Macrocyclic RAS inhibitors

Abstract

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

Description

[0001] This application is a divisional application of the invention patent application with application date of June 9, 2023, application number 2023800582279, and invention name “Macrocyclic RAS Inhibitors”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Application No. 63 / 351,146, filed on June 10, 2022, and U.S. Application No. 63 / 455,649, filed on March 30, 2023, each of which is hereby incorporated by reference in its entirety. Background Art

[0004] The vast majority of small molecule drugs work by binding to functionally important pockets on the target protein, thereby regulating the activity of the protein. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. The fact that many such drug / target interaction pairs are known may have misled some people into believing that, given reasonable time, effort, and resources, small molecule modulators for most (if not all) proteins can be found. This is far from the case. According to current estimates, 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 other 90% are currently considered to be refractory or intractable to the discovery of small molecule drugs. Such targets are often referred to as "undruggable". These undruggable targets include a large number of human proteins of important medical significance that have not yet been developed. Therefore, there is great interest in discovering new molecular patterns that can regulate the functions of such undruggable targets.

[0005] It has been confirmed in the literature that Ras proteins (K-Ras, H-Ras and N-Ras) play an important role in various human cancers and are therefore suitable targets for anticancer therapy. In fact, mutations in Ras proteins account for approximately 30% of all human cancers in the United States, many of which are fatal. Ras proteins are commonly dysregulated in human tumors through activating mutations, overexpression or upstream activation, and activating mutations of Ras are often found in human cancers. For example, activating mutations at codon 12 in Ras proteins function by inhibiting both the GTPase activating protein (GAP) dependency and the intrinsic hydrolysis rate of GTP, significantly biasing the population of Ras mutant proteins towards the "on" (GTP-bound) state (Ras (on)), thereby causing oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Ras mutations at codons 13 (eg, G13D) and 61 (eg, Q61K) also cause oncogenic activity in some cancers.

[0006] Despite extensive drug discovery efforts targeting Ras over the past few decades, drugs that directly target the "on" form of Ras have yet to be approved. Further efforts are needed to discover additional drugs for cancers driven by various Ras mutations. Summary of the Invention

[0007] Provided herein are Ras inhibitors. These Ras inhibitors target, i.e., selectively bind to or inhibit Ras (turn on) (e.g., selectively bind to the inactive state of GDP compared to Ras). The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: a target protein of interest (e.g., Ras), and a cytoplasmic chaperone (presenting protein) (e.g., cyclophilin A) that is widely expressed in cells. More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity three-complex between the Ras protein and the widely expressed cytoplasmic chaperone cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way in which the inhibitory effect of Ras is affected by the compounds of the present invention and the complexes they form is through the spatial closure of the interaction site between Ras and downstream effector molecules (such as RAF and PI3K), which are required for the propagation of oncogenic signals.

[0008] Thus, in some embodiments, the disclosure features a compound having structural formula Ia, or a pharmaceutically acceptable salt thereof:

[0009]

[0010] where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds;

[0011] A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene;

[0012] G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(where C is bound to -C(R 7 R 8 )-)、-C(O)NH-CH(R 6 )-(where C is bound to -C(R 7 R 8 )-), optionally substituted C1-C4 heteroalkylene or 3 to 8 membered heteroarylene;

[0013] swIp (switch I / P-loop) is an organic moiety that non-covalently binds to residues 12 or 13 of the switch I binding pocket and P-loop of the Ras protein (see, e.g., Johnson et al., 292: 12981-12993 (2017), incorporated herein by reference);

[0014] X 1 is an optionally substituted C1-C2 alkylene, NR, O or S(O) n ;

[0015] X 2 is O or NH;

[0016] X 3 N or CH;

[0017] n is 0, 1, or 2;

[0018] R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2;

[0019] Each R ’ are independently H or optionally substituted C1-C4 alkyl;

[0020] Y 1 is C, CH or N;

[0021] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0022] Y 5 is CH, CH2 or N;

[0023] Y 6 is C(O), CH, CH2 or N;

[0024] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or

[0025] R 1 and R 2 are combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0026] R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl;

[0027] R 3 does not exist, or

[0028] R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0029] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0030] R 5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl;

[0031] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or

[0032] R 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0033] R 8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0034] R 7 and R 8 Combined with the carbon atoms to which they are attached, they form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0035] R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl;

[0036] R 7’ is hydrogen, halogen or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0037] R 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0038] R 10 is hydrogen, halogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl;

[0039] R 10a is hydrogen or halogen;

[0040] R 16 is hydrogen or C1-C3 alkyl; and

[0041] Wherein, in some embodiments,

[0042] i. The compound is not

[0043]

[0044] or

[0045] ii. When W is cyclopropyl, then the compound does not have formula X, wherein formula X is:

[0046]

[0047] where R 1X is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0048] R 2X is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; and

[0049] Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2 or -NHS(O)2NH-.

