Ras inhibitors

Abstract

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

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511277613.4 (22) Application Date 2020.11.04 (30) Priority Data 62 / 930406 2019.11.04 US 62 / 951562 2019.12.20 US 63 / 000355 2020.03.26 US 63 / 043523 2020.06.24 US (62) Divisional Application Data 202080091075.9 2020.11.04 (71) Applicant Ruixin Pharmaceutical Company Address California, USA (72) Inventor Liu Yang J. Craig (74) Patent Agency China Patent Agency (Hong Kong) Limited 72001 Patent Attorney Yu Miaopeng Chang (51) Int.Cl. C07D 213 / 61 (2006.01) C07D 213 / 55 (2006.01) C07F 5 / 02 (2006.01) (54) Invention Title RAS Inhibitor (57) Abstract This invention relates to RAS inhibitors. The present disclosure is characterized by macrocyclic compounds capable of inhibiting Ras protein, pharmaceutical compositions thereof, and protein complexes thereof, and their use in cancer treatment. Claims 2 pages Description 391 pages Drawings 1 page CN 121471132 A 2026.02.06 CN 1 21 47 11 32 A 1. A compound selected from: . 2. The compound of claim 1, wherein the compound has the following structure: . 3. The compound of claim 1, wherein the compound has the following structure: . 4. The compound of claim 1, wherein the compound has the following structure: . 5. The compound of claim 1, wherein the compound has the following structure: . 6. The compound of claim 1, wherein the compound has the following structure: . Claims 1 / 2 pages 2 CN 121471132 A 7. The compound of claim 1, wherein the compound has the following structure: . Claims 2 / 2 pages 3 CN 121471132 A RAS Inhibitor

[0001] This application is a divisional application of the invention patent application filed on November 4, 2020, with application number 202080091075.9 and entitled "RAS Inhibitor".

[0002] Cross-Reference to Related Applications This application claims U.S. Application No. 62 / 930,406, filed on November 4, 2019; U.S. Application No. 62 / 951, filed on December 20, 2019.Priority interests in U.S. Application No. 562, filed March 26, 2020; and U.S. Application No. 63 / 000, 355, filed June 24, 2020; all of which are hereby incorporated by reference in their entirety. Background Art

[0003] The vast majority of 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. In fact, many such drug / target interaction pairs are known, which may mislead one into believing that small molecule regulators targeting most (if not all) proteins can be discovered, thus providing a reasonable amount of time, effort, and resources. But this is far from the case. Currently, it is estimated that only about 10% of all human proteins are available as targets for small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The remaining 90% are currently considered difficult to cure or treat with the small molecule drugs mentioned above. Such targets are often referred to as “undruggable.” These undruggable targets comprise a large portion of medically important human proteins and are often untapped reservoirs. Therefore, there is great interest in discovering novel molecular modalities that can modulate the function of such undruggable targets.

[0004] It has been well established in the literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play a crucial role in a variety of human cancers and are therefore suitable targets for anticancer therapies. In fact, in the United States, about 30% of all human cancers are caused by Ras protein mutations, many of which are fatal. Dysregulation of Ras proteins caused by 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 activation 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 GTPase-activated protein (GAP) dependence and intrinsic GTP hydrolysis rate, leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolal affinity for GTP, enabling activation even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) in Ras have also contributed to oncogenic activity in some cancers.

[0005] Despite extensive drug discovery efforts targeting Ras over the past decades, drugs directly targeting Ras have not yet been widely developed.The drug has not yet been approved. More effort is needed to discover other medicines for cancers driven by various Ras mutations. Summary of the Invention

[0006] This document provides Ras inhibitors. 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 cytosolic 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 or conjugate 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 in which the compounds of the present invention and the complexes or conjugates thereform 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.

[0007] Therefore, in some embodiments, this disclosure is characterized by a compound of formula I or a pharmaceutically acceptable salt thereof: Formula I Wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heterocyclic arylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; an optionally substituted C1-C4 heteroalkylene group; or a 3- to 8-membered heteroaryl group; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium, or enosylate;X1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R2 is absent, 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 heteroalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl; R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or R7 and R8. Combined with the carbon atom to which it is attached, it forms C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;R7a and R8a are independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogenated, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogenated, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered cycloalkyl. The alkyl group or optionally substituted 3- to 7-membered heterocyclic alkyl group, or R9 and L combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halogenated, hydroxylated, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halogenated; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0008] Pharmaceutical compositions are also provided comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] A conjugate or a salt thereof is also provided, the conjugate comprising the structure of formula IV: M-L-P Formula IV where L is a linker; P is a monovalent organic moiety; and M has the structure of formula V: Formula V where the dashed line represents zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to a carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to a carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-;Optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; X1 is an optionally substituted C1-C2 heteroalkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Specification 4 / 391 page 7 CN 121471132 A Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocycloalkyl. R2 is absent, 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; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atoms they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl)R7a and R8a are independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogenated, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogenated, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocyclic alkyl. R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R9 and L combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halogenated, hydroxylated, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halogenated; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0010] 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. Specification 5 / 391 pages 8 CN 121471132 A

[0011] In some embodiments, a method of treating a subject with Ras protein-related conditions is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0012] A method of inhibiting Ras protein in cells is also provided, the method comprising contacting the cells with an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0013] Specifically, upon careful consideration, any limitations discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the present invention may be used in any method of the present invention, and any method of the present invention may be used to manufacture or utilize any compound or composition of the present invention. Brief Description of the Drawings

[0014] Figure 1A: The compound of the present invention, namely compound A, strongly and persistently inhibits oncogenic signals in a pancreatic CDX model (HPAC CDX model, PDAC, KRAS G12D / WT). Single-dose experiments, n = 3 animals / time point, all dose levels were well tolerated.

[0015] Figure 1B: In vivo treatment of tumor regression in a KRAS G12D tumor-driven pancreatic CDX model (HPAC CDX model, PDAC, KRAS G12D / WT) with the compound of the present invention, namely compound A. n = 10 animals / group. ***p<0.001. All dose levels were well tolerated.

[0016] Definitions and Chemical Terms In this application, unless clearly stated 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 as 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” shall be understood to encompass the listed components or steps, whether presented alone or in combination with one or more additional components or steps; and (iv) when providing a scope, endpoints are included.

[0017] 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 ​​along 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 of the value, unless otherwise specified or otherwise apparent from the context (e.g., when the number would exceed 100% of the possible value).

[0018] As used herein, in the case of describing adjacent atoms, the term “adjacent” refers to divalent atoms directly connected by covalent bonds.

[0019] As used herein, “compound of the invention” and similar terms, whether explicitly indicated or not, refer to the Ras inhibitors described herein, including compounds of formula I and its derivatives, as well as the compounds listed in Tables 1 and 2, and their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including transisomers), and tautomers.

[0020] The term “wild-type” means an entity having 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 wild-type genes and polypeptides often exist in a variety of different forms (e.g., alleles).

[0021] 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 from the context.It is clear that the described structures can be understood to represent any such isomer or isotopic form, individually or in combination. Specification 6 / 391 pages 9 CN 121471132 A

[0022] 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. The compounds of this disclosure containing asymmetrically substituted carbon atoms may be isolated in an optically active form or a racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as alkenes, C=N double bonds, etc., 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 may be isolated in the form of mixtures of isomers or in separate isomeric forms.

[0023] In some embodiments, one or more compounds described herein may be present in different tautomeric forms. As will become clear from the context, unless explicitly excluded, references to such compounds encompass all such tautomers. In some embodiments, the tautomer is obtained by exchanging a single bond with an adjacent double bond, accompanied by proton migration. In some embodiments, the tautomer can 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 proton-transfer tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, and cyclic forms in which the proton may occupy two or more positions in the heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 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 to one form by appropriate substitution. In some embodiments, the tautomer form is obtained by interconversion of acetals.

[0024] 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 the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. Isotopically labeled compounds (e.g., compounds labeled with 3H and 14C) can be used in the determination of compound or substrate tissue distribution. Tritium (i.e., 3H) and carbon-14 (i.e.,14C isotopes are available due to their ease of preparation and detection. Additionally, substitution with heavier isotopes, such as deuterium (i.e., 2H), 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 substituted with 2H or 3H, or one or more carbon atoms are substituted with carbon enriched in 13C or 14C. Positron emission isotopes, such as 15O, 13N, 11C, and 18F, can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents, following procedures similar to those disclosed for the compounds of the invention described herein.

[0025] 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 may be used in any such form, including any solid form. In some embodiments, the compounds described or depicted herein may be provided in hydrate or solvate form.

[0026] Throughout this specification, substituents of the compounds disclosed herein are disclosed in groups or ranges. Specifically, this disclosure is intended to include every individual combination of members of each of the groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound comprises multiple positions, and where substituents are disclosed in groups or ranges at these positions, unless otherwise indicated, this disclosure is intended to cover individual compounds and groups of compounds (e.g., species and subclasses) containing every individual combination of members at each position.

[0027] 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 is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) itself is optional. As described herein, some compounds of interest may contain one or more “optionally substituted” moieties. In general, the term “substituted”, whether or not preceded by the term “optionally”, means that one or more hydrogens of the specified moieties are replaced by suitable substituents, such as any of the substituents or groups described herein. Unless otherwise indicated, the “optionally substituted” group may have suitable substituents at each substituted position of the group, and when more than one position in any given structure is substituted by more than one substituent selected from the specified group, the substituents at each position may be the same or different.Similarly, 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 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 the compound to be produced, detected, and in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0028] Suitable monovalent substituents on the substituted carbon atoms of the “optionally substituted” group can independently be deuterium; halogen; -(CH2)O-4R°; -(CH2)O-4OR°; -O(CH2)O-4R°; -O-(CH2)O-4C(O)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CH2)O-4Ph, which can be substituted by R°; -(CH2)O-4O(CH2)O-1Ph, which can be substituted by R°; -CH= CHPh, this group can be substituted with R°; -(CH2)0-4O(CH2)0-1-pyridyl, this group can be substituted with R°; 4 to 8-membered saturated or unsaturated heterocyclic alkyl (e.g., pyridyl); 3 to 8-membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O) NR°2;‑N(R°)N(R°)C(O)OR°;‑(CH2)0‑4C(O)R°;‑C(S)R°;‑(CH2)0‑4C(O)OR°;‑(CH2)0‑4‑C(O)‑ N(R°)2;‑(CH2)0‑4‑C(O)‑N(R°)‑S(O)2‑R°;‑C(NCN)NR°2;‑(CH2)0‑4C(O)SR°;‑(CH2)0‑4C(O) OSiR°3;‑(CH2)0‑4OC(O)R°;‑OC(O)(CH2)0‑4SR°;‑SC(S)SR°;‑(CH2)0‑4SC(O)R°;‑(CH2)0‑4C (O)NR°2;‑C(S)NR°2;‑C(S)SR°;‑(CH2)0‑4OC(O)NR°2;‑C(O)N(OR°)R°;‑C(O)C(O)R°;‑C(O)CH2C(O)R°;‑C(NOR°)R°;‑(CH2)0‑4SSR°;‑(CH2)0‑4S(O)2R°;‑(CH2)0‑4S(O)2OR°;‑(CH2)0‑4OS (O)2R°;‑S(O)2NR°2;‑(CH2)0‑4S(O)R°;‑N(R°)S(O)2NR°2;‑N(R°)S(O)2R°;‑N(OR°)R°;‑C (NOR°)NR°2;‑C(NH)NR°2;‑P(O)2R°;‑P(O)R°2;‑P(O)(OR°)2;‑OP(O)R°2;‑OP(O)(OR°)2;‑OP (O)(OR°)R°; -SiR°3; -(C1-C4 straight-chain or branched-chain alkylene)O-N(R°)2; or -(C1-C4 straight-chain or branched-chain alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-C6 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, -CH2- (5 to 6-membered heteroaryl ring), or a 3 to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, despite the above definitions, two independently existing R° together with their inserted atoms form a 3 to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0029] Suitable monovalent substituents on R° (or a ring formed by two independently existing R° and their inserted atoms) can independently be halogens, -(CH2)O-2R, -(halogenated R), -(CH2)O-2OH, -(CH2)O-2OR, -(CH2)O-2CH(OR)2, -O (halogenated R), -CN, -N3, -(CH2)O-2C(O)R, -(CH2)O-2C(O)OH, -(CH2)O-2C(O)OR, -(CH2)O-2SR, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR, -(CH2)O-2NR, -NO2, -SiR, -OSiR, -C(O)SR, - (C1-4 straight-chain or branched alkylene)C(O)OR● or -SSR●, wherein each R● is unsubstituted or, if preceded by "halogenated", substituted only by one or more halogens, and is independently selected from C1-C4 aliphatic groups, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S. (Specification 8 / 391 pages 11 CN)121471132 A

[0030] 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))2-3O- or -S(C(R*2))2-3S-, wherein R* is selected from hydrogen each time it appears independently; C1-C6 aliphatic groups that may be substituted as defined below; or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently 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-, wherein R* is selected from hydrogen each time it appears independently; C1-C6 aliphatic groups that may be substituted as defined below; or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] Suitable substituents on the aliphatic group of R* include halogen, -R●, -(halogenated R●), -OH, -OR●, -O(halogenated R●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2 or -NO2, wherein each R● is unsubstituted or substituted with only one or more halogens when "halogenated" is added before it, and is independently a C1-C4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, -C(S)NR†2, -C(NH)NR†2 or -N(R†)S(O)2R† ; wherein each R† is independently hydrogen; a C1-C6 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 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, despite the above definition, two independently existing R†s together with their inserted atoms form a 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on the aliphatic group of R† are independently halogen, -R●, -(halogenated R●), -OH, -OR●, -O(halogenated R●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2 or -NO2, wherein each R● is unsubstituted or, if preceded by "halogenated", is substituted only by one or more halogens, and is independently a C1-C4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom of R† include =O and =S.

