RAS inhibitor

Abstract

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

Description

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

[0002] Cross-reference to related applications

[0003] This application claims the priority benefits of U.S. Application No. 62 / 930,406 filed on November 4, 2019; U.S. Application No. 62 / 951,562 filed on December 20, 2019; U.S. Application No. 63 / 000,355 filed on March 26, 2020; and U.S. Application No. 63 / 043,523 filed on June 24, 2020, and all of the applications are hereby incorporated by reference in their entireties. Background art

[0004] The vast majority of small molecule drugs act by binding to a functionally important pocket on a target protein and thereby modulating the activity of that protein. For example, cholesterol-lowering drugs called statins bind to the enzymatic active site of HMG-CoA reductase, thereby preventing the enzyme from engaging its substrate. In fact, many such drug / target interaction pairs are known, which might mislead one to believe that small molecule modulators for most, if not all, proteins can be discovered with a reasonable amount of time, effort, and resources. However, this is far from the case. Currently, it is estimated that only about 10% of all human proteins can be targeted by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18:674-699 (2019). The remaining 90% are currently considered intractable or difficult to handle for small molecule drug discovery as mentioned above. Such targets are often referred to as "undruggable". These undruggable targets include a large and generally untapped reservoir of medically important human proteins. Therefore, there is great interest in discovering novel molecular modalities that can modulate the functions of such undruggable targets.

[0005] 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 have thus emerged as suitable targets for anticancer therapies. In fact, in the United States, approximately 30% of all human cancers are caused by Ras protein mutations, and many of these cancers are fatal. Dysregulation of Ras proteins due to activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations of Ras are frequently found in human cancers. For example, activating mutations at codon 12 in the Ras protein significantly bias the population of Ras mutant proteins towards the "on" (GTP-bound) state (Ras(ON)) by inhibiting GTPase-activating protein (GAP)-dependent and intrinsic GTP hydrolysis rates, leading to oncogenic MAPK signaling. Notably, Ras exhibits picomolar affinity for GTP, enabling Ras to be activated even in the presence of this nucleotide at low concentrations. Mutations at codon 13 (e.g., G13D) and 61 (e.g., Q61K) in Ras also confer oncogenic activity in some cancers.

[0006] Despite extensive drug discovery efforts targeting Ras over the past several decades, drugs that directly target Ras have not been approved. Additional efforts are needed to discover other medicaments for cancers driven by various Ras mutations. Summary of the Invention

[0007] Provided herein are Ras inhibitors. The methods described herein require the formation of a high-affinity ternary complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a cytoplasmic chaperone protein (presenter protein) that is widely expressed in cells (e.g., cyclophilin A). 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 ternary 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 in which the compounds of the present invention and the complexes or conjugates formed thereby exert an inhibitory effect on Ras is to sterically block the interaction site between Ras and downstream effector molecules such as RAF and PI3K required for propagating oncogenic signals.

[0008] Accordingly, in some embodiments, the present disclosure features a compound of formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] wherein the dashed line represents zero, one, two, three, or four non-adjacent double bonds;

[0011] A is -N(H or CH 3 )C(O)-(CH 2 )-, where the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; 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 heteroarylene;

[0012] B is -CH(R 9 )- or >C=CR 9 R 9’ , where the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene;

[0013] G is optionally substituted C 1 -C 4 alkylene; optionally substituted C 1 -C 4 alkenylene; optionally substituted C 1 -C 4 heteroalkylene; -C(O)O-CH(R 6 ), where C is bonded to -C(R 7 R 8 )-; -C(O)NH-CH(R 6 ), where C is bonded to -C(R 7 R 8 )-; optionally substituted C 1 -C 4 heteroalkylene; or 3- to 8-membered heteroarylene;

[0014] L is absent or is a linker;

[0015] W is a crosslinking group, said group comprising a carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or enose;

[0016] X 1 is optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[0017] X 2 is O or NH;

[0018] X 3 is N or CH;

[0019] n is 0, 1 or 2;

[0020] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 , S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0021] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0022] Y 1 is C, CH or N;

[0023] Y 2 , Y 3 , Y 4 and Y 7 are independently C or N;

[0024] Y 5 is CH, CH 2 or N;

[0025] Y 6 is C(O), CH, CH 2 or N;

[0026] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or

[0027] R 1 and R 2 together with the atoms to which they are attached form an optionally substituted 3- to 14-membered heteroalkyl;

[0028] R 2is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[0029] R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0030] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0031] R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0032] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or C 1 -C 3 alkyl optionally substituted, or

[0033] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0034] R 8 is hydrogen, halogen, hydroxy, cyano, C 1 -C 3 alkoxy optionally substituted, C 1 -C 3 alkyl optionally substituted, C 2 -C 6 alkenyl optionally substituted, C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0035] R 7and R 8 Combined with the carbon atom to which it is attached to form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0036] R 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combined with the carbon to which it is attached to form a carbonyl;

[0037] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0038] R 7’ and R 8’ combined with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[0039] R 9 is hydrogen, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl, or

[0040] R 9 and L combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0041] R 9’ is hydrogen or optionally substituted C 1 -C 6Alkyl;

[0042] R 10 is hydrogen, halogenated, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl;

[0043] R 10a is hydrogen or halogenated;

[0044] R 11 is hydrogen or C 1 -C 3 alkyl; and

[0045] R 34 is hydrogen or C 1 -C 3 alkyl (such as methyl).

[0046] There is also provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0047] There is also provided a conjugate or a salt thereof, the conjugate comprising a structure of formula IV:

[0048] M-L-P

[0049] Formula IV

[0050] wherein L is a linker;

[0051] P is a monovalent organic moiety; and

[0052] M has a structure of formula V:

[0053]

[0054] wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[0055] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; optionally substituted 3- to 6-membered cycloalkylidene; optionally substituted 3- to 6-membered heterocycloalkylidene; optionally substituted 6-membered arylidene; or optionally substituted 5- to 6-membered heteroarylidene;

[0056] B is -CH(R 9 )- or >C=CR 9 R 9’ , wherein the carbon is bonded to -N(R 11)The carbonyl carbon of C(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[0057] G is an optionally substituted C 1 -C 4 alkylene; an optionally substituted C 1 -C 4 alkenylene; an optionally substituted C 1 -C 4 heteroalkylene; -C(O)O-CH(R 6 )-, where C is bonded to -C(R 7 R 8 )-; -C(O)NH-CH(R 6 )-, where C is bonded to -C(R 7 R 8 )-; an optionally substituted C 1 -C 4 heteroalkylene; or a 3- to 8-membered heteroarylene;

[0058] X 1 is an optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[0059] X 2 is O or NH;

[0060] X 3 is N or CH;

[0061] n is 0, 1 or 2;

[0062] R is hydrogen, cyano, an optionally substituted C 1 -C 4 alkyl, an optionally substituted C 2 -C 4 alkenyl, an optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0063] Each R’ is independently H or an optionally substituted C 1 -C 4 alkyl;

[0064] Y 1 is C, CH or N;

[0065] Y 2 , Y 3 , Y 4 and Y 7 are independently C or N;

[0066] Y 5 It is CH, CH 2 or N;

[0067] Y 6 is C(O), CH, CH 2 or N;

[0068] R 1 is cyano, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl, or

[0069] R 1 and R 2 and the atoms to which they are attached are taken together to form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0070] R 2 is absent, hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or

[0071] R 2 and R 3 and the atoms to which they are attached are taken together to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0072] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0073] R 5 is hydrogen, optionally substituted by halogen 1 -C 4 Alkyl, cyano, hydroxyl or C1 -C 4 is an alkoxy group, a cyclopropyl group or a cyclobutyl group;

[0074] R 6 is hydrogen or methyl; R 7 is hydrogen, a halogen or an optionally substituted C 1 -C 3 alkyl group, or

[0075] R 6 and R 7 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0076] R 8 is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy group, an optionally substituted C 1 -C 3 alkyl group, an optionally substituted C 2 -C 6 alkenyl group, an optionally substituted C 2 -C 6 alkynyl group, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group or an optionally substituted 6- to 10-membered aryl group, or

[0077] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl group); C=O; C=S; C=NH; an optionally substituted 3- to 6-membered cycloalkyl group; or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0078] R 7a and R 8a are independently hydrogen, halo, an optionally substituted C 1 -C 3 alkyl group, or together with the carbon to which they are attached form a carbonyl group;

[0079] R 7’ is hydrogen, a halogen or an optionally substituted C 1 -C 3 alkyl group; R 8’ is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy group, an optionally substituted C 1 -C3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0080] R 7’ and R 8’ together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[0081] R 9 is hydrogen, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl, or

[0082] R 9 and L together with the atoms to which it is attached form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0083] R 9’ is hydrogen or optionally substituted C 1 -C 6 alkyl;

[0084] R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl;

[0085] R 10a is hydrogen or halo;

[0086] R 11 is hydrogen or C 1 -C 3 alkyl; and

[0087] R 34 is hydrogen or C 1 -C 3 alkyl (such as methyl).

[0088] There is also provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, a method for treating a Ras protein-related disorder in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0090] A method for inhibiting Ras protein in a cell is also provided, the method comprising contacting the cell with an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0091] Specifically, upon due consideration, any limitation discussed with respect to one embodiment of the invention may be applicable to any other embodiment of the invention. Additionally, any compound or composition of the invention can be used in any method of the invention, and any method of the invention can be used to make or utilize any compound or composition of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1A : The compound of the invention, namely Compound A, strongly and persistently inhibits oncogenic signaling in a pancreatic CDX model (HPAC CDX model, PDAC, KRAS G12D / WT). Single-dose experiment, n = 3 per time point, and all dose levels were well tolerated.

[0093] Figure 1B : Tumor regression in a KRAS G12D tumor-driven pancreatic CDX model (HPAC CDX model, PDAC, KRAS G12D / WT) treated in vivo with the compound of the invention, namely Compound A. n = 10 per group. ***p < 0.001. All dose levels were well tolerated.

[0094] DEFINITIONS AND CHEMICAL TERMS

[0095] In this application, unless the context clearly dictates otherwise, (i) the term "a" means "one or more"; (ii) the term "or" is used to mean "and / or", unless it is clearly indicated that the term refers to an alternative that is exclusive or that the alternatives are mutually exclusive, however, the definitions supported by the present disclosure refer to exclusive alternatives as well as "and / or"; (iii) the terms "comprising" and "including" should be understood to cover the recited components or steps, whether the recited components or steps are presented by themselves or in combination with one or more additional components or steps; and (iv) when ranges are provided, the endpoints are included.

[0096] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the error of the device or method used to determine that value. In certain embodiments, the term "about" means a range within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of that value in either direction (greater than or less than) of the value, unless otherwise specified or otherwise apparent from the context (e.g., when the number would exceed 100% of a possible value).

[0097] As used herein, in the context of describing adjacent atoms, the term "adjacent" refers to divalent atoms directly connected by a covalent bond.

[0098] As used herein, the term "compounds of the invention" and like terms, whether expressly indicated or not, refer to the Ras inhibitors described herein, including compounds of Formula I and its sub-formulas, and the compounds of Tables 1 and 2, and their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers) and tautomers.

[0099] The term "wild type" refers to an entity having a structure or activity as seen in the "normal" (as opposed to mutant, diseased, altered, etc.) state or situation in nature. Those skilled in the art will understand that wild type genes and polypeptides generally exist in a variety of different forms (e.g., alleles).

[0100] Those skilled in the art will appreciate that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., where one or more atoms are replaced by different isotopes of that atom, such as hydrogen replaced by deuterium). Unless otherwise indicated or clearly visible from the context, the depicted structures are to be understood as representing any such isomeric or isotopic forms, individually or in combination.

[0101] 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 encompassed. Compounds of the present disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active form or as a racemate. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthetic methods. Many geometric isomers, such as for alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are encompassed in the present disclosure. The cis and trans geometric isomers of the compounds of the present disclosure have been described and may be isolated as a mixture of isomers or in separate isomeric forms.

[0102] In some embodiments, one or more of the compounds depicted herein may exist in different tautomeric forms. As will be clear from the context, unless explicitly excluded, reference to such compounds encompasses all such tautomeric forms. In some embodiments, tautomeric forms are obtained by the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton. In certain embodiments, the tautomeric forms may be prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge as the reference form. Examples of moieties having prototropic tautomeric forms are keto-enol pairs, amide-imino acid pairs, lactam-lactim pairs, amide-imino acid pairs, enamine-imine pairs, and cyclic forms in which a proton may occupy two or more positions of a heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-triazole, 2H-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, the tautomeric forms may be in equilibrium or locked in one form spatially by appropriate substitution. In certain embodiments, the tautomeric forms are obtained by acetal interconversion.

[0103] Unless otherwise specified, the structures depicted herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Isotopically labeled compounds (e.g., compounds labeled with 3 H and 14 C) can be used in compound or substrate tissue distribution assays. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are useful because of their ease of preparation and detection. Additionally, substitution with heavier isotopes, such as deuterium (i.e., 2 H), can provide certain therapeutic benefits due to enhanced metabolic stability (e.g., increased in vivo half-life or decreased dosage requirements). In some embodiments, one or more hydrogen atoms are replaced with2 H or 3 H substitution, or one or more carbon atoms are 13 C or 14 C-enriched carbon substitution. Positron-emitting isotopes, such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to examine substrate 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 substituting an unlabeled reagent with an isotopically labeled reagent following procedures similar to those disclosed for the compounds of the present invention described herein.

[0104] As is known in the art, many chemical entities can exist in multiple different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including any solid form. In some embodiments, the compounds described or depicted herein can be provided in hydrate form or solvate form.

[0105] Throughout this specification, the substituents of the disclosed compounds are disclosed in groups or in ranges. Specifically, it is contemplated that the present disclosure includes every individual sub-combination of each member of said groups and ranges. For example, the term "C 1 -C 6 alkyl" is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl. Further, when a compound contains multiple positions and at these positions the substituents are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., species and subclasses) containing every individual sub-combination of members at each position.

[0106] The term "optionally substituted X" (e.g., "optionally substituted alkyl") is intended to be equivalent to "X, where X is optionally substituted" (e.g., "alkyl, where the alkyl is optionally substituted"). It is not intended to mean that the feature "X" (e.g., alkyl) itself is optional. As described herein, certain 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 designated moiety are replaced by a suitable substituent, such as any of the substituents or groups described herein. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the designated group, the substituents at each position may be the same or different. For example, in the term "optionally substituted C 1 -C 6 alkyl-C 2 -C 9 heteroaryl", the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. Combinations of substituents contemplated by this disclosure are preferably combinations of substituents that form stable or chemically viable compounds. As used herein, the term "stable" means that a compound does not substantially change when subjected to conditions that allow the compound to be generated, detected, and in some embodiments, allow the compound to be recovered, purified, and used for one or more of the purposes disclosed herein.

[0107] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group can independently be deuterium; halogen; -(CH 2 ) 0-4 R o ; -(CH 2 ) 0-4 OR o ; -O(CH 2 ) 0-4 R o ; -O-(CH 2 ) 0-4 C(O)OR o ; -(CH 2 ) 0-4 CH(OR o ) 2 ; -(CH 2 ) 0- 4 SR o ; -(CH 2 ) 0-4 Ph, which group may be substituted by R o ; -(CH 2 ) 0-4 O(CH 2 ) 0-1Ph, which group may be substituted by R o -CH=CHPh, which group may be substituted by R o -(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl, which group may be substituted by R o ; 4- to 8-membered saturated or unsaturated heterocycloalkyl (such as pyridyl); 3- to 8-membered saturated or unsaturated cycloalkyl (such as cyclopropyl, cyclobutyl or cyclopentyl); -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0-4 N(R o ) 2 ; -(CH 2 ) 0-4 N(R o )C(O)R o ; -N(R o )C(S)R o ; -(CH 2 ) 0-4 N(R o )C(O)NR o 2 ; -N(R o )C(S)NR o 2 ; -(CH 2 ) 0-4 N(R o )C(O)OR o ; -N(R o )N(R o )C(O)R o ; -N(R o )N(R o )C(O)NR o 2 ; -N(R o )N(R o )C(O)OR o ; -(CH 2 ) 0-4 C(O)R o ; -C(S)R o ; -(CH 2 ) 0-4 C(O)OR o ; -(CH 2 ) 0-4 -C(O)-N(R o ) 2 ; -(CH 2 ) 0-4-C(O)-N(R o )-S(O) 2 -R o ;-C(NCN)NR o 2 ;-(CH 2 ) 0-4 C(O)SR o ;-(CH 2 ) 0-4 C(O)OSiR o 3 ;-(CH 2 ) 0-4 OC(O)R o ; -OC(O)(CH 2 ) 0-4 SR o ; -SC(S)SR o ;-(CH 2 ) 0-4 SC(O)R o ;-(CH 2 ) 0-4 C(O)NR o 2 ; -C(S)NR o 2 ; -C(S)SR o ;-(CH 2 ) 0-4 OC(O)NR o 2 ; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH 2 C(O)R o ; -C(NOR o )R o ;-(CH 2 ) 0-4 SSR o ;-(CH 2 ) 0-4 S(O) 2 R o ;-(CH 2 ) 0-4 S(O) 2 OR o ;-(CH 2 ) 0-4 OS(O) 2 R o ; -S(O) 2 NR o 2 ;-(CH2 ) 0-4 S(O)R o ; - N(R o )S(O) 2 NR o 2 ; - N(R o )S(O) 2 R o ; - N(OR o )R o ; - C(NOR o )NR o 2 ; - C(NH)NR o 2 ; - P(O) 2 R o ; - P(O)R o 2 ; - P(O)(OR o ) 2 ; - OP(O)R o 2 ; - OP(O)(OR o ) 2 ; - OP(O)(OR o )R o ; - SiR o 3 ; - (C 1 - C 4 straight - chain or branched - chain alkylene)O - N(R o ) 2 ; or - (C 1 - C 4 straight - chain or branched - chain alkylene)C(O)O - N(R o ) 2 , where each R o may be substituted as defined below and is independently hydrogen, - C 1 - C 6 aliphatic group, - CH 2 Ph, - O(CH 2 ) 0-1 Ph, - CH 2 - (5 - to 6 - membered heteroaryl ring), or a 3 - to 6 - membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independently existing R o together with their intervening atoms form a 3 - to 12 - membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0108] R o(or a ring formed by two independently existing Rs o together with the inserted atom) the suitable monovalent substituents on it can independently be halogen, -(CH 2 ) 0-2 R · , -(haloalkyl R · ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR · , -(CH 2 ) 0-2 CH(OR · ) 2 , -O(haloalkyl R · ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R · , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR · , -(CH 2 ) 0-2 SR · , -(CH 2 ) 0- 2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR · , -(CH 2 ) 0-2 NR · 2 , -NO 2 , -SiR · 3 , -OSiR · 3 , -C(O)SR · , -(C 1-4 straight-chain or branched-chain alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, in the case of being preceded by "halo-", is substituted only by one or more halogens, and is independently selected from C 1 -C 4 aliphatic group, -CH 2 Ph, -O(CH 2 ) 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. R o Suitable divalent substituents on the saturated carbon atoms of R

[0109] include =O and =S. Suitable divalent substituents on the saturated carbon atoms of an "optionally substituted" group include the following: =O, =S, =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2-3 O- or -S(C(R * 2 )) 2-3 S-, where R * is independently selected, each time it appears, from hydrogen; C 1 -C 6 aliphatic group, which may be substituted as defined below; or an unsubstituted 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 bonded to an adjacent substitutable carbon of an "optionally substituted" group include: -O(CR * 2 ) 2- 3 O-, where R * is independently selected, each time it appears, from hydrogen; C 1 -C 6 aliphatic group, which may be substituted as defined below; or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0110] R * Suitable substituents on the aliphatic group of include halogen, -R · , -(haloR · ), -OH, -OR · , -O(haloR · ), -CN, -C(O)OH, -C(O)OR · , -NH 2 , -NHR · , -NR · 2 or -NO 2 , where each R ·Unsubstituted or, when preceded by "halo-", substituted by one or more halogens only, and independently is C 1 -C 4 an aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0111] Suitable substituents on the nitrogen of a group which is "optionally substituted" include or wherein each is independently hydrogen; C 1 -C 6 an aliphatic group which may be substituted as defined hereinafter; unsubstituted -OPh; or an unsubstituted 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independently occurring together with their intervening atom form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0112] Suitable substituents on the aliphatic group of · are independently halogen, -R · , -(halo-R · ), -OH, -OR · ), -CN, -C(O)OH, -C(O)OR · , -NH 2 , -NHR · , -NR · 2 or -NO 2 , wherein each R · is unsubstituted or, when preceded by "halo-", substituted by one or more halogens only, and independently is C 1 -C 4 an aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph 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 a saturated carbon atom of

[0113] include =O and =S. As used herein, the term "acetyl" refers to the group -C(O)CH3 .