[0050] In some embodiments, the disclosure features a compound having structural formula Ib, or a pharmaceutically acceptable salt thereof:

[0051]

[0052] where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds;

[0053] A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene;

[0054] B does not exist, is -NH-, -N(CH3)-, -O-, -CH(R 9 )-or>C=CR 9 R 9’ (wherein the carbon is bound to -N(R 11 )C(O)-), an optionally substituted 3- to 6-membered cycloalkylene group, an optionally substituted 3- to 6-membered heterocycloalkylene group, an optionally substituted 6-membered arylene group, or a 5- to 6-membered heteroarylene group;

[0055] G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(where C is bound to -C(R 7 R 8)-)、-C(O)NH-CH(R 6 )-(where C is bound to -C(R 7 R 8 )-), optionally substituted C1-C4 heteroalkylene or 3 to 8 membered heteroarylene;

[0056] L does not exist or is a linker;

[0057] W is hydrogen, cyano, optionally substituted amino, optionally substituted amido, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 3- to 10-membered heteroaryl;

[0058] Z is -C(O)- or -S(O)2-;

[0059] X 1 is an optionally substituted C1-C2 alkylene, NR, O or S(O) n ;

[0060] X 2 is O or NH;

[0061] X 3 N or CH;

[0062] n is 0, 1, or 2;

[0063] R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2;

[0064] Each R ’ are independently H or optionally substituted C1-C4 alkyl;

[0065] Y 1 is C, CH or N;

[0066] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0067] Y 5 is CH, CH2 or N;

[0068] Y 6is C(O), CH, CH2 or N;

[0069] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or

[0070] R 1 and R 2 are combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0071] R 2 R is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

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

[0073] R 5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl;

[0074] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or

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

[0076] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0077] R 7 and R8 Combined with the carbon atoms to which they are attached, they form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0078] R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl;

[0079] R 7’ is hydrogen, halogen or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0080] R 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0081] R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0082] R 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0083] R 9’ is hydrogen or an optionally substituted C1-C6 alkyl group;

[0084] R 10 is hydrogen, halogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl;

[0085] R 10a is hydrogen or halogen;

[0086] R 11 is hydrogen or C1-C3 alkyl;

[0087] R 16 is hydrogen or C1-C3 alkyl; and

[0088] Wherein, in some embodiments,

[0089] i. The compound is not

[0090]

[0091]

[0092] or

[0093] ii. When W is cyclopropyl, then the compound does not have formula X, wherein formula X is:

[0094]

[0095] where R 1X is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0096] R 2X is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; and

[0097] Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2 or -NHS(O)2NH-.

[0098] Also provided are pharmaceutical compositions comprising a compound of Formula Ia or Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0099] Also provided is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, provided is a method of treating a Ras protein-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0101] Further provided is a method for inhibiting Ras protein in a cell, comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0102] In particular, it is contemplated that any limitation discussed with respect to one embodiment of the present invention may be applicable to any other embodiment of the present invention. In addition, any compound or composition of the present invention may be used in any method of the present invention, and any method of the present invention may be used to produce or utilize any compound or composition of the present invention.

[0103] Definitions and Chemical Terms

[0104] In this application, unless the context indicates otherwise, (i) the term "a / a" means "one or more"; (ii) the term "or" is used to mean "and / or" (unless explicitly indicated to refer to only alternatives or the alternatives are mutually exclusive), although this disclosure supports definitions referring only to alternatives and "and / or"; (iii) the terms "comprising" and "including" are understood to cover the listed components or steps alone or together with one or more other components or steps; and (iv) where a range is provided, the endpoints are included.