[0034] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0035] As used herein, the term "alkoxy" refers to an -O-C1-C20 alkyl group, wherein the alkoxy group is connected to the remainder of the compound by an oxygen atom.

[0036] As used herein, the term "alkyl" refers to a saturated, straight or branched monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10 or 1 to 6) carbons. In some embodiments, the alkyl group is non-branched (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.

[0037] 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 "Cx-Cy alkylene" refers to an alkylene group having between x and y carbon atoms. The exemplary x values ​​are 1, 2, 3, 4, 5, and 6, and the exemplary y values ​​are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C10, C2-C20, C2-C6, C2-C10, or C2-C20 alkylene groups). In some embodiments, the alkylene group may be further substituted with 1, 2, 3, or 4 substituents as defined herein.

[0038] Unless otherwise specifically stated, as used herein, the term "alkenyl" means a monovalent straight-chain or branched chain 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 specifically stated, as used herein, the term "alkenyl" means 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. Specification 9 / 391 page 12 CN 121471132 A

[0039] As used herein, the term "alkynyl" means a monovalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 4, 2 to 6 or 2 to 10 carbons) containing a carbon-carbon triple bond, and examples include ethynyl and 1-propynyl.

[0040] As used herein, the term "alkynyl sulfone" means a group containing a structure, wherein R is any chemically feasible substituent described herein.

[0041] As used herein, the term "amino" means -N(R†)2, such as -NH2 and -N(CH3)2.

[0042] As used herein, the term "aminoalkyl" means an alkyl moiety in which one or more carbon atoms are substituted by one or more amino groups.

[0043] 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 through 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 hydroxyvaline, isoleucine, leucine, lysine, methionine, valine, ornithine, phenylalanine, proline, pyrrolidone, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0044] 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 include phenyl, naphthyl, phenanthryl, and anthracene. An aromatic ring may be attached to its side group at any heteroatom or carbon ring atom that produces a stable structure, and unless otherwise specifically stated, any ring atom may optionally be substituted.

[0045] As used herein, the term “CO” represents a bond. For example, a portion of the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, and is also represented as -N(C(O)-H)-.

[0046] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to a monovalent, optionally substituted 3- to 12-membered 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. Examples of carbocyclic groups include cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, dihydroindenyl, and decahydronaphthyl.The carbon ring may be attached to its side group at any ring atom that produces a stable structure, and any ring atom may optionally be substituted unless otherwise specified.

[0047] As used herein, the term “carbonyl” means a C(O) group, which may also be represented as C=O.

[0048] As used herein, the term “carboxyl” means -CO2H, (C=O)(OH), COOH or C(O)OH, or its unprotonated counterpart.

[0049] As used herein, the term “cyano” means a -CN group.

[0050] As used herein, the term “cycloalkyl” means a monovalent saturated cyclic hydrocarbon group, which may be a bridging ring, fused ring or spiro ring having three to eight ring carbons, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloheptyl.

[0051] As used herein, the term “cycloalkenyl” means a monovalent, non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specifically stated, can be a bridging ring, fused ring, or spiroring having three to eight cyclic carbons and containing one or more carbon-carbon double bonds.

[0052] As used herein, the term “diastereomer” means stereoisomers that are not mirror images of each other and do not overlap.

[0053] As used herein, the term “enantiomer” means each individual optically active form of the compounds of the present 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).

[0054] The term “guanidinyl” refers to a group having the following structure: , wherein each R is independently any chemically feasible substituent described herein.

[0055] As used herein, the term “guanidinyl alkyl alkyl” means an alkyl moiety in which one or more carbon atoms are substituted by one or more guanidinyl moieties.

[0056] As used herein, the term “haloacetyl” means an acetyl group in which at least one hydrogen atom is substituted by a halogen.

[0057] As used herein, the term “haloalkyl” means an alkyl moiety in which one or more carbon atoms are substituted by one or more identical or different halogen moieties.

[0058] As used herein, the term “halogen” means a halogen selected from bromine, chlorine, iodine, or fluorine.

[0059] As used herein, the term “heteroalkyl” means an alkyl group as defined herein in which at least one carbon atom is substituted by a heteroatom (e.g., O, N, or S atom). The heteroatom may appear in the middle or at the end of the group.

[0060] As used herein, the term “heteroaryl” means a monovalent, monocyclic, or polycyclic group containing at least one fully aromatic ring.Structure: That is, it contains 4n+2 π electrons within the monocyclic or polycyclic system and at least one heteroatom selected from N, O, or S in the aromatic ring. An illustrative unsubstituted heteroaryl group 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) carbon atoms. The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups fused with any of the aforementioned heteroaryl rings to one or more aromatic or carbon 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 may 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.

[0061] 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, which may be a bridging ring, a fused ring, or a spirocyclic ring. A 5-membered ring has zero to two double bonds, and 6-membered and 7-membered rings have zero to three double bonds. An exemplary unsubstituted heterocyclic alkyl group 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 "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 include 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 any ring atom may optionally be substituted unless otherwise specifically stated. Specification 11 / 391 pages 14 CN 121471132 A

[0062] As used herein, the term "hydroxyl" refers to a -OH group.

[0063] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted by one or more -OH portions.

[0064] 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 compounds of the present invention may have oneThe compound may contain multiple chiral centers or double bonds, and thus exist in stereoisomers, 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 invention, the chemical structures described herein, and therefore the compounds of the 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. Mixtures of enantiomers and stereoisomers of the compounds of the 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 by well-known asymmetric synthetic methods from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts.

[0065] As used herein, the term "linker" refers to linking part B of a compound of formula I to part W, such that the resulting compound can obtain a divalent organic moiety with an IC50 value of 2 μM or lower, as provided in the following examples and in the Ras-RAF disruption assay provided herein: The purpose of this biochemical assay is to measure the ability of the test compound to promote the formation of a ternary complex between a nucleotide-loaded Ras isoform and a cyclic protein A; the resulting ternary complex disrupts the binding of the BRAFRBD construct, inhibiting Ras signal transduction via the RAF effector.

[0066] In a assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, label-free cyclophilic protein A, His6-K-Ras-GMPPNP (or other Ras variants), and GST-BRAFRBY were combined in 384-well assay plates at final concentrations of 25 µM, 12.5 nM, and 50 nM, respectively. The compounds present in each well of the assay plate were obtained by serially diluting the final concentration of 30 µM at 10 points. After incubation at 25°C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay sample wells to achieve final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for another 1.5 hours. TR-FRET signals were read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promoted the destruction of the Ras:RAF complex were identified as compounds that reduced the TR-FRET ratio relative to the DMSO control wells.

[0067] In some embodiments, the linker comprises 20 or fewer linear atoms. In some embodiments, the linker...The linker contains 15 or fewer linear atoms. In some embodiments, the linker contains 10 or fewer linear atoms. In some embodiments, the molecular weight of the linker is less than 500 g / mol. In some embodiments, the molecular weight of the linker is less than 400 g / mol. In some embodiments, the molecular weight of the linker is less than 300 g / mol. In some embodiments, the molecular weight of the linker is less than 200 g / mol. In some embodiments, the molecular weight of the linker is less than 100 g / mol. In some embodiments, the molecular weight of the linker is less than 50 g / mol.

[0068] As used herein, a “monovalent organic moiety” is less than 500 kDa. In some embodiments, a “monovalent organic moiety” is less than 400 kDa. In some embodiments, a “monovalent organic moiety” is less than 300 kDa. In some embodiments, a “monovalent organic moiety” is less than 200 kDa. In some embodiments, a “monovalent organic moiety” is less than 100 kDa. In some embodiments, a “monovalent organic moiety” is less than 50 kDa. In some embodiments, a “monovalent organic moiety” is less than 25 kDa. In some embodiments, the “monovalent organic fraction” is less than 20 kDa. In some embodiments, the “monovalent organic fraction” is less than 15 kDa (page 12 / 391, CN 121471132 A). In some embodiments, the “monovalent organic fraction” is less than 10 kDa. In some embodiments, the “monovalent organic fraction” is less than 1 kDa. In some embodiments, the “monovalent organic fraction” is less than 500 g / mol. In some embodiments, the “monovalent organic fraction” is in the range between 500 g / mol and 500 kDa.

[0069] As used herein, the term “stereoisomer” means that a compound (e.g., any compound of any formula described herein) may have all possible different isomers and configurational forms, 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.

[0070] As used herein, the term "sulfonyl" refers to a -S(O)2- group.

[0071] As used herein, the term "thiocarbonyl" refers to a -C(S)- group.

[0072] As used herein, the term "vinyl ketone" refers to a group comprising a carbonyl group directly attached to a carbon-carbon double bond.

[0073] As used herein, the term "vinyl sulfone" refers to a group comprising a sulfonyl group directly attached to a carbon-carbon double bond.

[0074] As used herein, the term "acetylenolone" refers to a group comprising a structure, wherein R is the structure described herein.Any chemically feasible substituent.

[0075] 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 form, protected form, prodrug form, ester form, isomer form (e.g., optical or structural isomers), isotopic form, etc. In some embodiments, a specific compound mentioned may refer to a specific form of the compound. In some embodiments, a specific compound mentioned may refer to the compound in any form. In some embodiments, for example, a formulation of a single stereoisomer of a compound may be considered as a different form of the compound rather than a racemic mixture of the compound; a specific salt of a compound may be considered as 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 as a different form from a formulation of another configurational isomer ((E) or (Z)) containing the double bond; a formulation of one or more atoms having an isotope different from the isotope present in a reference formulation may be considered as a different form. Detailed Description

[0076] Compounds This document provides Ras inhibitors. The methods described herein require the formation of a high-affinity three-component complex or conjugate 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 three-component complex or conjugate 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 or conjugates thereto 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.

[0077] Without being bound by theory, the inventors assume that the covalent and non-covalent interactions of the compounds of the present invention with Ras and the chaperone protein (e.g., cyclophilin A) can contribute to the inhibition of Ras activity. In some embodiments, the compounds of the present invention form covalent adducts with the side chains of Ras proteins (e.g., the -CH2-COOH or -CH2-COO- side chain of aspartic acid at positions 12 or 13 of the mutant Ras protein). Covalent adducts may also be formed with other side chains of Ras. Additionally or alternatively, non-covalent interactions may play a role: for example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, and combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors. Therefore, the present invention…The inventive compounds can inhibit a variety of Ras proteins (e.g., K-Ras, N-Ras, H-Ras, and mutants thereof with mutations at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, as well as other mutants described herein).

[0078] Methods for determining covalent adduct formation are known in the art. One method for determining covalent adduct formation is to perform a “crosslinking” assay, as described in the examples and below: Note: The following protocol describes a procedure for monitoring the crosslinking of K-Ras G12C (GMP-PNP) with the compounds of the present invention. This protocol can also be performed using other Ras proteins or nucleotides, such as K-Ras G12D.

[0079] The purpose of this biochemical assay is to measure the ability of the test compound to covalently label K-Ras isoforms carrying nucleotides. In an assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCl, 1 mM MgCl2, 1 mM BME, 5 µM cyclic protein A, and 2 µM test compound, a 5 µM stock solution of K-Ras (1-169) G12C loaded with GMP-PNP was diluted 10-fold to a final concentration of 0.5 µM; and the final sample volume was 100 µL.

[0080] The sample was incubated at 25°C for up to 24 hours, followed by quenching with 10 µL of 5% formic acid. The quenched sample was centrifuged at 15,000 rpm for 15 minutes in a benchtop centrifuge, and then 10 µL aliquots were injected into a reversed-phase C4 column and eluted to a mass spectrometer with an increasing acetonitrile gradient in the mobile phase. Analysis of the raw data was performed using Waters MassLynx MS software, where the binding percentage was calculated from the unconvolution of labeled and unlabeled K-Ras protein peaks.

[0081] Therefore, this document provides a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof: Formula I Wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heterocyclic arylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; G is an optionally substituted C1-C4 alkylene group; optionally substituted C1-C4 alkenyl group; optionally substituted C1-C4 alkenyl group. (See page 14 / 391 of the specification, 17 CN)121471132 A Heteroalkyl group; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene group; or 3 to 8-membered heteroaryl group; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium or enolic acid; X1 is optionally substituted C1-C2 heteroalkylene group, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 The alkyl group is a cyclic alkyl group, optionally substituted 3- to 6-membered alkenyl group, optionally substituted 3- to 6-membered heterocyclic alkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl group, optionally substituted C2-C6 alkenyl group, optionally substituted C2-C6 ynyl group, optionally substituted 3- to 6-membered cyclic alkyl group, optionally substituted 3- to 7-membered heterocyclic alkyl group, optionally substituted 6-membered aryl group, optionally substituted 5- or 6-membered heteroaryl group; R3 is absent, or R2 and R3 combined with the atoms to which they are attached to form optionally substituted 3- to 8-membered cyclic alkyl groups or optionally substituted 3- to 14-membered heterocyclic alkyl groups; R4 is absent, hydrogen, halogen, cyano group, or methyl group optionally substituted with 1 to 3 halogens; R5 is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano, a hydroxyl or a C1-C4 alkoxy, a cyclopropyl or a cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, a halogen or an optionally substituted C1-C3 alkyl group, or R6 and R7 combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group.R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; Specification 15 / 391 pages 18 CN 121471132 A R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atoms they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered cycloalkyl. The alkyl group or optionally substituted 3- to 7-membered heterocyclic alkyl group, or R9 and L combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halo; and R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0082] In some embodiments, R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocyclic alkyl.

[0083] In some embodiments, R34 is hydrogen.

[0084] In some embodiments of the compounds of the present invention, G is optionally substituted C1-C4 heteroalkylene.

[0085] In some embodiments, the compounds of the present invention have the structure of formula Ia, or a pharmaceutically acceptable salt thereof: Formula Ia wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds;A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cyclohexane; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or optionally substituted 5- to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cyclohexane; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; L is absent or is a linker; Specification 16 / 391 pages 19 CN 121471132 AW is a crosslinking group, said group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, Chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium or enolic acid; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl; R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano, a hydroxyl or a C1-C4 alkoxy, a cyclopropyl or a cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, a halogen or an optionally substituted C1-C3 alkyl group, or R6 and R7 combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group.R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; Specification 17 / 391 pages 20 CN 121471132 A R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0086] In some embodiments of the compounds of the present invention, X2 is NH. In some embodiments, X3 is CH.