[0114] As used herein, the term "alkoxy" refers to -O-C 1 -C 20 alkyl, wherein the alkoxy is attached to the remainder of the compound through an oxygen atom.

[0115] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched-chain monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10 or 1 to 6) carbons. In some embodiments, the alkyl is unbranched (i.e., linear); in some embodiments, the alkyl is branched. Alkyl is, for example but not limited to, methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0116] As used herein, the term "alkylene" denotes a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight-chain or branched-chain saturated hydrocarbon, and examples thereof are methylene, ethylene, isopropylidene, etc. The term "C x -C y alkylene" denotes an alkylene having between x and y carbons. Exemplary x values are 1, 2, 3, 4, 5 and 6, and exemplary y values are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18 or 20 (e.g., C 1 -C 6 , C 1 -C 10 , C 2 -C 20 , C 2 -C 6 , C 2 -C 10 or C 2 -C 20 alkylene). In some embodiments, the alkylene may be further substituted with 1, 2, 3 or 4 substituents as defined herein.

[0117] Unless otherwise specifically stated, as used herein, the term "alkenyl" denotes a monovalent straight-chain or branched-chain group having 2 to 20 (e.g., 2 to 6 or 2 to 10) carbons containing one or more carbon-carbon double bonds, and examples thereof are vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. Alkenyl includes both cis and trans isomers. Unless otherwise specifically stated, as used herein, the term "alkenylene" denotes a divalent straight-chain or branched-chain group having 2 to 20 (e.g., 2 to 6 or 2 to 10) carbons containing one or more carbon-carbon double bonds.

[0118] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched-chain 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 thereof include ethynyl and 1-propynyl.

[0119] As used herein, the term "alkynyl sulfone" refers to a group containing the structure wherein R is any chemically viable substituent as described herein.

[0120] As used herein, the term "amino" refers to e.g., -NH 2 and -N(CH 3 ) 2 .

[0121] As used herein, the term "aminoalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted by one or more amino moieties.

[0122] As described herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO 2 H or -SO 3 H), wherein the amino acid is attached to the parent molecular group through the side chain, amino group, or acid group (e.g., side chain). As used herein, the term "amino acid" in the 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 general structure H 2 N-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. A "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 hydroxy-norvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0123] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic system formed by carbon atoms, wherein the ring attached to the pendant group is an aromatic ring. Examples of aryl include phenyl, naphthyl, phenanthryl, and anthracenyl. The aromatic ring can be attached to its pendant group at any heteroatom or carbocyclic atom that results in a stable structure, and any ring atom can be optionally substituted unless otherwise specifically stated.

[0124] As used herein, the term "C" 0 " represents a bond. For example, a portion of the term -N(C(O)-(C 0 -C 5 -alkylene-H)- includes -N(C(O)-(C 0 -alkylene-H)-, also represented as -N(C(O)-H)-.

[0125] 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 bridged ring, a fused ring or a spiro 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 cycloalkynyl. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, dihydroindenyl, decahydronaphthyl, etc. The carbocycle may be attached to its pendant group at any ring atom that results in a stable structure, and any ring atom may be optionally substituted unless otherwise specifically stated.

[0126] As used herein, the term "carbonyl" represents the C(O) group, which may also be represented as C═O.

[0127] As used herein, the term "carboxyl" means -CO 2 H, (C═O)(OH), COOH or C(O)OH, or the unprotonated counterpart.

[0128] As used herein, the term "cyano" represents the -CN group.

[0129] As used herein, the term "cycloalkyl" represents a monovalent saturated cyclic hydrocarbon group, which may be a bridged ring, a fused ring or a spiro ring having three to eight ring carbons unless otherwise specifically stated, and examples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0130] As used herein, the term "cycloalkenyl" represents a monovalent, non-aromatic saturated cyclic hydrocarbon group, which may be a bridged ring, a fused ring or a spiro ring having three to eight ring carbons and containing one or more carbon-carbon double bonds unless otherwise specifically stated.

[0131] As used herein, the term "diastereomer" means stereoisomers that are not mirror images of each other and are non-superimposable on each other.

[0132] As used herein, the term "enantiomer" means each individual optically active form of a compound of the invention having an optical purity or enantiomeric excess of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98% (as determined by standard methods in the art).

[0133] The term "guanidyl" refers to a group having the following structure: wherein each R is independently any chemically viable substituent as described herein.

[0134] As used herein, the term "guanidylalkylalkyl" means an alkyl moiety in which one or more carbon atoms are substituted by one or more guanidyl moieties.

[0135] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen is replaced by a halogen.

[0136] 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.

[0137] As used herein, the term "halogen" means a halogen selected from bromine, chlorine, iodine or fluorine.

[0138] As used herein, the term "heteroalkyl" means "alkyl" as defined herein in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N or S atom). The heteroatom may be present in the middle or at the end of the group.

[0139] As used herein, the term "heteroaryl" means a monovalent, monocyclic or polycyclic structure containing at least one fully aromatic ring: i.e., it contains 4n + 2 π electrons within the monocyclic or polycyclic system and contains at least one heteroatom selected from N, O or S in the aromatic ring. Exemplary unsubstituted heteroaryls have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10 or 2 to 9) carbons. The term "heteroaryl" includes bicyclic, tricyclic and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more aromatic or carbocyclic rings, such as a phenyl ring or a cyclohexane ring. Examples of heteroaryls 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 pendant group at any ring atom that results in a stable structure, and unless otherwise specifically stated, any ring atom may be optionally substituted. In one embodiment, the heteroaryl is substituted with 1, 2, 3 or 4 substituents.

[0140] As used herein, the term "heterocycloalkyl" refers to a monovalent, monocyclic, bicyclic, or polycyclic system in which at least one ring is non-aromatic and in which the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and the ring system may be a bridged ring, a fused ring, or a spiro ring. The 5-membered ring has zero to two double bonds, and the 6-membered and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocycloalkyls have from 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 "heterocycloalkyl" also refers to heterocyclic compounds having a bridged polycyclic structure in which one or more carbons or heteroatoms bridge non-adjacent members of a monocyclic ring, such as quinuclidinyl. The term "heterocycloalkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocycles is fused to one or more aromatic rings, carbocyclic rings, heteroaromatic rings, or heterocycles, such as aryl rings, cyclohexane rings, cyclohexene rings, cyclopentane rings, cyclopentene rings, pyridine rings, or pyrrolidine rings. Examples of heterocycloalkyls are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridinyl, and decahydronaphthyridinyl. The heterocycloalkyl ring may be attached to its pendant groups at any ring atom that results in a stable structure, and any ring atom may be optionally substituted unless otherwise specifically stated.

[0141] As used herein, the term "hydroxy" refers to the -OH group.

[0142] 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 moieties.

[0143] As used herein, the term "isomer" means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the invention. It should be recognized that the compounds of the invention may have one or more chiral centers or double bonds and, accordingly, exist in stereoisomeric forms, such as in the form of double bond 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 depicted herein and thus 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 phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0144] As used herein, the term "linker" refers to a divalent organic moiety that connects moiety B to moiety W in a compound of formula I such that the resulting compound is capable of providing in the examples hereinafter and obtaining an IC50 value of 2 μM or lower in the Ras-RAF disruption assay protocol provided herein:

[0145] The purpose of this biochemical assay is to measure the ability of a test compound to promote the formation of a ternary complex between a nucleotide-bearing Ras isoform and cyclophilin A; the resulting ternary complex disrupts the binding to the BRAF RBD construct and inhibits Ras signaling through the RAF effector.

[0146] In an assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl 2 unlabeled cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variant), and GST-BRAF RBD were combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. The compounds present in each well of the assay plate were dilutions starting from a final concentration of 30 μM and undergoing 10-point 3-fold serial dilutions. After incubation at 25 °C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was then added to the assay sample wells to final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for an additional 1.5 hours. The TR-FRET signal was read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote the disruption of the Ras:RAF complex were identified as those that decrease the TR-FRET ratio relative to the DMSO control wells.

[0147] In some embodiments, the linker contains 20 or fewer linear atoms. In some embodiments, the linker contains 15 or fewer linear atoms. In some embodiments, the linker contains 10 or fewer linear atoms. In some embodiments, the linker has a molecular weight of less than 500 g / mol. In some embodiments, the linker has a molecular weight of less than 400 g / mol. In some embodiments, the linker has a molecular weight of less than 300 g / mol. In some embodiments, the linker has a molecular weight of less than 200 g / mol. In some embodiments, the linker has a molecular weight of less than 100 g / mol. In some embodiments, the linker has a molecular weight of less than 50 g / mol.

[0148] As used herein, a "monovalent organic moiety" is less than 500 kDa. In some embodiments, the "monovalent organic moiety" is less than 400 kDa. In some embodiments, the "monovalent organic moiety" is less than 300 kDa. In some embodiments, the "monovalent organic moiety" is less than 200 kDa. In some embodiments, the "monovalent organic moiety" is less than 100 kDa. In some embodiments, the "monovalent organic moiety" is less than 50 kDa. In some embodiments, the "monovalent organic moiety" is less than 25 kDa. In some embodiments, the "monovalent organic moiety" is less than 20 kDa. In some embodiments, the "monovalent organic moiety" is less than 15 kDa. In some embodiments, the "monovalent organic moiety" is less than 10 kDa. In some embodiments, the "monovalent organic moiety" is less than 1 kDa. In some embodiments, the "monovalent organic moiety" is less than 500 g / mol. In some embodiments, the "monovalent organic moiety" is in the range between 500 g / mol and 500 kDa.

[0149] As used herein, the term "stereoisomer" refers to all possible different isomeric and configurational forms that a compound (e.g., a compound of any formula described herein) may have, particularly all possible stereochemical and configurational isomeric forms of the underlying molecular structure, all diastereomers, enantiomers or configurational isomers, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, and all such tautomeric forms are included within the scope of the present invention.

[0150] As used herein, the term "sulfonyl" means -S(O) 2 - group.

[0151] As used herein, the term "thiocarbonyl" refers to a -C(S)- group.

[0152] As used herein, the term "vinyl ketone" refers to a group containing a carbonyl group directly attached to a carbon-carbon double bond.

[0153] As used herein, the term "vinyl sulfone" refers to a group containing a sulfonyl group directly attached to a carbon-carbon double bond.

[0154] As used herein, the term "alkynone" refers to a group containing the structure wherein R is any chemically viable substituent described herein.

[0155] Those skilled in the art will understand upon reading this disclosure that certain compounds described herein may be provided or utilized in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, a particular compound mentioned may refer to a particular form of the compound. In some embodiments, a particular compound mentioned may refer to the compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound rather than a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt of the compound; a preparation of a configurational isomer ((Z) or (E)) containing a double bond may be considered a different form from a preparation of another configurational isomer ((E) or (Z)) containing the double bond; a preparation of an isotope of one or more atoms different from the isotope present in a reference preparation may be considered to be in a different form. Detailed Description

[0156] Compound

[0157] Ras inhibitors are provided herein. 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 with each other under normal physiological conditions: a target protein of interest (e.g., Ras), and a cytoplasmic chaperone protein (presenting protein) that is widely expressed in cells (e.g., cyclophilin A). 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 cytoplasmic 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 formed thereby exert an inhibitory effect on Ras is to sterically block the interaction site between Ras and downstream effector molecules such as RAF required for propagating oncogenic signals.

[0158] Without being bound by theory, the inventors postulate that the covalent and non-covalent interactions of the compounds of the present invention with Ras and the chaperone protein (e.g., cyclophilin A) may contribute to the inhibition of Ras activity. In some embodiments, the compounds of the present invention interact with the side chain of the Ras protein (e.g., the -CH 2 -COOH or -CH 2-COO-side chains) to form covalent adducts. Covalent adducts can also be formed with other side chains of Ras. Additionally or alternatively, non-covalent interactions can play a role: for example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bond interactions, and combinations thereof can contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors. Thus, the compounds of the present invention can inhibit a variety of Ras proteins (such as K-Ras, N-Ras, H-Ras, and their mutants mutated at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, as well as other mutants described herein).

[0159] Methods for determining covalent adduct formation are known in the art. One method for determining covalent adduct formation is to perform a "crosslinking" assay, such as the assays described in the Examples and hereinafter:

[0160] Note: The following protocol describes a procedure for monitoring the crosslinking of K-Ras G12C (GMP-PNP) with a compound of the present invention. This protocol can also be implemented using other Ras proteins or nucleotides, such as K-Ras G12D.

[0161] The purpose of this biochemical assay is to measure the ability of a test compound to covalently label nucleotide-bearing K-Ras isoforms. In an assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCl, 1 mM MgCl 2 , 1 mM BME, 5 μM cyclophilin A, and 2 μM test compound, a 10-fold dilution of a 5 μM stock solution of nucleotide-bearing GMP-PNP K-Ras (1-169) G12C is made to a final concentration of 0.5 μM; and the final sample volume is 100 μL.

[0162] At 25 °C, the sample is incubated for up to 24 hours, followed by quenching with 10 μL of 5% formic acid. The quenched sample is centrifuged at 15,000 rpm for 15 minutes in a tabletop centrifuge, and then a 10 μL aliquot is injected onto a reversed-phase C4 column and eluted with an increasing acetonitrile gradient in the mobile phase into a mass spectrometer. Analysis of the raw data can be performed using Waters MassLynx MS software, where the binding % is calculated from the deconvoluted protein peaks of labeled and unlabeled K-Ras.

[0163] Accordingly, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof:

[0164]

[0165] Wherein the dashed line represents zero, one, two, three or four non - adjacent double bonds;

[0166] A is - N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of - CH(R 10 )-; 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 heteroarylene;

[0167] B is - CH(R 9 )- or >C = CR 9 R 9’ , wherein the carbon is bonded to the carbonyl carbon of - N(R 11 )C(O)-; optionally substituted 3 - to 6 - membered cycloalkylene; optionally substituted 3 - to 6 - membered heteroalkylene; optionally substituted 6 - membered arylene; or 5 - to 6 - membered heteroarylene;

[0168] G is optionally substituted C 1 - C 4 alkylene; optionally substituted C 1 - C 4 alkenylene; optionally substituted C 1 - C 4 heteroalkylene; - C(O)O - CH(R 6 )-, wherein C is bonded to - C(R 7 R 8 )-; - C(O)NH - CH(R 6 )-, wherein C is bonded to - C(R 7 R 8 )-; optionally substituted C 1 - C 4 heteroalkylene; or 3 - to 8 - membered heteroarylene;

[0169] L is absent or is a linker;

[0170] W is a cross - linking group, said 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), iso - EEDQ or other EEDQ derivatives, epoxide, oxazolium or enose;

[0171] X 1 is optionally substituted C 1 - C 2 alkylene, NR, O or S(O) n ;

[0172] X 2 is O or NH;

[0173] X 3 is N or CH;

[0174] n is 0, 1, or 2;

[0175] R is hydrogen, cyano, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 2 -C 4 Alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 、S(O)R'、S(O) 2 R' or S(O) 2 N(R') 2 ;

[0176] Each R' is independently H or optionally substituted C 1 -C 4 alkyl;

[0177] Y 1 is C, CH or N;

[0178] Y 2 , Y 3 , Y 4 and Y 7 are independently C or N;

[0179] Y 5 It is CH, CH 2 or N;

[0180] Y 6 is C(O), CH, CH 2 or N;

[0181] R 1 is cyano, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl, or

[0182] R 1 and R 2 and the atoms to which they are attached are taken together to form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0183] R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[0184] R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0185] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0186] R 5 is hydrogen, optionally halogen-substituted C 1 -C 4 alkyl, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0187] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl, or

[0188] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0189] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0190] R 7 and R 8 combine with the carbon atom to which it is attached to form C═CR 7’ R 8’ ; C═N(OH); C═N(O-C 1 -C 3 alkyl); C═O; C═S; C═NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0191] R 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which it is attached to form a carbonyl;

[0192] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0193] R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0194] R 9 is hydrogen, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl, or

[0195] R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0196] R 9’ is hydrogen or optionally substituted C1 -C 6 alkyl;

[0197] R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl;

[0198] R 10a is hydrogen or halo; and

[0199] R 11 is hydrogen or C 1 -C 3 alkyl; and

[0200] R 34 is hydrogen or C 1 -C 3 alkyl (such as methyl).

[0201] In some embodiments, R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl.

[0202] In some embodiments, R 34 is hydrogen.

[0203] In some embodiments of the compounds of the present invention, G is optionally substituted C 1 -C 4 heteroalkylene.