[0105] 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 for determining the value. In certain embodiments, the term "about" refers to a range of values within a range of (greater than or less than) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction of the stated value, unless otherwise stated or otherwise apparent from the context (e.g., wherein such numerals will exceed 100% of possible values).

[0106] As used herein, the term "adjacent," in the context of describing adjacent atoms, refers to divalent atoms that are directly connected by a covalent bond.

[0107] As used herein, “compounds of the invention” and similar terms, whether explicitly mentioned or not, refer to the Ras inhibitors described herein, including compounds of Formula Ia or Formula Ib and subformulas thereof and compounds of Table 1, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof.

[0108] The term "wild-type" refers to an entity having structure or activity as found in nature in a "normal" (as opposed to mutant, diseased, altered, etc.) state or background. Those skilled in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0109] Those skilled in the art will appreciate that certain compounds described herein may exist in one or more different isomers (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., wherein one or more atoms have been substituted with a different isotope of an atom, such as hydrogen for deuterium). Unless otherwise indicated or clear from the context, the structures shown are understood to represent any such isomers or isotopic forms, either individually or in combination.

[0110] 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 intended. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of 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. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be separated as mixtures of isomers or as separated isomeric forms.

[0111] In some embodiments, one or more compounds presented herein can exist in different tautomeric forms. As will be clear from the context, reference to such compounds encompasses all such tautomeric forms unless expressly excluded. In some embodiments, tautomeric forms result from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, 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 with prototropic tautomeric forms are keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-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 sterically locked into one form by appropriate substitution. In certain embodiments, the tautomeric forms are caused by acetal interconversion.

[0112] Unless otherwise stated, structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled ones) can be used in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful due to their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H replacement, or one or more carbon atoms are 13 C or 14 C-enriched carbon replacement. 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 following procedures analogous to those disclosed for the compounds of the invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0113] As is known in the art, many chemical entities can adopt a variety of different solid forms, such as amorphous forms 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 in any solid form. In some embodiments, the compounds described or illustrated herein can be provided or used in the form of a hydrate or solvate.

[0114] At various positions in this specification, substituents of compounds of the present disclosure are disclosed as groups or in ranges. The disclosure is specifically intended to include every individual subcombination of members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. Furthermore, where a compound includes multiple positions where substituents are disclosed as groups or in ranges, unless otherwise indicated, the disclosure is intended to cover individual compounds and groups of compounds (e.g., classes and subclasses) containing every individual subcombination of members at each position.

[0115] The term "optionally substituted X" (e.g., "optionally substituted alkyl") is intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). The feature "X" (e.g., alkyl) itself is not intended to mean that it is optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with 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 may be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. For example, in the term "optionally substituted C1-C6 alkyl-C2-C9 heteroaryl," the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are not substantially altered when subjected to conditions that allow for the compound's production, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0116] Suitable monovalent substituents on the substitutable carbon atoms of the "optionally substituted" group may independently be deuterium; halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o ;-O-(CH2)0-4C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ; -(CH2) 0-4 Ph, which can be R oSubstitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substituted; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be R o substituted; 4-11 membered saturated or unsaturated heterocycloalkyl (e.g., 4-8 membered saturated or unsaturated heterocycloalkyl (e.g., pyridyl)), which may be further optionally substituted (e.g., substituted with methyl); 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl or cyclopentyl); -NO2; -CN; -N3; -(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ;-C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 -C(O)-N(R o )2;-(CH2) 0-4 -C(O)-N(R o )-S(O)2-R o ;-C(NCN)NR o 2; -(CH2) 0-4 C(O)SR o ;-(CH2)0-4C(O)OSiRo 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ; -(CH2) 0-4 SC(O)R o ; -(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-(CH2)0-4OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NOR o )NR o 2;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-P(O)(OR o )2;-OP(O)R o 2;-OP(O)(OR o )2;-OP(O)(OR o )R o , -SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, -C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with their intervening atom(s), they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which monocyclic or bicyclic ring may be substituted as defined below.

[0117] R o (or by two independent occurrences of R o Suitable monovalent substituents on the ring formed by taking into account one or more of their intervening atoms are independently halogen, -(CH2) 0-2 R · 、-(halogenated R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0- 2CH(OR · )2;-O(halogenated R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2)0-2NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently selected from C1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0118] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0119] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0120] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh or an unsubstituted 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of Together with their intervening atom(s), they form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0121] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0122] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0123] As used herein, the term "alkoxy" refers to -O-C1-C 20 Alkyl groups, wherein the alkoxy group is attached to the rest of the compound through an oxygen atom.

