the Ras inhibitor targets Ras in an active or GTP-bound state. In some embodiments, the Ras inhibitor targets Ras in an inactive or GDP-bound state. In some implementations, the Ras inhibitor is, for example, a K-Ras G12C inhibitor, such as AMG 510 (sottorazib), MRTX1257, MRTX849 (adagraxib), JNJ-74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21000, RMC-6291, or GDC-6036, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is a K-Ras G12D inhibitor, such as 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, such as 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 the following patents, which are incorporated herein by reference in their entirety, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers thereof: WO 2021091982, WO 2021091967, WO 2021091956, and WO 2020132597. Other examples of Ras inhibitors that can be combined with the Ras inhibitor of the present invention are provided in the following patents (which are incorporated herein by reference in their entirety): WO 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO2021139678、WO2021129824、WO 2021129820、WO 2021127404、WO 2021126816、WO 2021126799、WO2021124222、WO 2021121371、WO 2021121367、WO 2021121330、WO 2020050890、WO2020047192、WO 2020035031、WO 2020028706、WO 2019241157、WO 2019232419、WO2019217691、WO 2019217307、WO 2019215203、WO 2019213526、WO 2019213516、WO2019155399、WO 2019150305、WO 2019110751、WO 2019099524、WO 2019051291、WO2018218070、WO 2018217651、WO 2018218071、WO 2018218069、WO 2018206539、WO2018143315、WO 2018140600、WO 2018140599、WO 2018140598、WO 2018140514、WO2018140513、WO 2018140512、WO 2018119183, WO 2018112420, WO 2018068017, WO2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659 and WO2013155223, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs or tautomers thereof.

[0658] In some embodiments, therapeutic agents that can be combined with the compounds of the present invention are MAP kinase (MAPK) pathway inhibitors (or "MAPK inhibitors"). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancer (Basel) September 2015; 7(3):1758–1784. For example, MAPK inhibitors may be selected from one or more of the following: trametinib, binimetinib, selumetinib, cobimetinib, LERafAON (NeoPharm), ISIS 5132; vemurafenib, pimaertib, 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, described in PLoS) One. November 25, 2014; 9(11) in; and GSK1120212 (or JTP-74057, described in Clin Cancer Res. March 1, 2011; 17(5):989-1000 in). MAPK inhibitors may be PLX8394, LXH254, GDC-5573 or LY3009120.

[0659] In some implementations, the anticancer agent is a disruptor or an inhibitor of the RAS-RAF-ERK, PI3K-AKT-TOR, or PI3K-AKT signaling pathway. PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancer (Basel) 2015 Sep; 7(3):1758–1784. For example, PI3K / AKT inhibitors may be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0660] In some implementations, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0661] In some implementations, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapy. In some implementations, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0662] IGF-1R inhibitors include linsitinib or its pharmaceutically acceptable salts.

[0663] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors for EGFR include cetuximab. Panitumumab Zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by natural ligands. 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. EGFR inhibitors can be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.) or Mab C225 (ATCC accession number HB-8508) or antibodies or antibody fragments that have specific binding to them.

[0664] Small molecule antagonists of EGFR include gefitinib Erlotinib and lapatinib 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 implementations, the EGFR inhibitor is osimertinib. Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in the following patent publications, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; EP0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP 837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP 682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0665] MEK inhibitors include, but are not limited to, pimasetinib, selumetinib, and cobitinib. trametinib and Bimetinib In some embodiments, the MEK inhibitor targets a MEK mutation selected from the following type I MEK1 mutations: D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is selected from the following type II MEK1 mutations: ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0666] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs as described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methanesulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941, and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ) 235, and described in WO06 / 122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-(morpholino)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (described in WO08 / 070740); LY294002(2-(4-morpholino)-8-phenyl-4H-l-benzopyran-4-one (purchased from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinopyridino[3',2':4,5]furano[3,2-d]pyrimidin-2-yl]phenol hydrochloride (purchased from Axon Medchem); PIK 75(2-methyl-5-nitro-2-[(6-bromoimidazolo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (purchased from Axon Medchem); PIK 90(N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)nicotinamide) (purchased from Axon Medchem); AS-252424(5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione) (purchased from Axon Medchem); TGX-221(7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one) (purchased from Axon Medchem) Medchem); XL-765; and XL-147.Other PI3K inhibitors include demethoxyviridin, 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.

[0667] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibiting Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt.2):399-408); Akt-1-1,2 (inhibiting Akl and Ak2) (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]pyridyl compounds (e.g., WO 05 / 011700); indole-3-methanol and its derivatives (e.g., US Patent No. 6,656,963; Sarkar and Li J). Nutr. 2004, 134(12 Supplement): 3493S-3498S); perifoxine (e.g., interfering with Akt membrane localization; Dasmahapatra et al., Clin. Cancer Res. 2004, 10(15): 5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13: 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64: 4394-9).

[0668] mTOR inhibitors include, but are not limited to, 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, including temsirolimus. Everolimus WO94 / 09010); deforolimus (also known as deforolimus or AP23573); rapalogs, such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapalog; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapalog (also known as CC1779); 40-epio-(tetrazole)-rapalog (also known as ABT578); 32-deoxyrapalog; 16-pentyneoxy-32(S)-dihydrorapalog; derivatives disclosed in WO05 / 005434; United States Derivatives disclosed in patents No. 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 in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g. WO05 / 016252). In some implementations, the mTOR inhibitor is a bisteric inhibitor (see, for example, WO2018204416, WO2019212990, and WO2019212991), such as RMC-5552, which has the following structure

[0669]

[0670] BRAF inhibitors that can be used in combination with the compounds of the present invention include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF may contain type 3 BRAF mutations. In some embodiments, the type 3 BRAF mutation is 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.

[0671] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid leukemia-1 (MCL-1) protein is a key anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance to not only traditional chemotherapy but also targeted therapies, including BCL-2 inhibitors such as ABT-263.