[0204] In some embodiments, the compounds of the present invention have the structure of formula Ia, or a pharmaceutically acceptable salt thereof:

[0205]

[0206] wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[0207] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; 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;

[0208] B is -CH(R 9)-, wherein carbon is bonded to -N(R 11 ) the carbonyl carbon of -C(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[0209] L is absent or is a linker;

[0210] W is a crosslinking group, the group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, an aziridine, a trifluoromethyl ketone, boric acid, a borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, an epoxide, an oxazolium or an enose;

[0211] X 2 is O or NH;

[0212] X 3 is N or CH;

[0213] n is 0, 1 or 2;

[0214] R is hydrogen, cyano, an optionally substituted C 1 -C 4 alkyl, an optionally substituted C 2 -C 4 alkenyl, an optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’or S(O) 2 N(R’) 2 ;

[0215] Each R’ is independently H or an optionally substituted C 1 -C 4 alkyl;

[0216] Y 1 is C, CH or N;

[0217] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0218] Y 5 and Y 6 are independently CH or N;

[0219] R 1 is cyano, an optionally substituted C 1-C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl;

[0220] R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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; R 3 is absent, or

[0221] R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl;

[0222] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0223] R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0224] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or C 1 -C 3 alkyl optionally substituted, or

[0225] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heteroalkyl;

[0226] R 8 is hydrogen, halogen, hydroxy, cyano, C 1 -C 3 alkoxy optionally substituted, C 1 -C 3 alkyl optionally substituted, C 2 -C 6 alkenyl optionally substituted, C2 -C 6 an alkynyl group, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group, or an optionally substituted 6- to 10-membered aryl group, or

[0227] R 7 and R 8 together with the carbon atom to which it is attached forms C═CR 7’ R 8’ ; C═N(OH); C═N(O-C 1 -C 3 alkyl); C═O; C═S; C═NH; an optionally substituted 3- to 6-membered cycloalkyl group; or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0228] R 7’ is hydrogen, a halogen, or an optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy group, an optionally substituted C 1 -C 3 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group, or an optionally substituted 6- to 10-membered aryl group, or

[0229] R 7’ and R 8’ together with the carbon atom to which it is attached forms an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0230] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0231] R 10 is hydrogen, a hydroxyl group, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl; and

[0232] R11 is hydrogen or C 1 -C 3 alkyl.

[0233] In some embodiments of the compounds of the present invention, X 2 is NH. In some embodiments, X 3 is CH.

[0234] In some embodiments of the compounds of the present invention, R 11 is hydrogen. In some embodiments, R 11 is C 1 -C 3 alkyl, such as methyl.

[0235] In some embodiments, the compounds of the present invention have the structure of formula Ib, or a pharmaceutically acceptable salt thereof:

[0236]

[0237] wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[0238] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; optionally substituted 3- to 6-membered cycloalkylidene; optionally substituted 3- to 6-membered heteroalkylidene; optionally substituted 6-membered arylidene; or optionally substituted 5- to 6-membered heteroarylidene;

[0239] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylidene; optionally substituted 3- to 6-membered heteroalkylidene; optionally substituted 6-membered arylidene; or 5- to 6-membered heteroarylidene;

[0240] L is absent or is a linker;

[0241] W is a crosslinking group, the 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), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or enose;

[0242] n is 0, 1 or 2;

[0243] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 , S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0244] Each R ’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0245] Y 1 is C, CH or N;

[0246] Y 2 , Y 3 , Y 4 and Y 7 are independently C or N;

[0247] Y 5 and Y 6 are independently CH or N;

[0248] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl;

[0249] R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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; R 3 is absent, or

[0250] R 2 and R 3 together with the atom to which they are attached form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl;

[0251] R 4is absent, hydrogen, halogen, cyano or methyl optionally substituted with 1 to 3 halogens;

[0252] R 5 is hydrogen, C 1 -C 4 alkyl, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0253] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl, or

[0254] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0255] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0256] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0257] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0258] R 7’ and R 8’ together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[0259] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; and

[0260] R 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl.

[0261] In some embodiments of the compounds of the present invention, X 1 is optionally substituted C 1 -C 2 alkylene. In some embodiments, X 1 is methylene.

[0262] In some embodiments of the compounds of the present invention, R 4 is hydrogen.

[0263] In some embodiments of the compounds of the present invention, R 5 is hydrogen. In some embodiments, R 5 is C 1 -C 4 alkyl optionally substituted with halogen. In some embodiments, R 5 is methyl.

[0264] In some embodiments of the compounds of the present invention, Y 4 is C. In some embodiments, R 4 is hydrogen. In some embodiments, Y 5 is CH. In some embodiments, Y 6 is CH. In some embodiments, Y1 is C. In some embodiments, Y 2 is C. In some embodiments, Y 3 is N. In some embodiments, R 3 is absent. In some embodiments, Y 7 is C.

[0265] In some embodiments, the compounds of the invention have the structure of formula Ic, or a pharmaceutically acceptable salt thereof:

[0266]

[0267] wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; an optionally substituted 3- to 6-membered cycloalkylidene; an optionally substituted 3- to 6-membered heteroalkylidene; an optionally substituted 6-membered arylidene; or an optionally substituted 5- to 6-membered heteroarylidene;

[0268] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylidene; an optionally substituted 3- to 6-membered heteroalkylidene; an optionally substituted 6-membered arylidene; or a 5- to 6-membered heteroarylidene;

[0269] L is absent or is a linker;

[0270] W is a crosslinking group comprising a carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or glycals;

[0271] R 1 is cyano, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 6-membered heteroalkyl, an optionally substituted 6- to 10-membered aryl or an optionally substituted 5- to 10-membered heteroaryl;

[0272] R 2 is hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C6 an alkenyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 7-membered heterocycloalkyl group, an optionally substituted 6-membered aryl group, an optionally substituted 5- or 6-membered heteroaryl group; R 3 is absent, or

[0273] R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl group or an optionally substituted 3- to 14-membered heterocycloalkyl group;

[0274] R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0275] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or C 1 -C 3 alkyl optionally substituted, or

[0276] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0277] R 8 is hydrogen, halogen, hydroxy, cyano, C 1 -C 3 alkoxy optionally substituted, C 1 -C 3 alkyl optionally substituted, C 2 -C 6 alkenyl optionally substituted, C 2 -C 6 alkynyl optionally substituted, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group or an optionally substituted 6- to 10-membered aryl group, or

[0278] R 7 and R 8 together with the carbon atom to which it is attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; an optionally substituted 3- to 6-membered cycloalkyl group; or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0279] R 7’ is hydrogen, a halogen, or an optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy, an optionally substituted C 1 -C 3 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 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

[0280] R 7’ and R 8’ together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0281] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; and

[0282] R 10 is hydrogen, a hydroxyl group, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl.

[0283] In some embodiments of the compounds of the present invention, R 6 is hydrogen.

[0284] In some embodiments of the compounds of the present invention, R 2 is hydrogen, a cyano group, an optionally substituted C 1 -C 6 alkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 2 is an optionally substituted C 1 -C 6 alkyl, such as ethyl.

[0285] In some embodiments of the compounds of the present invention, R 7 is an optionally substituted C 1 -C3 Alkyl. In some embodiments, R 7 is C 1 -C 3 alkyl.

[0286] In some embodiments of the compounds of the present invention, R 8 is optionally substituted C 1 -C 3 alkyl. In some embodiments, R 8 is C 1 -C 3 alkyl.

[0287] In some embodiments, the compounds of the present invention have the structure of formula Id, or a pharmaceutically acceptable salt thereof:

[0288]

[0289] wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; 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;

[0290] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene;

[0291] L is absent or is a linker;

[0292] W is a crosslinking group, the group comprising a carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or glycals;

[0293] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl;

[0294] R 2 is C 1 -C 6 alkyl or 3- to 6-membered cycloalkyl;

[0295] R 7 is C 1 -C 3 alkyl;

[0296] R 8 is C 1 -C 3 alkyl; and

[0297] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl.

[0298] In some embodiments of the compounds of the present invention, R 1 is a 5- to 10-membered heteroaryl. In some embodiments, R 1 is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[0299] In some embodiments, the compounds of the present invention have the structure of formula Ie, or a pharmaceutically acceptable salt thereof:

[0300]

[0301] wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; optionally substituted 3- to 6-membered subcycloalkyl; optionally substituted 3- to 6-membered subheterocycloalkyl; optionally substituted 6-membered subaryl; or optionally substituted 5- to 6-membered subheteroaryl;

[0302] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered subcycloalkyl; optionally substituted 3- to 6-membered subheterocycloalkyl; optionally substituted 6-membered subaryl; or 5- to 6-membered subheteroaryl;

[0303] L is absent or is a linker;

[0304] W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or glycals;

[0305] R 2 is C 1 -C 6 alkyl or 3- to 6-membered cycloalkyl;

[0306] R 7 is C 1 -C 3 alkyl;

[0307] R 8 is C 1 -C 3 alkyl; and

[0308] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[0309] X e is N or CH; and

[0310] R 12 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 heteroalkyl.

[0311] In some embodiments of the compounds of the present invention, X e is N. In some embodiments, X e is CH.

[0312] In some embodiments of the compounds of the present invention, R 12 is optionally substituted C 1 -C 6 heteroalkyl. In some embodiments, R 12 is In some embodiments, R 12 is

[0313] In some embodiments, the compounds of the present invention have the structure of formula If, or a pharmaceutically acceptable salt thereof:

[0314]

[0315] Wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[0316] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; 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;

[0317] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene;

[0318] G is optionally substituted C 1 -C 4 alkylene; optionally substituted C 1 -C 4 alkenylene; optionally substituted C 1 -C 4 heteroalkylene; -C(O)O-CH(R 6 )-, wherein C is bonded to -C(R 7 R 8 )-; -C(O)NH-CH(R 6 )-, wherein C is bonded to -C(R 7 R 8 )-; optionally substituted C 1 -C 4 heteroalkylene; or 3- to 8-membered heteroarylene;

[0319] L is absent or is a linker;

[0320] W is a crosslinking group, said 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), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or enose;

[0321] X 1 is optionally substituted C 1 -C 2Alkylene, NR, O or S(O) n ;

[0322] X 2 is O or NH;

[0323] X 3 is N or CH;

[0324] n is 0, 1 or 2;

[0325] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 , S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0326] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0327] Y 1 is C, CH or N;

[0328] Y 2 , Y 3 , Y 4 and Y 7 are independently C or N;

[0329] Y 5 and Y 6 are independently CH or N;

[0330] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl;

[0331] R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6Alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[0332] R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0333] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0334] R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0335] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl, or

[0336] R 6 and R 7 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0337] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0338] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3(alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0339] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0340] R 7’ and R 8’ together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[0341] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[0342] R 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl; and

[0343] R 11 is hydrogen or C 1 -C 3 alkyl.

[0344] In some embodiments, the compounds of the invention have the structure of formula VI, or a pharmaceutically acceptable salt thereof:

[0345]

[0346] wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[0347] A is -N(H or CH3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene (e.g., phenyl or phenol); or an optionally substituted 5- to 10-membered heteroarylene;

[0348] B is -CH(R 9 )- or >C=CR 9 R 9’ , wherein the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[0349] G is an optionally substituted C 1 -C 4 alkylene; an optionally substituted C 1 -C 4 alkenylene; an optionally substituted C 1 -C 4 heteroalkylene; -C(O)O-CH(R 6 )-, wherein the C is bonded to -C(R 7 R 8 )-; -C(O)NH-CH(R 6 )-, wherein the C is bonded to -C(R 7 R 8 )-; an optionally substituted C 1 -C 4 heteroalkylene; or a 3- to 8-membered heteroarylene;

[0350] L is absent or is a linker;

[0351] W is a crosslinking group, said group comprising a carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or enose;

[0352] X 1 is an optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[0353] X 2 is O or NH;

[0354] X 3 is N or CH;

[0355] n is 0, 1 or 2;

[0356] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0357] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0358] Y 1 is C, CH or N;

[0359] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0360] Y 5 is CH, CH 2 or N;

[0361] Y 6 is C(O), CH, CH 2 or N;

[0362] R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[0363] R 2 and R 3 together with the atom to which they are attached form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl;

[0364] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0365] R 5 is hydrogen, C 1 -C 4 alkyl, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0366] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl, or

[0367] R 6 and R 7 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0368] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0369] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0370] R 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or together with the carbon to which they are attached form a carbonyl;

[0371] R7’ is hydrogen, a halogen, or an optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy group, an optionally substituted C 1 -C 3 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group, or an optionally substituted 6- to 10-membered aryl group, or

[0372] R 7’ and R 8’ together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0373] R 9 is hydrogen, F, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group, or

[0374] R 9 and L together with the atoms to which they are attached form an optionally substituted 3- to 14-membered heterocycloalkyl group;

[0375] R 9’ is hydrogen or an optionally substituted C 1 -C 6 alkyl;

[0376] R 10 is hydrogen, halogenated, hydroxyl, C 1 -C 3 alkoxy or C 1 -C 3 alkyl;

[0377] R 10a is hydrogen or halogenated;

[0378] R 11 is hydrogen or C 1 -C 3 alkyl;

[0379] R 34 is hydrogen or C 1 -C3 alkyl; and

[0380] X e and X f are independently N or CH.

[0381] In some embodiments, the compounds of the invention have the structure of formula VIa, or a pharmaceutically acceptable salt thereof:

[0382]

[0383] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heteroalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene;

[0384] B is -CH(R 9 )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[0385] L is absent or is a linker;

[0386] W is a crosslinking group that includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium, or glycals;

[0387] X 1 is an optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) n ;

[0388] X 2 is O or NH;

[0389] n is 0, 1, or 2;

[0390] R is hydrogen, cyano, an optionally substituted C 1 -C 4 alkyl, an optionally substituted C 2 -C 4 alkenyl, an optionally substituted C 2 -C 4 alkynyl, C(O)R', C(O)OR', C(O)N(R')[[]] 2 , S(O)R', S(O)[[]] 2 R' or S(O)2 N(R’) 2 ;

[0391] Each R ’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0392] R 2 is C 1 -C 6 alkyl or a 3- to 6-membered cycloalkyl;

[0393] R 7 is C 1 -C 3 alkyl;

[0394] R 8 is C 1 -C 3 alkyl; and

[0395] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[0396] X e and X f are independently N or CH;

[0397] R 11 is hydrogen or C 1 -C 3 alkyl; and

[0398] R 21 is hydrogen or C 1 -C 3 alkyl.

[0399] In some embodiments of the compounds of the invention, X e is N and X f is CH. In some embodiments, X e is CH and X f is N.

[0400] In some embodiments, the compounds of the invention have the structure of formula VIb, or a pharmaceutically acceptable salt thereof:

[0401]

[0402] Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heteroalkylene, an optionally substituted 6-membered arylene (such as phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene;

[0403] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[0404] L is absent or is a linker;

[0405] W is a crosslinking group, the group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, an aziridine, a trifluoromethyl ketone, boric acid, a borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, an epoxide, an oxazolium or an enose;

[0406] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; and

[0407] X e and X f are independently N or CH.

[0408] In some embodiments of the compounds of the present invention, X e is N, and X f is CH. In some embodiments, X e is CH, and X f is N.

[0409] In some embodiments, the compounds of the present invention have the structure of formula VII, or a pharmaceutically acceptable salt thereof:

[0410]

[0411] wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[0412] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to -CH(R 10) - the carbon atom; 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 heteroarylene;

[0413] B is -CH(R 9 ) - or >C═CR 9 R 9’ , where the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene;

[0414] G is optionally substituted C 1 -C 4 alkylene; optionally substituted C 1 -C 4 alkenylene; optionally substituted C 1 -C 4 heteroalkylene; -C(O)O-CH(R 6 ), where C is bonded to -C(R 7 R 8 ) -; -C(O)NH-CH(R 6 ), where C is bonded to -C(R 7 R 8 ) -; optionally substituted C 1 -C 4 heteroalkylene; or 3- to 8-membered heteroarylene;

[0415] L is absent or is a linker;

[0416] W is a crosslinking group, the group comprising a carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolinium or enose;

[0417] X 1 is optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[0418] X 2 is O or NH;

[0419] X 3 is N or CH;

[0420] n is 0, 1 or 2;

[0421] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0422] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0423] Y 1 is C, CH or N;

[0424] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0425] Y 5 is CH, CH 2 or N;

[0426] Y 6 is C(O), CH, CH 2 or N;

[0427] R 1 is

[0428]

[0429] R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[0430] R 2 and R 3 together with the atom to which they are attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0431] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0432] R 5 is hydrogen, C 1 -C 4 alkyl, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0433] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl, or

[0434] R 6 and R 7 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0435] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0436] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0437] R 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or together with the carbon to which they are attached form a carbonyl;

[0438] R 7’ is hydrogen, a halogen, or an optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy group, an optionally substituted C 1 -C 3 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group, or an optionally substituted 6- to 10-membered aryl group, or

[0439] R 7’ and R 8’ together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0440] R 9 is hydrogen, F, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group, or

[0441] R 9 and L together with the atoms to which they are attached form an optionally substituted 3- to 14-membered heterocycloalkyl group;

[0442] R 9’ is hydrogen or an optionally substituted C 1 -C 6 alkyl;

[0443] R 10 is hydrogen, halogenated, hydroxyl, C 1 -C 3 alkoxy or C 1 -C 3 alkyl;

[0444] R 10a is hydrogen or halogenated;

[0445] R 11 is hydrogen or C 1 -C 3 alkyl; and

[0446] R 34 is hydrogen or C1 -C 3 alkyl (such as methyl).

[0447] In some embodiments of the compounds of the present invention, A is an optionally substituted 6-membered arylene group. In some embodiments, A has the following structure:

[0448]

[0449] wherein R 13 is hydrogen, hydroxyl, amino, optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 heteroalkyl. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is hydroxyl.

[0450] In some embodiments of the compounds of the present invention, B is -CHR 9 -. In some embodiments, R 9 is optionally substituted C 1 -C 6 alkyl or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R 9 is: In some embodiments, R 9 is: In some embodiments, R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl.

[0451] In some embodiments, B is an optionally substituted 6-membered arylene group. In some embodiments, B is a 6-membered arylene group. In some embodiments, B is:

[0452] In some embodiments of the compounds of the present invention, R 7 is methyl.

[0453] In some embodiments of the compounds of the present invention, R 8 is methyl.

[0454] In some embodiments, R 34 is hydrogen.