[0124] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon radical containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbon atoms. In some embodiments, the alkyl group is unbranched (i.e., straight-chain); in some embodiments, the alkyl group is branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso-, and tert-butyl, and neopentyl.

[0125] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight-chain or branched saturated hydrocarbon by removing two hydrogen atoms, and examples are methylene, ethylene, isopropylene, etc. The term "C x -C y "Alkylene" means an alkylene group having x to y carbons. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C 10 、C2-C 20 , C2-C6, C2-C 10 or C2-C 20 In some embodiments, the alkylene group may be further substituted with 1, 2, 3, or 4 substituents as defined herein.

[0126] Unless otherwise indicated, as used herein, the term "alkenyl" refers to a monovalent straight or branched chain group of 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and examples are ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl includes both cis and trans isomers. Unless otherwise indicated, as used herein, the term "alkenylene" refers to a divalent straight or branched chain group of 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0127] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl and 1-propynyl.

[0128] As used herein, the term "alkynyl sulfone" refers to a group comprising the following structure: wherein R is any chemically feasible substituent described herein.

[0129] As used herein, the term "amino" refers to For example -NH2 and -N(CH3)2.

[0130] As used herein, the term "aminoalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.

[0131] As described herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is connected to a parent molecular group via a side chain, an amino group, or an acid group (e.g., a side chain). As used herein, the term "amino acid" broadly 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, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. "Standard amino acid" refers to any 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 hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0132] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed from carbon atoms, wherein the ring connected to the side group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. The aromatic ring can be connected to its side group at any heteroatom or carbocyclic atom that produces a stable structure, and unless otherwise indicated, any one of the ring atoms can be optionally substituted.

[0133] As used herein, the term "CO" represents a bond. For example, the term -N(C(O)-(CO-C5 alkylene-H)- includes -N(C(O)-(CO alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0134] As used herein, the terms "carbocycle" and "carbocyclyl" refer to a monovalent optionally substituted C3-C 12 Monocyclic, bicyclic or tricyclic structures, the ring structure can be a bridged ring, a condensed ring or a spirocycle, wherein all rings are formed by carbon atoms and at least one ring is non-aromatic.Carbocyclic ring structures include cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decahydronaphthyl etc. Carbocyclic ring can be connected to its side group at any ring atom producing a stable structure, and unless otherwise indicated, any one of the ring atoms can be optionally substituted.

[0135] As used herein, the term "carbonyl" refers to a C(O) group, which may also be represented as C=O.

[0136] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH or the unprotonated counterpart.

[0137] As used herein, the term "cyano" refers to a -CN group.

[0138] As used herein, the term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon radical which may be a bridged, fused, or spiro ring having from three to eight ring carbons unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0139] As used herein, the term "cycloalkenyl" refers to a monovalent, non-aromatic, saturated cyclic hydrocarbon group which may be bridged, fused, or spiro having from three to eight ring carbons and containing one or more carbon-carbon double bonds unless otherwise specified.

[0140] As used herein, the term "diastereomers" refers to stereoisomers that are not mirror images of each other and are not superimposable on each other.

[0141] 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 methods standard in the art).

[0142] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen has been replaced by a halogen.

[0143] As used herein, the term "haloalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more halogen moieties, which may be the same or different.

[0144] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine or fluorine.

[0145] As used herein, the term "heteroalkyl" refers to an "alkyl" as defined herein, wherein at least one carbon atom has been 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. As used herein, the term "heteroalkylene" refers to a divalent alkylene linear or branched group having from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons), unless otherwise specified, wherein at least one carbon atom has been 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.

[0146] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic structure containing at least one fully aromatic ring: that is, it contains 4n+2 π electrons within the monocyclic or polycyclic ring system and contains at least one ring heteroatom selected from N, O or S in the aromatic ring. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10 or 2 to 9) carbon atoms. The term "heteroaryl" includes bicyclic, tricyclic and tetracyclic groups, wherein 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 heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl and 4-azaindolyl. The heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted. In some embodiments, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents.