[0672] In some implementations, the additional therapeutic agent is an SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which facilitates a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in a stable, inactive, self-inhibiting conformation through a binding network involving residues from the N-SH2 and PTP domains. Stimulation with cytokines or growth factors, such as those acting via receptor tyrosine kinases (RTKs), leads to exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0673] SHP2 is involved in signaling via the RAS-mitogen-activated protein kinase (MAPK) pathway, namely the JAK-STAT or phosphoinositol 3-kinase-AKT pathway. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental disorders, such as Noonan Syndrome and Leopard Syndrome, and human cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancers. Some of these mutations destabilize the autoinhibitory conformation of SHP2 and promote autoactivation or enhanced growth factor-driven activation of SHP2. Therefore, SHP2 represents a particularly promising target for developing novel therapies for treating a variety of diseases, including cancer. It has been shown that combinations of SHP2 inhibitors (e.g., RMC-4550 or SHP099) with RAS pathway inhibitors (e.g., MEK inhibitors) can inhibit the proliferation of various cancer cell lines (e.g., pancreatic, lung, ovarian, and breast cancer) in vitro. Therefore, combination therapy involving SHP2 inhibitors and RAS pathway inhibitors can be a general strategy for preventing tumor resistance in a variety of malignancies.

[0674] Comprehensive practical examples of SHP2 suppression in this area: Chen et al., MolPharmacol.2006, 70, 562; Sarver et al., J.Med.Chem.2017, 62, 179 3; 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO2021143680, WO2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO2020156242, WO 2020108590, WO 2020104635, WO 2020094104, WO 2020094018, WO2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO 2020033828, WO2020033286, WO 2020022323, WO 2019233810, WO 2019213318, WO 2019183367, WO2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO 2019158019, WO2019152454, WO 2019051469, WO 2019051084, WO 2018218133, WO2018172984, WO2018160731, WO 2018136265, WO 2018136264, WO 2018130928, WO 2018129402, WO2018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO 2017211303, WO2017210134, WO 2017156397, WO 2017100279, WO 2017079723, WO 2017078499, WO2016203406, WO 2016203405, WO 2016203404, WO WO 2016196591, WO 2016191328, WO2015107495, WO 2015107494, WO 2015107493, WO 2014176488, WO 2014113584, US20210085677, US10858359, US10934302, US10954243, US 10988466, US11001561, US11033547, US11034705 or US11044675, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs or tautomers thereof, are each incorporated herein by reference.

[0675] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, such as a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor targeting a cysteine ​​residue (C333) located 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, with the following structure: Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer.

[0676] In some implementations, the SHP2 inhibitor is RMC-4550, having the following structure

[0677]

[0678] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RMC-4630, having the following structure:

[0679]

[0680] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer.

[0681] In some implementations, the SHP2 inhibitor is JAB-3068, having the following structure

[0682]

[0683] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is JAB-3312. In some embodiments, the SHP2 inhibitor is the following compound,

[0684]

[0685] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RLY-1971, having the following structure

[0686]

[0687] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is ERAS-601, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is BBP-398, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is SH3809. In some embodiments, the SHP2 inhibitor is PF-07284892, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0688] In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors. 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 MEK inhibitors and SOS1 inhibitors. In some embodiments, the Ras inhibitor of the present invention is used in combination with PD-L1 inhibitors and SOS1 inhibitors. In some embodiments, the Ras inhibitor of the present invention is used in combination with PD-L1 inhibitors and SHP2 inhibitors. In some embodiments, the Ras inhibitor of the present invention is used in combination with MEK inhibitors and SHP2 inhibitors. In some implementations, the cancer is colorectal cancer, and the treatment comprises administering a combination of the Ras inhibitor of the present invention with a second or third therapeutic agent.

[0689] Proteasome inhibitors include, but are not limited to, carfilzomib. Bortezomib And opozomib.

[0690] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiD), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1 agents, anti-PD-L1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0691] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs containing imide groups (drugs that regulate immune responses). IMiD drugs include thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0692] Exemplary anti-PD-1 antibodies and their methods of use 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 / 121168A1), and are also described elsewhere in this paper.

[0693] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent Nos. 6,111,090, 8,586,023, WO2010 / 003118, and WO2011 / 090754; or, for example, U.S. Patent Nos. 7,025,962, EP Anti-GITR antibodies as described in 1947183, U.S. Patent No. 7,812,135; U.S. Patent No. 8,388,967; U.S. Patent No. 8,591,886; U.S. Patent No. 7,618,632; EP1866339; and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0694] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions synthesized in vitro, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally can be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or arresting cell growth. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0695] Anti-angiogenic agents can be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, tesiromolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO 98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are inhibitors with very low or no MMP-1 inhibitory activity. More preferably, they are inhibitors that selectively inhibit MMP-2 or AMP-9 relative 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 include AG-3340, RO 32-3555, and RS13-0830.

[0696] Other exemplary anti-angiogenic agents include kinase domain KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding domains that specifically bind to kinase domain receptors), and anti-VEGF agents (e.g., antibodies or antigen-binding domains that specifically bind to VEGF (e.g., bevacizumab) or soluble VEGF receptors or their ligand-binding domains), such as VEGF-TRAP. TM And anti-VEGF receptor agents (e.g., antibodies or antigen-binding domains that specifically bind to the VEGF receptor), EGFR inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to EGFR), for example (panitumumab), erlotinib Anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding domains that specifically bind to Angle and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to Tie2 kinase). Other anti-angiogenic agents include Camppath, IL-8, β-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 disintegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), and antibodies or antigens that specifically bind to anti-eph receptors or anti-pterygium receptors. Binding regions (US Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and their patent families), and anti-PDGF-BB antagonists (e.g., specifically bound antibody or antigen-binding regions), as well as antibody or antigen-binding regions specifically bound to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibody or antigen-binding regions specifically bound to PDGFR kinases). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptaniboctasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US 5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecrolaveacetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands); DAC anti-angiogenic agent (ConjuChem, Canada);Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); 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, JP 02233610); Platelet-4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); Second-generation α5β3 integrin MAb (Applied Molecular Glucose) Evolution (USA) and Medlmmune (USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA); PI 88 (Progen, Australia); silengitide (Merck KGaA, Germany);Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE8062 (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); pINN (Novartis, Switzerland and Schering) AG (Germany); Tissue factor pathway inhibitor (EntreMed, USA); Pinn (Gilead Sciences, USA); Xanthorrhizol (Yonsei University, South Korea); Gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SU6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); Motuporamine C (British Columbia University, Canada); CDP 791 (Celltech) Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK);E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); Angiogenesis vaccine (EntreMed, USA); Urokinase plasminogen activator inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); InKine (InKine, USA); A6 (Angstrom, USA); KR31372 (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 (KirinBrewery, Japan); Drug delivery system, intraocular 2-methoxyestradiol; Angnex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL993 (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, α5β (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS706 (Sankyo, Japan);Cobretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); Irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (Genaera, USA); RPI 4610 (Sirna, USA); Heparinase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); and Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel) Hospital, USA; truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thromboprotein 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0697] Other examples of therapeutic agents that can be used in combination with the compounds of the present invention include agents that specifically bind to and inhibit the activity of growth factors (e.g., antibodies, antigen-binding domains, or soluble receptors), such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding domains that specifically bind to receptor c-Met.