[0087] In some embodiments of the compounds of the present invention, R11 is hydrogen. In some embodiments, R11 is C1-C3 alkyl, such as methyl.

[0088] In some embodiments, the compounds of the present invention have the structure of formula Ib, or a pharmaceutically acceptable salt thereof: Formula Ib wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to a carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloene alkyl; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to a carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloene alkyl; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5- to 6-membered heterocyclic arylene; L is absent or is a linker;W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium, or enolic acid; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; Specification 18 / 391 pages 21 CN 121471132 A R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms to which they are attached, form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, an optionally substituted C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or an optionally substituted C1-C3 alkyl, or R6 and R7, together with the carbon atoms to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl)R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocyclic alkyl; R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0089] In some embodiments of the compounds of the present invention, X1 is an optionally substituted C1-C2 alkylene. In some embodiments, X1 is methylene.

[0090] In some embodiments of the compounds of the present invention, R4 is hydrogen.

[0091] In some embodiments of the compounds of the present invention, R5 is hydrogen. In some embodiments, R5 is an optionally halogen-substituted C1-C4 alkyl. In some embodiments, R5 is methyl.

[0092] In some embodiments of the compounds of the present invention, Y4 is C. In some embodiments, R4 is hydrogen. In some embodiments, Y5 is CH. In some embodiments, Y6 is CH. In some embodiments, Y1 is C. In some embodiments, Y2 is C. In some embodiments, Y3 is N. In some embodiments, R3 is absent. In some embodiments, Y7 is C.

[0093] In some embodiments, the compounds of the present invention have the structure of formula Ic, or a pharmaceutically acceptable salt thereof: Specification 19 / 391 Page 22 CN 121471132 A Formula Ic Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cyclohexane; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cyclohexane; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; L is absent or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, etc.Chloroethyl carbamate, thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium or enolate; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R5 is hydrogen, an optionally halogenated C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or an optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocyclic alkyl; Specification 20 / 391 pages 23 CN 121471132 A R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl.R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0094] In some embodiments of the compounds of the present invention, R6 is hydrogen.

[0095] In some embodiments of the compounds of the present invention, R2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heteroalkyl. In some embodiments, R2 is an optionally substituted C1-C6 alkyl, such as ethyl.

[0096] In some embodiments of the compounds of the present invention, R7 is an optionally substituted C1-C3 alkyl. In some embodiments, R7 is C1-C3 alkyl.

[0097] In some embodiments of the compounds of the present invention, R8 is an optionally substituted C1-C3 alkyl. In some embodiments, R8 is C1-C3 alkyl.

[0098] In some embodiments, the compounds of the present invention have the structure of formula Id, or a pharmaceutically acceptable salt thereof: Formula Id wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cyclohexane; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or optionally substituted 5- to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cyclohexane; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; L is absent or is a linker; W is a crosslinking group, said group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, Chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium or enolic acid; Specification 21 / 391 pages 24 CN 121471132 A R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is a C1-C3 alkyl group; and R9 is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heteroalkyl group.

[0099] In some embodiments of the compounds of the present invention, R1 is a 5- to 10-membered heteroaryl group. In some embodiments, R1 is an optionally substituted 6-membered aryl group or an optionally substituted 6-membered heteroaryl group.

[0100] In some embodiments, the compounds of the present invention have the structure of formula Ie, or a pharmaceutically acceptable salt thereof: Formula Ie wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to a carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cyclohexane; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or optionally substituted 5- to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to a carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cyclohexane; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; L is absent or is a linker; W is a crosslinking group, said group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, Chloroethyl carbamate, thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazonium or enolate; R2 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heteroalkyl; Xe is N or CH; and R12 is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl. Specification 22 / 391 pages 25 CN 121471132 A

[0101] In some embodiments of the compounds of the present invention, Xe is N. In some embodiments, Xe is CH.

[0102] In some embodiments of the compounds of the present invention, R12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R12 is, or. In some embodiments, R12 is.

[0103] In some embodiments, the compounds of the present invention have the structure of formula If, or a pharmaceutically acceptable salt thereof: Formula If where the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocycloene alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heterocycloene arylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6-membered cycloene alkyl.The group is: a 3- to 6-membered heterocyclic alkylene group; a 6-membered arylene group; or a 5- to 6-membered heterocyclic arylene group; G is a substituted C1-C4 alkylene group; a substituted C1-C4 alkenyl group; a substituted C1-C4 heterocyclic alkylene group; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; a substituted C1-C4 heterocyclic alkylene group; or a 3- to 8-membered heterocyclic arylene group; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1 2-Dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazonium or enolic acid; X1 is an optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R' is independently H or optionally substituted C1-C4 alkyl; Specification 23 / 391 page 26 CN 121471132 A Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl; R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano, a hydroxyl, or a C1-C4 alkoxy, a cyclopropyl, or a cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, a halogen, or an optionally substituted C1-C3 alkyl group, or R6 and R7 combined with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted cycloalkyl group.The substituted 3- to 7-membered heterocyclic alkyl group; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocyclic alkyl. R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0104] In some embodiments, the compounds of the present invention have the structure of formula VI, or a pharmaceutically acceptable salt thereof: Specification 24 / 391 pages 27 CN 121471132 A Formula VI Wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene (e.g., phenyl or phenol); or optionally substituted 5 to 10-membered heterocyclic arylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloene alkylene; optionally substituted 3- to 6-membered heterocycloene alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenyl; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein the C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein the C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium, or enolic acid; X1 is optionally substituted C1-C2 heteroalkylene, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2- C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; Specification 25 / 391 pages 28 CN 121471132 A R2 is absent, 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; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atoms they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl)R7a and R8a are independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogenated, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogenated, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocyclic alkyl. R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R9 and L combined with the atoms they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; R34 is hydrogen or C1-C3 alkyl; and Xe and Xf are independently N or CH.

[0105] In some embodiments, the compounds of the present invention have the structure of formula VIa, or a pharmaceutically acceptable salt thereof: Specification 26 / 391 pages 29 CN 121471132 A Formula VIa Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered aryl (e.g., phenyl or phenol) or optionally substituted 5- to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; L is absent or is a linker; W is a crosslinking group, said group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, Chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium or enolic acid; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; n is 0, 1 or 2;R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; R2 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heteroalkyl; Xe and Xf are independently N or CH; R11 is hydrogen or C1-C3 alkyl; and R21 is hydrogen or C1-C3 alkyl.

[0106] In some embodiments of the compounds of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0107] In some embodiments, the compounds of the present invention have the structure of formula VIb, or a pharmaceutically acceptable salt thereof: Specification 27 / 391 pages 30 CN 121471132 A Formula VIb Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered aryl (e.g., phenyl or phenol) or optionally substituted 5- to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; L is absent or is a linker; W is a crosslinking group, said group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, Chloroethyl carbamate, thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazonium, or enolic acid; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and Xe and Xf are independently N or CH.

[0108] In some embodiments of the compounds of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0109] In some embodiments, the compounds of the present invention have the structure of Formula VII, or a pharmaceutically acceptable salt thereof: Formula VII Specification 28 / 391 pages 31 CN 121471132 A Wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds;A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; an optionally substituted C1-C4 heteroalkylene group; or a 3- to 8-membered heteroaryl group; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium, or enosylate; X1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is or; R2 is absent, 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; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl;R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atoms they are attached to form C=CR7'R8'. ; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halosubstituted, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered cycloalkyl. The alkyl group or optionally substituted 3- to 7-membered heterocyclic alkyl group, or R9 and L combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0110] In some embodiments of the compounds of the present invention, A is optionally substituted 6-membered aryl. In some embodiments, A has the following structure: wherein R13 is hydrogen, hydroxyl, amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments, R13 is hydrogen. In some embodiments, R13 is hydroxyl.

[0111] In some embodiments of the compounds of the present invention, B is -CHR9-. In some embodiments, R9 is optionally substitutedThe substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R9 is: , or. In some embodiments, R9 is: . In some embodiments, R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heteroalkyl. Specification 30 / 391 pages 33 CN 121471132 A

[0112] In some embodiments, B is optionally substituted 6-membered arylene. In some embodiments, B is 6-membered arylene. In some embodiments, B is: .

[0113] In some embodiments of the compounds of the present invention, R7 is methyl.

[0114] In some embodiments of the compounds of the present invention, R8 is methyl.

[0115] In some embodiments, R34 is hydrogen.

[0116] In some embodiments of the compounds of the present invention, the linker has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula II Wherein A1 is the bond between the linker and B; A2 is the bond between W and the linker; B1, B2, B3 and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3 to 14 The heterocyclic alkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted C1- to C7 heteroalkyl group; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; and D1 is optionally substituted C1- to C10 alkylene group, optionally substituted C2- to C10 alkenyl group, optionally substituted C2- to C10 alkyne group, optionally substituted 3- to 14-membered heterocyclic alkylene group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted 3- to 8-membered heterocyclic alkylene group, optionally substituted 6- to 10-membered aryl group, optionally substituted C2- to C10 polyethylene glycol-like polyol, or optionally substituted C1- to C10 heteroalkylene group, or A1-(B1)f-(C1)g-(B2)h- linked to -(B3)i-(C2)j-(B 4) The chemical bond of k–A2. In some embodiments, the linker is an acyclic linker. In some embodiments, the linker has the structure of formula IIa: Formula IIa Where Xa is absent or N; R14 is absent, hydrogen or optionally substituted C1-C6 alkyl; and L2 is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.At least one of Xa, R14, or L2 is present. In some embodiments, the linker has the following structure: Specification 31 / 391, page 34, CN 121471132 A. In some embodiments, the linker is or contains a cyclic group. In some embodiments, the linker has the structure of formula IIb: Formula IIb where o is 0 or 1; R15 is hydrogen or optionally substituted C1-C6 alkyl; Cy is optionally substituted 3- to 8-membered cycloene alkyl, optionally substituted 3- to 8-membered heterocycloene alkyl, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and L3 is absent, -SO2-, optionally substituted C1- to 4-membered alkylene, or optionally substituted C1- to 4-heteroalkyl. In some embodiments, the linker has the following structure: (Specification 32 / 391, page 35, CN 121471132 A; Specification 33 / 391, page 36, CN 121471132 A). In some embodiments, the linker of formula II is selected from the group consisting of: .

[0117] In some embodiments of the compounds of the present invention, W comprises carbodiimide. In some embodiments, W has the structure of formula IIIa: Formula IIIa, wherein R14 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W has the following structure: (Specification 34 / 391, page 37, CN 121471132 A).

[0118] In some embodiments, W comprises oxazoline or thiazoline. In some embodiments, W has the structure of formula IIIb: Formula IIb Wherein X1 is O or S; X2 is absent or NR19; R15, R16, R17 and R18 are independently hydrogen or optionally substituted C1-C6 alkyl; and R19 is hydrogen, C(O) (optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 aryl, optionally substituted 3 to 14 heterocyclic alkyl or optionally substituted 5 to 10 heteroaryl. In some embodiments, W is.

[0119] In some embodiments, W comprises chloroethylurea, chloroethylthiourea, chloroethyl carbamate or chloroethyl thiocarbamate. In some embodiments, W has the structure of formula IIIc: Formula IIIc where X3 is O or S; X4 is O, S, or NR26; R21, R22, R23, R24, and R26 are independently hydrogen or optionally substituted C1-C6 alkyl groups; andR25 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W is...

[0120] In some embodiments, W comprises aziridine propane. In some embodiments, W has the structure of formula IIId1, IIId2, IIId3, or IIId4: wherein X5 is absent or NR30; Y is absent or C(O), C(S), S(O), SO2, or optionally substituted C1-C3 alkylene; R27 is hydrogen, -C(O)R32, -C(O)OR32, -SOR33, -SO2R33, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl; R28 and R29 are independently hydrogen, CN, C(O)R31, CO2R31, C(O)R31R31, optionally substituted C1-C6 alkyl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl. (See page 39 of specification 36 / 391, CN 121471132 A) The substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; each R31 is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; R30 is hydrogen or optionally substituted C1-C6 alkyl; and R32 and R33 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W is: Specification 37 / 391 pages 40 CN 121471132 A.

[0121] In some embodiments, W comprises an epoxide. In some embodiments, W is.

[0122] In some embodiments, W is a crosslinking group bound to an organic portion, which is a Ras-binding portion, i.e., RBM-W, wherein after the RBM-W compound contacts the Ras protein, the RBM-W binds to the Ras protein to form a conjugate. For example, the W portion of the RBM-W compound may bind to an amino acid of the Ras protein, for example, by crosslinking, to form a conjugate. In some embodiments, the Ras-binding portion is a K-Ras-binding portion. In some embodiments, the K-Ras-binding portion binds to residues of the K-Ras Switch-II binding pouch of the K-Ras protein. In some embodiments, the Ras-binding portion is an H-Ras-binding portion.It binds to residues of the H-Ras Switch-II binding pouch of the H-Ras protein. In some embodiments, the Ras-binding moiety is an N-Ras-binding moiety that binds to residues of the N-Ras Switch-II binding pouch of the N-Ras protein. The W in the RBM-W compound may include any W described herein. The molecular weight of the Ras-binding moiety is typically less than 1200 Da. For a description of the domains of the Ras protein, see, for example, Johnson et al., 292:12981-12993 (2017), which is incorporated herein by reference.

[0123] In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or transisomers thereof.