[0147] As used herein, the term "heterocycloalkyl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system that can be a bridged ring, a fused ring, or a spirocyclic ring, wherein at least one ring is non-aromatic and wherein the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. 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 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term "heterocycloalkyl" also refers to a heterocyclic compound having a bridged polycyclic structure in which one or more carbon atoms or heteroatoms bridge two non-adjacent members of the monocyclic ring, such as quinuclidine. The term "heterocycloalkyl" includes bicyclic, tricyclic and tetracyclic groups, wherein any of the above heterocycles is fused to one or more aromatic rings, carbocyclic rings, heteroaromatic rings or heterocyclic rings, such as aromatic 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, dihydropyrrolopyridine and decahydronaphthyridine. The heterocycloalkyl ring can be connected to its side group at any ring atom that produces a stable structure, and unless otherwise indicated, any of the ring atoms can be optionally substituted.

[0148] As used herein, the term "hydroxy" refers to an -OH group.

[0149] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more -OH moieties.

[0150] As used herein, the term "isomer" means any tautomer, stereoisomer, atropisomer, enantiomer or diastereomer of any compound of the present invention. It should be recognized that the compounds of the present invention may have one or more chiral centers or double bonds and therefore exist as stereoisomers (e.g., double bond isomers, i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures shown herein and therefore the compounds of the present invention include all corresponding stereoisomers (i.e., stereoisomerically pure forms, e.g., geometrically pure, enantiomerically pure or diastereomerically pure) as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can generally be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0151] As used herein, the term "linker" refers to a divalent organic moiety that connects a first moiety (e.g., a macrocyclic moiety) to a second moiety (e.g., a cross-linking group). In some embodiments, the linker enables the compound to achieve an IC50 of 2 μM or less in the Ras-RAF disruption assay protocol provided in the Examples below and provided herein:

[0152] The purpose of this biochemical assay is to measure the ability of a test compound to induce the formation of a ternary complex between nucleotide-loaded Ras isoforms and cyclophilin A; the resulting ternary complex disrupts the binding of BRAF to RBD The binding of the construct to the cytokine receptor agonist inhibits Ras signaling through RAF effectors.

[0153] Untagged cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variants) and GST-BRAF were mixed in an assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween 20, 0.1% BSA, 100 mM NaCl and 5 mM MgCl2. RBDThe final concentrations of 25 μM, 12.5 nM and 50 nM were combined in a 384-well assay plate. The compounds were present in the wells of the culture plate in a 10-point 3-fold dilution series starting at a final concentration of 30 μM. After incubation at 25°C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reactants were incubated for another 1.5 hours. The TR-FRET signal was read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote the destruction of the Ras:RAF complex were identified as those that triggered a decrease in the TR-FRET ratio relative to the DMSO control wells.

[0154] In some embodiments, the linker comprises 20 or fewer straight-chain atoms. In some embodiments, the linker comprises 15 or fewer straight-chain atoms. In some embodiments, the linker comprises 10 or fewer straight-chain 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.

[0155] As used herein, the term "stereoisomers" refers to all possible different isomeric and conformational forms that a compound (e.g., a compound of any formula described herein) may possess, specifically all possible stereochemical and conformational isomeric forms of the basic molecular structure, all diastereomers, enantiomers, or conformers, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of which are encompassed within the scope of the present invention.

[0156] As used herein, the term "sulfonyl" refers to a -S(O)2- group.

[0157] As used herein, the term "thiocarbonyl" refers to a -C(S)- group.

[0158] Those of ordinary skill in the art reading this disclosure will understand that certain compounds described herein may be provided or used 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, and the like. In some embodiments, reference to a particular compound may refer to a particular form of that compound. In some embodiments, reference to a particular compound may refer to any form of that compound. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound than a racemic mixture of the compound; a particular salt of a compound may be considered a different form than another salt form of the compound; a preparation of one conformational isomer ((Z) or (E)) containing a double bond may be considered a different form than the form of the other conformational isomer ((E) or (Z)) containing the double bond; a preparation in which one or more atoms are different isotopes than those present in a reference preparation may be considered a different form. DETAILED DESCRIPTION