[0698] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, and hydroxychloroquine (Plaquenil). TM Bafilomycin A1, 5-amino-4-imidazolamide riboside (AICAR), leucocyanidin, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vincristine. Additionally, antisense RNA or siRNA that inhibits protein expression, including but not limited to ATG5 (involved in autophagy), may be used. In some embodiments, one or more of the additional therapies include autophagy inhibitors.

[0699] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an antitumor agent. In some embodiments, the one or more additional therapies include an antitumor agent. Non-limiting examples of antitumor agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, aifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, and cytarabine. ocfosfate), DA3030 (Dong-A), daclizumab, and denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac (HIT), interferon-alpha, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate Phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphatephosphate), formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid Interferon α, Idarubicin, Imiquimod, Interferon α, Natural Interferon α, Interferon α-2, Interferon α-2a, Interferon α-2b, Interferon α-Nl, Interferon α-n3, Compound Interferon-1, Natural Interferon α, Interferon β, Interferon β-la, Interferon β-lb, Interferon γ, Natural Interferon γ-la, Interferon γ-lb, Leukocyte-1β, Iobenguane, Irinotecan, Isograstim, Lanreotide, LC 9018 (Yakult), Leflunomide, Lenograstim, Lentinan sulfate sulfate), letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double strand RNA, mitoxazone, dibromoceroxyl, mitoxazone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, niluamide, noscapine, novel erythropoietin, NSC631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronateacid), pegaspargase, pegylated interferon α-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirubicin, rabbit anti-thymocyte polyclonal antibody, pegylated interferon α-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium hydroxyethylphosphonate Re 186, retinamide (RII), rituximab, romurtide, samarium 153Sm (lexiconazole) Lexidronam, Sargramostim, Sizofiran, Sobuzoxane, Sonermin, Strontium-89 Chloride, Suramin, Tasonermin, Tazarotene, Tegafur, Temoporfin, Temozolomide, Teniposide, Tetrachlorodecaoxide, Thalidomide, Thymalfasin, Thyrotropin A, Topotecan, Toremifene, Tositumomab-iodine 131) Trastuzumab, treosulfan, retinoic acid, trilostane, trimetrexate, triptorelin, natural tumor necrosis factor α, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysis product vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim, SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomabtiuxetan, ilomastat, IM 862 (Cytran), leukocyte-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA125MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), Idiotype 105AD7 MAb (CRC Technology), Idiotype CEA MAb (Trilex), LYM-1-Iodine-131 MAb (Techni clone), Polymorphic Epithelial Mucin-Yttrium 90 MAb (Antisoma), Marimastat, Menogaril, Mitumomab, Motexafingadolinium, MX 6 (Galderma), Nelarabine, Nolatrexed, P30 Protein, Pegvisomant, Pemetrexed, Porfiromycin, Prinomastat, RL 0903 (Shire), Rubitecan, Satraplatin, Sodium Phenylacetate, Sparfosic Acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York)The vaccines available include: University, Sloan Kettering Institute, New York Medical College, Royal Newcastle Hospital, and valspodar.

[0700] Additional examples of therapeutic agents that can be used in combination with the compounds of the present invention include ipilimumab. Trimelimumab; Galiximab; Nivolumab, also known as BMS-936558 Pembrolizumab Avelumab 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; Atecicept; CP-870893; Lucarumumab; Dacetuzumab; Muromonab-CD3; Ipilumumab; MEDI4736 MSB0010718C; AMP224; Adalimumab ADO-trastuzumab bemtansine aflibercept alemtuzumab Baliximab belimumab Baliximab belimumab Brentuximab vedotin Canakinumab Polyethylene glycol combined with certolizumab pegol Daktarizumab daratumumab denosumab eculizumab efalizumab Gemtuzumab ozogamicin golimumab ibritumomab tiuxetan infliximab Motavizumab Natalizumab obinutuzumab ofatumumab Omalizumab palivizumab pertuzumab pertuzumab ranibizumab raxibacumab Tocilizumab Tositumomab; Tositumomab-i-131; Tositumomab and Tositumomab-i-131 ustekinumab AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0701] Depending on the condition being treated, the compounds described herein may be used in combination with the pharmaceutical agents disclosed herein or other suitable pharmaceutical agents. Therefore, in some embodiments, one or more compounds of this disclosure will be co-administered with other therapies described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with a second pharmaceutical agent. This combination administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein may be formulated together with any pharmaceutical agent described herein into the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any therapies described herein may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compounds of this disclosure may be administered first, followed by any therapies described herein, or vice versa. In some embodiments of separate administration, the compounds of the present invention and any therapies described herein are administered at intervals of minutes, hours, or days.

[0702] In some embodiments of any of the methods described herein, a first therapy (e.g., a compound of the present invention) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent may be administered immediately before or after the administration of the one or more additional therapies, for up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7 days, 1-14 days, 1-21 days, or 1-30 days.

[0703] The invention is also characterized by a kit comprising: (a) a pharmaceutical composition comprising the agents described herein (e.g., compounds of the invention) and (b) a packaging insert with instructions on performing any of the methods described herein. In some embodiments, the kit comprises: (a) a pharmaceutical composition comprising the agents described herein (e.g., compounds of the invention), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a packaging insert with instructions on performing any of the methods described herein.