[0455] In some embodiments of the compounds of the present invention, the linker is a structure of Formula II:

[0456] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2

[0457] Formula II

[0458] wherein A 1 is a bond between the linker and B; A 2 is a bond between W and the linker; B 1 , B 2 , B 3 and B 4 are each independently selected from optionally substituted C 1 -C 2 alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S and NR N ; R N is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3- to 14-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted C 1 -C 7 heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D 1 is optionally substituted C 1 -C 10 alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted 3- to 14-membered heteroalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C 2-C 10 Polyethylene glycol or optionally substituted C 1 -C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - is linked to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 chemical bond. In some embodiments, the linker is an acyclic linker. In some embodiments, the linker has the structure of Formula IIa:

[0459]

[0460] wherein X a is absent or is N;

[0461] R 14 is absent, hydrogen or optionally substituted C 1 -C 6 alkyl; and

[0462] L 2 is absent, -SO 2 -, optionally substituted C 1 -C 4 alkylene or optionally substituted C 1 -C 4 heteroalkylene, wherein at least one of X a , R 14 or L 2 is present. In some embodiments, the linker has the following structure:

[0463] In some embodiments, the linker is or comprises a cyclic group. In some embodiments, the linker has the structure of Formula IIb:

[0464]

[0465] wherein o is 0 or 1;

[0466] R 15 is hydrogen or optionally substituted C 1 -C 6 alkyl;

[0467] Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heteroalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; and

[0468] L 3 is absent, -SO 2 -, an optionally substituted C 1 -C 4 alkylene, or an optionally substituted C 1 -C 4 heteroalkylene. In some embodiments, the linker has the following structure:

[0469]

[0470]

[0471] In some embodiments, the linker of Formula II is selected from the group consisting of:

[0472]

[0473] In some embodiments of the compounds of the present invention, W comprises a carbodiimide. In some embodiments, W has the structure of Formula IIIa:

[0474]

[0475] wherein R 14 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 14-membered heterocycloalkyl, or an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W has the following structure:

[0476]

[0477]

[0478] In some embodiments, W comprises an oxazoline or a thiazoline. In some embodiments, W has the structure of Formula IIIb:

[0479]

[0480] wherein X 1 is O or S;

[0481] X 2Does not exist or is NR 19 ;

[0482] R 15 , R 16 , R 17 and R 18 are independently hydrogen or optionally substituted C 1 -C 6 Alkyl; and

[0483] R 19 is hydrogen, C(O) (optionally substituted C 1 -C 6 alkyl), optionally substituted C 1 -C 6 In some embodiments, W is

[0484] In some embodiments, W comprises chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate or chloroethyl thiocarbamate. In some embodiments, W has the structure of Formula IIIc:

[0485]

[0486]

[0487] Where X 3 is O or S;

[0488] X 4 O, S, NR 26 ;

[0489] R 21 , R 22 , R 23 , R 24 and R 26 are independently hydrogen or optionally substituted C 1 -C 6 Alkyl; and

[0490] R 25 is hydrogen, optionally substituted C 1 -C 6 In some embodiments, W is

[0491] In some embodiments, W comprises aziridine. In some embodiments, W has a structure of Formula IIId1, Formula IIId2, Formula IIId3, or Formula IIId4:

[0492]

[0493] wherein X 5 is absent or is NR 30 ;

[0494] Y is absent or is C(O), C(S), S(O), SO 2 or optionally substituted C 1 -C 3 alkylene;

[0495] R 27 is hydrogen, -C(O)R 32 , -C(O)OR 32 , -SOR 33 , -SO 2 R 33 , optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl;

[0496] R 28 and R 29 are independently hydrogen, CN, C(O)R 31 , CO 2 R 31 , C(O)R 31 R 31 , optionally substituted C 1 -C 6 alkyl, optionally 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;

[0497] Each R 31 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl;

[0498] R 30 is hydrogen or optionally substituted C 1 -C 6 alkyl; and

[0499] R 32 and R 33Independently hydrogen, optionally substituted C 1 -C 6 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:

[0500]

[0501]

[0502] In some embodiments, W comprises an epoxide. In some embodiments, W is

[0503] In some embodiments, W is a crosslinking group attached to an organic moiety that is a Ras-binding moiety, i.e., RBM-W, where after contact of the RBM-W compound with a Ras protein, the RBM-W binds to the Ras protein to form a conjugate. For example, the W moiety of the RBM-W compound can bind to an amino acid of the Ras protein, e.g., crosslink, to form a conjugate. In some embodiments, the Ras-binding moiety is a K-Ras-binding moiety. In some embodiments, the K-Ras-binding moiety binds to residues in the K-Ras Switch-II binding pocket of the K-Ras protein. In some embodiments, the Ras-binding moiety is an H-Ras-binding moiety that binds to residues in the H-Ras Switch-II binding pocket of the H-Ras protein. In some embodiments, the Ras-binding moiety is an N-Ras-binding moiety that binds to residues in the N-Ras Switch-II binding pocket of the N-Ras protein. The W of the RBM-W compound can comprise any W described herein. The molecular weight of the Ras-binding moiety is typically less than 1200 Da. For a description of the various domains of the Ras protein, see, e.g., Johnson et al., 292:12981-12993 (2017), which is incorporated herein by reference.

[0504] In some embodiments, the compounds of the invention are selected from Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compounds of the invention are selected from Table 1, or a pharmaceutically acceptable salt or atropisomer thereof.

[0505] Table 1: Certain Compounds of the Invention

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587] *Assume the stereochemistry of the aziridine carbon.

[0588] It should be noted that the bonds in some compounds are shown as straight lines or wedge lines. 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 above table are covered in the present invention. In certain embodiments, atropisomers of the compounds in the above table are covered.

[0589] In some embodiments, there are provided the compounds of Table 2, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of the present invention are selected from Table 2, or pharmaceutically acceptable salts or stereoisomers thereof.

[0590] Table 2: Certain Compounds of the Present Invention

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606] It should be noted that the bonds in some compounds are shown as straight lines or wedge lines. 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 above table are covered by the present invention. In certain embodiments, atropisomers of the compounds in the above table are covered.

[0607] In some embodiments, the compounds of the present invention are or are used as prodrugs, such as for administration to cells or a subject in need.

[0608] There are also provided pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0609] There is also provided a conjugate or a salt thereof, the conjugate comprising a structure of Formula IV:

[0610] M-L-P

[0611] Formula IV

[0612] wherein L is a linker;

[0613] P is a monovalent organic moiety; and

[0614] M has a structure of Formula Va:

[0615]

[0616] wherein the dotted line represents zero, one, two, three or four non-adjacent double bonds;

[0617] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heterocycloalkylene; an optionally substituted 6-membered arylene; or an optionally substituted 5- to 6-membered heteroarylene;

[0618] B is -CH(R 9 )- or >C=CR 9 R 9’ , wherein the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heterocycloalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[0619] G is an optionally substituted C 1 -C 4 alkylene; an optionally substituted C 1 -C 4Alkenylene; optionally substituted C 1 -C 4 Heteroalkylene; -C(O)O-CH(R 6 )-, where C is bonded to -C(R 7 R 8 )-; -C(O)NH-CH(R 6 )-, where C is bonded to -C(R 7 R 8 )-; optionally substituted C 1 -C 4 Heteroalkylene; or a 3- to 8-membered heteroaryl;

[0620] X 1 is optionally substituted C 1 -C 2 Alkylene, NR, O or S(O) n ;

[0621] X 2 is O or NH;

[0622] X 3 is N or CH;

[0623] n is 0, 1 or 2;

[0624] R is hydrogen, cyano, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 2 -C 4 Alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0625] Each R’ is independently H or optionally substituted C 1 -C 4 Alkyl;

[0626] Y 1 is C, CH or N;

[0627] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0628] Y 5 is CH, CH 2 or N;

[0629] Y 6 is C(O), CH, CH 2 or N;

[0630] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or

[0631] R 1 and R 2 together with the atom to which it is attached form an optionally substituted 3- to 14-membered heteroalkyl;

[0632] R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[0633] R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl;

[0634] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0635] R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0636] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or C 1 -C 3 alkyl optionally substituted, or

[0637] R6 and R 7 combines with the carbon atom to which it is attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0638] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0639] R 7 and R 8 combines with the carbon atom to which it is attached to form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0640] R 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;

[0641] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0642] R7’ and R 8’ Combined with the carbon atom to which it is attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0643] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; or

[0644] R 9 and L combined with the atoms to which they are attached form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0645] R 9’ is hydrogen or an optionally substituted C 1 -C 6 alkyl;

[0646] R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl;

[0647] R 10a is hydrogen or halo; and

[0648] R 11 is hydrogen or C 1 -C 3 alkyl.

[0649] In some embodiments, the conjugate has the structure of Formula IV:

[0650] M-L-P

[0651] Formula IV

[0652] wherein L is a linker;

[0653] P is a monovalent organic moiety; and

[0654] M has the structure of Formula Vb:

[0655]

[0656] wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[0657] A is -N(H or CH 3 )C(O)-(CH 2)-, where the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; 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;

[0658] B is -CH(R 9 )-, where the carbon is bonded to -N(R 11 )C(O)- carbonyl carbon; 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;

[0659] G is optionally substituted C 1 -C 4 alkylene; optionally substituted C 1 -C 4 alkenylene; optionally substituted C 1 -C 4 heteroalkylene; -C(O)O-CH(R 6 )-, where C is bonded to -C(R 7 R 8 )-; -C(O)NH-CH(R 6 )-, where C is bonded to -C(R 7 R 8 )-; optionally substituted C 1 -C 4 heteroalkylene; or 3- to 8-membered heteroarylene;

[0660] X 1 is optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[0661] X 2 is O or NH;

[0662] X 3 is N or CH;

[0663] n is 0, 1 or 2;

[0664] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’、S(O) 2R’ or S(O) 2 N(R’) 2 ;

[0665] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0666] Y 1 is C, CH or N;

[0667] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0668] Y 5 and Y 6 are independently CH or N;

[0669] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl;

[0670] R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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; R 3 is absent, or

[0671] R 2 and R 3 together with the atom to which they are attached form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl;

[0672] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0673] R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0674] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl, or

[0675] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0676] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0677] R 7 and R 8 together with the carbon atom to which it is attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0678] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0679] R 7’ and R 8’ combines with the carbon atom to which it is attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0680] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0681] R 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl; and

[0682] R 11 is hydrogen or C 1 -C 3 alkyl.

[0683] In some embodiments, the conjugate has the structure of Formula IV:

[0684] M-L-P

[0685] Formula IV

[0686] wherein L is a linker;

[0687] P is a monovalent organic moiety; and

[0688] M has the structure of Formula Vc:

[0689]

[0690] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heteroalkylene, an optionally substituted 6-membered arylene (such as phenyl or phenol) or an optionally substituted 5- to 6-membered heteroarylene;

[0691] B is -CH(R 9 )-, where the carbon is attached to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[0692] X 1 is an optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[0693] X 2 is O or NH;

[0694] n is 0, 1 or 2;

[0695] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0696] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0697] X e and X f are independently N or CH;

[0698] R 2 is C 1 -C 6 alkyl or 3- to 6-membered cycloalkyl;

[0699] R 7 is C 1 -C 3 alkyl;

[0700] R 8 is C 1 -C 3 alkyl; and

[0701] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[0702] R 11 is hydrogen or C 1 -C 3 alkyl; and

[0703] R 34 is hydrogen or C 1 -C 3 alkyl.

[0704] In some embodiments of the compounds of the present invention, X e is N, and X f is CH. In some embodiments, X e is CH, and X f is N.

[0705] In some embodiments, the conjugate has the structure of Formula IV:

[0706] M-L-P

[0707] Formula IV

[0708] wherein L is a linker;

[0709] P is a monovalent organic moiety; and

[0710] M has the structure of Formula Vd:

[0711]

[0712] wherein A is an optionally substituted 3- to 6-membered cycloalkylidene, an optionally substituted 3- to 6-membered heteroalkylidene, an optionally substituted 6-membered arylidene (such as phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylidene;

[0713] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylidene; an optionally substituted 3- to 6-membered heteroalkylidene; an optionally substituted 6-membered arylidene; or a 5- to 6-membered heteroarylidene;

[0714] L is absent or is a linker;

[0715] W is a crosslinking group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, an aziridine, a trifluoromethyl ketone, boric acid, a borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, an epoxide, an oxazolium, or an enose;

[0716] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; and

[0717] X e and X fIndependently N or CH.

[0718] In some embodiments of the compounds of the present invention, X e is N, and X f is CH. In some embodiments, X e is CH, and X f is N.

[0719] In some embodiments of the conjugates of the present invention, the linker has the structure of Formula II:

[0720] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2

[0721] Formula II

[0722] wherein A 1 is the bond between the linker and B; A 2 is the bond between P and the linker; B 1 , B 2 , B 3 and B 4 each independently selected from optionally substituted C 1 -C 2 alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S and NR N ; R N is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3- to 14-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted C 1 -C 7 heteroalkyl; C 1 and C 2 each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D 1is an optionally substituted C 1 -C 10 alkylene, an optionally substituted C 2 -C 10 alkenylene, an optionally substituted C 2 -C 10 alkynylene, an optionally substituted 3- to 14-membered heteroalkylenyl, an optionally substituted 5- to 10-membered heteroarylene, an optionally substituted 3- to 8-membered cycloalkylenyl, an optionally substituted 6- to 10-membered arylene, an optionally substituted C 2 -C 10 polyethylene glycol, or an optionally substituted C 1 -C 10 heteroalkylenyl, or linking A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -linked to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 chemical bond. In some embodiments of the conjugates of the present invention, the linker is attached to the monovalent organic moiety by a bond to the carboxyl group in an amino acid residue of the monovalent organic moiety.

[0723] In some embodiments of the conjugates 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.

[0724] There is also provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The cancer can be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid 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.

[0725] There is also provided a method of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0726] Also provided is a method of inhibiting Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12D or K-Ras G13D. Other Ras proteins are also described herein. The cell can be a cancer cell, such as a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid adenocarcinoma cell, a myelodysplastic syndrome cell, or a squamous cell lung cancer cell. Other cancer types are also described herein. The cell can be in vivo or in vitro.

[0727] For the compounds of the present invention, one stereoisomer may exhibit better inhibitory effect than the other stereoisomer. For example, one atropisomer may exhibit inhibitory effect while the other atropisomer may exhibit very low or no inhibitory effect.

[0728] In some embodiments, the methods or uses described herein further comprise administering an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is 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 anti-cancer therapy is an SHP2 inhibitor. Other additional anti-cancer therapies are also described herein.

[0729] Synthesis methods

[0730] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0731] 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 the art of synthetic organic chemistry or modifications of said methods understood by those skilled in the art. The methods include but are not limited to the methods described in the following schemes.

[0732] The compounds in Table 1 herein are prepared using the methods disclosed herein, or prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art. The compounds in Table 2 can be prepared using the methods disclosed herein, or can be prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art.

[0733] Scheme 1. General synthetic method of macrocyclic esters

[0734]

[0735] The general synthetic method of the macrocyclic ester is outlined in Scheme 1. The appropriately substituted aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (1) can be prepared in three steps using the protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and the appropriately substituted boronic acid as starting materials, including palladium-mediated coupling, alkylation, and deprotection reactions.

[0736] The amino-hexahydropyridazine-3-carboxylic acid methyl ester-borate (2) can be prepared in three steps, including protection, iridium-catalyst-mediated borylation, and coupling with (S)-hexahydropyridazine-3-carboxylic acid methyl ester.

[0737] The final macrocyclic ester can be prepared by coupling the amino-hexahydropyridazine-3-carboxylic acid methyl ester-borate (2) with the aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (1) in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps to obtain the appropriately 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 -B-L-W group required for the compound of formula (I) into the macrocyclic ester, where B, L, and W are as defined herein, including by using the methods exemplified in certain of the following schemes and in the Examples section herein.

[0738] Scheme 2. Alternative general synthetic method of the macrocyclic ester

[0739]

[0740] Alternatively, the macrocyclic ester can be prepared as described in Scheme 2. The appropriately protected bromo-indolyl (5) can be coupled with the borate (3) in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Subsequent coupling with (S)-hexahydropyridazine-3-carboxylic acid methyl ester, followed by hydrolysis and macrolactonization, can produce the iodo intermediate (6). Coupling with the appropriately substituted borate in the presence of a Pd catalyst can give the 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 -B-L-W group required for the compound of formula (I) into the macrocyclic ester, where B, L, and W are as defined herein, including by using the methods exemplified in certain of the following schemes and in the Examples section herein.

[0741] Scheme 3. General synthetic method of the macrocycle containing a nitrogen heterocycle

[0742]

[0743] As shown in Scheme 3, such compounds can be prepared by reacting an appropriate amine (1) with a carboxylic acid containing a nitrogen heterocyclopropane (2) in the presence of a standard amide coupling reagent. If R 1 is a protecting group, the aziridine is then deprotected, and if necessary, the phenol is deprotected to obtain the final compound (4).

[0744] Scheme 4. General synthetic method of macrocycles containing carbodiimide

[0745]

[0746] As shown in Scheme 4, such compounds can be prepared by reacting an appropriate amine (1) with a carboxylic acid containing thiourea (2) in the presence of a standard amide coupling reagent, and then converting the thiourea (3) into a carbodiimide (4) in the presence of 2-chloro-1-methylpyridin-1-ium iodide.

[0747] Scheme 5. General synthetic method of macrocycles containing chloroethylurea

[0748]

[0749] As shown in Scheme 5, such compounds can be prepared by reacting an appropriate amine (1) with an isocyanate (2) under basic conditions, and if necessary, subsequently deprotecting the phenol to produce the final compound (4).

[0750] Scheme 6. General synthetic method of macrocycles containing aminooxazoline

[0751]

[0752] 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).

[0753] Scheme 7. General synthetic method of macrocycles containing epoxy groups

[0754]

[0755] As shown in Scheme 7, such compounds can be prepared by reacting an appropriate amine (1) with a carboxylic acid containing epoxy groups (2) in the presence of a standard amide coupling reagent to produce the final compound (3).

[0756] In addition, the compounds of the present 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 such methods 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 -B-L-W group required for the compounds of formula (I) into the macrocyclic ester, where B, L, and W are as defined herein, including by using the methods illustrated in certain of the above schemes and in the Examples section herein.

[0757] Pharmaceutical Compositions and Methods of Use

[0758] Pharmaceutical Compositions and Methods of Administration

[0759] The compounds of the present invention are Ras inhibitors and can be used to treat cancer. Accordingly, one embodiment of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, as well as a method for preparing such a composition using the compound of the present invention.

[0760] As used herein, the term "pharmaceutical composition" refers to a compound formulated with a pharmaceutically acceptable excipient, such as a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0761] In some embodiments, the compound is present in the pharmaceutical composition in an amount that is a unit dose suitable for administration in a treatment regimen, and the compound shows a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition can be specifically formulated for administration in solid or liquid form, including those suitable for administration by: oral administration, such as potions (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those designed for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for administration to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as, for example, sterile solutions or suspensions, or sustained-release formulations; topical administration, such as creams, ointments, or controlled-release patches or sprays for administration to the skin, lung, or oral cavity; intravaginal or rectal administration, such as pessaries, creams, or foams; sublingual administration; ophthalmic administration; transdermal administration; or nasal, pulmonary administration, and administration to other mucosal surfaces.

[0762] As used herein, "pharmaceutically acceptable excipient" refers to any inactive ingredient (e.g., an agent capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in a subject. Typical excipients include, for example: anti-adhesives, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (pigments), emollients, emulsifiers, fillers (diluents), film formers or coating agents, flavoring agents, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweetening agents or water for hydration. Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, cross-linked carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, 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 starch glycolate, sorbitol, starch (corn starch), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are aware of the various 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 includes at least two different pharmaceutically acceptable excipients.

[0763] Unless clearly stated to the contrary, the compounds described herein, whether or not clearly stated, may be in salt form, e.g., provided or used in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds described herein that are within the scope of sound medical judgment, suitable for use in contact with human tissues without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (P.H. Stahl and C.G. Wermuth eds.), Wiley-VCH, 2008. The salts may be prepared in situ during the final isolation and purification of the compounds described herein, or by separating the free basic groups by reaction with a suitable organic acid.

[0764] The compounds of the invention may have ionizable groups, whereby they are capable of being prepared in the form of pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or in the case where the compounds of the invention are in acid form, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared as or used in the form of pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases. 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 the appropriate salts are well recognized in the art.

[0765] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2 - optionally substituted hydroxy - ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 - naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 - phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, etc., and non - toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0766] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, the "subject" refers to a human at any stage of development. In some embodiments, the "subject" refers to a human patient. In some embodiments, the "subject" refers to a non - human animal. In some embodiments, the non - human animal is a mammal (e.g., rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate or pig). In some embodiments, the subject includes but is not limited to mammals, birds, reptiles, amphibians, fish or insects. In some embodiments, the subject can be a transgenic animal, a genetically engineered animal or a clone.