[0124] Table 1: Some of the compounds of the present invention Specification 38 / 391 pages 41 CN 121471132 A Specification 39 / 391 pages 42 CN 121471132 A Specification 40 / 391 pages 43 CN 121471132 A Specification 41 / 391 pages 44 CN 121471132 A Specification 42 / 391 pages 45 CN 121471132 A Specification 43 / 391 pages 46 CN 121471132 A Specification 44 / 391 pages 47 CN 121471132 A Specification 45 / 391 pages 48 CN 121471132 A Specification 46 / 391 pages 49 CN 121471132 A Specification 47 / 391 pages 50 CN 121471132 A Instruction manual 48 / 391 pages 51 CN 121471132 A Instruction manual 49 / 391 pages 52 CN 121471132 A Instruction manual 50 / 391 pages 53 CN 121471132 A Instruction manual 51 / 391 pages 54 CN 121471132 A Instruction manual 52 / 391 pages 55 CN 121471132 A Instruction manual 53 / 391 pages 56 CN 121471132 A Instruction manual 54 / 391 pages 57 CN 121471132 A Instruction manual 55 / 391 pages 58 CN 121471132 A Instruction manual 56 / 391 pages 59 CN 121471132 A Instruction manual 57 / 391 pages 60 CN 121471132 A Instruction manual 58 / 391 pages 61 CN121471132 A Instruction Manual 59 / 391 pages 62 CN 121471132 A Instruction Manual 60 / 391 pages 63 CN 121471132 A Instruction Manual 61 / 391 pages 64 CN 121471132 A Instruction Manual 62 / 391 pages 65 CN 121471132 A Instruction Manual 63 / 391 pages 66 CN 121471132 A Instruction Manual 64 / 391 pages 67 CN 121471132 A Instruction Manual 65 / 391 pages 68 CN 121471132 A Instruction Manual 66 / 391 pages 69 CN 121471132 A Instruction Manual 67 / 391 pages 70 CN 121471132 A Instruction Manual 68 / 391 pages 71 CN 121471132 A Instruction manual 69 / 391 pages 72 CN 121471132 A Instruction manual 70 / 391 pages 73 CN 121471132 A Instruction manual 71 / 391 pages 74 CN 121471132 A Instruction manual 72 / 391 pages 75 CN 121471132 A Instruction manual 73 / 391 pages 76 CN 121471132 A Instruction manual 74 / 391 pages 77 CN 121471132 A Instruction manual 75 / 391 pages 78 CN 121471132 A Instruction manual 76 / 391 pages 79 CN 121471132 A Instruction manual 77 / 391 pages 80 CN 121471132 A Instruction manual 78 / 391 pages 81 CN 121471132 A Instruction manual 79 / 391 pages 82 CN 121471132 A Instruction Manual 80 / 391 pages 83 CN 121471132 A Instruction Manual 81 / 391 pages 84 CN 121471132 A Instruction Manual 82 / 391 pages 85 CN 121471132 A Instruction Manual 83 / 391 pages 86 CN 121471132 A Instruction Manual 84 / 391 pages 87 CN 121471132 A Instruction Manual 85 / 391 pages 88 CN 121471132 A Instruction Manual 86 / 391 pages 89 CN 121471132 A Instruction Manual 87 / 391 pages 90 CN 121471132 A Instruction Manual 88 / 391 pages 91 CN 121471132A Instruction Manual 89 / 391 Page 92 CN 121471132 A Instruction Manual 90 / 391 Page 93 CN 121471132 A Instruction Manual 91 / 391 Page 94 CN 121471132 A Instruction Manual 92 / 391 Page 95 CN 121471132 A Instruction Manual 93 / 391 Page 96 CN 121471132 A Instruction Manual 94 / 391 Page 97 CN 121471132 A Instruction Manual 95 / 391 Page 98 CN 121471132 A Instruction Manual 96 / 391 Page 99 CN 121471132 A Instruction Manual 97 / 391 Page 100 CN 121471132 A Instruction Manual 98 / 391 Page 101 CN 121471132 A Instruction Manual 99 / 391 Page 102 CN 121471132 A Instruction Manual 100 / 391 Page 103 CN 121471132 A Instruction Manual 101 / 391 Page 104 CN 121471132 A Instruction Manual 102 / 391 Page 105 CN 121471132 A Instruction Manual 103 / 391 Page 106 CN 121471132 A Instruction Manual 104 / 391 Page 107 CN 121471132 A Instruction Manual 105 / 391 Page 108 CN 121471132 A Instruction Manual 106 / 391 Page 109 CN 121471132 A Instruction Manual 107 / 391 Page 110 CN 121471132 A Instruction Manual 108 / 391 Page 111 CN 121471132 A Instruction Manual 109 / 391 Page 112 CN 121471132 A Instruction Manual 110 / 391 Page 113 CN 121471132 A Instruction Manual 111 / 391 Page 114 CN 121471132 A Instruction Manual 112 / 391 Page 115 CN 121471132 A Instruction Manual 113 / 391 Page 116 CN 121471132 A Instruction Manual 114 / 391 Page 117 CN 121471132 A Instruction Manual 115 / 391 Page 118 CN 121471132 A Instruction Manual 116 / 391 Page 119 CN 121471132 A Instruction Manual 117 / 391 Page 120 CN 121471132 APage 118 / 391, CN 121471132 A *Assuming the stereochemistry of aziridine carbon.

[0125] 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 some cases, the absolute stereochemistry has been determined. In some cases, a single example number corresponds to a mixture of stereoisomers. 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.

[0126] In some embodiments, the compounds of Table 2 are provided, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of this invention are selected from Table 2, or pharmaceutically acceptable salts thereof, or stereoisomers thereof.

[0127] Table 2: Some of the compounds of the present invention (Pages 119 / 391, CN 121471132 A, Pages 120 / 391, CN 121471132 A, Pages 121 / 391, CN 121471132 A, Pages 122 / 391, CN 121471132 A, Pages 123 / 391, CN 121471132 A, Pages 124 / 391, CN 121471132 A, Pages 125 / 391, CN 121471132 A, Pages 125 / 391, CN 121471132 A, Pages 126 / 391, CN 121471132 A, Pages 126 / 391, CN 121471132 A, Pages 127 / 391, CN 121471132 A, Pages 128 / 391) Page 131 CN 121471132 A Specification 129 / 391 Page 132 CN 121471132 A Specification 130 / 391 Page 133 CN 121471132 A Specification 131 / 391 Page 134 CN 121471132 A Specification 132 / 391 Page 135 CN 121471132 A.

[0128] 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 some cases, 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.

[0129] In some embodiments, the compounds of the present invention are or are used as prodrugs, such as for administration to cells or to a subject in need.

[0130] Pharmaceutical compositions are also provided, which comprise the compounds of the present invention or pharmaceutically acceptable salts thereof, to...And pharmaceutically acceptable excipients.

[0131] A conjugate or a salt thereof is also provided, the conjugate comprising the structure of formula IV: M-L-P Formula IV Wherein L is a linker; P is a monovalent organic moiety; and M has the structure of formula Va: Formula Va Wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 6-membered heteroalkylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O); optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 6-membered heteroalkylene; 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenyl; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3- to 8-membered heteroarylene; X1 is optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2- C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl or optionally substituted 5 to 10-membered heteroaryl, or R1 and R2 combined with the atoms they are attached to form optionally substituted 3 to 14-membered heterocycloalkyl; R2 is absent, 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 heterocyclic alkyl, optionally substituted 6-membered alkyl.Aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; or R9 and L combined with the atoms to which they are attached form an optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halo; and R11 is hydrogen or C1-C3 alkyl.

[0132] In some embodiments, the conjugate has the structure of formula IV: M-L-P Formula IV where L is the linker;P is a monovalent organic moiety; and M has the structure of formula Vb: Vb where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene; an optionally substituted C1-C4 alkenyl; an optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; an optionally substituted C1-C4 heteroalkylene; or a 3- to 8-membered heteroaryl; Specification 135 / 391 pages 138 CN 121471132 A X1 is an optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2- C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl or optionally substituted 5 to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl;R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8' ; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0133] In some embodiments, the conjugate has the structure of formula IV: (Specification 136 / 391, page 139, CN 121471132 AM-L-P Formula IV) where L is the linker; P is the monovalent organic moiety; and M has the structure of formula Vc: Formula Vc where A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered aryl (e.g., phenyl or phenol), or optionally substituted 5- to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heteroaryl; X1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; n is 0, 1, or 2;R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Xe and Xf are independently N or CH; R2 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl.

[0134] In some embodiments of the compounds of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0135] In some embodiments, the conjugate has the structure of formula IV: M-L-P Specification 137 / 391 pages 140 CN 121471132 A Formula IV Wherein L is a linker; P is a monovalent organic moiety; and M has the structure of formula Vd: Formula Vd Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered aryl (e.g., phenyl or phenol) or optionally substituted 5- to 6-membered heterocycloalkylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heterocycloalkylene; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, Chloroethyl carbamate, thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazonium, or enolic acid; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and Xe and Xf are independently N or CH.

[0136] In some embodiments of the compounds of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0137] In some embodiments of the conjugate of the present invention, the linker has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula IIWherein A1 is the bond between the linker and B; A2 is the bond between P and the linker; B1, B2, B3, and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3 to 14 The heterocyclic alkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted C1-C7 heteroalkyl group; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; and D1 is optionally substituted C1-C10 alkylene group, optionally substituted C2-C10 alkenyl group, optionally substituted C2-C10 alkyne group, optionally substituted 3- to 8-membered heterocyclic alkylene group, optionally substituted 6- to 10-membered aryl group, optionally substituted C2-C10 polyethylene glycol group, or optionally substituted C1-C10 heteroalkylene group, or A1-(B1)f-(C1)g-(B 2) h- linked to -(B3)i-(C2)j-(B4)k–A2 chemical bond. In some embodiments of the conjugate of the present invention, the linker is linked to the monovalent organic moiety by a bond to the carboxyl group in the amino acid residue of the monovalent organic moiety.

[0138] In some embodiments of the conjugate of the present invention, the monovalent organic moiety is a protein. In some embodiments, the protein is a Ras protein. In some embodiments, the Ras protein is K-Ras G12D or K-Ras G13D.

[0139] 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 G12D or K-Ras G13D. Other Ras mutations are also described herein.

[0140] A method for treating a subject with Ras protein-related conditions is also provided, comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0141] 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. For example, the Ras protein is K-Ras G12D or K-Ras G13D.Other Ras proteins are also described herein. The cells may be cancer cells, such as pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, acute myeloid leukemia cells, multiple myeloma cells, thyroid adenocarcinoma cells, myelodysplastic syndrome cells, or squamous cell lung cancer cells. Other cancer types are also described herein. The cells may be in vivo or in vitro.

[0142] For the compounds of the present invention, one stereoisomer may exhibit inhibitory activity superior to another stereoisomer. For example, one transtransisomer may exhibit inhibitory activity, while another transtransisomer may exhibit very low or no inhibitory activity.

[0143] In some embodiments, the methods or uses described herein further include the administration of additional anticancer therapies. In some embodiments, the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are also described herein.

[0144] Synthetic Methods The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0145] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described in the following schemes, as well as synthetic methods known in synthetic organic chemistry techniques or modifications of the methods understood by those skilled in the art. The methods include, but are not limited to, the methods described in the following schemes.

[0146] The compounds in Table 1 herein were prepared using the methods disclosed herein, or using the methods disclosed herein in combination with knowledge of those skilled in the art. The compounds in Table 2 can be prepared using the methods disclosed herein, or using the methods disclosed herein in combination with the knowledge of those skilled in the art. Specification 139 / 391 pages 142 CN 121471132 A

[0147] Scheme 1. General Synthetic Method of Macrocyclic Esters Scheme 1 outlines a general synthetic method of macrocyclic esters. Appropriately substituted aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylprop-1-ol (1) can be prepared in three steps using protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boric acid as starting materials, including palladium-mediated coupling, alkylation and deprotection reactions.

[0148] The amino-hexahydropyridazine-3-carboxylate-boronate (2) can be prepared in three steps, including protection, iridium catalyst-mediated borylation, and coupling with (S)-hexahydropyridazine-3-carboxylate.

[0149] The final macrocyclic ester can be prepared by coupling amino-hexahydropyridazine-3-carboxylate-boronate (2) with aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylprop-1-ol (1) in the presence of a Pd catalyst, followed by hydrolysis and macrocyclic lactone-esterification steps to obtain a suitably protected macrocyclic intermediate (4). Additional deprotection or functionalization steps are required to prepare the final compound. For example, those skilled in the art will be able to load the desired -B-L-W groups of the compound of formula (I) into the macrocyclic ester, wherein B, L, and W are as defined herein, including by using methods illustrated in some of the following schemes and in the Examples section herein.

[0150] Scheme 2. Alternative General Synthetic Methods for Macrocyclic Esters Alternatively, macrocyclic esters can be prepared as described in Scheme 2. A suitably protected bromo-indole group (5) can be coupled with a borate ester (3) in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Coupling with (S)-hexahydropyridazine-3-carboxylic acid methyl ester, followed by hydrolysis and macrocyclic lactone formation, yields an iodine intermediate (6). Coupling with a suitably substituted borate ester in the presence of a Pd catalyst yields a fully protected macrocycle (4). Additional deprotection or functionalization steps are required to prepare the final compound. For example, those skilled in the art will be able to load the desired -B-L-W groups of the compound of formula (I) into the macrocyclic ester, wherein B, L, and W are as defined herein, including by using methods illustrated in some of the following schemes and in the Examples section herein.

[0151] Scheme 3. A general synthetic method for a macrocycle containing a nitrogen-containing heterocyclic propane is shown in Scheme 3. Such compounds can be prepared by reacting a suitable amine (1) with a carboxylic acid (2) containing a nitrogen-containing heterocyclic propane in the presence of a standard amide coupling agent, and if R1 is a protecting group, then the azacyclic propane is subsequently deprotected, and if necessary, the phenol is deprotected, to obtain the final compound (4).

[0152] Scheme 4. A general synthetic method for a macrocycle containing a carbodiimide is shown in Scheme 4. Such compounds can be prepared by reacting a suitable amine (1) with a carboxylic acid (2) containing a thiourea in the presence of a standard amide coupling agent, and then converting the thiourea (3) into a carbodiimide (4) in the presence of a 2-chloro-1-methylpyridin-1-onium salt of iodide.