[0704] Since one aspect of the invention covers the treatment of diseases or related symptoms by combination of separately administerable pharmaceutically active compounds, the invention also relates to the combination of independent pharmaceutical compositions in the form of a kit. The kit may contain two independent pharmaceutical compositions: the compounds of the present invention and one or more additional therapies. The kit may include a container for containing the independent compositions into a container, such as a dispensing vial or a dispenser foil package. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions on the use of the independent components. The kit format is particularly advantageous when the independent components are preferably administered in different dosage forms (e.g., oral or parenteral), when administered at different dose intervals, or when the prescribing healthcare professional wishes to adjust the individual components in the combination.

[0705] Implementation plan with numbering

[0706] [1] A compound or a pharmaceutically acceptable salt thereof having the structure of formula Ia:

[0707]

[0708] Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene.

[0709] Y is

[0710] W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3- to 10-membered heterocyclic alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0711] X 1 and X 4 Each can be independently CH2 or NH;

[0712] R 1 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, a 3- to 6-membered cycloalkenyl group that is optionally substituted, a 3- to 15-membered heterocycloalkyl group that is optionally substituted, a 6- to 10-membered aryl group that is optionally substituted, or a 5- to 10-membered heteroaryl group that is optionally substituted.

[0713] R 2It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and

[0714] R 10 It is hydrogen, hydroxyl, optionally substituted C1-C3 alkyl or optionally substituted C1-C6 heteroalkyl.

[0715] [2] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [1], wherein R 1 It is a 6- to 10-membered aryl group that is optionally substituted or a 5- to 10-membered heteroaryl group that is optionally substituted.

[0716] [3] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [2], wherein R 1 It is either a phenyl group that has been optionally substituted or a pyridine group that has been optionally substituted.

[0717] [4] A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [3], wherein A is a substituted thiazole, a substituted triazole, a substituted morpholino, a substituted piperidinyl, a substituted pyridine, or a substituted phenyl.

[0718] [5] The compound as described in any one of paragraphs [1] to [3] (or a pharmaceutically acceptable salt thereof), wherein A is not optionally a substituted phenyl or benzimidazole.

[0719] [6] The compound or a pharmaceutically acceptable salt thereof as described in paragraph 5, wherein A is not a hydroxyphenyl.

[0720] [7] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [6], wherein the compound is not one of the compounds in Table 2.

[0721] [8] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [7], wherein the compound is not one of the compounds in Table 3.

[0722] [9] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [8], wherein Y is -NHC(O)- or -NHC(O)NH-.

[0723]

[10] The compounds described in paragraph [9] or their pharmaceutically acceptable salts have the structure of formula IIa:

[0724]

[0725] Where a is 0 or 1.

[0726]

[11] The compounds described in paragraph

[10] or their pharmaceutically acceptable salts have the structure of formula II-1a:

[0727]

[0728] Where X 2 It is N or CH;

[0729] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0730] n is an integer from 1 to 4.

[0731]

[12] The compounds described in paragraph

[11] or their pharmaceutically acceptable salts have the structure of formula IIa-2:

[0732]

[0733]

[13] The compounds described in paragraph

[12] or their pharmaceutically acceptable salts have the structure of formula IIa-3:

[0734]

[0735] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0736]

[14] The compounds described in paragraph

[13] or their pharmaceutically acceptable salts have the structure of formula IIa-4:

[0737]

[0738]

[15] The compounds described in paragraph

[14] or their pharmaceutically acceptable salts have the structure of formula IIa-5:

[0739]

[0740] Where X 3 It is N or CH;

[0741] m is 1 or 2;

[0742] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0743] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0744] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0745] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0746]

[16] The compounds described in paragraph

[15] or their pharmaceutically acceptable salts have the structure of formula IIa-6:

[0747]

[0748]

[17] The compounds described in paragraph

[15] or their pharmaceutically acceptable salts have the structure of formula IIa-7:

[0749]

[0750]

[18] The compounds as described in paragraph

[16] or

[17] , wherein R 6 It is a methyl group.

[0751]

[19] The compounds described in paragraph

[15] or their pharmaceutically acceptable salts have the structure of formula IIa-8 or IIa-9:

[0752]

[0753]

[20] The compounds described in paragraph [9] or their pharmaceutically acceptable salts have the structure of formula IIIa:

[0754]

[0755] Where a is 0 or 1.

[0756]

[21] The compounds described in paragraph

[20] or their pharmaceutically acceptable salts have the structure of formula IIIa-1:

[0757]

[0758] Where X 2 It is N or CH;

[0759] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0760] n is an integer from 1 to 4.

[0761]

[22] The compounds described in paragraph

[21] or their pharmaceutically acceptable salts have the structure of formula IIIa-2:

[0762]

[0763]

[23] . The compounds described in paragraph

[22] or their pharmaceutically acceptable salts have the structure of formula IIIa-3:

[0764]

[0765] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0766]

[24] The compounds described in paragraph

[23] or their pharmaceutically acceptable salts have the structure of formula IIIa-4:

[0767]

[0768]

[25] The compounds described in paragraph

[24] or their pharmaceutically acceptable salts have the structure of formula IIIa-5:

[0769]

[0770] Where X 3 It is N or CH;

[0771] m is 1 or 2;

[0772] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0773] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0774] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0775] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0776]

[26] The compounds described in paragraph

[25] or their pharmaceutically acceptable salts have the structure of formula IIIa-6:

[0777]

[0778]

[27] The compounds described in paragraph

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

[0779]

[0780]

[28] The compounds as described in paragraph

[26] or

[27] , wherein R 6 It is a methyl group.

[0781]

[29] The compounds described in paragraph

[25] or their pharmaceutically acceptable salts have the structure of formula IIIa-8 or IIIa-9:

[0782]

[0783]

[30] The compounds described in paragraph [9] or their pharmaceutically acceptable salts have the structure of formula IVa:

[0784]

[0785] Where R 9 It is an H or C1-C6 alkyl group; and

[0786] a is 0 or 1.

[0787]

[31] The compounds described in paragraph

[30] or their pharmaceutically acceptable salts have the structure of formula IVa-1:

[0788]

[0789] Where X 2 It is N or CH;

[0790] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0791] n is an integer from 1 to 4.