[0767] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (e.g., a compound of the present invention) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, the amount is an amount of a unit dose (or an integral part thereof) suitable for administration according to a dosing regimen, which amount, when administered to a relevant population (i.e., according to a therapeutic dosing regimen), is determined to be related to the desired or beneficial outcome. 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.

[0768] As used herein, the term "dose regimen" refers to a set of unit doses (typically more than one unit dose) administered individually to a subject, the unit doses typically being spaced apart by a period of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dose regimen, which may involve one or more doses. In some embodiments, the dose regimen comprises multiple doses, the doses each being spaced apart from one another by the same length of time period; in some embodiments, the dose regimen comprises multiple doses and at least two different time periods separate the individual doses. In some embodiments, all of the doses within the dose regimen are of the same unit dose amount. In some embodiments, the different doses within the dose regimen are different amounts. In some embodiments, the dose regimen comprises a first dose in an amount of a first dose, followed by one or more additional doses in an amount of a second dose different from the first dose. In some embodiments, the dose regimen comprises a first dose in an amount of a first dose, followed by one or more additional doses in an amount of a second dose the same as the amount of the first dose. In some embodiments, the dose regimen, when administered to a relevant population (i.e., is a therapeutic dose regimen), is associated with a desired or beneficial outcome.

[0769] A "treatment regimen" refers to a dose regimen in which administration to a relevant population is associated with a desired or beneficial therapeutic outcome.

[0770] The term "treatment" ("treatment / treat / treating") in its broadest sense refers to the partial or complete remission, amelioration, mitigation, inhibition of one or more symptoms, features, or causes of a particular disease, disorder, or affliction; delay of its onset; reduction of its severity; or decrease in its incidence by the administration of a substance (e.g., a compound of the present invention). In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder, or affliction or who exhibits only early signs of the disease, disorder, or affliction. Alternatively or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder, or affliction. In some embodiments, treatment may be used for a subject diagnosed as suffering from the relevant disease, disorder, or affliction. In some embodiments, treatment may be used for a subject known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, or affliction.

[0771] The term "therapeutically effective amount" means an amount sufficient to treat a disease, disorder or condition when administered to a population suffering from or susceptible to the disease, disorder or condition according to a therapeutic dosage 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, disorder or condition or delays its onset. Those skilled in the art will understand that the term "therapeutically 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 particular desired pharmacological response in a significant number of subjects when administered to a patient in need of the treatment. It is particularly to be understood that a particular subject can actually be "refractory" to a "therapeutically effective amount". In some embodiments, the therapeutically effective amount referred to may be the amount measured in one or more specific tissues (e.g., tissues affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount can be formulated as a single dose or administered as a single dose. In some embodiments, a therapeutically effective amount can be formulated as multiple doses, e.g., formulated as part of a dosage regimen, or administered as multiple doses.

[0772] For use in the treatment of a subject, the compounds of the invention or pharmaceutically acceptable salts thereof may be formulated in the form of a pharmaceutical composition or a veterinary composition. Depending on the subject to be treated, the mode of administration and the type of treatment desired, e.g., prophylaxis, prophylaxis or treatment, the compound or its pharmaceutically acceptable salt is formulated in a manner consistent with the said parameters. An overview of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. Boylan, 1988 - 1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0773] The compositions can be prepared according to conventional mixing, granulating or coating methods respectively, and the pharmaceutical compositions of the invention may contain from about 0.1% to about 99%, from about 5% to about 90% or from about 1% to about 20% of the compounds of the invention or pharmaceutically acceptable salts thereof by weight or volume. In some embodiments, the amount of the compounds or pharmaceutically acceptable salts thereof described herein may be present in the composition, such as the total amount of the pharmaceutical composition, in an amount of 1 - 95% by weight.

[0774] The composition can be provided in dosage forms suitable for the following administrations: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intracapsular, intraurethral, intrathecal, epidural, otic or ophthalmic administration, or by injection, inhalation or direct contact with the nasal, urogenital, genital or oral mucosa. Thus, the pharmaceutical composition can be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, lotions, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoretic delivery or aerosols. The composition can be formulated according to conventional medical practice.

[0775] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be effected by any suitable route. For example, in some embodiments, the administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intracapsular, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by tracheal instillation), transdermal, vaginal or intravitreal administration.

[0776] Formulations can be prepared by means suitable for systemic administration or for topical or local administration. Systemic formulations include formulations designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or can be prepared for transdermal, transmucosal or oral administration. Formulations will generally include a diluent and, in some cases, adjuvants, buffers, preservatives, etc. The compound or its pharmaceutically acceptable salt can also be administered in the form of liposomal compositions or in the form of microemulsions.

[0777] For injection, the formulation can be prepared in conventional forms, such as a liquid solution or suspension, or a solid form suitable for preparation as a solution or suspension in a liquid before injection, or an emulsion. Suitable excipients include, for example, water, physiological saline, dextrose, glycerol, etc. These compositions can also contain a certain amount of non-toxic auxiliary substances, such as wetting agents or emulsifying agents, pH buffering agents, etc., such as sodium acetate, sorbitan monolaurate, and so on.

[0778] A variety of sustained-release drug systems have also been devised. See, for example, U.S. Patent No. 5,624,677.

[0779] Systemic administration can also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery and nasal administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. It should be understood in the art that suitable forms include syrups, capsules and tablets.

[0780] Each compound described herein or a pharmaceutically acceptable salt thereof can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in a combination therapy can be formulated together or separately. Other modes of combination therapy are also described herein.

[0781] Agents formulated individually or separately can be packaged together in the form of 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 topical creams, etc. The kit can include optional components that facilitate the administration of unit doses to a subject, such as vials for reconstitution of a powder form, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit-dose kit can contain instructions regarding the preparation and administration of the composition. The kit can be manufactured as a single-use unit dose for one subject, for multiple uses for a particular subject (at a constant dose, or where the potency of an individual compound or its pharmaceutically acceptable salt can vary with the progression of treatment); or the kit can contain multiple doses suitable for administration to multiple subjects ("bulk pack"). The kit components can be assembled in a cardboard box, blister pack, bottle, tube, etc.

[0782] Formulations for oral use include tablets containing a mixture of the active ingredient and a non-toxic pharmaceutically acceptable excipient. The excipient can be, for example, an inert diluent or filler (such as sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (such as cellulose derivatives including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (such as sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methyl cellulose, optionally substituted hydroxypropyl methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adherent agents (such as magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be coloring agents, flavoring agents, plasticizers, humectants, buffering agents, etc.

[0783] Two or more compounds can be mixed together in a tablet, capsule, or other vehicle, or can be separated. In one embodiment, the first compound is contained on the inner side of the tablet and the second compound is on the outer side, such that the majority of the second compound is released before the first compound.

[0784] Formulations for oral use may also be presented as chewable tablets or in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil. Powders, granules and pellets may be prepared in a conventional manner using the ingredients mentioned above for tablets and capsules, using for example a mixer, a fluid bed apparatus or a spray drying equipment.

[0785] Dissolution or diffusion controlled release may be achieved by appropriately coating tablets, capsules, pellets or granular formulations of the compound, or by incorporating the compound or its pharmaceutically acceptable salts into a suitable matrix. The controlled release coating 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 palmitostearate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogels, 1,3 butanediol, ethylene glycol methacrylate or polyethylene glycol. In the controlled release matrix formulations, the matrix material may also include for example hydrated methyl cellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene or fluorinated hydrocarbons.

[0786] Liquid forms for oral administration which may incorporate the compounds or their pharmaceutically acceptable salts and compositions of the invention include aqueous solutions, properly flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0787] Generally, when administered to humans, the oral dose of any compound of the invention or its pharmaceutically acceptable salts will depend on the nature of the compound and can be readily determined by those skilled in the art. The dose may be for example about 0.001 mg to about 2000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 100 mg to about 1500 mg per day, about 500 mg to about 1500 mg per day, about 500 mg to about 2000 mg per day or any range derived therefrom.

[0788] In some embodiments, the pharmaceutical composition may further comprise an additional compound having antiproliferative activity. Depending on the mode of administration, the compound or its pharmaceutically acceptable salt will be formulated in a composition suitable for facilitating delivery. Each compound or its pharmaceutically acceptable salt in the combination therapy can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in the combination therapy can be formulated together or separately. Desirably, the first agent and the second agent are formulated together so as to administer the agents simultaneously or nearly simultaneously.

[0789] It is to 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 with or administered simultaneously with, before, or after 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 is also to be understood that the therapies employed can achieve the desired effect for the same disease condition, or these therapies can achieve different effects (e.g., control any adverse effects).

[0790] As described herein, the administration of each drug in the combination therapy can independently be one to four times per day for one day to one year, or even for the lifetime of the subject. Chronic / long - term administration is also applicable.

[0791] Method of Use

[0792] In some embodiments, the present invention discloses a method of treating a disease or disorder characterized by abnormal Ras activity caused by a Ras mutant. In some embodiments, the disease or disorder is cancer.

[0793] Accordingly, there is also provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or its pharmaceutically acceptable salt or a pharmaceutical composition comprising such compound or salt. In some embodiments, the cancer is colorectal cancer, non - small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small intestine cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary site, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord - stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal cancer, endometrial cancer, or melanoma. There is also provided a method of treating a Ras - protein - related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or its pharmaceutically acceptable salt or a pharmaceutical composition comprising such compound or salt.

[0794] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein can be used to treat a 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 salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods include, but are not limited to, the following tumor types: astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example:

[0795] Heart, such as: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

[0796] Lung, 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;

[0797] Gastrointestinal, such as: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet cell tumor, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal polypeptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0798] Genitourinary 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 (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[0799] Liver, such as: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0800] Biliary tract, such as: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma;

[0801] Bones, such as: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor;

[0802] Nervous system, such as: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal nerve fibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma);

[0803] Gynecology, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer of the uterine body), cervix (cervical cancer, cervical pre-cancerous atypia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube (cancer);

[0804] Hematopoietic system, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0805] Skin, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and

[0806] Adrenal gland, such as: neuroblastoma.

[0807] In some embodiments, the Ras protein is wild-type (Ras WT ). Thus, in some embodiments, the compounds of the present invention are used to treat a subject having Ras WT (e.g., K-Ras WT , H-Ras WT or N-Ras WT) in a method for a patient with cancer. In some embodiments, the Ras protein is Ras amplified (e.g., K-Ras amp ). Thus, in some embodiments, the compounds of the present invention are used in a method for treating a patient with cancer containing Ras amp (K-Ras amp , H-Ras amp or N-Ras amp ). In some embodiments, the cancer contains a Ras mutation, such as the Ras mutations described herein. In some embodiments, the mutations are selected from:

[0808] (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations thereof;

[0809] (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;

[0810] (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;

[0811] or a combination of any of the foregoing. In some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of: G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer comprises an N-Ras mutation selected from the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit multiple Ras mutants. For example, the compound can inhibit both K-Ras G12C and K-Ras G13C. The compound can inhibit both N-Ras G12C and K-Ras G12C. The compound can inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compound can inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the compound can inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compound can inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the present invention inhibit Ras WT and one or more additional Ras mutations (e.g., K, H, or N-Ras WT and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H, or N-Ras WT and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Ras WTand N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T). In some embodiments, the compounds of the invention inhibit Ras amp and one or more additional Ras mutations (e.g., K-, H-, or N-Ras amp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K-, H-, or N-Ras amp and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K-, H-, or N-Ras amp and N-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).

[0812] Methods for detecting Ras mutations are known in the art. Such methods include, but are not limited to, direct sequencing and the use of highly sensitive diagnostic assays (using CE-IVD labels), such as the methods described in Domagala et al., Pol J Pathol 3:145-164 (2012), which is incorporated herein by reference in its entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreenPyro. See also, e.g., WO 2020 / 106640.

[0813] In some embodiments, the cancer is non-small cell lung cancer and the Ras mutation comprises a K-Ras mutation such as K-Ras G12C, K-Ras G12V or K-Ras G12D. In some embodiments, the cancer is colorectal cancer and the Ras mutation comprises 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 comprises 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 comprises an N-Ras mutation such as N-Ras G12D. In some embodiments, the cancer is melanoma and the Ras mutation comprises an N-Ras mutation such as N-Ras Q61R or N-Ras Q61K. In some embodiments, the cancer is non-small cell lung cancer and the Ras protein is K-Ras amp . In any of the foregoing, if not specifically stated, the compound may also inhibit Ras WT (such as K-, H- or N-Ras WT ) or Ras amp (such as K-, H- or N-Ras amp ).

[0814] In some embodiments, the cancer comprises a Ras mutation and a STK11 LOF , KEAP1, EPHA5 or NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and a STK11 LOF mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and a STK11 LOF mutation. In some embodiments, the cancer comprises a K-RasG13C Ras mutation and a STK11 LOF, KEAP1, EPHA5 or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and comprises a K-Ras G12C mutation. In any of the foregoing, the compound may also inhibit Ras WT (e.g., K-, H- or N-Ras WT ) or Ras amp (e.g., K-, H- or N-Ras amp ).

[0815] Also provided is a method of inhibiting Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. Also provided is a method of inhibiting RAF-Ras binding, the method comprising contacting the cell with an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. The cell may be a cancer cell. The cancer cell may be of any type of cancer described herein. The cell may be in vivo or in vitro.

[0816] Combination therapy

[0817] The methods of the invention may comprise a compound of the 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 the standard dose. For example, the dose may be determined empirically based on the drug combination and regimen, or may be inferred by isoeffective dose determination (e.g., Black et al., Neurology 65: S3-S6 (2005)).

[0818] The compounds of the invention may be administered before, after or simultaneously with one or more of the additional therapies. When combined, the dose of the compound of the invention and the dose of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The compounds of the invention and additional therapies, such as anti-cancer agents, may be administered together, such as in the form of a single pharmaceutical composition, or separately, and when administered separately, the administrations may occur simultaneously or sequentially. Such sequential administrations may be close in time or far apart.

[0819] In some embodiments, the additional therapy is the administration of a side effect limiting agent (e.g., an agent intended to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of the invention may also be used in combination with a therapeutic agent for treating nausea. Examples of agents useful for treating nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0820] In some embodiments, the one or more additional therapies include non-pharmacological therapies (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies include therapeutic agents (e.g., compounds or biological agents as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, the one or more additional therapies include non-pharmacological therapies (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biological agents as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, the one or more additional therapies include two therapeutic agents. In still other embodiments, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0821] In this combination therapy section, all references are incorporated by reference for the agents described, whether or not so expressly stated.

[0822] Non-pharmacological therapies

[0823] Examples of non-pharmacological therapies include, but are not limited to, radiation therapy, cryotherapy, hyperthermia treatment, surgery (e.g., surgical removal of tumor tissue), and adoptive T cell transfer (ACT) therapy.

[0824] In some embodiments, the compounds of the invention can be used as postoperative adjuvant therapy. In some embodiments, the compounds of the invention can be used as preoperative neoadjuvant therapy.

[0825] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative disorders, such as cancer, in a subject (e.g., a mammal (e.g., a human)). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, brachytherapy, stereotactic radiosurgery, total body radiation therapy, radiosurgery, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by spatially defined radioactive material inserted at or near the site of a tumor or other hyperproliferative tissue disease within the body. This term is intended to but not limited to include exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as the cell conditioning agent of the present invention include solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from a solution of any radionuclide, such as a solution of I-125 or I-131, or the radioactive fluid can be prepared using a slurry of a suitable fluid containing small particles of a solid radionuclide such as Au-198 or Y-90. In addition, the radionuclide can be embedded in a gel or radioactive microspheres.

[0826] In some embodiments, the compounds of the present invention can render abnormal cells sensitive to radiotherapy for the purpose of killing or inhibiting the growth of such cells. Accordingly, the present invention further relates to a method for rendering abnormal cells in a mammal sensitive to radiotherapy, the method comprising administering to the mammal an amount of a compound of the present invention effective to render the abnormal cells sensitive to radiotherapy. The amount of the compound in the method can be determined in a manner for determining the effective amount of the compound described herein. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0827] In some embodiments, the non-pharmacological treatment is adoptive T cell transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR into T cells. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from an infected site, ascites, pleural effusion, spleen tissue, and tumor. In certain embodiments of the invention, a variety of T cell lines available in the art can be used. In some embodiments, the T cells are autologous T cells. Before or after genetically modifying the T cells to express the desired protein (e.g., CAR), these T cells can generally be activated and expanded using methods described in, for example, 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.

[0828] Therapeutic agent

[0829] The therapeutic agent can be a compound for treating cancer or its related symptoms.

[0830] For example, the therapeutic agent can be a steroid. Thus, in some embodiments, the one or more additional therapies include steroids. Suitable steroids can include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasolpropionate), halometasone, hydrocortisone, loteprednole tabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25 - diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednisolone valerate, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0831] Other examples of therapeutic agents that can be used in combination therapy with the compounds of the present invention include the compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Applications 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.

[0832] The therapeutic agent can be a biological agent for treating cancer or its related symptoms (e.g., cytokines (e.g., interferons or interleukins such as IL-2)). In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof). Antibody-drug conjugates are also included.

[0833] The therapeutic agent can be a T cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody can be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-2 inhibitor or antagonist (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) (e.g., a PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, a B-7 family ligand, or a combination thereof (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene&Celgene), or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0834] The therapeutic agent can be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0835] The therapeutic agent can be an agent for treating cancer or its related symptoms (e.g., a cytotoxic agent, a non-peptide small molecule, or other compounds useful for treating cancer or its related symptoms, collectively referred to as "anticancer agents"). The anticancer agent can be, for example, a chemotherapeutic agent or a targeted therapeutic agent.

[0836] Anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, luteinizing hormone, estrogen, antiestrogen, androgen, antiandrogen, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, the one or more additional therapies include two or more anticancer agents. The two or more anticancer agents can be used in admixture for combined administration or administered 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).

[0837] Other non-limiting examples of anticancer agents include (Imatinib Mesylate); (carfilzomib); (bortezomib); Casodex (bicalutamide); Gefitinib; alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, prosulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimine and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; polyacetates (especially bullatacin and bullatacinone); camptothecin (including the 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 analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicin, such as calicheamicin γll and calicheamicin ωll (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), N-morpholinodoxorubicin, cyanomorpholinodoxorubicin, (2-pyrrolinyl-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU);Folic acid analogs, such as denopterin, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-thioguanine, carmofur, cytarabine, didanosine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenal, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilones, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;Losoxantrone; Podophyllinic acid; (2-Ethylhydrazide; Procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2”-Trichloroethylamine; Trichothecenes, such as T-2 toxin, Verracurin A, Roridin A, and Anguidine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside (“Ara-C”); Cyclophosphamide; Thiotepa; Taxoid, for example (Paclitaxel), (nanoparticle formulation of paclitaxel without polyoxyethylated hydrogenated castor oil, albumin-engineered paclitaxel), and (Docetaxel); Chlorambucil; Tamoxifen (Nolvadex TM ); Raloxifene; Aromatase inhibitor 4(5)-imidazole; 4-Hydroxytamoxifen; Trioxifene; Keoxifene; LY117018; Onapristone; Toremifene Flutamide, Nilutamide, Bicalutamide, Leuprolide, Goserelin; Chlorambucil; Gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (Vinorelbine); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g. CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicins; capecitabine (e.g. ); and pharmaceutically acceptable salts of any of the foregoing.