[0159] Compound

[0160] Provided herein are Ras inhibitors. These Ras inhibitors target, i.e., selectively bind to or inhibit Ras (on) (e.g., selectively bind to or inhibit the GDP-bound inactive state of Ras). As used herein, the term "RAS (on) inhibitor" refers to an inhibitor that targets (i.e., selectively binds to or inhibits) the GTP-bound active state of RAS (e.g., selectively binds to or inhibits the GDP-bound inactive state of RAS). The inhibition of the GTP-bound active state of RAS includes, for example, inhibition of oncogenic signaling from the GTP-bound active state of RAS. In some embodiments, a RAS (on) inhibitor is an inhibitor that selectively binds to and inhibits the GTP-bound active state of RAS. In certain embodiments, a RAS (on) inhibitor may also bind to or inhibit the GDP-bound inactive state of RAS (e.g., with a lower affinity or inhibition constant compared to the GTP-bound active state of RAS). In some embodiments, a RAS (on) inhibitor has a molecular weight between 800 and 1100 Da (including endpoints). Thus, for example, the term "KRAS (on) inhibitor" refers to any inhibitor that binds to KRAS in its GTP-bound "on" position. G12C A "(on) inhibitor" is a KRAS inhibitor that selectively binds to or targets the G12C mutant form of KRAS. Non-limiting examples of RAS (on) inhibitors are provided in WO 2021091982, WO 2021091967, WO 2021091956 and WO2020132597, some of which are KRAS G12C (Turn on) inhibitor.

[0161] As used herein, the term "RAS (off) inhibitor" refers to an inhibitor that targets (i.e., selectively binds to or inhibits) the GDP-bound inactive state of RAS (e.g., is selective over the GTP-bound active state of RAS). Inhibition of the GDP-bound inactive state of RAS includes, for example, sequestering the inactive state by inhibiting the exchange of GDP for GTP, thereby inhibiting RAS from adopting an active conformation. In certain embodiments, a RAS (off) inhibitor may also bind to or inhibit the GTP-bound active state of RAS (e.g., with a lower affinity or inhibition constant than the GDP-bound inactive state of RAS). In some embodiments, a RAS (off) inhibitor has a molecular weight of less than 700 Da. In some embodiments, a RAS (off) inhibitor has a molecular weight of less than 700 Da. Thus, for example, the term "KRAS (off) inhibitor" refers to any inhibitor that binds to KRAS in its GDP-bound "off" position. "KRAS G12C A "(off) inhibitor" is a KRAS inhibitor that selectively binds to or targets the G12C mutant form of KRAS. G12C KRAS (off) inhibitors are known in the art, and non-limiting examples include adagrasib and sotorasib. Additional KRAS (off) inhibitors are provided herein.

[0162] The term "inhibitor" means a compound or agent (eg, peptide, antibody) that prevents a biomolecule (eg, protein) from completing or initiating a reaction. An inhibitor can inhibit a reaction by competitive, non-competitive, or non-competitive means.

[0163] The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: a target protein of interest (e.g., Ras), and a cytoplasmic chaperone (presenting protein) (e.g., cyclophilin A) that is widely expressed in cells. More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity three-complex between the Ras protein and the widely expressed cytoplasmic chaperone cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way in which the inhibition of Ras is affected by the compounds of the invention and the complexes they form is through steric closure of the interaction site between Ras and downstream effector molecules (such as RAF), which are required for propagation of oncogenic signals.

[0164] Without being bound by theory, the inventors speculate that non-covalent interactions of the compounds of the present invention with Ras and chaperone proteins (e.g., cyclophilin A) may contribute to the inhibition of Ras activity. For example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, as well as combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors. Thus, the compounds of the present invention may inhibit a variety of Ras proteins (e.g., wild-type Ras or Ras amp , or K-Ras, N-Ras, H-Ras, and mutants thereof at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, as well as other mutants described herein, and combinations of Ras proteins).