[0153] Scheme 5. A general synthetic method for macrocyclic compounds containing chloroethylurea is shown in Scheme 5. Such compounds can be prepared by reacting a suitable amine (1) with an isocyanate (2) under basic conditions, followed by deprotection of the phenol if necessary, to produce the final compound (4).

[0154] Scheme 6. General synthetic method for macrocycles containing aminooxazoline As shown in Scheme 6, such compounds can be prepared by cyclizing an appropriate chloroethylurea (1) at high temperature to produce the final compound (2).

[0155] Scheme 7. General synthetic method for macrocycles containing epoxy groups As shown in Scheme 7, such compounds can be prepared by reacting an appropriate amine (1) with an epoxy-containing carboxylic acid (2) in the presence of a standard amide coupling agent to produce the final compound (3).

[0156] Furthermore, the compounds of this disclosure can be synthesized using the methods described in the following examples, as well as synthetic methods known in synthetic organic chemistry, or modifications of the methods as understood by those skilled in the art. The methods include, but are not limited to, the methods described in the following examples. For example, those skilled in the art will be able to load the desired -B-L-W group of the compound of formula (I) into the macrocyclic ester, wherein B, L, and W are as defined herein, including by using the methods exemplified in some of the above schemes and in the Examples section herein.

[0157] Pharmaceutical Compositions and Methods of Use The compounds involved in this invention are Ras inhibitors and can be used to treat cancer. Therefore, one embodiment of the invention provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and a method for preparing such a composition using the compounds of the invention.

[0158] As used herein, the term "pharmaceutical composition" refers to a compound formulated with a pharmaceutically acceptable excipient, such as a compound of the invention or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the compound is present in the pharmaceutical composition in an amount suitable for a unit dose administered in a treatment regimen, which shows a statistically significant likelihood of achieving a predetermined 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 in the following ways: 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, or 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.

[0160] As used herein, “pharmaceuticalally acceptable excipient” means any excipient that is non-toxic and non-inflammatory in the body of a subject.Excipients without active ingredients (e.g., a medium that can suspend or dissolve an active compound). Typical excipients include, for example: anti-adhesion agents, antioxidants, binders, 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 methyl cellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methyl cellulose, 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 instructions 142 / 391 pages 145 CN 121471132 AC and xylitol. Those skilled in the art will recognize a variety of reagents and materials that can 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.

[0161] Unless explicitly stated otherwise, the compounds described herein, whether explicitly stated or not, may be provided or used in salt form, for example, in a pharmaceutically acceptable salt form. As used herein, the term "pharmaceutically acceptable salt" means suitable for use in contact with human tissues without excessive toxicity, irritation, or allergic reaction, within the limits of reasonable medical judgment.Reaction, etc., and salts of the compounds described herein that are 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 PHStahl and CGWermuth), Wiley-VCH, 2008. The salts may be prepared in situ during the final separation and purification of the compounds described herein, or separated by reacting a free basic group with a suitable organic acid.

[0162] The compounds of the present invention may have ionizable groups, thereby enabling their preparation into pharmaceutically acceptable salt forms. These salts may be acid addition salts involving inorganic or organic acids, or, in the case that the compounds of the present invention are in acid form, the salts may be prepared from inorganic or organic bases. In some embodiments, the compound is prepared as a pharmaceutically acceptable salt form 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.

[0163] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, transbutenedioate, glucono-heptahydrate, glycerol phosphate, hemisulfate, heptahydrate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-optionally substituted hydroxy-ethanesulfonate. Lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0164] 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.

[0165] 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 the dosing instructions 143 / 391 pages 146 CN 121471132 A, which is determined to be associated with a desired or beneficial outcome when administered to the 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.

[0166] 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 different time intervals separate 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 the dosing regimen are different amounts. In some embodiments, the dosing regimen comprises 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 that first dose. In some embodiments, the dosing regimen comprises 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 that first dose. In some implementations, the dosage regimen, when administered to the relevant population (i.e., a therapeutic dosage regimen), is associated with a desired or beneficial outcome.

[0167] A “treatment regimen” refers to a dosage regimen administered to the relevant population that is associated with a desired or beneficial therapeutic outcome.

[0168] The term “treatment” (“treatment / treat / treating”) in its broadest sense refers to any application of a substance (e.g., 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 who exhibits one or more identified signs of the relevant disease, condition, or disorder. In some embodiments, treatment may be used on a subject who has been 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.

[0169] The term “therapeutic effective amount” means an amount sufficient to treat the disease, condition, or disorder when administered to a population suffering from or susceptible to the disease, condition, or disorder according to a therapeutic dosing regimen. 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 the treatment. It is particularly important to understand that a particular subject can indeed be "therapeuticly effective" and "refractory." In some embodiments, a referred therapeutically effective amount can mean an amount measured, such as 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 embodiments, a therapeutically effective amount may be formulated as multiple doses, for example, as part of a dosing regimen, or administered in multiple doses.

[0170] For use as treatment of a subject, the compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as pharmaceutical compositions or veterinary compositions. Depending on the subject to be treated, the administration method, and the desired type of treatment, such as prevention, treatment, or therapy, the compound or a pharmaceutically acceptable salt thereof is formulated in accordance with the parameters stated therein. An overview of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia ofPharmaceutical labelling, 144 / 391 pages, 147 CN 121471132 A Technology, edited by J. Swarbrick and J. C. Boylan, 1988–1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0171] The compositions may be prepared according to conventional 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 presence of the compounds described herein or pharmaceutically acceptable salts thereof may be, by weight, 1–95% of the total amount of the pharmaceutical composition.

[0172] The composition may be provided in dosage forms suitable for administration as follows: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, sac-like, intraurethral, ​​intrathecal, epidural, ocular, or by injection, inhalation, or direct contact with the mucous membranes of the nose, genitourinary, genital, or oral cavity. Therefore, the pharmaceutical composition may be, for example, in the form of 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 routine pharmaceutical practice.

[0173] 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. Administering to animal subjects (e.g., to humans) may be done via any suitable route. For example, in some embodiments, administration may be bronchial (including intrabronchial infusion), buccal, intestinal, intradermal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrasheath, intravenous, intrasacral, transmucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including intratracheal infusion), percutaneous, vaginal, or vitreous administration.

[0174] The formulation may be prepared in a manner suitable for systemic or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or those prepared for percutaneous, 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.

[0175] For injection, the formulation may be prepared in conventional forms, such as liquid solutions or suspensions, or suitable for administration by injection.The preparation is carried out in a liquid as a solution or suspension in a solid form, or in an emulsion form. Suitable excipients include, for example, water, physiological saline, dextran, 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, dehydrated sorbitol monolaurate, etc.

[0176] Various sustained-release drug delivery systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0177] 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 pharmaceutically acceptable salts thereof. It will be understood in the art that suitable forms include syrups, capsules, and tablets.

[0178] Each compound or pharmaceutically acceptable salt thereof described herein may be formulated in a variety of ways known in the art. For example, the first and second agents in a combination therapy may be formulated together or separately. Other modes of combination therapy are also described herein.

[0179] Individual 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 a powder, a suppository, or a liquid in a vial, two surface 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 unit dose for one subject, for multiple uses for a specific subject (at a constant dose, or where the potency of individual compounds or their pharmaceutically acceptable salts may vary with treatment progress); or the kit may contain multiple doses suitable for administration to multiple subjects (“integrated package”). The kit components may be assembled in a carton, blister pack, bottle, tube, etc.

[0180] Formulations for oral use include tablets containing a mixture of an active ingredient and a non-toxic, pharmaceutically acceptable excipient. The excipient may be, for example, an inert diluent or filler (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); a granulating agent and disintegrant (e.g., a cellulose derivative, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); a binder (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 a lubricant.Agents, gliding agents, and anti-adhesion agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0181] Two or more compounds may be mixed together in tablets, capsules, or other media, or may be spaced apart. In one embodiment, the first compound is contained on the inside of the tablet, and the second compound is on the outside, thereby releasing the majority of the second compound before the first compound is released.

[0182] Formulations for oral use may also be provided in the form of chewable tablets or 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 in the form of 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 fine spherical particles can 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 drying device.

[0183] Controlled release of dissolution or diffusion can be achieved by appropriately coating the compound with tablets, capsules, fine spherical particles, or granular formulations, 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 hydrogel, 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, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0184] Liquid forms of compounds of the present invention or pharmaceutically acceptable salts and compositions thereof, for oral administration, include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical mediators.

[0185] 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. Dosages may be, for example, about 0.001 mg to about 2000 mg daily, about 1 mg to about 1000 mg daily, or about 5 mg daily.

[0186] In some embodiments, the pharmaceutical composition may further comprise additional compounds having antiproliferative activity. Depending on the administration mode, the compound or a pharmaceutically acceptable salt thereof will be formulated to suit the composition for easy 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. Consistently, the first agent and the second agent are formulated together for simultaneous or near-simultaneous administration.

[0187] It should be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, i.e., 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 one or more other desired therapeutic agents or medical procedures. The specific combination of each therapy (therapeutic agent or procedure) 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 these therapies may achieve different effects (e.g., control any adverse effects).

[0188] As described herein, the administration of each drug in the combination therapy can be independent of the administration of one to four times daily for one day to one year, or even for the lifetime of the subject. Chronic / long-term administration is also applicable.

[0189] Method of Use 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.

[0190] Therefore, a method for 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, 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, appendix 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 appendix cancer, endometrial cancer, or melanoma. A method for treating a subject with Ras protein-related conditions 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.Pharmaceutically acceptable salts or pharmaceutical compositions comprising such compounds or salts.

[0191] 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, tumor types such as astrocytoma, breast, cervix, colon and rectum, endometrium, esophagus, stomach, head and neck, hepatocellular carcinoma, larynx, lung, oral cavity, ovary, prostate, and thyroid carcinoma and sarcoma. Other cancers include, for example: Heart cancer, such as sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung cancer, such as bronchogenic carcinoma (squamous cell lung cancer, undifferentiated small cell lung cancer, undifferentiated large cell lung cancer, lung adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancer, 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), leiomyosarcoma, hemangioma, lipoma, etc. Neurofibroma, fibroma); colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); 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); liver, such as: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, vascular tumor; biliary tract, such as: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; Skeletal structures, 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 osteoma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumors; Nervous system structures, such as: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meninges)Tumors, meningeal sarcomas, gliomas); brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumors (pineal gland tumors), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors); spinal neurofibromas, neurofibromatosis type 1, meningiomas, gliomas, sarcomas; gynecological diseases, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, etc.). Botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer); hematopoietic system, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodyplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands, such as: neuroblastoma.

[0192] In some embodiments, the Ras protein is wild-type (RasWT). Therefore, in some embodiments, the compounds of the present invention are used in methods of treating patients with cancers containing RasWT (e.g., K-RasWT, H-RasWT, or N-RasWT). In some embodiments, the Ras protein is Ras amplification (e.g., K-Rasamp). Therefore, in some embodiments, the compounds of the present invention are used in methods of treating patients with cancers containing Rasamp (K-Rasamp, H-Rasamp, or N-Rasamp). In some embodiments, the cancer comprises a Ras mutation, as described herein. In some embodiments, the mutation is selected from: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, (a) G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C,K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R, and combinations thereof; (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof; or any combination thereof. In some embodiments, the cancer includes 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 includes N-Ras mutations selected from the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer includes H-Ras mutations selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer includes 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. 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 RasWT and one or more additional Ras mutations (e.g., K, H, or N-RasWT 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-RasWT 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-RasWT and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T). In some embodiments, the compounds of the present invention inhibit Rasamp and one or more additional Ras mutations (e.g., K-, H-, or N-Rasamp 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-Rasamp 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-Rasamp and N-Ras. Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P. A59D, E132K, E49K, T50I, A146V, or A59T).

[0193] Methods for detecting Ras mutations are known in the art. Such methods include, but are not limited to, direct sequencing and methods using 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 reference in their entirety, including TheraScreen PCR; AmoyDx;PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreenPyro. See also, for example, WO 2020 / 106640.

[0194] 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-Rasamp. In any of the foregoing, unless otherwise specified, the compound may also inhibit RasWT (e.g., K-, H-, or N-RasWT) or Rasamp (e.g., K-, H-, or N-Rasamp).

[0195] In some embodiments, the cancer includes a Ras mutation and a STK11LOF, KEAP1, EPHA5, or NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and includes a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and includes both a K-Ras G12C mutation and an STK11LOF mutation. In some embodiments, the cancer is non-small cell lung cancer and contains K-Ras G12C and STK11LOF mutations. In some embodiments, the cancer contains K-Ras G13C Ras mutations and STK11LOF, KEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and contains K-Ras G12D mutations. In some embodiments, the cancer is non-small cell lung cancer and contains K-Ras G12V mutations. In some embodiments, the cancer is colorectal cancer and contains K-Ras G12C mutations. In some embodiments, the cancer is pancreatic cancer and contains K-Ras G12D mutations. In some embodiments, the cancer is pancreatic cancer and contains K-Ras G12V mutations.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, the compound may also inhibit RasWT (e.g., K-, H-, or N-RasWT) or Rasamp (e.g., K-, H-, or N-Rasamp).

[0196] 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. 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.

[0197] Combination therapy The methods of the present invention may include the compound 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 dosage can be determined empirically based on the combination and arrangement of drugs, or inferred by isoradiometric measurements (e.g., Black et al., Neurology 65: S3-S6 (2005)).

[0198] The compounds of the present invention can be administered before, after, or simultaneously with one or more of the additional therapies. When combined, the dosage of the compounds of the present invention and the dosage of one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). The compounds of the present invention and additional therapies, such as anticancer agents, can be administered together, such as in the form of a single pharmaceutical composition, or separately, and when administered separately, the administration can occur simultaneously or sequentially. Such sequential administration can be close or distant in time.