[0838] Additional non-limiting examples of anticancer agents include trastuzumab Bevacizumab Cetuximabv Rituximab ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridine-2-carbaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, anti-tumor agents (such as cell cycle non-specific anti-tumor agents and other anti-tumor agents described herein), anti-tumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthioninesulfoximine), CBV (chemotherapy), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 and zosuquidar.

[0839] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin / actinomycin D), daunomycin and idarubicin), anthracycline, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and eliminates cells that cannot synthesize asparagine on their own), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, and analogs such as melphalan and chlorambucil), ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors such as abemaciclib, ribociclib, palbociclib, seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs,and streptozocin, trazenes-dacarbazinine (DTIC), anti-proliferative / anti-mitotic antimetabolites (such as folic acid analogues), pyrimidine analogues (e.g., fluorouracil, azaribine, and cytarabine), purine analogues and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binders (e.g., ) PI3K inhibitors such as PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), PI3Kδ and γ inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multi-kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin)), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38)), anti-CSl (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS953), PI3K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTI (e.g., Zarnestra TM ) anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0840] In some embodiments, the anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, sorafenib or any analogue or derivative variant thereof as described above.

[0841] In some embodiments, the anti-cancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab and pertuzumab small molecule tyrosine kinase inhibitors such as gefitinib erlotinib Pilitinib, CP-654577, CP-724714, Canertinib (CI 1033), HKI-272, Lapatinib (GW-572016; ), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, JNJ-26483327, and JNJ-26483327.

[0842] In some embodiments, the anti-cancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include Ceritinib, TAE-684 (NVP-TAE694), PF02341066 (Crizotinib or 1066), Alectinib; Brigatinib; Entrectinib; Ensartinib (X-396); Lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005; and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0843] In some embodiments, the anti-cancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, RLY-1971), SOS1 inhibitor (e.g., BI-1701963, BI-3406), Raf inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, AKT inhibitor or mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor)). In some embodiments, the anti-cancer agent is JAB-3312. In some embodiments, the anti-cancer agent is an additional Ras inhibitor (e.g., AMG 510, MRTX1257, MRTX849, ARS-853, ARS-1620, ARS-3248 (or JNJ-74699157), LY3499446) or a Ras vaccine or another therapeutic modality designed to directly or indirectly reduce the oncogenic activity of Ras.Other examples of Ras inhibitors that can be combined with the Ras inhibitor of the present invention are provided in the following patents (which are incorporated herein by reference in their entirety): WO2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO2019051291, WO 2018218070, WO 2018217651, WO 2018218071, WO 2018218069, WO2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO2018068017, WO 2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO2014143659 and WO 2013155223.

[0844] In some embodiments, the therapeutic agent that can be combined with the compounds of the present invention is a MAP kinase (MAPK) pathway inhibitor (or "MAPK inhibitor"). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancers (Basel) September 2015; 7(3):1758–1784. For example, the MAPK inhibitor can 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 can be PLX8394, LXH254, GDC-5573 or LY3009120.

[0845] In some embodiments, the anti-cancer agent is a disruptor or an inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway. PI3K / AKT inhibitors can include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) September 2015; 7(3):1758–1784. For example, the PI3K / AKT inhibitor can be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0846] In some embodiments, the anti-cancer agent is a PD-1 or PD-L1 antagonist.

[0847] In some embodiments, the additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies. In some embodiments, the therapeutic agent can be a pan-RTK inhibitor such as afatinib.

[0848] IGF-1R inhibitors include linsitinib or a pharmaceutically acceptable salt thereof.

[0849] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab panitumumab zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra) or Mab C225 (ATCC accession number HB-8508) or an antibody or antibody fragment having binding specificity for EGFR.

[0850] Small molecule antagonists of EGFR include gefitinib erlotinib and lapatinib See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in the following patent publications, as well as all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; EP 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; DE19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP 682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described by 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 contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0851] MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib trametinib and binimetinib In some embodiments, the MEK inhibitor targets a MEK mutation, which is a class I MEK1 mutation selected from D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0852] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxy wortmannin analogs as described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 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]propanenitrile (also known as BEZ 235 or NVP-BEZ 235 and described in WO06 / 122806); (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (purchased from Axon Medchem); PI103 hydrochloride (3-[4-(4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride (purchased from Axon Medchem); PIK75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (purchased from Axon Medchem); PIK90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide (purchased from Axon Medchem); AS-252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-methyl-(Z)-methylene]-thiazolidine-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); 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.

[0853] 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 (inhibiting Akt1 and 2) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91: 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05 / 011700); indole-3-methanol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134 (12 Suppl.): 3493S-3498S); perifosine (e.g., interfering with Akt membrane localization; Dasmahapatra et al., Clin. Cancer Res. 2004, 10 (15): 5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13: 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64: 4394-9).

[0854] mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including temsirolimus everolimus (WO94 / 09010); Deforolimus (also known as deforolimus or AP23573); Rapalogs, such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-Hydroxyethyl)rapamycin; 40-[3-Hydroxy(hydroxymethyl)methyl propionate]-rapamycin (also known as CC1779); 40-Epi-(tetrazolyl)-rapamycin (also known as ABT578); 32-Deoxyrapamycin; 16-Pentyloxy-32(S)-dihydrorapamycin; Derivatives disclosed in WO05 / 005434; U.S. Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416; and Phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO2018204416, WO2019212990, and WO2019212991), such as RMC-5552.

[0855] BRAF inhibitors that can be used in combination with the compounds of the present invention include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF can include class 3 BRAF mutations. In some embodiments, the class 3 BRAF mutations are selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0856] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance to not only conventional chemotherapy but also targeted therapeutic agents including BCL-2 inhibitors such as ABT-263.

[0857] 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 contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, auto-inhibited conformation stabilized by a binding network involving residues from the N-SH2 and PTP domains. Stimulation with cytokines or growth factors that act through receptor tyrosine kinases (RTKs), for example, causes exposure of the catalytic site, leading to enzymatic activation of SHP2.

[0858] SHP2 is involved in signal transduction through the RAS-mitogen-activated protein kinase (MAPK), i.e., JAK-STAT or phosphoinositide 3-kinase-AKT pathways. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental diseases such as Noonan Syndrome and Leopard Syndrome, as well as human cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancers. Some of these mutations destabilize the auto-inhibited conformation of SHP2 and promote auto-activation of SHP2 or enhanced growth factor-driven activation. Thus, SHP2 represents a particularly interesting target for the development of novel therapies for treating various 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 multiple cancer cell lines (e.g., pancreatic, lung, ovarian, and breast cancers) in vitro. Thus, combination therapies involving SHP2 inhibitors and RAS pathway inhibitors can be a general strategy for preventing tumor resistance in multiple malignancies.

[0859] 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, each incorporated herein by reference.

[0860] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed-type irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, 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) outside the phosphatase active site. 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.

[0861] In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitor, HER2 inhibitor, SHP2 inhibitor, CDK4 / 6 inhibitor, mTOR inhibitor, SOS1 inhibitor, and PD-L1 inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitor, SHP2 inhibitor, and PD-L1 inhibitor. See, for example, Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (October 28, 2019), and Canon et al., Nature, 575:217 (2019). In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and a SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and a SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and a SHP2 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and a SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer, and the treatment comprises administering a combination of the Ras inhibitor of the present invention and a second or third therapeutic agent.

[0862] Proteasome inhibitors include, but are not limited to, carfilzomib bortezomib and oprozomib.

[0863] Immunotherapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0864] Immunomodulatory imides (IMiDs) are a class of immunomodulatory drugs (drugs that regulate the immune response) containing an imide group. IMiD drugs include thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0865] Exemplary anti-PD-1 antibodies and methods of use thereof are described in Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168A1), and are also described elsewhere herein.

[0866] 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, EP1866339, and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0867] 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, chemically synthesized compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof prepared in vitro. An anti-angiogenic agent can be an agonist, antagonist, allosteric modulator, toxin, or more generally can be used to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth. In some embodiments, the one or more additional therapies include an anti-angiogenic agent.

[0868] An anti-angiogenic agent can be an MMP-2 (matrix metalloproteinase 2) inhibitor, an MMP-9 (matrix metalloproteinase 9) inhibitor, and a COX-II (cyclooxygenase 11) inhibitor. Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include 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 that selectively inhibit MMP-2 or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830.

[0869] Other exemplary anti-angiogenic agents include kinase domain KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind VEGF (such as bevacizumab) or soluble VEGF receptors or their ligand-binding regions), such as VEGF-TRAP TM , and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF receptors), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to EGFR), such as (panitumumab), erlotinib Agents against Ang1 and agents against Ang2 (e.g., antibodies or antigen-binding regions that specifically bind to Ang1 and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to the Tie2 kinase). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., antibodies or antigen-binding regions that specifically bind, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM disintegrin domains that antagonize the binding of integrin to its ligand (US2002 / 0042368), anti-eph receptor or anti-ephrin antibodies or antigen-binding regions that specifically bind (U.S. Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and members of their patent families), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind), and antibodies or antigen-binding regions that specifically bind to the PDGF-BB ligand, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to the PDGFR kinase). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO0770622); 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); TLCELL-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, JP 02233610); platelet factor 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); BC1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived angiogenesis inhibitor (XOMA, USA); PI 88 (Progen, Australia); cilengitide (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA);AVE8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); Endostatin (Boston Childrens Hospital, USA); ATN 161 (Attenuon, USA); 2-Methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD9935 (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); Vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue Factor Pathway Inhibitor (EntreMed, USA); Pegaptanib (Pinn) (Gilead Sciences, USA); Xanthorrhizol (Yonsei University, South Korea); Gene-based VEGF-2 Vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SU6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-Guanidine (Dimensional Pharmaceuticals, USA); Motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); Angiogenesis Vaccine (EntreMed, USA);Urokinase plasminogen activator inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angucidin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN633 (KirinBrewery, Japan); Drug delivery system, intravitreal 2-methoxyestradiol; Anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-α inhibitor; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, α5β (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS706 (Sankyo, Japan); Combretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada);BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); 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); 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 thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).;

[0870] Other examples of therapeutic agents that can be used in combination with the compounds of the present invention include agents that specifically bind and inhibit growth factor activity (e.g., antibodies, antigen-binding regions, or soluble receptors), such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding regions that specifically bind to the receptor c-Met.

[0871] 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 TM ), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting microcystins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-thioguanosine, and vincristine. In addition, antisense RNAs or siRNAs that inhibit the expression of proteins, including but not limited to ATG5 (involved in autophagy), can also be used. In some embodiments, the one or more additional therapies include an autophagy inhibitor.

[0872] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-tumor agent. In some embodiments, the one or more additional therapies include an anti-tumor agent. Non-limiting examples of anti-tumor agents include acemannan, aclarithromycin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, amifostine, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancesterim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunomycin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate(phosphate), formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, imiquimod, interferon alpha, natural interferon alpha, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-n3, consensus interferon-1, natural interferon alpha, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b), interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, dibromodulcitol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoietic protein, NSC631570 Octreotide, Oprelvekin, Osaterone, Oxaliplatin, Paclitaxel, Pamidronic Acid, Pegaspargase, Peginterferon Alfa-2b, Pentosan Polysulfate Sodium, Pentostatin, Picibanil, Pirarubicin, Rabbit Anti-Thymocyte Polyclonal Antibody, Peginterferon Alfa-2a, Porfimer Sodium, Raloxifene, Raltitrexed, Rasburiembodiment, Rhenium (Re 186) Hydroxyethylidene Diphosphonate, RII Isotretinoinamide, Rituximab, Romurtide, Samarium (153Sm) 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, Treosulfan, Tretinoin, Trilostane, Trimetrexate, Triptorelin, Native Tumor Necrosis Factor Alpha, Ubenimex, Bladder Cancer Vaccine, Maruyama Vaccine, Melanoma Lysate Vaccine, Valrubicin, Verteporfin, Vinorelbine, Virulizin, Zinostatin Stimalamer or Zoledronic Acid; Abarelix; AE 941 (Aeterna), Ambamustine, Antisense Oligonucleotide, bcl-2 (Genta), APC8015 (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 (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyletiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital) or valspodar.

[0873] Additional examples of therapeutic agents that can be used in combination with the compounds of the present invention include ipilimumab trametinib; galiximab; nivolumab, also known as BMS-936558 pembrolizumab avelumab AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumumab; MEDI4736 MSB0010718C; AMP224; adalimumab ado-trastuzumab emtansine aflibercept alemtuzumab basiliximab belimumab basiliximab belimumab brentuximab vedotin Canakinumab Certolizumab pegol Daclizumab Daratumumab Denosumab Eculizumab Efalizumab Gemtuzumab ozogamicin Golimumab Ibritumomab tiuxetan Infliximab Motavizumab Natalizumab Obinutuzumab Ofatumumab Omalizumab Palivizumab Pertuzumab Pertuzumab Ranibizumab Raxibacumab Tocilizumab Tositumomab; Tositumomab-I-131; Tositumomab and Tositumomab-I-131 Ustekinumab AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG745; and AMG 951.

[0874] Depending on the disorder being treated, the compounds described herein can be used in combination with the agents disclosed herein or other suitable agents. Thus, in some embodiments, one or more of the compounds of the present disclosure will be co-administered with other therapies described herein. When used in combination therapy, the compounds described herein can be administered simultaneously with or separately from a second agent. Such co-administration can include administering both agents in the same dosage form simultaneously, administering in separate dosage forms simultaneously, and administering separately. That is, the compounds described herein can be formulated together with any of the agents described herein into the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention can be administered simultaneously with any of the therapies described herein, where the two agents are present in separate formulations. In another alternative, the compounds of the present disclosure can be administered first, followed by any of the therapies described herein, or vice versa. In some embodiments of the separate administration scenario, the compounds of the present invention and any of the therapies described herein are administered at intervals of minutes, hours, or days.

[0875] In some embodiments of any of the methods described herein, a first therapy (such as a compound of the present invention) and one or more additional therapies are administered simultaneously or sequentially in either order. The first therapeutic agent can be administered immediately before or after, 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 the administration of the one or more additional therapies.

[0876] The present invention is further characterized by a kit that includes (a) a pharmaceutical composition comprising an agent described herein (such as a compound of the present invention) and (b) a package insert with instructions for performing any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition comprising an agent described herein (such as a compound of the present invention), (b) one or more additional therapies (such as non - pharmaceutical treatments or therapeutic agents), and (c) a package insert with instructions for performing any of the methods described herein.

[0877] Since one aspect of the present invention encompasses treating a disease or its related symptoms with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit may comprise two separate pharmaceutical compositions: a compound of the present invention and one or more additional therapies. The kit may comprise a container for holding the separate compositions, such as a vial or a foil pack. Additional examples of containers include syringes, cartridges, and bags. In some embodiments, the kit may comprise instructions regarding the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., orally or parenterally), at different dosing intervals, or when a prescribing healthcare provider wishes to titrate the individual components in the combination.

[0878] Numbered embodiments

[0879] [1] A compound or a pharmaceutically acceptable salt thereof, having the structure of Formula I:

[0880]

[0881] wherein the dashed line represents zero, one, two, three, or four non-adjacent double bonds;

[0882] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or an optionally substituted 5- to 10-membered heteroarylene;

[0883] B is -CH(R 9 )- or >C=CR 9 R 9’ , wherein the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[0884] G is an optionally substituted C 1 -C 4 alkylene; an optionally substituted C 1 -C 4 alkenylene; an optionally substituted C 1 -C 4 heteroalkylene; -C(O)O-CH(R 6 )-, wherein the C is bonded to -C(R 7 R 8 )-; -C(O)NH-CH(R6 )-, where C is bonded to -C(R 7 R 8 )-; optionally substituted C 1 -C 4 heteroalkyl; or 3- to 8-membered heteroaryl;

[0885] L is absent or is a linker;

[0886] W is a crosslinking group, the group comprising a carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or glycals;

[0887] X 1 is optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[0888] X 2 is O or NH;

[0889] X 3 is N or CH;

[0890] n is 0, 1 or 2;

[0891] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0892] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0893] Y 1 is C, CH or N;

[0894] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0895] Y 5 is CH, CH 2 or N;

[0896] Y 6 is C(O), CH, CH 2 or N;

[0897] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or

[0898] R 1 and R 2 together with the atom to which it is attached form an optionally substituted 3- to 14-membered heteroalkyl;

[0899] R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[0900] R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl;

[0901] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0902] R 5 is hydrogen, optionally halogen-substituted C 1 -C 4 alkyl, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0903] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1 -C 3 alkyl, or

[0904] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0905] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0906] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0907] R 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or together with the carbon to which they are attached form a carbonyl;

[0908] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6an alkynyl group, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group or an optionally substituted 6- to 10-membered aryl group, or

[0909] R 7’ and R 8’ combines with the carbon atom to which it is attached to form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[0910] R 9 is hydrogen, F, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group, or

[0911] R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl group;

[0912] R 9’ is hydrogen or an optionally substituted C 1 -C 6 alkyl group;

[0913] R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl group;

[0914] R 10a is hydrogen or halo;

[0915] R 11 is hydrogen or C 1 -C 3 alkyl group; and

[0916] R 34 is hydrogen or C 1 -C 3 alkyl group.

[0917] [2] The compound according to paragraph [1] or a pharmaceutically acceptable salt thereof, wherein G is an optionally substituted C 1 -C 4 heteroalkylene group.

[0918] [3] The compound according to paragraph [1] or [2] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Ia:

[0919]

[0920] Wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[0921] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; 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;

[0922] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene;

[0923] L is absent or is a linker;

[0924] W is a crosslinking group, said 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), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or enose;

[0925] X 2 is O or NH;

[0926] X 3 is N or CH;

[0927] n is 0, 1 or 2;

[0928] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0929] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0930] Y 1 is C, CH or N;

[0931] Y 2 , Y 3 , Y 4 and Y 7 are independently C or N;

[0932] Y 5 and Y 6 are independently CH or N;

[0933] R 1 is cyano, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 1 -C 6 -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl;

[0934] R 2 is hydrogen, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -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; R 3 is absent, or

[0935] R 2 and R 3 together with the atom to which they are attached form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl;

[0936] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0937] R 5 is hydrogen, C 1 -C 4 -alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 -alkoxy, cyclopropyl or cyclobutyl;

[0938] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or C 1 -C 3 -alkyl optionally substituted, or

[0939] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0940] R 8 is hydrogen, halogen, hydroxy, cyano, an optionally substituted C 1 -C 3 alkoxy, an optionally substituted C 1 -C 3 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 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

[0941] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl); C=O; C=S; C=NH; an optionally substituted 3- to 6-membered cycloalkyl; or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0942] R 7’ is hydrogen, halogen or an optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, an optionally substituted C 1 -C 3 alkoxy, an optionally substituted C 1 -C 3 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 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

[0943] R 7’ and R 8’ together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0944] R9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0945] R 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl; and

[0946] R 11 is hydrogen or C 1 -C 3 alkyl.