[0792]

[32] The compounds described in paragraph

[31] or their pharmaceutically acceptable salts have the structure of formula IVa-2:

[0793]

[0794]

[33] The compounds described in paragraph

[32] or their pharmaceutically acceptable salts have the structure of formula IVa-3:

[0795]

[0796] Where R 4 and R 5Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0797]

[34] The compounds described in paragraph

[33] or their pharmaceutically acceptable salts have the structure of formula IVa-4:

[0798]

[0799]

[35] The compounds described in paragraph

[34] or their pharmaceutically acceptable salts have the structure of formula IVa-5:

[0800]

[0801] Where X 3 It is N or CH;

[0802] m is 1 or 2;

[0803] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0804] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0805] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0806] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0807]

[36] The compounds described in paragraph

[35] or their pharmaceutically acceptable salts have the structure of formula IVa-6:

[0808]

[0809]

[37] The compounds described in paragraph

[35] or their pharmaceutically acceptable salts have the structure of formula IVa-7:

[0810]

[0811]

[38] The compounds as described in paragraph

[36] or

[37] , wherein R 6 It is a methyl group.

[0812]

[39] The compounds described in paragraph

[35] or their pharmaceutically acceptable salts have the structure of formula IVa-8 or IVa-9:

[0813]

[0814]

[40] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[30] to

[39] , wherein R 9 It is a methyl group.

[0815]

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

[0816]

[42] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[41] have the structure of formula Va:

[0817]

[0818] Where a is 0 or 1.

[0819]

[43] The compounds described in paragraph

[42] or their pharmaceutically acceptable salts have the structure of formula Va-1:

[0820]

[0821] Where X 2 It is N or CH;

[0822] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0823] n is an integer from 1 to 4.

[0824]

[44] The compounds described in paragraph

[43] or their pharmaceutically acceptable salts have the structure of formula Va-2:

[0825]

[0826]

[45] The compounds described in paragraph

[44] or their pharmaceutically acceptable salts have the structure of formula Va-3:

[0827]

[0828] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0829]

[46] The compounds described in paragraph

[45] or their pharmaceutically acceptable salts have the structure of formula Va-4:

[0830]

[0831]

[47] The compounds described in paragraph

[46] or their pharmaceutically acceptable salts have the structure of formula Va-5:

[0832]

[0833] Where X 3 It is N or CH;

[0834] m is 1 or 2;

[0835] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0836] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0837] R7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0838] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0839]

[48] ​​The compounds described in paragraph

[41] or their pharmaceutically acceptable salts have the structure of formula VIa:

[0840]

[0841] Where a is 0 or 1.

[0842]

[49] The compounds described in paragraph

[48] or their pharmaceutically acceptable salts have the structure of formula VIa-1:

[0843]

[0844] Where X 2 It is N or CH;

[0845] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0846] n is an integer from 1 to 4.

[0847]

[50] The compounds described in paragraph

[49] or their pharmaceutically acceptable salts have the structure of formula VIa-2:

[0848]

[0849]

[51] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[50] have the structure of formula VIa-3:

[0850]

[0851] Where R 4 and R 5Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0852]

[52] The compounds described in paragraph

[51] or their pharmaceutically acceptable salts have the structure of formula VIa-4:

[0853]

[0854]

[53] The compounds described in paragraph

[52] or their pharmaceutically acceptable salts have the structure of formula VIa-5:

[0855]

[0856] Where X 3 It is N or CH;

[0857] m is 1 or 2;

[0858] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0859] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0860] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0861] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0862]

[54] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[41] have the structure of formula VIIa:

[0863]

[0864] Where R 9 It is an H or C1-C6 alkyl group; and

[0865] a is 0 or 1.

[0866]

[55] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[54] have the structure of formula VIIa-1:

[0867]

[0868] Where X 2 It is N or CH;

[0869] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0870] n is an integer from 1 to 4.

[0871]

[56] The compounds described in paragraph

[55] or their pharmaceutically acceptable salts have the structure of formula VIIa-2:

[0872]

[0873]

[57] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[56] have the structure of formula VIIa-3:

[0874]

[0875] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0876]

[58] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[57] have the structure of formula VIIa-4:

[0877]

[0878]

[59] The compounds described in paragraph

[58] or their pharmaceutically acceptable salts have the structure of formula VIIa-5:

[0879]

[0880] Where X 3 It is N or CH;

[0881] m is 1 or 2;

[0882] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0883] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0884] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0885] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0886]

[60] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[54] to

[59] , wherein R 9 It is a methyl group.

[0887]

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

[0888]

[62] The compounds described in paragraph

[61] or their pharmaceutically acceptable salts have the structure of formula VIIIa:

[0889]

[0890] Where a is 0 or 1.

[0891]

[63] The compounds described in paragraph

[62] or their pharmaceutically acceptable salts have the structure of formula VIIIa-1:

[0892]

[0893] Where X 2 It is N or CH;

[0894] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0895] n is an integer from 1 to 4.

[0896]

[64] The compounds described in paragraph

[63] or their pharmaceutically acceptable salts have the structure of formula VIIIa-2:

[0897]

[0898]

[65] The compounds described in paragraph

[64] or their pharmaceutically acceptable salts have the structure of formula VIIIa-3:

[0899]

[0900] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0901]

[66] The compounds described in paragraph

[65] or their pharmaceutically acceptable salts have the structure of formula VIIIa-4:

[0902]

[0903]

[67] The compounds described in paragraph

[66] or their pharmaceutically acceptable salts have the structure of formula VIIIa-5:

[0904]

[0905] Where X 3 It is N or CH;

[0906] m is 1 or 2;

[0907] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0908] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0909] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0910] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0911]

[68] The compounds described in paragraph

[61] or their pharmaceutically acceptable salts have the structure of formula IXa:

[0912]

[0913] Where a is 0 or 1.

[0914]

[69] The compounds described in paragraph

[68] or their pharmaceutically acceptable salts have the structure of formula IXa-1:

[0915]

[0916] Where X 2 It is N or CH;

[0917] Each R 3Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0918] n is an integer from 1 to 4.

[0919]

[70] The compounds described in paragraph

[69] or their pharmaceutically acceptable salts have the structure of formula IXa-2:

[0920]

[0921]

[71] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[70] have the structure of formula IXa-3:

[0922]

[0923] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0924]

[72] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[71] have the structure of formula IXa-4:

[0925]

[0926]

[73] The compounds described in paragraph

[72] or their pharmaceutically acceptable salts have the structure of formula IXa-5:

[0927]

[0928] Where X 3 It is N or CH;

[0929] m is 1 or 2;

[0930] R 6 R 7 R 8 and R 11Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0931] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0932] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0933] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0934]

[74] The compounds described in paragraph

[61] or their pharmaceutically acceptable salts have the structure of formula Xa:

[0935]

[0936] Where R 9 It is an H or C1-C6 alkyl group; and

[0937] a is 0 or 1.