[0199] 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 can 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.

[0200] 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., as anti-angiogenic agents,The compound or biologic that is a signal transduction inhibitor, antiproliferator, glycolysis inhibitor, or autophagy inhibitor. In some embodiments, the one or more additional therapies comprise non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics that are anti-angiogenic agents, signal transduction inhibitors, antiproliferators, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, the one or more additional therapies comprise two therapeutic agents. In still other embodiments, the one or more additional therapies comprise three therapeutic agents. In some embodiments, the one or more additional therapies comprise four or more therapeutic agents.

[0201] In this combination therapy section, all references are incorporated by way of citation for the pharmaceutical agents described, whether or not so explicitly stated.

[0202] Non-pharmacological therapies Examples of non-pharmacological treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical resection of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0203] In some embodiments, the compounds of the present invention may be used as postoperative adjuvant therapy. In some embodiments, the compounds of the present invention, as described on pages 150 / 391 of CN 121471132 A, can be used as neoadjuvant therapy before surgery.

[0204] Radiotherapy 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 radiotherapy are known in the art. Radiotherapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, internal 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 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 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 radioactive 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 radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides emitting photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from a solution of any radionuclide, 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 solid radionuclide such as Au-198 or Y-90. Furthermore, the radionuclide can be embedded in a condensate.In gels or radioactive microspheres.

[0205] In some embodiments, the compounds of the present invention can sensitize abnormal cells to radiotherapy in order to kill or inhibit 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 an amount of the compound of the present invention, the amount of which effectively sensitizes the abnormal cells to radiotherapy. The amount of the compound in the method may be determined according to the manner used to determine the effective amount of the compound described herein. In some embodiments, the compounds of the present invention may be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0206] In some embodiments, the non-pharmacological treatment is adoptive transfer of T cells (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells may be generated by any method known in the art. For example, CAR-T cells may be generated by introducing a suitable expression vector encoding CAR into T cells. The source of T cells is obtained from a subject before T cells are amplified 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 sites of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of the invention, various T cell lines available in the art can 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), these 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.

[0207] Therapeutic agents Therapeutic agents can be compounds used to treat cancer or related symptoms.

[0208] For example, the therapeutic agent may be a steroid. Therefore, in some embodiments, the one or more additional therapies include a steroid. Suitable steroids may include, but are not limited to, acetoxypregnenolone, alclometasone, algestone, amcinonide, and beclomethasone.(beclomethasone), betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, product information 151 / 391, page 154, CN 121471132 A Deflazacort, Desonide, Desoximetasone, Dexamethasone, Diflorasone, Diflucortolone, Difuprednate, Enoxolone, Fluazacort, Fiucloronide, Flumethasone, Flunisolide, Fluocinolone acetonide, Fluocinonide, Fluocortin butyl, Fluocortolone, Flumetholone, Fluperolone acetate, Fluprednidene Acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, peramisoneParamethasone, prednicarbate, prednisolone, prednisolone 2,5-diethylaminoacetic acid, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0209] 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 Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885; and International Patent Applications 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.

[0210] The therapeutic agent may be a biological agent (e.g., cytokines (e.g., interferon or interleukin, such as IL-2)) for treating cancer or related symptoms. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof) that arouses a target to stimulate an anticancer response or antagonizes an antigen important for cancer. Antibody-drug conjugates are also included.

[0211] 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 checkpoint proteins, such as an antibody. In some embodiments, the checkpoint inhibitor...These are agents, such as antibodies, that interact with ligands of checkpoint proteins. In some embodiments, checkpoint inhibitors are CTLA-4 inhibitors (e.g., inhibitory antibodies or small molecule inhibitors) (e.g., anti-CTLA-4 antibodies or fusion proteins). In some embodiments, checkpoint inhibitors are PD-1 inhibitors or antagonists (e.g., inhibitory antibodies or small molecule inhibitors). In some embodiments, checkpoint inhibitors are PDL-1 inhibitors or antagonists (e.g., inhibitory antibodies or small molecule inhibitors). In some embodiments, checkpoint inhibitors are PDL-2 inhibitors or antagonists (e.g., inhibitory antibodies or Fc fusions or small molecule inhibitors) (e.g., PDL-2 / Ig fusion proteins). In some implementations, checkpoint inhibitors are inhibitors or antagonists (e.g., inhibitory antibodies or small molecule inhibitors) 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 the checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0212] The therapeutic agent may be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0213] Therapeutic agents can be agents 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, chemotherapeutic agents or targeted therapies.

[0214] 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. These two or more anticancer agents may be used in a mixture for combined administration or separately. Suitable dosing regimens for combined anticancer agents are known in the art and 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).

[0215] Other non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; azacyclopropanes such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneIminoides and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and tris(hydroxymethyl)melamine; polyacetyl (especially bullatacin and bullatacinone); camptothecin (including its synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, 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 mustard, product manual 153 / 391 pages 156 CN 121471132 A such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil Mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as acetylenic antibiotics (e.g., calicheamicin, such as calicheamicin γ-II and calicheamicin ω-II (see, for example, Agnew, Chem. Intl. Ed Engl. 33:183-186)(1994)); dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophore and related chromogens, aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, actinomycin C (cactinomycin), calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, adriamycin, doxorubicin, N-morpholino-doxorubicin, cyanomorpholino-doxorubicin, (2-pyrrololino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (e.g., mitomycin C), mycophenolic acid Drugs containing: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, pteropterin, and trimetrexate; and purine analogs such as fludarabine, 6-mercaptopurine, and thioimidine.Thiamipridine and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-thioazolidin, carmofur, cytarabine, doxifluridine, enocitabine, and fluxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenergics, such as aminoglutethimide, mitotane, and trilostane; and folic acid supplements, such as frolic acid. 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 ansamitocins; Mitoguazone (instructions for use, 154 / 391 pages, 157 CN 121471132 A); Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Phenamet; Pirarubicin; Losoxantrone; Podophyllinic acid; (2-ethylhydrazine; Procarbazine)(procarbazine); PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes, such as T-2 toxin, verracurin A, roridin A A) and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, such as Taxol® (paclitaxel), Abraxane® (a nanoparticle formulation of paclitaxel without polyoxyethylene hydrogenated castor oil and albumin-engineered), and Taxotere® (docetaxel); chloranbucil; tamoxifen. (Nolvadex™); raloxifene; aromatase inhibitor 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine(vincristine); Navelbine® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicins; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above.

[0216] Additional non-limiting examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, and 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, belotecone, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, butionine sulfoximine.CBV (chemotherapy), calyculin, dichloroacetic acid, discormolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol (instructions for use, page 155 / 391, CN 121471132), ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, 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, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0217] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vincristine, vinblastine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), and antibiotics (e.g., actinomycin D).(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., methomyl mustard, cyclophosphamide and analogues melphalan and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors such as abemaciclib and 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), and trazenes-dacarbazinine. (DTIC), antiproliferative / antimitotic antimetabolites (such as folic acid analogs), pyrimidine analogs (such as fluorouracil, azuridine, and cytarabine), purine analogs and related inhibitors (such as mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (such as anastrozole, exemestane, and letrozole), and platinum coordination complexes (such as cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, amylglutathione, histone deacetylase (HDAC) inhibitors (such as trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, and romidepsin). ACY-1215 and panobinostat), mTOR inhibitors (such as vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus)(sirolimus)), KSP (Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., Zalypsis®), PI3K inhibitors such as PI3K δ inhibitors (e.g., GS-1101 and TGR-1202), PI3K δ 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), telomerase inhibitors (e.g., GRN) 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38, HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS 953), PI3K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTI (e.g., Zarnestra™), 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.

[0218] In some embodiments, the anticancer agent is selected from methicillin, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or derivative variant of the foregoing.

[0219] In some embodiments, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®). Small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa®)), erlotinib (Tarceva®), piritinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, JNJ-26483327 and JNJ-26483327.

[0220] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005; and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0221] In some embodiments, the anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitors (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, RLY-1971), SOS1 inhibitors (e.g., BI-1701963, BI-3406), 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. In some embodiments, the anticancer agent is an additional Ras inhibitor (e.g., AMG 510, MRTX1257, MRTX849, ARS-853, ARS-1620, ARS-3248). (or JNJ-74699157), LY3499446) or Ras vaccines or other treatments designed to directly or indirectly reduce the carcinogenic activity of Ras. Other examples of Ras inhibitors that can be combined with the Ras inhibitors of this invention are provided in the following patents (which are incorporated herein by reference in their entirety): WO 2020050890, WO 2020047192, WO2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399、WO 2019150305、WO 2019110751、WO 2019099524、WO 2019051291、WO 2018218070、WO 2018217651、WO 2018218071、WO 2018218069、WO 2018206539、WO 2018143315、WO 2018140600、WO 2018140599、WO 2018140598、WO 2018140514、WO 2018140513、WO 2018140512、WO 2018119183、WO 2018112420、WO 2018068017、WO 2018064510、WO 2017201161、WO 2017172979、WO 2017100546、WO 2017087528、WO 2017058807、WO 2017058805、WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659 and WO 2013155223. Specification 157 / 391 pages 160 CN 121471132 A

[0222] In some embodiments, the 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, pimasertib, 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)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. March 1, 2011; 17) (5):989-1000). The MAPK inhibitor may be PLX8394, LXH254, GDC-5573 or LY3009120.

[0223] In some embodiments, the anticancer agent is a disruptor or an inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway. The PI3K / AKT inhibitor may include, but is not limited to, one or more PI3K / AKT inhibitors described in Cancer (Basel) Sep 2015; 7 (3): 1758–1784. For example, the PI3K / AKT inhibitor 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.

[0224] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0225] In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapy. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0226] IGF-1R inhibitors include linsitinib or a pharmaceutically acceptable salt thereof.

[0227] 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 (Erbitux®) and panitumumab.(Vectibix®), 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 binding specificity to EGFR.

[0228] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some implementations, the EGFR inhibitor is osimertinib (Tagrisso®). 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; EP Specification 158 / 391 pages 161CN 121471132 A 0787772; 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; 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).

[0229] MEK inhibitors include, but are not limited to, pimasiteti, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and bimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets MEK mutations selected from the following Class I MEK1 mutations: D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is selected from the following Class II MEK1 mutations: ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0230] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs as described in WO06 / 044453; 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thiopheno[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-morpholinothieno[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-bromoimidazo[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.

[0231] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibiting Akt1) (Barnett et al., Biochem).J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91: 1808-12); 1-H-imidazo[4,5-c]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., Gilles and Dennis, 159 / 391 pages, 162 CN 121471132 A 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).

[0232] 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 (Torisel®); everolimus (Afinitor®). ; 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)-dihydrorapamycin; derivatives disclosed in WO05 / 005434; U.S. Patents 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842 and 5,256,790, and WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / Derivatives disclosed in WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0233] 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 class 3 BRAF mutations. In some implementations, 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.

[0234] 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 targeted therapies, including not only conventional chemotherapy but also BCL-2 inhibitors such as ABT-263.

[0235] In some embodiments, 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 is modified by involving N-SH2 andThe PTP domain residues bind to a stable, inactive, self-inhibiting conformation. Stimulation with cytokines or growth factors, such as receptor tyrosine kinases (RTKs), exposes the catalytic site, leading to enzymatic activation of SHP2.

[0236] SHP2 is involved in signal transduction via the RAS-mitogen-activated protein kinase (MAPK) pathway, namely JAK-STAT or phosphoinositol 3-kinase-AKT. 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 cancer. Some of these mutations destabilize the self-inhibiting conformation of SHP2 and promote self-activation or enhanced growth factor-driven activation of SHP2. Therefore, SHP2 represents a particularly promising target for developing novel therapies to treat 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 cancer, lung cancer, ovarian cancer, and breast cancer) in vitro. Therefore, combination therapies involving SHP2 inhibitors and RAS pathway inhibitors could be a general strategy for preventing tumor resistance in various malignancies.

[0237] Non-limiting examples of such SHP2 inhibitors known in the art include: Chen et al., Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications: WO2015107493; WO2015107494; WO201507495; WO2016203404; WO2016203405; WO2016203406; WO2011022440; WO2017156397; WO2017079723; WO2017211303; WO2012041524; WO2017211303; WO2019051084; WO2017211303; US20160030594; US20110281942;WO2010011666; WO2014113584; WO2014176488; WO2017100279; WO2019051469; US8637684; WO2007117699; WO2015003094; WO2005094314; WO2008124815; WO2009049098; WO2009135000; WO2016191328; WO2016196591; WO2017078499; WO2017210134; WO2018013597; WO2018129402; WO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731; WO2018172984; and WO2010121212 are each incorporated herein by reference.

[0238] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a hybrid 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. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RMC-4630. In some embodiments, the SHP2 inhibitor is JAB-3068. In some embodiments, the SHP2 inhibitor is RLY-1971.

[0239] 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. In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitors, SHP2 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 combined with a MEK inhibitor andSOS1 inhibitors are used in combination. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and an SHP2 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer, and the treatment comprises administering the Ras inhibitor of the present invention in combination with a second or third therapeutic agent.

[0240] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0241] 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-PDL-1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0242] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that regulate immune responses) containing imide. IMiD drugs include thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0243] 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 / 121168 A1), and are also described elsewhere herein.

[0244] 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 No. 6,111,090, U.S. Patent No. 8,586,023, WO2010 / 003118, and WO2011 / 090754; or, for example, U.S. Patent No. 7,025,962, EP 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, EPAnti-GITR antibodies as described in WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0245] 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, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof synthesized in vitro. Anti-angiogenic agents may be agonists, antagonists, allosteric modulators, toxins, or more generally may 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, the one or more additional therapies include an anti-angiogenic agent.

[0246] The anti-angiogenic agent may be an MMP-2 (matrix metalloproteinase 2) inhibitor, an MMP-9 (matrix metalloproteinase 9) inhibitor, and a COX-II (cyclooxygenase 11) inhibitor. Non-limiting examples of anti-angiogenic agents include rapamycin, tesiromoximide (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, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are inhibitors with very low or no MMP-1 inhibitory activity. More preferably, they are inhibitors relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-9).7. Inhibitors that selectively inhibit MMP-2 or AMP-9 (MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors include AG-3340, RO 32-3555, and RS 13-0830.