[0947] [4] The compound according to any one of paragraphs [1] to [3] or a pharmaceutically acceptable salt thereof, wherein X 2 is NH.

[0948] [5] The compound according to any one of paragraphs [1] to [4] or a pharmaceutically acceptable salt thereof, wherein X 3 is CH.

[0949] [6] The compound according to any one of paragraphs [1] to [5] or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen.

[0950] [7] The compound according to any one of paragraphs [1] to [5] or a pharmaceutically acceptable salt thereof, wherein R 11 is C 1 -C 3 alkyl.

[0951] [8] The compound according to paragraph [7] or a pharmaceutically acceptable salt thereof, wherein R 11 is methyl.

[0952] [9] The compound according to any one of paragraphs [1] to [6] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Ib:

[0953]

[0954] wherein the dotted line represents zero, one, two, three or four non-adjacent double bonds;

[0955] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to -CH(R 10)-carbon atom; 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;

[0956] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene;

[0957] L is absent or is a linker;

[0958] 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), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolinium or enose;

[0959] n is 0, 1 or 2;

[0960] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[0961] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[0962] Y 1 is C, CH or N;

[0963] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0964] Y 5 and Y 6 are independently CH or N;

[0965] R 1 is cyano, optionally substituted C1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl;

[0966] R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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; R 3 is absent, or

[0967] R 2 and R 3 together with the atom to which they are attached form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl;

[0968] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0969] R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[0970] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or C 1 -C 3 alkyl optionally substituted, or

[0971] R 6 and R 7 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heteroalkyl;

[0972] R 8 is hydrogen, halogen, hydroxy, cyano, C 1 -C 3 alkoxy optionally substituted, C 1 -C 3 alkyl optionally substituted, C 2 -C 6Alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0973] R 7 and R 8 together with the carbon atom to which it is attached form C═CR 7’ R 8’ ; C═N(OH); C═N(O-C 1 -C 3 alkyl); C═O; C═S; C═NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[0974] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[0975] R 7’ and R 8’ together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0976] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -Cheteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; and

[0977] R 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl.

[0978]

[10] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [9], wherein X 1 is optionally substituted C 1 -C 2 alkylene.

[0979]

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

[10] , wherein X 1 is methylene.

[0980]

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

[11] , wherein R 5 is hydrogen.

[0981]

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

[11] , wherein R 5 is optionally halogen-substituted C 1 -C 4 alkyl.

[0982]

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

[13] , wherein R 5 is methyl.

[0983]

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

[14] , wherein Y 4 is C.

[0984]

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

[15] , wherein R 4 is hydrogen.

[0985]

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

[16] , wherein Y 5 is CH.

[0986]

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

[17] , wherein Y 6 is CH.

[0987]

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

[18] , wherein Y 1 is C.

[0988]

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

[19] , wherein Y 2 is C.

[0989]

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

[20] , wherein Y3 is N.

[0990]

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

[21] , wherein R 3 is absent.

[0991]

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

[22] , wherein Y 7 is C.

[0992]

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

[23] , wherein the compound has the structure of formula Ic:

[0993]

[0994] wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; optionally substituted 3- to 6-membered subcycloalkyl; optionally substituted 3- to 6-membered subheterocycloalkyl; optionally substituted 6-membered subaryl; or optionally substituted 5- to 6-membered subheteroaryl;

[0995] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered subcycloalkyl; optionally substituted 3- to 6-membered subheterocycloalkyl; optionally substituted 6-membered subaryl; or 5- to 6-membered subheteroaryl;

[0996] L is absent or is a linker;

[0997] W is a crosslinking group, the 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), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or enose;

[0998] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl;

[0999] R 2 is hydrogen, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[1000] R 2 and R 3 together with the atom to which they are attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[1001] R 5 is hydrogen, C 1 -C 4 -alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 -alkoxy, cyclopropyl or cyclobutyl;

[1002] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 -alkyl, or

[1003] R 6 and R 7 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[1004] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 -alkoxy, optionally substituted C 1 -C 3 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[1005] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C3 alkyl); C═O; C═S; C═NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[1006] R 7’ is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[1007] R 7’ and R 8’ together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[1008] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; and

[1009] R 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl.

[1010]

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

[24] or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.

[1011]

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

[25] or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl.

[1012]

[27] The compound as described in paragraph

[26] or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted C 1 -C 6 alkyl.

[1013]

[28] The compound as described in paragraph

[27] or a pharmaceutically acceptable salt thereof, wherein R 2 is ethyl.

[1014]

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

[28] or a pharmaceutically acceptable salt thereof, wherein R 7 is optionally substituted C 1 -C 3 alkyl.

[1015]

[30] The compound as described in paragraph

[29] or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1 -C 3 alkyl.

[1016]

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

[30] or a pharmaceutically acceptable salt thereof, wherein R 8 is optionally substituted C 1 -C 3 alkyl.

[1017]

[32] The compound as described in paragraph

[31] or a pharmaceutically acceptable salt thereof, wherein R 8 is C 1 -C 3 alkyl.

[1018]

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

[32] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Id:

[1019]

[1020] wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; optionally substituted 3- to 6-membered subcycloalkyl; optionally substituted 3- to 6-membered subheterocycloalkyl; optionally substituted 6-membered subaryl; or optionally substituted 5- to 6-membered subheteroaryl;

[1021] B is -CH(R 9)-, wherein carbon is bonded to the carbonyl carbon of -NHC(O); an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[1022] L is absent or is a linker;

[1023] W is a crosslinking group comprising a carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or glycals;

[1024] R 1 is cyano, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 6-membered heteroalkyl, an optionally substituted 6- to 10-membered aryl or an optionally substituted 5- to 10-membered heteroaryl;

[1025] R 2 is C 1 -C 6 alkyl or a 3- to 6-membered cycloalkyl;

[1026] R 7 is C 1 -C 3 alkyl;

[1027] R 8 is C 1 -C 3 alkyl; and

[1028] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heteroalkyl.

[1029]

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

[33] or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5- to 10-membered heteroaryl.

[1030]

[35] A compound according to paragraph

[34] or a pharmaceutically acceptable salt thereof, wherein R 1is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[1031]

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

[35] , wherein the compound has the structure of formula Ie:

[1032]

[1033] wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; an optionally substituted 3- to 6-membered cycloalkylidene; an optionally substituted 3- to 6-membered heteroalkylidene; an optionally substituted 6-membered arylidene; or an optionally substituted 5- to 6-membered heteroarylidene;

[1034] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylidene; an optionally substituted 3- to 6-membered heteroalkylidene; an optionally substituted 6-membered arylidene; or a 5- to 6-membered heteroarylidene;

[1035] L is absent or is a linker;

[1036] W is a crosslinking group, the group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, an aziridine, a trifluoromethyl ketone, boric acid, a borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, an epoxide, an oxazolium or an enose;

[1037] R 2 is C 1 -C 6 alkyl or a 3- to 6-membered cycloalkyl;

[1038] R 7 is C 1 -C 3 alkyl;

[1039] R 8 is C 1 -C 3 alkyl; and

[1040] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[1041] X e and X f is independently N or CH; and

[1042] R 12 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[1043]

[37] The compound as described in paragraph

[36] or a pharmaceutically acceptable salt thereof, wherein X e is N, and X f is CH.

[1044]

[38] The compound as described in paragraph

[36] or a pharmaceutically acceptable salt thereof, wherein X e is CH, and X f is N.

[1045]

[39] The compound as described in any one of paragraphs

[36] to

[38] or a pharmaceutically acceptable salt thereof, wherein R 12 is optionally substituted C 1 -C 6 heteroalkyl.

[1046]

[40] The compound as described in any one of paragraphs

[36] to

[39] or a pharmaceutically acceptable salt thereof, wherein R 12 is

[1047]

[41] The compound as described in paragraph [1] or [2] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula VI:

[1048]

[1049]

[1050] wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds;

[1051] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; optionally substituted 3- to 6-membered subcycloalkyl; optionally substituted 3- to 6-membered subheterocycloalkyl; optionally substituted 6-membered subaryl; or optionally substituted 5- to 10-membered subheteroaryl;

[1052] B is -CH(R 9 )- or >C=CR 9 R 9’ , where the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[1053] G is an optionally substituted C 1 -C 4 alkylene; an optionally substituted C 1 -C 4 alkenylene; an optionally substituted C 1 -C 4 heteroalkylene; -C(O)O-CH(R 6 )-, where C is bonded to -C(R 7 R 8 )-; -C(O)NH-CH(R 6 )-, where C is bonded to -C(R 7 R 8 )-; an optionally substituted C 1 -C 4 heteroalkylene; or a 3- to 8-membered heteroarylene;

[1054] L is absent or is a linker;

[1055] W is a crosslinking group that includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or glycals;

[1056] X 1 is an optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[1057] X 2 is O or NH;

[1058] X 3 is N or CH;

[1059] n is 0, 1 or 2;

[1060] R is hydrogen, cyano, an optionally substituted C 1 -C 4 alkyl, an optionally substituted C 2 -C 4Alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 , S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[1061] Each R’ is independently H or optionally substituted C 1 -C 4 Alkyl;

[1062] Y 1 is C, CH or N;

[1063] Y 2 , Y 3 , Y 4 and Y 7 are independently C or N;

[1064] Y 5 is CH, CH 2 or N;

[1065] Y 6 is C(O), CH, CH 2 or N;

[1066] R 2 is absent, hydrogen, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[1067] R 2 and R 3 together with the atom to which they are attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[1068] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[1069] R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C4 an alkoxy group, a cyclopropyl group or a cyclobutyl group;

[1070] R 6 is hydrogen or methyl; R 7 is hydrogen, a halogen or an optionally substituted C 1 -C 3 alkyl group, or

[1071] R 6 and R 7 together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[1072] R 8 is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy group, an optionally substituted C 1 -C 3 alkyl group, an optionally substituted C 2 -C 6 alkenyl group, an optionally substituted C 2 -C 6 alkynyl group, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group or an optionally substituted 6- to 10-membered aryl group, or

[1073] R 7 and R 8 together with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 alkyl group); C=O; C=S; C=NH; an optionally substituted 3- to 6-membered cycloalkyl group; or an optionally substituted 3- to 7-membered heterocycloalkyl group;

[1074] R 7a and R 8a are independently hydrogen, halo, an optionally substituted C 1 -C 3 alkyl group, or together with the carbon to which they are attached form a carbonyl group;

[1075] R 7’ is hydrogen, a halogen or an optionally substituted C 1 -C 3 alkyl group; R 8’ is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy group, an optionally substituted C 1 -C 3 alkyl group, an optionally substituted C2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[1076] R 7’ and R 8’ together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[1077] R 9 is hydrogen, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl, or

[1078] R 9 and L together with the atoms to which they are attached form an optionally substituted 3- to 14-membered heterocycloalkyl;

[1079] R 9’ is hydrogen or optionally substituted C 1 -C 6 alkyl;

[1080] R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy or C 1 -C 3 alkyl;

[1081] R 10a is hydrogen or halo;

[1082] R 11 is hydrogen or C 1 -C 3 alkyl;

[1083] R 34 is hydrogen or C 1 -C 3 alkyl; and

[1084] X e and X f are independently N or CH.

[1085]

[42] The compound according to paragraph

[41] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula VIa:

[1086]

[1087] Wherein A is an optionally substituted 3- to 6-membered cycloalkylene group, an optionally substituted 3- to 6-membered heteroalkylene group, an optionally substituted 6-membered arylene group, or an optionally substituted 5- to 6-membered heteroarylene group;

[1088] B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylene group; an optionally substituted 3- to 6-membered heteroalkylene group; an optionally substituted 6-membered arylene group; or a 5- to 6-membered heteroarylene group;

[1089] L is absent or is a linker;

[1090] W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or enose;

[1091] X 1 is an optionally substituted C 1 -C 2 alkylene group, NR, O or S(O) n ;

[1092] X 2 is O or NH;

[1093] n is 0, 1 or 2;

[1094] R is hydrogen, cyano, an optionally substituted C 1 -C 4 alkyl group, an optionally substituted C 2 -C 4 alkenyl group, an optionally substituted C 2 -C 4 alkynyl group, C(O)R', C(O)OR', C(O)N(R') 2 、S(O)R', S(O) 2 R' or S(O) 2 N(R') 2 ;

[1095] Each R' is independently H or an optionally substituted C 1 -C 4 alkyl group;

[1096] R 2 is C 1 -C 6alkyl or 3- to 6-membered cycloalkyl;

[1097] R 7 is C 1 -C 3 alkyl;

[1098] R 8 is C 1 -C 3 alkyl; and

[1099] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[1100] X e and X f are independently N or CH;

[1101] R 11 is hydrogen or C 1 -C 3 alkyl; and

[1102] R 21 is hydrogen or C 1 -C 3 alkyl.

[1103]

[43] A compound as described in paragraph

[41] or

[42] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula VIb:

[1104]

[1105] wherein A is optionally substituted 3- to 6-membered subcycloalkyl, optionally substituted 3- to 6-membered subheterocycloalkyl, optionally substituted 6-membered subaryl or optionally substituted 5- to 6-membered subheteroaryl;

[1106] B is -CH(R 9 )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered subcycloalkyl; optionally substituted 3- to 6-membered subheterocycloalkyl; optionally substituted 6-membered subaryl; or 5- to 6-membered subheteroaryl;

[1107] L is absent or is a linker;

[1108] W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium or glycals;

[1109] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; and

[1110] X e and X f are independently N or CH.

[1111]

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

[43] or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered arylene.

[1112]

[45] The compound as described in paragraph

[44] or a pharmaceutically acceptable salt thereof, wherein A has the following structure:

[1113]

[1114] wherein R 13 is hydrogen, hydroxyl, amino, an optionally substituted C 1 -C 6 alkyl or an optionally substituted C 1 -C 6 heteroalkyl.

[1115]

[46] The compound as described in paragraph

[45] or a pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen.

[1116]

[47] The compound as described in paragraph

[45] or a pharmaceutically acceptable salt thereof, wherein R 13 is hydroxyl.

[1117]

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

[47] or a pharmaceutically acceptable salt thereof, wherein B is -CHR 9 -.

[1118]

[49] The compound as described in paragraph

[48] or a pharmaceutically acceptable salt thereof, wherein R 9 is an optionally substituted C 1 -C 6An alkyl group or an optionally substituted 3- to 6-membered cycloalkyl group.

[1119]

[50] The compound as described in paragraph

[49] or a pharmaceutically acceptable salt thereof, wherein R 9 is

[1120]

[51] The compound as described in paragraph

[50] or a pharmaceutically acceptable salt thereof, wherein R 9 is

[1121]

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

[47] or a pharmaceutically acceptable salt thereof, wherein B is an optionally substituted 6-membered arylene group.

[1122]

[53] The compound as described in paragraph

[52] or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered arylene group.

[1123]

[54] The compound as described in paragraph

[53] or a pharmaceutically acceptable salt thereof, wherein B is:

[1124]

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

[54] or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.

[1125]

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

[55] or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl.

[1126]

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

[56] or a pharmaceutically acceptable salt thereof, wherein the linker is a structure of formula II:

[1127] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2

[1128] Formula II

[1129] wherein A 1 is a bond between the linker and B; A2 is a bond between W and the linker; B 1 , B 2 , B 3 and B 4 each independently selected from optionally substituted C 1 -C 2 alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S and NR N ; R N is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted C 1 -C 7 heteroalkyl; C 1 and C 2 each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D 1 is optionally substituted C 1 -C 10 alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted 3- to 14-membered heteroalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C 2 -C 10 polyethylene glycol or optionally substituted C 1 -C 10 heteroalkylene, or connecting A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -connected to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 by a chemical bond.

[1130]

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

[57] , wherein the linker is acyclic.

[1131]

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

[58] , wherein the linker has the structure of formula IIa:

[1132]

[1133] wherein X a is absent or is N;

[1134] R 14 is absent, hydrogen or optionally substituted C 1 -C 6 alkyl; and

[1135] L 2 is absent, -SO 2 -, optionally substituted C 1 -C 4 alkylene or optionally substituted C 1 -C 4 heteroalkylene,

[1136] wherein X a , R 14 or L 2 at least one of which is absent.

[1137]

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

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

[1138]

[1139]

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

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

[1140]

[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:

[1141]

[1142] wherein o is 0 or 1;

[1143] R 15 is hydrogen or optionally substituted C 1 -C 6 alkyl;

[1144] Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heteroalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; and

[1145] L 3 is absent, -SO 2 -, an optionally substituted C 1 -C 4 alkylene, or an optionally substituted C 1 -C 4 heteroalkylene.

[1146]

[63] A compound as described in paragraph

[62] or a pharmaceutically acceptable salt thereof, wherein the linker has the following structure:

[1147]

[1148]

[1149]

[1150]

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

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

[1151]

[65] A compound as described in paragraph

[64] or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIa:

[1152]

[1153]

[1154] wherein R 14 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 14-membered heteroalkyl, or an optionally substituted 5- to 10-membered heteroaryl.

[1155]

[66] A compound as described in paragraph

[65] or a pharmaceutically acceptable salt thereof, wherein W has the following structure:

[1156]

[1157]

[1158]

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

[63] , wherein W comprises oxazoline or thiazoline.

[1159]

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

[67] , wherein W has the structure of formula IIIb:

[1160]

[1161] wherein X 1 is O or S;

[1162] X 2 is absent or is NR 19 ;

[1163] R 15 、R 16 、R 17 and R 18 are independently hydrogen or optionally substituted C 1 -C 6 alkyl; and

[1164] R 19 is hydrogen, C(O)(optionally substituted C 1 -C 6 alkyl), optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5- to 10-membered heteroaryl.

[1165]

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

[68] , wherein W is

[1166]

[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.

[1167]

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

[70] , wherein W has the structure of formula IIIc:

[1168]

[1169] wherein X 3 is O or S;

[1170] X 4 is O, S, NR 26 ;

[1171] R 21 、R 22, R 23 , R 24 and R 26 are independently hydrogen or optionally substituted C 1 -C 6 alkyl; and

[1172] R 25 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

[1173]

[72] The compound as described in paragraph

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

[1174]

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

[63] or a pharmaceutically acceptable salt thereof, wherein W contains aziridine.

[1175]

[74] The compound as described in paragraph

[73] or a pharmaceutically acceptable salt thereof, wherein W has a structure of Formula IIId1, Formula IIId2, Formula IIId3, or Formula IIId4:

[1176]

[1177] wherein X 5 is absent or is NR 30 ;

[1178] Y is absent or is C(O), C(S), S(O), SO 2 or optionally substituted C 1 -C 3 alkylene;

[1179] R 27 is hydrogen, -C(O)R 32 , -C(O)OR 32 , -SO 2 R 33 , -SOR 33 , optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl;

[1180] R 28 and R 29 are independently hydrogen, CN, C(O)R 31 , CO 2 R 31 , C(O)R31 R 31 、 an optionally substituted C 1 -C 6 alkyl, an optionally substituted 3- to 10-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 14-membered heterocycloalkyl, or an optionally substituted 5- to 10-membered heteroaryl;

[1181] Each R 31 is hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 14-membered heterocycloalkyl, or an optionally substituted 5- to 10-membered heteroaryl;

[1182] R 30 is hydrogen or an optionally substituted C 1 -C 6 alkyl; and

[1183] R 32 and R 33 are independently hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 14-membered heterocycloalkyl, or an optionally substituted 5- to 10-membered heteroaryl.