[0938]

[75] The compounds described in paragraph

[74] or their pharmaceutically acceptable salts have the structure of formula Xa-1:

[0939]

[0940] Where X 2 It is N or CH;

[0941] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[0942] n is an integer from 1 to 4.

[0943]

[76] The compounds described in paragraph

[75] or their pharmaceutically acceptable salts have the structure of formula Xa-2:

[0944]

[0945]

[77] The compounds described in paragraph

[76] or their pharmaceutically acceptable salts have the structure of formula Xa-3:

[0946]

[0947] Where R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0948]

[78] The compounds described in paragraph

[77] or their pharmaceutically acceptable salts have the structure of formula Xa-4:

[0949]

[0950]

[79] The compounds described in paragraph

[78] or their pharmaceutically acceptable salts have the structure of formula Xa-5:

[0951]

[0952] Where X 3 It is N or CH;

[0953] m is 1 or 2;

[0954] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[0955] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[0956] R7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[0957] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0958]

[80] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[74] to

[79] , wherein R 9 It is a methyl group.

[0959]

[81] A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[10] to

[40] ,

[42] to

[60] or

[62] to

[80] , wherein a is 0.

[0960]

[82] A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[10] to

[40] ,

[42] to

[60] or

[62] to

[80] , wherein a is 1.

[0961]

[83] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[82] , wherein R 2 It is a C1-C6 alkyl group that is optionally substituted.

[0962]

[84] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[83] , wherein R 2 Selected from -CH2CH3 or -CH2CF3.

[0963]

[85] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[84] , wherein W is a C1-C4 alkyl group.

[0964]

[86] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[84] , 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.

[0965]

[87] A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[84] , wherein W is a substituted 3- to 10-membered heterocyclic alkyl, a substituted 3- to 10-membered cycloalkyl, a substituted 6- to 10-membered aryl or a substituted 5- to 10-membered heteroaryl.

[0966]

[88] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[84] , wherein W is an optionally substituted 3- to 10-membered heterocyclic alkyl group.

[0967]

[89] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[88] , wherein W is selected from the following or their stereoisomers:

[0968]

[0969]

[0970]

[0971]

[0972]

[90] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[84] , wherein W is optionally a substituted 3- to 10-membered cycloalkyl group.

[0973]

[91] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[90] , wherein W is selected from the following or their stereoisomers:

[0974]

[0975]

[92] The compound or a pharmaceutically acceptable salt thereof as described in any of paragraphs [1] to

[84] , wherein W is a substituted 5- to 10-membered heteroaryl group.

[0976]

[93] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[92] , wherein W is selected from the following or their stereoisomers:

[0977]

[0978]

[0979]

[94] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[84] , wherein W is an optionally substituted 6 to 10 aryl group.

[0980]

[95] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[94] , wherein W is an optionally substituted phenyl group.

[0981]

[96] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[84] , wherein W is an optionally substituted C1-C3 heteroalkyl group.

[0982]

[97] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[96] , wherein W is selected from the following or their stereoisomers:

[0983]

[0984]

[98] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[85] , wherein W is selected from:

[0985]

[0986]

[99] A compound of Table 1a or a pharmaceutically acceptable salt thereof.

[0987]

[100] A compound of Table 1b or a pharmaceutically acceptable salt thereof.

[0988]

[101] A compound or a pharmaceutically acceptable salt thereof having the structure of formula Ib:

[0989]

[0990] Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene.

[0991] Y is

[0992] W is hydrogen, a C1-C4 alkyl group, an optionally substituted C1-C3 heteroalkyl group, an optionally substituted 3- to 10-membered heterocyclic alkyl group, an optionally substituted 3- to 10-membered cycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group; or W is -R 14 C(=O)R 15 , where R 14 It is a 3- to 10-membered cycloalkylene group, and R 15 Selected from optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0993] X 1 and X 4 Each can be independently CH2, CH(CH3) or NH;

[0994] R 1 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, a 3- to 6-membered cycloalkenyl group that is optionally substituted, a 3- to 15-membered heterocycloalkyl group that is optionally substituted, a 6- to 10-membered aryl group that is optionally substituted, or a 5- to 10-membered heteroaryl group that is optionally substituted.

[0995] R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl.

[0996] R 10 It 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 heterocyclic alkyl; and

[0997] R 12 and R 13 Each is independently selected from F, CH3, or R. 12 and R 13 It combines with the atoms it is attached to to form a 3-membered cycloalkyl group.

[0998]

[102] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[101] , wherein R 1 It is a 6- to 10-membered aryl group that is optionally substituted or a 5- to 10-membered heteroaryl group that is optionally substituted.

[0999]

[103] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[102] , wherein R 1 It is either a phenyl group that has been optionally substituted or a pyridine group that has been optionally substituted.

[1000]

[104] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[103] , wherein A is a substituted thiazole, a substituted triazole, a substituted morpholino, a substituted piperidinyl, a substituted pyridine, or a substituted phenyl.

[1001]

[105] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[103] , wherein A is not optionally a substituted phenyl or benzimidazole.

[1002]

[106] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[105] , wherein A is not a hydroxyphenyl.

[1003]

[107] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[106] , wherein the compound is not one of the compounds in Table 2.

[1004]

[108] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[107] , wherein the compound is not one of the compounds in Table 3.

[1005]

[109] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[108] , wherein Y is -NHC(O)- or -NHC(O)NH-.

[1006]

[110] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[109] have the structure of formula IIb:

[1007]

[1008] Where a is 0 or 1.

[1009]

[111] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[110] have the structure of formula IIb-1:

[1010]

[1011] Where X 2 It is N or CH;

[1012] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1013] n is an integer from 1 to 4.

[1014]

[112] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[111] have the structure of formula IIb-2:

[1015]

[1016]

[113] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[112] have the structure of formula IIb-3:

[1017]

[1018] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1019] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIb-3, wherein W is a optionally substituted 3- to 10-membered heterocyclic alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or W is -R 14 C(=O)R 15 , where R 14 It is a 3- to 10-membered cycloalkyl group, and R 15 Selected from optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and R 10 It 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 heterocyclic alkyl.