[0247] 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), 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™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding domains that specifically bind to VEGF receptors), EGFR inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to EGFR), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 agents 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., specifically binding antibodies or antigen-binding domains, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM unintegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), and specifically binding anti-eph receptor or anti-pterygium antibodies or antigen-binding domains (US Patent No. 5,981, specification 162 / 391 pages 165 CN 121471132 A) Patents Nos. 245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, and 6,057,124 and their families, and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands), and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to PDGFR kinases). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead).Sciences, USA; Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); Ilomastat (Arriva, USA, US5892112); Emaxanib (Pfizer, USA, US 5792783); Vatalanib (Novartis, Switzerland); 2-Methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecortave acetate (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, JP02233610); 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 Evolution, USA and Medlmmune, USA); Enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA); PI 88 (Progen, Australia); Ciprofloxacin (Merck KGaA, German; Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); pINN (Novartis, Switzerland and Schering AG, Germany); Tissue factor pathway inhibitors (EntreMed)Pinetanib (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); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); Instructions for use 163 / 391 pages 166 CN 121471132 A 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 RES 2622 (Bayer, Germany); InKine (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline) (UK); EHT 0101 (ExonHit,France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); Drug delivery system, intraocular 2-methoxyestradiol; Angnex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitor; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed) MAb, KDR (ImClone Systems, USA); MAb, α5β (Protein Design, USA); KDR kinase inhibitors (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); cobretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang,South Korea); 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 FLT 1 (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).

[0248] 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.

[0249] 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, hydroxychloroquine (Plaquenil™), and bafilomycin A1.A1), 5-amino-4-imidazolamide riboside (AICAR), leucocyanidin, inhibitors of type 2A or type 1 protein phosphatases, product manual 164 / 391 pages 167 CN 121471132 A autophagy-inhibiting algal toxins, 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 also be used. In some embodiments, the one or more additional therapies include autophagy inhibitors.

[0250] 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, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, and DA. 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac (HIT), interferon-alpha, doxorubicin, doxorubicinBeta-carboxim, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, beta-carboxim, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, formmustine, gallium nitrate, gemcitabine, gemtuzumab, oxazolidin Zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, imiquimod, interferon α, natural interferon α, interferon α-2, interferon α-2a, interferon α-2b, interferon α-N1, interferon α-n3, compound interferon-1, natural interferon α, interferon β, interferon β-1a, interferon β-1b, interferon γ, natural interferon γ-1a, interferon γ-1b, interleukin-1 β, iobenguane, irinotecan, isoladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristoneMifepristone, Miltefosine, Mirimostim, Mismatched Double-Stranded RNA, Mitoguanidine, Dibromoceroxyl, Mitoantrone, Molgramostim, Nafarelin, Naloxone + Pentazocine, Nartograstim, Nedaplatin, Nilutamide, Noscapine, Novel Erythropoietin, NSC 631570 Octreotide, Oprelvekin, Osaterone, Oxaliplatin, Pacific Paclitaxel, Pamidronic Acid, Pegaspargase, Pegylated Interferon Alpha-2b, Pentosan Polysulfate Sodium), pentostatin, picibanil, bisacodyl, rabbit anti-thymocyte multiclonal antibody, pegylated interferon α-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium hydroxyethylphosphonate Re 186, retinamide, rituximab, romurtide, samarium (153 Sm) Lexidronam), Sargramostim, Sizofiran, Sobuzoxane, Sonermin, Strontium-89 chloride, Suramin, Tasonermin, Tazarotene, Tegafur, Temoporfin, Temozolomide, Teniposide, Tetrachlorodecaoxide, Thalidomide, Thymalfasin, Thyrotropin Alfa, Topotecan, Toremifene, Tositumomab-iodine 131, Trastuzumab, Triosmectin(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), EM 800 Endorecherche, eniluracil, etanidazole, fenretinide, filgrastim, SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), Idiotype 105AD7 MAb (CRC Technology), Idiotype CEA MAb (Trilex), LYM-1-Iodine-131 MAb (Techni clone), Polymorphic Epithelial Mucin-Yttrium 90 MAb (Antisoma), Marimastat, Menogaril, MitomoMonoclonal antibody (mitumomab), motexafin gadolinium, 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, tin ethyletiopurpurpurin, 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.

[0251] Additional examples of therapeutic agents that can be used in combination with the compounds of the present invention include ipilimumab (Yervoy®); trimemumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; [Instructions for Use] 166 / 391 pages 169 CN 121471132 A OX40 (Providence Health) Services); huMAbOX40L; atacecept; CP-870893; lucarumumab; dacetuzumab; muromonab-CD3; EipIpilumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); ado-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®) Canakinumab (Ilaris®); certolizumab pegol (Cimzia®); Zenapax®; daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); gemtuzumab ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (Remicade) ®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®); ranitidine(ranibizumab) (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); tositumomab; tositumomab-i-131; tositumomab and tositumomab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0252] Depending on the disease 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 administered co-administered with other therapies described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately from a second 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 agent described herein into the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention may be administered simultaneously with any therapy described herein, wherein the two agents are present in separate formulations. In another alternative, the compounds of the present disclosure may be administered first, followed by any therapy described herein, or vice versa. In some embodiments of the separate administration regimen, the compounds of the present invention and any therapy described herein are administered at intervals of minutes, hours, or days.

[0253] In some embodiments of any of the methods described herein, a first therapy (e.g., the compounds 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, 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, before or after administration of the one or more additional therapies.

[0254] The invention is further 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).The invention relates to (a) a compound, (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.

[0255] Since one aspect of the invention covers the treatment of diseases or related symptoms with combinations 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 compound of the invention and one or more additional therapies. The kit may contain a container for containing the independent compositions, such as a dispensing bottle or a dispensing foil package. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may contain instructions on the use of the independent components. The kit form is particularly advantageous when the independent components are preferably administered in different dosage forms (e.g., oral or parenteral), at different dose intervals, or when the prescribing healthcare professional wishes to adjust the individual components in the combination.

[0256] Numbered embodiments [1] A compound or a pharmaceutically acceptable salt thereof having the structure of Formula I: Formula I Wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heterocyclic arylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; an optionally substituted C1-C4 heteroalkylene group; or a 3- to 8-membered heteroaryl group; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium, or enosylate; The specification is on pages 168 / 391, 171 CN 121471132 A X1 is an optionally substituted C1-C2 alkylene, NR, O or S(O)n;X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 The alkyl group is a cyclic alkyl group, optionally substituted 3- to 6-membered alkenyl group, optionally substituted 3- to 6-membered heterocyclic alkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl group, optionally substituted C2-C6 alkenyl group, optionally substituted C2-C6 ynyl group, optionally substituted 3- to 6-membered cyclic alkyl group, optionally substituted 3- to 7-membered heterocyclic alkyl group, optionally substituted 6-membered aryl group, optionally substituted 5- or 6-membered heteroaryl group; R3 is absent, or R2 and R3 combined with the atoms to which they are attached to form optionally substituted 3- to 8-membered cyclic alkyl groups or optionally substituted 3- to 14-membered heterocyclic alkyl groups; R4 is absent, hydrogen, halogen, cyano group, or methyl group optionally substituted with 1 to 3 halogens; R5 is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano, a hydroxyl, or a C1-C4 alkoxy group, a cyclopropyl, or a cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, a halogen, or a C1-C3 alkyl group optionally substituted, or R6 and R7 combined with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, a halogen, a hydroxyl, a cyano, an optionally substituted C1-C3 alkoxy group, an optionally substituted C1-C3 alkyl group, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 14-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heteroaryl, or an optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'. ; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halosubstituted, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl group;R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered alkyl. (Specification 169 / 391 pages 172 CN 121471132 A) A cyclic alkyl group or optionally substituted 3 to 7-membered heterocyclic alkyl group, or R9 and L combined with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocyclic alkyl group; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl.

[0257] [2] The compound as described in paragraph [1] or a pharmaceutically acceptable salt thereof, wherein G is optionally substituted C1-C4 heteroalkylene.

[0258] [3] The compound as described in paragraph [1] or [2] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Ia: Formula Ia Wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazonium, or enolic acid; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2;R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; (Specification 170 / 391, page 173, CN 121471132 A) Each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 R1 is a cycloalkyl group, optionally substituted 3- to 6-membered cycloalkenyl group, optionally substituted 3- to 6-membered heterocycloalkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group; R2 is hydrogen, optionally substituted C1-C6 alkyl group, optionally substituted C2-C6 alkenyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 7-membered heterocycloalkyl group, optionally substituted 6-membered aryl group, or optionally substituted 5- or 6-membered heteroaryl group; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3- to 8-membered cycloalkyl group or optionally substituted 3- to 14-membered heterocycloalkyl group; R4 is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl group, cyano, hydroxyl or C1-C4 alkoxy group, cyclopropyl or cyclobutyl group; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8' C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or anyThe substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0259] [4] The compound of any one of paragraphs [1] to [3] or a pharmaceutically acceptable salt thereof, wherein X2 is NH.

[0260] [5] The compound of any one of paragraphs [1] to [4] or a pharmaceutically acceptable salt thereof, wherein X3 is CH.

[0261] [6] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [5], wherein R11 is hydrogen.

[0262] [7] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [5], wherein R11 is a C1-C3 alkyl group.

[0263] [8] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [7], wherein R11 is methyl.

[0264] [9] A compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [6], wherein the compound has the structure of formula Ib: Formula Ib wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; L is absent or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazonium, or enolic acid; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl or optionally substituted 5 to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8' C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, orR7' and R8', together with the carbon atoms to which they are attached, form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0265]

[10] The compound of any one of paragraphs [1] to [9] or a pharmaceutically acceptable salt thereof, wherein X1 is optionally substituted C1-C2 alkylene.

[0266]

[11] The compound of any one of paragraphs

[10] or a pharmaceutically acceptable salt thereof, wherein X1 is methylene.

[0267]

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

[11] or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.

[0268]

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

[11] , wherein R5 is a C1-C4 alkyl group optionally substituted with a halogen.

[0269]

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

[13] , wherein R5 is methyl.

[0270]

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

[14] , wherein Y4 is C.

[0271]

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

[15] , wherein R4 is hydrogen.

[0272]

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

[16] , wherein Y5 is CH.

[0273]

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

[17] , wherein Y6 is CH.

[0274]

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

[18] , wherein Y1 is the specification 176 CN 121471132 AC on page 173 / 391.

[0275]

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

[19] , wherein Y2 is C.

[0276]

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

[20] , wherein Y3 is N.

[0277]

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

[21] , wherein R3 is absent.

[0278]

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

[22] , wherein Y7 is C.

[0279]

[24] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [6] or [9] to

[23] .Salts, wherein the compound has the structure of formula Ic: Formula Ic wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cyclohexane; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or optionally substituted 5- to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cyclohexane; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, Chloroethyl carbamate, thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium or enolate; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R3 is absent, or as per specification page 174 / 391, 177 CN 121471132 A, R2 and R3, together with the atoms to which they are attached, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R5 is hydrogen, optionally halogenated C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7, together with the carbon atoms to which they are attached, form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl)R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocyclic alkyl; R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0280]

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

[24] , wherein R6 is hydrogen.

[0281]

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

[25] , wherein R2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heteroalkyl.

[0282]

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

[26] , wherein R2 is an optionally substituted C1-C6 alkyl.

[0283]

[28] The compound as described in paragraph

[27] or a pharmaceutically acceptable salt thereof, wherein R2 is an ethyl.

[0284]

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

[28] or a pharmaceutically acceptable salt thereof, wherein R7 is an optionally substituted C1-C3 alkyl.

[0285]

[30] The compound as described in paragraph

[29] or a pharmaceutically acceptable salt thereof, wherein R7 is a C1-C3 alkyl.

[0286]

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

[30] or a pharmaceutically acceptable salt thereof, wherein R8 is an optionally substituted C1-C3 alkyl.

[0287]

[32] The compound as described in paragraph

[31] or a pharmaceutically acceptable salt thereof, wherein R8 is a C1-C3 alkyl.

[0288]

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

[32] , wherein the compound has the structure of formula Id: Specification 175 / 391 pages 178 CN 121471132 A Formula Id Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionallyThe substituted 3- to 6-membered heterocyclic alkyl group; optionally substituted 3- to 6-membered heterocyclic alkyl group; optionally substituted 6-membered aryl group; or optionally substituted 5- to 6-membered heterocyclic aryl group; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered heterocyclic alkyl group; optionally substituted 3- to 6-membered heterocyclic alkyl group; optionally substituted 6-membered aryl group; or 5- to 6-membered heterocyclic aryl group; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazonium, or enosylate; R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is a C1-C6 alkyl or 3- to 6-membered cycloalkyl; R7 is a C1-C3 alkyl; R8 is a C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0289]

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

[33] , wherein R1 is a 5- to 10-membered heteroaryl.

[0290]

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

[34] , wherein R1 is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[0291]

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

[35] , wherein the compound has the structure of formula Ie: Specification 176 / 391 Page 179 CN 121471132 A Formula Ie Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; L is absent or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, etc.Chloroethyl carbamate, thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazonium or enolate; R2 is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R7 is a C1-C3 alkyl; R8 is a C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heteroalkyl; Xe and Xf are independently N or CH; and R12 is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heteroalkyl.

[0292]

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

[36] , wherein Xe is N and Xf is CH.

[0293]

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

[36] , wherein Xe is CH and Xf is N.

[0294]

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

[36] to

[38] , wherein R12 is an optionally substituted C1-C6 heteroalkyl group.

[0295]

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

[36] to

[39] , wherein R12 is, or.