[0165] Thus, provided herein are compounds having the structure of Formula Ia or pharmaceutically acceptable salts thereof:

[0166]

[0167] where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds;

[0168] A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene;

[0169] G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(where C is bound to -C(R 7 R 8 )-)、-C(O)NH-CH(R 6 )-(where C is bound to -C(R 7 R 8 )-), optionally substituted C1-C4 heteroalkylene or 3 to 8 membered heteroarylene;

[0170] swIp (switch I / P-loop) is an organic moiety that non-covalently binds to residues 12 or 13 of the switch I binding pocket and P-loop of the Ras protein (see, e.g., Johnson et al., 292: 12981-12993 (2017), incorporated herein by reference);

[0171] X 1 is an optionally substituted C1-C2 alkylene, NR, O or S(O) n ;

[0172] X 2 is O or NH;

[0173] X3 N or CH;

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

[0175] R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2;

[0176] Each R' is independently H or optionally substituted C1-C4 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 is CH, CH2 or N;

[0180] Y 6 is C(O), CH, CH2 or N;

[0181] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or

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

[0183] R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl;

[0184] R 3 does not exist, or

[0185] R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0186] R4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0187] R 5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl;

[0188] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or

[0189] R 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0190] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0191] R 7 and R 8 Combined with the carbon atoms to which they are attached, they form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0192] R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl;

[0193] R 7’ is hydrogen, halogen or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0194] R 7’ and R 8’are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0195] R 10 is hydrogen, halogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl;

[0196] R 10a is hydrogen or halogen;

[0197] R 16 is hydrogen or C1-C3 alkyl; and

[0198] Wherein, in some embodiments,

[0199] i. The compound is not

[0200]

[0201]

[0202] or

[0203] ii. When W is cyclopropyl, then the compound does not have formula X, wherein formula X is:

[0204]

[0205] where R 1X is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0206] R 2X is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; and

[0207] Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2 or -NHS(O)2NH-.

[0208] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ib:

[0209]

[0210] where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds;

[0211] A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene;

[0212] B does not exist, is -NH-, -N(CH3)-, -O-, -CH(R 9 )-or>C=CR 9 R 9’ (wherein the carbon is bound to -N(R 11 )C(O)-), an optionally substituted 3- to 6-membered cycloalkylene group, an optionally substituted 3- to 6-membered heterocycloalkylene group, an optionally substituted 6-membered arylene group, or a 5- to 6-membered heteroarylene group;

[0213] G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(where C is bound to -C(R 7 R 8 )-)、-C(O)NH-CH(R 6 )-(where C is bound to -C(R 7 R 8 )-), optionally substituted C1-C4 heteroalkylene or 3 to 8 membered heteroarylene;

[0214] L does not exist or is a linker;

[0215] W is hydrogen, cyano, optionally substituted amino, optionally substituted amido, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 3- to 10-membered heteroaryl;

[0216] Z is -C(O)- or -S(O)2-;

[0217] X 1 is an optionally substituted C1-C2 alkylene, NR, O or S(O) n ;

[0218] X 2 is O or NH;

[0219] X 3 N or CH;

[0220] n is 0, 1, or 2;

[0221] R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2;

[0222] Each R' is independently H or optionally substituted C1-C4 alkyl;

[0223] Y 1 is C, CH or N;

[0224] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0225] Y 5 is CH, CH2 or N;

[0226] Y 6 is C(O), CH, CH2 or N;

[0227] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or

[0228] R 1 and R 2 are combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0229] R 2 R is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0230] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0231] R 5is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl;

[0232] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or

[0233] R 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0234] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0235] R 7 and R 8 Combined with the carbon atoms to which they are attached, they form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0236] R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl;

[0237] R 7’ is hydrogen, halogen or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0238] R 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0239] R 9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0240] R 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0241] R 9’ is hydrogen or an optionally substituted C1-C6 alkyl group;

[0242] R 10 is hydrogen, halogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl;

[0243] R 10a is hydrogen or halogen;

[0244] R 11 is hydrogen or C1-C3 alkyl;

[0245] R 16 is hydrogen or C1-C3 alkyl; and

[0246] Wherein, in some embodiments,

[0247] i. The compound is not

[0248]

[0249]

[0250] or

[0251] ii. When W is cyclopropyl, then the compound does not have formula X, wherein formula X is:

[0252]

[0253] where R 1X is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0254] R 2X is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; and

[0255] Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2 or -NHS(O)2NH-.

[0256] In some embodiments, Z is -C(O)-.