[1020]

[114] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[113] have the structure of formula IIb-4:

[1021]

[1022] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIb-4, wherein W is a optionally substituted 3- to 10-membered heterocyclic alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or W is -R 14 C(=O)R 15 , where R 14 It is a 3- to 10-membered cycloalkyl group, and R 15 Selected from optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 5 Selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and R 10 It 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 heterocyclic alkyl.

[1023]

[115] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[114] have the structure of formula IIb-5:

[1024]

[1025] Where X 3 It is N or CH;

[1026] m is 1 or 2;

[1027] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1028] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1029] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1030] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1031]

[116] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[115] have the structure of formula IIb-6:

[1032]

[1033]

[117] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[115] have the structure of formula IIb-7:

[1034]

[1035]

[118] The compounds as described in paragraphs

[116] or

[117] , wherein R 6 It is a methyl group.

[1036]

[119] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[115] have the structure of formula IIb-8 or IIb-9:

[1037]

[1038]

[120] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[109] have the structure of formula IIIb:

[1039]

[1040] Where a is 0 or 1.

[1041]

[121] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[120] have the structure of formula IIIb-1:

[1042]

[1043] Where X 2 It is N or CH;

[1044] Each R 3Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1045] n is an integer from 1 to 4.

[1046]

[122] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[121] have the structure of formula IIIb-2:

[1047]

[1048]

[123] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[122] have the structure of formula IIIb-3:

[1049]

[1050] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1051]

[124] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[123] have the structure of formula IIIb-4:

[1052]

[1053]

[125] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[124] have the structure of formula IIIb-5:

[1054]

[1055] Where X 3 It is N or CH;

[1056] m is 1 or 2;

[1057] R 6 R 7 R8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1058] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1059] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1060] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1061]

[126] The compounds described in paragraph

[125] or pharmaceutically acceptable salts thereof have the structure of formula IIIb-6:

[1062]

[1063]

[127] The compounds described in paragraph

[125] or pharmaceutically acceptable salts thereof have the structure of formula IIIb-7:

[1064]

[1065]

[128] The compounds as described in paragraphs

[126] or

[127] , wherein R 6 It is a methyl group.

[1066]

[129] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[125] have the structure of formula IIIb-8 or IIIb-9:

[1067]

[1068]

[130] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[109] have the structure of formula IVb:

[1069]

[1070] Where R 9 It is an H or C1-C6 alkyl group; and

[1071] a is 0 or 1.

[1072]

[131] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[130] have the structure of formula IVb-1:

[1073]

[1074] Where X 2 It is N or CH;

[1075] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1076] n is an integer from 1 to 4.

[1077]

[132] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[131] have the structure of formula IVb-2:

[1078]

[1079]

[133] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[132] have the structure of formula IVb-3:

[1080]

[1081] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1082]

[134] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[133] have the structure of formula IVb-4:

[1083]

[1084]

[135] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[134] have the structure of formula IVb-5:

[1085]

[1086] Where X 3 It is N or CH;

[1087] m is 1 or 2;

[1088] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1089] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1090] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1091] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1092]

[136] The compounds described in paragraph

[135] or their pharmaceutically acceptable salts have the structure of formula IVb-6:

[1093]

[1094]

[137] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[135] have the structure of formula IVb-7:

[1095]

[1096]

[138] The compounds as described in paragraphs

[136] or

[137] , wherein R 6 It is a methyl group.

[1097]

[139] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[135] have the structure of formula IVb-8 or IVb-9:

[1098]

[1099]

[140] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[130] to

[139] , wherein R 9 It is a methyl group.

[1100]

[141] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[108] , wherein Y is -NHS(O)2- or -NHS(O)2NH-.

[1101]

[142] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[141] have the structure of formula Vb:

[1102]

[1103] Where a is 0 or 1.

[1104]

[143] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[142] have the structure of formula Vb-1:

[1105]

[1106] Where X 2 It is N or CH;

[1107] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1108] n is an integer from 1 to 4.

[1109]

[144] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[143] have the structure of formula Vb-2:

[1110]

[1111]

[145] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[144] have the structure of formula Vb-3:

[1112]

[1113] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1114]

[146] The compounds described in paragraph

[145] or their pharmaceutically acceptable salts have the structure of formula Vb-4:

[1115]

[1116]

[147] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[146] have the structure of formula Vb-5:

[1117]

[1118] Where X 3 It is N or CH;

[1119] m is 1 or 2;

[1120] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1121] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1122] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1123] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1124]

[148] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[141] have the structure of formula VIb:

[1125]

[1126] Where a is 0 or 1.

[1127]

[149] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[148] have the structure of formula VIb-1:

[1128]

[1129] Where X 2 It is N or CH;

[1130] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1131] n is an integer from 1 to 4.

[1132]

[150] The compounds described in paragraph

[149] or pharmaceutically acceptable salts thereof have the structure of formula VIb-2:

[1133]

[1134]

[151] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[150] have the structure of formula VIb-3:

[1135]

[1136] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1137]

[152] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[151] have the structure of formula VIb-4:

[1138]

[1139]

[153] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[152] have the structure of formula VIb-5:

[1140]

[1141] Where X 3 It is N or CH;

[1142] m is 1 or 2;

[1143] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1144] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1145] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1146] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1147]

[154] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[141] have the structure of formula VIIb:

[1148]

[1149] Where R 9 It is an H or C1-C6 alkyl group; and

[1150] a is 0 or 1.

[1151]

[155] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[154] have the structure of formula VIIb-1:

[1152]

[1153] Where X 2 It is N or CH;

[1154] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1155] n is an integer from 1 to 4.

[1156]

[156] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[155] have the structure of formula VIIb-2:

[1157]

[1158]

[157] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[156] have the structure of formula VIIb-3:

[1159]

[1160] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1161]

[158] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[157] have the structure of formula VIIb-4:

[1162]

[1163]

[159] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[158] have the structure of formula VIIb-5:

[1164]

[1165] Where X 3 It is N or CH;

[1166] m is 1 or 2;

[1167] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1168] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1169] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1170] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1171]

[160] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[154] to

[159] , wherein R 9 It is a methyl group.