[0296]

[41] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [1] or [2], wherein the compound has the structure of formula VI: Specification 177 / 391 pages 180 CN 121471132 A Formula VI Wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroalkylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein the C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein the C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3- to 8-membered heteroarylene; L is absent or is a linker;W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazonium, or enolic acid; X1 is an optionally substituted C1-C2 alkylene group, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2- C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; Specification 178 / 391 pages 181 CN 121471132 A R2 is absent, 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; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8' C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;R7a and R8a are independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogenated, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogenated, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered cycloalkyl. The alkyl group or optionally substituted 3- to 7-membered heterocyclic alkyl group, or R9 and L combined with the atoms they are attached to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; R34 is hydrogen or C1-C3 alkyl; and Xe and Xf are independently N or CH.

[0297]

[42] The compound as described in paragraph

[41] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula VIa: Specification 179 / 391 pages 182 CN 121471132 A Formula VIa Wherein A is an optionally substituted 3 to 6-membered cycloene alkyl, optionally substituted 3 to 6-membered heterocycloene alkyl, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heterocycloene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocycloene alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heterocycloene; L is absent or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazonium, or enolic acid; X1 is an optionally substituted C1-C2 alkylene group, NR, O, or S(O)n; X2 is O or NH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; R2 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heteroalkyl; Xe and Xf are independently N or CH; R11 is hydrogen or C1-C3 alkyl; and R21 is hydrogen or C1-C3 alkyl.

[0298]

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

[41] or

[42] , wherein the compound has the structure of formula VIb: Specification 180 / 391 Page 183 CN 121471132 A Formula VIb Wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered aryl or optionally substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heterocycloalkylene; optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoe-EEDQ or other EEDQ derivatives, epoxide, oxazonium or enolate; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; and Xe and Xf are independently N or CH.

[0299]

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

[43] , wherein A is optionally substituted 6-membered arylene.

[0300]

[45] The compound as described in paragraph

[44] or a pharmaceutically acceptable salt thereof, wherein A has the following structure: wherein R13 is hydrogen, hydroxyl, amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl.

[0301]

[46] The compound as described in paragraph

[45] or a pharmaceutically acceptable salt thereof, wherein R13 is hydrogen.

[0302]

[47] The compound as described in paragraph

[45] or a pharmaceutically acceptable salt thereof, wherein R13 is hydroxyl.

[0303]

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

[47] , wherein B is -CHR9-.

[0304]

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

[48] , wherein R9 is an optionally substituted C1-C6 alkyl or an optionally substituted 3- to 6-membered cycloalkyl.

[0305]

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

[49] , wherein R9 is 184 CN 121471132 A, page 181 / 391 of the specification.

[0306]

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

[50] , wherein R9 is.

[0307]

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

[47] , wherein B is an optionally substituted 6-membered aryl group.

[0308]

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

[52] , wherein B is a 6-membered aryl group.

[0309]

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

[53] , wherein B is: .

[0310]

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

[54] , wherein R7 is methyl.

[0311]

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

[55] , wherein R8 is methyl.

[0312]

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

[56] , wherein the linker is a structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula II Wherein A1 is the bond between the linker and B; A2 is the bond between W and the linker; B1, B2, B3, and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered heterocyclic alkyl. Aryl or optionally substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; and D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkyneyl, optionally substituted 3- to 14-membered heterocyclic alkylene, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 8-membered cycloalkylene.The linker may be a 6- to 10-membered arylene group, a C2-C10 polyethylene glycol or a C1-C10 heteroalkyl group, or a chemical bond of A1-(B1)f-(C1)g-(B2)h- linked to -(B3)i-(C2)j-(B4)k–A2.

[0313]

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

[57] , wherein the linker is acyclic.

[0314]

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

[58] , wherein the linker has the structure of formula IIa: Formula IIa wherein Xa is absent or N; R14 is absent, hydrogen or optionally substituted C1-C6 alkyl; and L2 is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene, wherein at least one of Xa, R14 or L2 is absent.

[0315]

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

[59] , wherein the linker has the following structure: .

[0316]

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

[57] , wherein the linker is or contains a cyclic group.

[0317]

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

[57] or

[61] , wherein the linker has the structure of formula IIb: Formula IIb wherein o is 0 or 1; R15 is hydrogen or optionally substituted C1-C6 alkyl; Cy is optionally substituted 3 to 8-membered cycloalkylene, optionally substituted 3 to 8-membered heterocycloalkylene, optionally substituted 6 to 10-membered aryl or optionally substituted 5 to 10-membered heteroaryl; and L3 is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0318]

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

[62] , wherein the linker has the following structure: [Specification 183 / 391 page 186 CN 121471132 A] [Specification 184 / 391 page 187 CN 121471132 A] [Specification 185 / 391 page 188 CN 121471132 A] .

[0319]

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

[63] , wherein W comprises carbodiimide.

[0320]

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

[64] , wherein W has the structure of formula IIIa: [Formula IIIa]Wherein R14 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

[0321]

[66] The compound as described in paragraph

[65] or a pharmaceutically acceptable salt thereof, wherein W has the following structure: Specification 186 / 391 pages 189 CN 121471132 A.

[0322]

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

[63] or a pharmaceutically acceptable salt thereof, wherein W comprises oxazoline or thiazoline.

[0323]

[68] The compound as described in paragraph

[67] or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIb: Formula IIb wherein X1 is O or S; X2 is absent or NR19; R15, R16, R17 and R18 are independently hydrogen or optionally substituted C1-C6 alkyl; and R19 is hydrogen, C(O) (optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 aryl, optionally substituted 3 to 14 heterocyclic alkyl or optionally substituted 5 to 10 heteroaryl.

[0324]

[69] The compound as described in paragraph

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

[0325]

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

[63] , wherein W comprises chloroethylurea, chloroethylthiourea, chloroethyl carbamate, or chloroethyl thiocarbamate.

[0326]

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

[70] , wherein W has the structure of formula IIIc: Formula IIIc wherein X3 is O or S; X4 is O, S, or NR26; R21, R22, R23, R24, and R26 are independently hydrogen or optionally substituted C1-C6 alkyl; and R25 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl.

[0327]

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

[71] , wherein W is...

[0328]

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

[63] , wherein W comprises azacyclopropane.

[0329]

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

[73] , wherein W has the structure of formula IIId1, IIId2, IIId3 or IIId4:Where X5 is absent or NR30; Y is absent or C(O), C(S), S(O), SO2 or optionally substituted C1-C3 alkylene; R27 is hydrogen, -C(O)R32, -C(O)OR32, -SO2R33, -SOR33, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl or optionally substituted 5- to 10-membered heteroaryl; R28 and R29 are independently hydrogen, CN, C(O)R31, CO2R31, C(O)R31R31, optionally substituted C1-C6 alkyl, optionally substituted 121471132 A (Description 188 / 391, page 191, CN 121471132 A) The substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; each R31 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; R30 is hydrogen or optionally substituted C1-C6 alkyl; and R32 and R33 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

[0330]

[75] A compound or a pharmaceutically acceptable salt thereof as described in paragraph

[73] or

[74] , wherein W is: Specification 189 / 391 pages 192 CN 121471132 A.

[0331]

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

[63] , wherein W comprises an epoxide.

[0332]

[77] A compound or a pharmaceutically acceptable salt thereof as described in paragraph

[76] , wherein W is.

[0333]

[78] A compound or a pharmaceutically acceptable salt thereof as described in Table 1 or Table 2.

[0334]

[79] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[78] and a pharmaceutically acceptable excipient.

[0335]

[80] A conjugate or a salt thereof, comprising the structure of formula IV: M-L-P Formula IV where L is a linker; P is a monovalent organic moiety; and M has the structure of formula V: Specification 190 / 391 pages 193 CN 121471132 A Formula V where the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenyl; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein the C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein the C is bonded to -C (R7R8)-;Optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; X1 is an optionally substituted C1-C2 heteroalkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R2 is absent, 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 heteroalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl; R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, a C1-C4 alkyl optionally substituted with halogens, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or a C1-C3 alkyl optionally substituted, orR6 and R7, together with the carbon atoms they are attached to, form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or as stated on pages 191 / 391 of the specification, CN 121471132 A. R7 and R8, together with the carbon atoms they are attached to, form C=CR7'R8'. ; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halosubstituted, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered cycloalkyl. The alkyl group or optionally substituted 3- to 7-membered heterocyclic alkyl group, or R9 and L combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10a is hydrogen or halogenated; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl.

[0336]

[81] The conjugate or salt thereof as described in paragraph

[80] , wherein M has the structure of formula Vc: Formula Vc wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; X1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; n is 0, 1, or 2;R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; (See specification 192 / 391, page 195, CN 121471132 A). Each R' is independently H or optionally substituted C1-C4 alkyl; Xe and Xf are independently N or CH; R2 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heteroalkyl; R11 is hydrogen or a C1-C3 alkyl group; and R34 is hydrogen or a C1-C3 alkyl group.

[0337] In some embodiments of the compounds of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0338]

[82] The conjugate or its salt as described in paragraph

[80] or

[81] , wherein M has the structure of formula Vd: Formula Vd wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered aryl, or optionally substituted 5- to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heteroaryl; L is absent or is a linker; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, Chloroethyl carbamate, thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazonium or enolate; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; and Xe and Xf are independently N or CH.

[0339]

[83] The conjugate or salt thereof as described in any one of paragraphs

[80] to

[82] , wherein the linker has the structure of Formula II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Specification 193 / 391 pages 196 CN 121471132 A Formula II Where A1 is the bond between the linker and B; A2 is the bond between P and the linker; B1, B2, B3 andB4 is independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C1 and C2 are independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j Each of them, k, is independently 0 or 1; and D1 is an optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkyneene, optionally substituted 3 to 14-membered heterocyclic alkylene, optionally substituted 5 to 10-membered heteroarylene, optionally substituted 3 to 8-membered heterocyclic alkylene, optionally substituted 6 to 10-membered arylene, optionally substituted C2-C10 polyethylene glycol or optionally substituted C1-C10 heteroalkylene, or a chemical bond connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k–A2.

[0340]

[84] A conjugate or a salt thereof as described in any one of paragraphs

[80] to

[83] , wherein the monovalent organic portion is a protein.

[0341]

[85] The conjugate or salt thereof as described in paragraph

[84] , wherein the protein is a Ras protein.

[0342]

[86] The conjugate or salt thereof as described in paragraph

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

[0343]

[87] The conjugate or salt thereof as described in any one of paragraphs

[80] to

[86] , wherein the linker is linked to the monovalent organic moiety by a bond to the carboxyl group of an amino acid residue of the monovalent organic moiety.

[0344]

[88] A method of treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[78] or a pharmaceutical composition as described in paragraph

[79] .

[0345]

[89] The method as described in paragraph

[88] , wherein the cancer is pancreatic cancer, non-small cell lung cancer, colorectal cancer, or endometrial cancer.

[0346]

[90] The method as described in paragraph

[88] or

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

[0347]

[91] The method as described in paragraph

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

[0348]

[92] A method for treating a subject with a Ras protein-related condition, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[78] .Or a pharmaceutical composition as described in paragraph

[79] .

[0349]

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

[78] or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in paragraph

[79] .

[0350]

[94] The method as described in paragraphs

[92] or

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

[0351]

[95] The method as described in paragraphs

[93] or

[94] , wherein the cells are cancer cells.

[0352]

[96] The method as described in paragraph

[95] , wherein the cancer cells are pancreatic cancer cells, non-small cell lung cancer cells, colorectal cancer cells, or endometrial cells.

[0353]

[97] The method or use as described in any one of paragraphs

[88] to

[96] , wherein the method further comprises administering additional anticancer therapy.

[0354]

[98] The method as described in paragraph

[97] , wherein the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

[0355]

[99] The method as described in paragraph

[97] or

[98] , wherein the additional anticancer therapy is an SHP2 inhibitor. Examples

[0356] This disclosure will be further illustrated by the following examples and synthetic examples, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples provided are intended to illustrate certain implementations and are not intended to limit the scope of this disclosure thereto. It should also be understood that various other embodiments, modifications and equivalents thereof may be conceived by those skilled in the art without departing from the spirit of this disclosure or the scope of the appended claims.

[0357] Chemical Synthesis The following examples and definitions used elsewhere herein are as follows: Instrumental mass spectrometry data collection was performed using a Shimadzu LCMS-2020 or Waters Acquity UPLC with a QDa detector or SQ detector 2. The sample was injected in liquid phase onto a C-18 reversed-phase column to remove the assay buffer and prepare the sample for mass spectrometry. The compound was eluted from the column using an acetonitrile gradient and fed into the mass analyzer. Initial data analysis was performed using Shimadzu LabSolutions or WatersMassLynx was used. NMR data were collected using a Bruker AVANCE III HD 400MHz or Bruker Ascend 500MHz instrument, and raw data were analyzed using TopSpin or Mestrelab Mnova.

[0358] Synthetic Intermediate Intermediate 1. Synthesis of 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylprop-1-ol Specification 195 / 391 pages 198 CN 121471132 A Step 1: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl one Under N2 atmosphere, at 0°C, a 1M SnCl4 solution in DCM (137 mL, 137 mmol) was slowly added to a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (65 g, 137 mmol, crude) in DCM (120 mL). The mixture was stirred at 0 °C for 30 min, followed by dropwise addition of 5-bromo-1H-indole (26.8 g, 137 mmol) to a solution in DCM (40 mL). The mixture was stirred at 0 °C for 45 min, then diluted with EtOAc (300 mL), washed with brine (4 × 100 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1-(5-bromo-1H-indole-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylprop-1-one (55 g,...

Claims

1. A compound selected from: 。 2. The compound of claim 1, wherein the compound has the following structure: 。 3. The compound of claim 1, wherein the compound has the following structure: 。 4. The compound of claim 1, wherein the compound has the following structure: 。 5. The compound of claim 1, wherein the compound has the following structure: 。 6. The compound of claim 1, wherein the compound has the following structure: 。 7. The compound of claim 1, wherein the compound has the following structure: 。

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