[1184]

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

[73] or

[74] , wherein W is:

[1185]

[1186]

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

[63] , wherein W contains an epoxide.

[1187]

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

[76] , wherein W is

[1188]

[78] A compound of Table 1 or Table 2 or a pharmaceutically acceptable salt thereof.

[1189]

[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.

[1190]

[80] A conjugate or a salt thereof, comprising a structure of Formula IV:

[1191] M-L-P

[1192] Formula IV

[1193] wherein L is a linker;

[1194] P is a monovalent organic moiety; and

[1195] M has the structure of Formula V:

[1196]

[1197] wherein the dashed line represents zero, one, two, three or four non - adjacent double bonds;

[1198] A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; 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;

[1199] B is -CH(R 9 )- or >C = CR 9 R 9’ , wherein the carbon is bonded to the carbonyl carbon of -N(R 11 )C(O)-; optionally substituted 3 - to 6 - membered cycloalkylene; optionally substituted 3 - to 6 - membered heteroalkylene; optionally substituted 6 - membered arylene; or 5 - to 6 - membered heteroarylene;

[1200] G is optionally substituted C 1 -C 4 alkylene; optionally substituted C 1 -C 4 alkenylene; optionally substituted C 1 -C 4 heteroalkylene; -C(O)O - CH(R 6 )-, wherein C is bonded to -C(R 7 R 8 )-; -C(O)NH - CH(R 6 )-, wherein C is bonded to -C(R 7 R 8 )-; optionally substituted C 1 -C 4 heteroalkylene; or 3 - to 8 - membered heteroarylene;

[1201] X 1 is optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[1202] X 2 is O or NH;

[1203] X 3 is N or CH;

[1204] n is 0, 1 or 2;

[1205] R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’, S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[1206] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[1207] Y 1 is C, CH or N;

[1208] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[1209] Y 5 is CH, CH 2 or N;

[1210] Y 6 is C(O), CH, CH 2 or N;

[1211] R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or

[1212] R 1 and R 2 together with the atoms to which they are attached form an optionally substituted 3- to 14-membered heteroalkyl;

[1213] R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or

[1214] R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[1215] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[1216] R 5 is hydrogen, optionally halogen-substituted C 1 -C 4 alkyl, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl;

[1217] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl, or

[1218] R 6 and R 7 together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[1219] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[1220] R 7 and R 8 combines with the carbon atom to which it is attached to form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 -alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;

[1221] R 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 -alkyl, or combines with the carbon to which it is attached to form a carbonyl;

[1222] R 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 -alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 -alkoxy, optionally substituted C 1 -C 3 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or

[1223] R 7’ and R 8’ combines with the carbon atom to which it is attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[1224] R 9 is hydrogen, F, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 1 -C 6 -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl, or

[1225] R 9 and L combines with the atoms to which it is attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;

[1226] R 9’ is hydrogen or optionally substituted C1 -C 6 alkyl;

[1227] R 10a is hydrogen or halo;

[1228] R 11 is hydrogen or C 1 -C 3 alkyl; and

[1229] R 34 is hydrogen or C 1 -C 3 alkyl.

[1230]

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

[80] , wherein M has the structure of formula Vc:

[1231]

[1232] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene;

[1233] B is -CH(R 9 )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heterocycloalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[1234] X 1 is an optionally substituted C 1 -C 2 alkylene, NR, O or S(O) n ;

[1235] X 2 is O or NH;

[1236] n is 0, 1 or 2;

[1237] R is hydrogen, cyano, an optionally substituted C 1 -C 4 alkyl, an optionally substituted C 2 -C 4 alkenyl, an optionally substituted C 2 -C 4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’) 2 、S(O)R’、S(O) 2 R’ or S(O) 2 N(R’) 2 ;

[1238] Each R’ is independently H or optionally substituted C 1 -C 4 alkyl;

[1239] X e and X f are independently N or CH;

[1240] R 2 is C 1 -C 6 alkyl or 3- to 6-membered cycloalkyl;

[1241] R 7 is C 1 -C 3 alkyl;

[1242] R 8 is C 1 -C 3 alkyl; and

[1243] R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;

[1244] R 11 is hydrogen or C 1 -C 3 alkyl; and

[1245] R 34 is hydrogen or C 1 -C 3 alkyl.

[1246] In some embodiments of the compounds of the invention, X e is N, and X f is CH. In some embodiments, X e is CH, and X f is N.

[1247]

[82] The conjugate or a salt thereof as described in paragraph

[80] or

[81] , wherein M has the structure of formula Vd:

[1248]

[1249] wherein A is optionally substituted 3- to 6-membered subcycloalkyl, optionally substituted 3- to 6-membered subheterocycloalkyl, optionally substituted 6-membered subaryl or optionally substituted 5- to 6-membered subheteroaryl;

[1250] B is -CH(R 9)-, wherein carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene;

[1251] L is absent or is a linker;

[1252] W is a crosslinking group, the group comprising a carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolinium or glycals;

[1253] R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; and

[1254] X e and X f are independently N or CH.

[1255]

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

[80] to

[82] , wherein the linker has the structure of formula II:

[1256] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2

[1257] Formula II

[1258] wherein A 1 is a bond between the linker and B; A 2 is a bond between P and the linker; B 1 、B 2 、B 3 and B 4 each independently selected from an optionally substituted C1 -C 2 Alkylene, optionally substituted C 1 -C 3 Heteroalkylene, O, S and NR N ; R N is hydrogen, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 2 -C 4 Alkenyl, optionally substituted C 2 -C 4 Alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted C 1 -C 7 Heteroalkyl; C 1 and C 2 each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D 1 is optionally substituted C 1 -C 10 Alkylene, optionally substituted C 2 -C 10 Alkenylene, optionally substituted C 2 -C 10 Alkynylene, optionally substituted 3- to 14-membered heteroalkylidene, optionally substituted 5- to 10-membered heteroarylidene, optionally substituted 3- to 8-membered cycloalkylidene, optionally substituted 6- to 10-membered arylidene, optionally substituted C 2 -C 10 Polyethylene glycol or optionally substituted C 1 -C 10 Heteroalkylene, or connecting A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 Chemical bond.

[1259]

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

[80] to

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

[1260]

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

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

[1261]

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

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

[1262]

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

[80] to

[86] , wherein the linker is bound to the monovalent organic moiety through a ...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound having the structure of Formula Ic: wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; optionally substituted 3- to 6-membered cycloalkylidene; optionally substituted 3- to 6-membered heteroalkylidene; optionally substituted 6-membered arylidene; or optionally substituted 5- to 6-membered heteroarylidene; B is -CH(R 9 )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene; L is absent or is a linker, said linker having the following structure: (i) Formula IIa: where X a does not exist or is N; R 14 is absent, hydrogen or optionally substituted C 1 -C 6 alkyl; and L 2 is absent, -SO 2 -, optionally substituted C 1 -C 4 alkylene or optionally substituted C 1 -C 4 heteroalkylene, wherein at least one of X a , R 14 or L 2 exists; or (ii) Formula IIb: wherein o is 0 or 1; R 15 is hydrogen or optionally substituted C 1 -C 6 alkyl; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heteroalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; and L 3 is absent, -SO 2 -, optionally substituted C 1 -C 4 alkylene or optionally substituted C 1 -C 4 heteroalkylene; W is a crosslinking group selected from carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, isoEEDQ, epoxide, oxazolium, and enose; R 1 is cyano, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 1 -C 6 -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or R 2 and R 3 together with the atom to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted by halogen, cyano, hydroxy or C 1 -C 4 alkoxy, cyclopropyl or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C 1 -C 3 alkyl, or R 6 and R 7 which together with the carbon atom to which it is attached forms an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 -alkoxy, optionally substituted C 1 -C 3 -alkyl, optionally substituted C 2 -C 6 -alkenyl, optionally substituted C 2 -C 6 -alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combines with the carbon atom to which it is attached to form C=CR 7’ R 8’ ; C=N(OH); C=N(O-C 1 -C 3 -alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, a halogen, or an optionally substituted C 1 -C 3 alkyl; R 8’ is hydrogen, a halogen, a hydroxyl group, a cyano group, an optionally substituted C 1 -C 3 alkoxy group, an optionally substituted C 1 -C 3 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group, or an optionally substituted 6- to 10-membered aryl group, or R 7’ and R 8’ together with the carbon atom to which it is attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is optionally substituted C 1 -C 6 -alkyl, optionally substituted C 1 -C 6 -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, a hydroxyl group, C 1 -C 3 -alkoxy or C 1 -C 3 -alkyl; and wherein each optional substituent is independently a monovalent substituent or a divalent substituent, wherein the monovalent substituents are independently selected from deuterium; halogen; -(CH 2 ) 0-4 R o ; -(CH 2 ) 0 - 4 OR o ; -O(CH 2 ) 0-4 R o ; -O-(CH 2 ) 0-4 C(O)OR o ; -(CH 2 ) 0-4 CH(OR o ) 2 ; -(CH 2 ) 0 - 4 SR o ; -(CH 2 ) 0-4 Ph, which group may be substituted by R o ; -(CH 2 ) 0- 4 O(CH 2 ) 0-1 Ph, which group may be substituted by R o ; -CH=CHPh, which group may be substituted by R o ; -(CH 2 ) 0-4 O(CH 2 ) 0 - 1 -pyridyl, which group may be substituted by R o ; 4- to 8-membered saturated or unsaturated heterocycloalkyl; 3- to 8-membered saturated or unsaturated cycloalkyl; -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0-4 N(R o ) 2 ; -(CH 2 ) 0 - 4 N(R o )C(O)R o ; -N(R o )C(S)R o ; -(CH 2 ) 0-4 N(R o )C(O)NR o 2 ; -N(R o )C(S)NR o 2 ; -(CH 2 ) 0-4 N(R o )C(O)OR o ; -N(R o )N(R o )C(O)R o ; -N(R o )N(R o )C(O)NR o 2 ; -N(R o )N(R o )C(O)OR o ; -(CH 2 ) 0-4 C(O)R o ; -C(S)R o ; -(CH 2 ) 0-4 C(O)OR o ; -(CH 2 ) 0-4 -C(O)-N(R o ) 2 ; -(CH 2 ) 0-4 -C(O)-N(R o )-S(O) 2 -R o ; -C(NCN)NR o 2 ; -(CH 2 ) 0-4 C(O)SR o ; -(CH 2 ) 0 - 4 C(O)OSiR o 3 ; -(CH 2 ) 0-4 OC(O)R o ; -OC(O)(CH 2 ) 0-4 SR o ; -SC(S)SR o ; -(CH 2 ) 0-4 SC(O)R o ; -(CH 2 ) 0-4 C(O)NR o 2 ; -C(S)NR o 2 ; -C(S)SR o ; -(CH 2 ) 0 - 4 OC(O)NR o 2 ; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH 2 C(O)R o ; -C(NOR o )R o ; -(CH 2 ) 0-4 SSR o ; -(CH 2 ) 0-4 S(O) 2 R o ; -(CH 2 ) 0-4 S(O) 2 OR o ; -(CH 2 ) 0-4 OS(O) 2 R o ; -S(O) 2 NR o 2 ; -(CH 2 ) 0-4 S(O)R o ; -N(R o )S(O) 2 NR o 2 ; -N(R o )S(O) 2 R o ; -N(OR o )R o ; -C(NOR o )NR o 2 ; -C(NH)NR o 2 ; -P(O) 2 R o ; -P(O)R o 2 ; -P(O)(OR o ) 2 ; -OP(O)R o 2 ; -OP(O)(OR o ) 2 ; -OP(O)(OR o )R o ; -SiR o 3 ; -(C 1 -C 4 a straight-chain or branched alkylene)O-N(R o ) 2 ; or -(C 1 -C 4 a straight-chain or branched alkylene)C(O)O-N(R o ) 2 , wherein each R o may be substituted as defined hereinafter and is independently hydrogen, -C 1 -C 6 an aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2 -(a 5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independently occurring R o together with the atoms inserted therebetween form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein R o or a ring formed by two independently existing Rs o together with the inserted atom is unsubstituted or substituted with one or more substituents independently selected from the following: halogen, -(CH 2 ) 0 - 2 R · , -(haloalkyl R · ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR · , -(CH 2 ) 0-2 CH(OR · ) 2 , -O(haloalkyl R · ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R · , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0 - 2 C(O)OR · , -(CH 2 ) 0-2 SR · , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR · , -(CH 2 ) 0-2 NR · 2 , -NO 2 , -SiR · 3 , -OSiR · 3 , -C(O)SR · , -(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · , wherein each R · is unsubstituted or, when preceded by halo, is substituted only with one or more halogens and is independently selected from C 1 -C 4 aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein R o the divalent substituents on the saturated carbon atoms are =O and =S; wherein the divalent substituents on the saturated carbon atoms of the optionally substituted groups are each independently selected from: =O, =S, =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2-3 O- or -S(C(R * 2 )) 2-3 S-, where R * is independently selected from hydrogen each time it appears; C 1 -C 6 an aliphatic group, which may be substituted as defined below; or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; Among the divalent substituents bonded to the adjacent replaceable carbon of the optionally substituted group are independently selected from: -O(CR * 2 ) 2- 3 O-, where R * is independently selected, each time it appears, from hydrogen; C 1 -C 6 an aliphatic group which may be substituted as defined below; or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein R * substituents on the aliphatic group are independently selected from: halogen, -R · , -(halo-R · ), -OH, -OR · , -O(halo-R · ), -CN, -C(O)OH, -C(O)OR · , -NH 2 , -NHR · , -NR · 2 or -NO 2 , wherein each R · is unsubstituted or, when preceded by "halo-", is substituted by one or more halogens only, and is independently C 1 -C 4 aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein the substituents on the optionally substituted nitrogen of the optionally substituted group are independently selected from: or wherein each is independently hydrogen; C 1 -C 6 an aliphatic group; unsubstituted -OPh; or an unsubstituted 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independently existing together with their inserted atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; Among them the substituents on the aliphatic group are independently selected from: halogen, -R · , -(halo-R · ), -OH, -OR · , -O(halo-R · ), -CN, -C(O)OH, -C(O)OR · , -NH 2 , -NHR · , -NR · 2 or -NO 2 , where each R · is unsubstituted or, in the case of being preceded by "halo-", is substituted only by one or more halogens and is independently C 1 -C 4 aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; and wherein The divalent substituents on the saturated carbon atoms are independently selected from: =O and =S.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound has the structure of Formula Id: wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered subcycloalkyl; an optionally substituted 3- to 6-membered subheterocycloalkyl; an optionally substituted 6-membered subaryl; or a 5- to 6-membered subheteroaryl; L is absent or is a linker; W is a crosslinking group selected from carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, isoEEDQ, epoxide, oxazolium, and enose; R 1 is cyano, optionally substituted C 1 -C 6 -alkyl, optionally substituted C 1 -C 6 -heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R 2 is C 1 -C 6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C 1 -C 3 alkyl; R 8 is C 1 -C 3 alkyl; and R 9 is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 1 is a 5- to 10-membered heteroaryl.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein R 1 is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein said compound has the structure of Formula Ie: wherein A is -N(H or CH 3 )C(O)-(CH 2 )-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R 10 )-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-; an optionally substituted 3- to 6-membered cycloalkylene; an optionally substituted 3- to 6-membered heteroalkylene; an optionally substituted 6-membered arylene; or a 5- to 6-membered heteroarylene; L is absent or is a linker; W is a crosslinking group selected from carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, isoEEDQ, epoxide, oxazolium, and enose; R 2 is C 1 -C 6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C 1 -C 3 alkyl; R 8 is C 1 -C 3 alkyl; and R 9 is an optionally substituted C 1 -C 6 -alkyl, an optionally substituted C 1 -C 6 -heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; X e and X f are independently N or CH; and R 12 is an optionally substituted C 1 -C 6 -alkyl or an optionally substituted C 1 -C 6 -heteroalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein A is an optionally substituted 6-membered arylene.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein B is -CHR 9 -.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein R 9 is optionally substituted C 1 -C 6 alkyl or optionally substituted C3-6 cycloalkyl.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein B is an optionally substituted 6-membered arylene.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein said linker is acyclic.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein said linker is or contains a cyclic group.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein W contains carbodiimide.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein W has the structure of Formula IIIa: wherein R 14 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 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.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein W contains oxazoline or thiazoline.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein W has the structure of Formula IIIb: wherein X 1 is O or S; X 2 Absent or NR 19 ; R 15 , R 16 , R 17 and R 18 are independently hydrogen or optionally substituted C 1 -C 6 Alkyl; and R 19 is hydrogen, C(O)-optionally substituted C 1 -C 6 -alkyl, optionally substituted C 1 -C 6 -alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W comprises chloroethylurea, chloroethylthiourea, chloroethyl carbamate or chloroethyl thiocarbamate.

17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIc: wherein X 3 is O or S; X 4 is O, S, NR 26 ; R 21 , R 22 , R 23 , R 24 and R 26 are independently hydrogen or optionally substituted C 1 -C 6 Alkyl; and R 25 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

18. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W comprises aziridine.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIId1, formula IIId2, formula IIId3 or formula IIId4: where X 5 does not exist or is NR 30 ; Y is absent or is C(O), C(S), S(O), SO 2 or optionally substituted C 1 -C 3 alkylene; R 27 is hydrogen, -C(O)R 32 、-C(O)OR 32 、-SO 2 R 33 、-SOR 33 、optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5- to 10-membered heteroaryl; R 28 and R 29 are independently hydrogen, CN, C(O)R 31 , CO 2 R 31 , C(O)R 31 R 31 , optionally substituted C 1 -C 6 -alkyl, optionally 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 R 31 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; R 30 is hydrogen or optionally substituted C 1 -C 6 alkyl; and R 32 and R 33 are independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

20. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W comprises an epoxide.

21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. Use of the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22 in the manufacture of a medicament for the treatment of cancer.

24. The use according to claim 23, wherein the cancer is pancreatic cancer, non-small cell lung cancer, colorectal cancer or endometrial cancer.

25. The use according to claim 23 or 24, wherein the cancer comprises a Ras mutation.

26. The use according to claim 25, wherein the Ras mutation is K-Ras G12D or K-Ras G13D.

27. Use of the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22 in the manufacture of a medicament for the treatment of Ras protein-related disorders.

28. The use according to any one of claims 23 to 27, wherein the medicament is administered in combination with an additional anti-cancer therapy.

29. The use according to claim 28, wherein the additional anti-cancer 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.

30. The use according to claim 28 or 29, wherein the additional anti-cancer therapy is an SHP2 inhibitor.

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