[1172]

[161] A compound or a pharmaceutically acceptable salt thereof as described in any of paragraphs

[101] to

[108] , wherein Y is -NHS(O)- or -NHS(O)NH-.

[1173]

[162] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[161] have the structure of formula VIIIb:

[1174]

[1175] Where a is 0 or 1.

[1176]

[163] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[162] have the structure of formula VIIIb-1:

[1177]

[1178] Where X 2It is N or CH;

[1179] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1180] n is an integer from 1 to 4.

[1181]

[164] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[163] have the structure of formula VIIIb-2:

[1182]

[1183]

[165] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[164] have the structure of formula VIIIb-3:

[1184]

[1185] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1186]

[166] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[165] have the structure of formula VIIIb-4:

[1187]

[1188]

[167] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[166] have the structure of formula VIIIb-5:

[1189]

[1190] Where X 3 It is N or CH;

[1191] m is 1 or 2;

[1192] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1193] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1194] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1195] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1196]

[168] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[161] have the structure of formula IXb:

[1197]

[1198] Where a is 0 or 1.

[1199]

[169] . The compounds described in paragraph

[168] or their pharmaceutically acceptable salts have the structure of formula IXb-1:

[1200]

[1201] Where X 2 It is N or CH;

[1202] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1203] n is an integer from 1 to 4.

[1204]

[170] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[169] have the structure of formula IXb-2:

[1205]

[1206]

[171] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[170] have the structure of formula IXb-3:

[1207]

[1208] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1209]

[172] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[171] have the structure of formula IXb-4:

[1210]

[1211]

[173] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[172] have the structure of formula IXb-5:

[1212]

[1213] Where X 3 It is N or CH;

[1214] m is 1 or 2;

[1215] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1216] R 6 and R 7The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1217] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1218] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1219]

[174] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[161] have the structure of formula Xb:

[1220]

[1221] Where R 9 It is an H or C1-C6 alkyl group; and

[1222] a is 0 or 1.

[1223]

[175] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[174] have the structure of formula Xb-1:

[1224]

[1225] Where X 2 It is N or CH;

[1226] Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heterocycloalkyl groups, optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and

[1227] n is an integer from 1 to 4.

[1228]

[176] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[175] have the structure of formula Xb-2:

[1229]

[1230]

[177] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[176] have the structure of formula Xb-3:

[1231]

[1232] Where 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- 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. In some embodiments, R 4 and R 5 It's not hydrogen.

[1233]

[178] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[177] have the structure of formula Xb-4:

[1234]

[1235]

[179] The compounds or pharmaceutically acceptable salts thereof described in paragraph

[178] have the structure of formula Xb-5:

[1236]

[1237] Where X 3 It is N or CH;

[1238] m is 1 or 2;

[1239] R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or

[1240] R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or

[1241] R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or

[1242] R 7 and R 11 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[1243]

[180] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[174] to

[179] , wherein R 9 It is a methyl group.

[1244]

[181] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[110] to

[140] ,

[142] to

[160] or

[162] to

[180] , wherein a is 0.

[1245]

[182] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[110] to

[140] ,

[142] to

[160] or

[162] to

[180] , wherein a is 1.

[1246]

[183] ​​The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[182] , wherein R 2 It is a C1-C6 alkyl group that is optionally substituted.

[1247]

[184] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[183] , wherein R 2 Selected from -CH2CH3 or -CH2CF3.

[1248]

[185] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[184] , wherein R 10 It is hydrogen.

[1249]

[186] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[184] , wherein R 10 It is a hydroxyl group, an optionally substituted C1-C6 alkoxy group, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C6 heteroalkyl group, or an optionally substituted 3- to 7-membered heterocyclic alkyl group.

[1250]

[187] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[186] , wherein R 10 It is an ethoxy group that is optionally substituted.

[1251]

[188] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[186] , wherein R 10 Selected from the following or their stereoisomers:

[1252]

[1253]

[189] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[188] , wherein W is a C1-C4 alkyl group.

[1254]

[190] A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[188] , 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.

[1255]

[191] A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[101] to

[188] , wherein W is a substituted 3- to 10-membered heterocyclic alkyl, a substituted 3- to 10-membered cycloalkyl, a substituted 6- to 10-membered aryl or a substituted 5- to 10-membered heteroaryl.

[1256]

[192] The compound or a pharmaceutically acceptable salt thereof as described in any of paragraphs

[101] to

[188] , wherein W is a substituted 3- to 10-membered heterocyclic alkyl group.

[1257]

[193] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[192] , wherein W is selected from the following or their stereoisomers:

[1258]

[1259]

[1260]

[1261]

[1262]

[194] The compound or a pharmaceutically acceptable salt thereof as described in any of paragraphs

[101] to

[188] , wherein W is optionally a substituted 3- to 10-membered cycloalkyl group.

[1263]

[195] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[194] , wherein W is selected from the following or their stereoisomers:

[1264]

[1265]

[1266]

[196] The compound or a pharmaceutically acceptable salt thereof as described in any of paragraphs

[101] to

[188] , wherein W is a substituted 5- to 10-membered heteroaryl group.

[1267]

[197] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[196] , wherein W is selected from the following or their stereoisomers:

[1268]

[1269]

[198] The compound or a pharmaceutically acceptable salt thereof as des...

Claims

1. Use of a compound having the following formula or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need of it: 。 2. The use as described in claim 1, wherein the cancer is pancreatic cancer.

3. The use as described in claim 2, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

4. The use as described in any one of claims 1-3, wherein the cancer comprises a K-Ras mutation selected from K-Ras G12C, K-Ras G12V, K-Ras G12R, K-Ras G12D, K-Ras G13D and K-Ras Q61H.

5. The use as described in any one of claims 1-3, wherein the cancer comprises a Ras mutation in G12, G13, or Q61.

6. The use as claimed in claim 5, wherein the cancer comprises a K-Ras mutation selected from K-Ras G12C, K-Ras G12V, K-Ras G12R, K-Ras G12D, K-Ras G13D and K-Ras Q61H.

7. Use of a compound having the following formula or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting Ras protein in cells: 。 8. Use of a compound having the following formula or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting Ras protein: 。 9. The use as described in claim 7 or 8, wherein the Ras protein is K-Ras.

10. The use as claimed in any one of claims 7 to 9, wherein the Ras protein comprises a mutation.

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