[0257] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ic:

[0258]

[0259] where Y 5 and Y 6 are independently CH or N;

[0260] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0261] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0262] R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and

[0263] R 10 is hydrogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

[0264] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Id:

[0265]

[0266] Where B does not exist, is -CH(R 9)- (wherein the carbon is bound 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;

[0267] W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl;

[0268] Y 5 and Y 6 are independently CH or N;

[0269] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0270] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0271] R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and

[0272] R 10 is hydrogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

[0273] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ie:

[0274]

[0275] Where B does not exist, is -CH(R 9)- (wherein the carbon is bound 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;

[0276] W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl;

[0277] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0278] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0279] R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and

[0280] R 10 is hydrogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

[0281] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula If:

[0282]

[0283]

[0284] B does not exist, is -CH(R 9)- (wherein the carbon is bound 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;

[0285] W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl;

[0286] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;

[0287] R 2 is a C1-C6 alkyl group or a 3- to 6-membered cycloalkyl group;

[0288] R 7 is a C1-C3 alkyl group;

[0289] R 8 is a C1-C3 alkyl group; and

[0290] R 9 is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group.

[0291] In some embodiments, R 1 is an optionally substituted 5- to 10-membered heteroaryl. 1 is an optionally substituted 6-membered aryl group or an optionally substituted 6-membered heteroaryl group.

[0292] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ig:

[0293]

[0294] B does not exist, is -CH(R 9 )- (wherein the carbon is bound 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;

[0295] W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl;

[0296] R 2 is a C1-C6 alkyl group or a 3- to 6-membered cycloalkyl group;

[0297] R 7 is a C1-C3 alkyl group;

[0298] R 8 is a C1-C3 alkyl group;

[0299] R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0300] X e N, CH or CR 17 ;

[0301] X f N or CH;

[0302] R 12 is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; and

[0303] R 17 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0304] In some embodiments, R 7 In some embodiments, R 8 It is a methyl group.

[0305] In some embodiments, A is an optionally substituted C2-C4 alkylene. In some embodiments, A is an optionally substituted C3 alkylene. In some embodiments, A is:

[0306]

[0307] In some embodiments, A is an optionally substituted C2-C4 alkenylene. In some embodiments, A is an optionally substituted C3 alkenylene. In some embodiments, A is an optionally substituted C1-C4 heteroalkylene. In some embodiments, A is an optionally substituted C2 heteroalkylene. In some embodiments, A is:

[0308]

[0309] In some embodiments, R 1 for

[0310]

[0311] In some embodiments, R 1 for

[0312]

[0313] In some embodiments, R 1 for

[0314]

[0315] where Z 1 N or CH;

[0316] m is 1 or 2;

[0317] R 18 、R 19 、R 20 and R 21 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or

[0318] R 18 and R 20 are combined with the atoms to which they are attached to form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0319] R 20 and R 21 taken together with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or

[0320] R 19 and R 20 Together with the atoms to which they are attached, they form an optionally substituted 4- to 8-membered heterocycloalkyl.

[0321] In some embodiments, R 1 for

[0322]

[0323] In some embodiments, R 1 for

[0324]

[0325] In some embodiments, R 18 It is a methyl group.

[0326] In some embodiments, R 1 for

[0327]

[0328] In some embodiments, B is -CHR 9 -. In some embodiments, R 9 In some embodiments, B is an optionally substituted C1-C6 alkyl or an optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, B is an optionally substituted 6-membered arylene. In some embodiments, B is absent.

[0329] In some embodiments, the linker has the structure of Formula II:

[0330] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2

[0331] Formula II

[0332] Among them A 1 A is the bond between the connector and B; 2 is the bond between W and the joint; B 1 、B 2 、B 3 and B 4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S and NR N ; R N is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 cycloalkyl, optionally substituted C 2-C4 alkenyl, optionally substituted C 2- C4 alkynyl, optionally substituted 3 to 14 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D 1 is an optionally substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 alkylene, optionally substituted 3- to 14-membered heterocycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C 10 Polyethylene glycol, or optionally substituted C1-C 10 Heteroalkylene or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -Connect to-(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 chemical bonds.

[0333] In some embodiments, the linker is acyclic. In some embodiments, the linker has the structure of Formula IIa:

[0334]

[0335] where X a Does not exist or is N;

[0336] R 14 is absent, hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C3 cycloalkyl; and

[0337] L 2 is absent, -C(O)-, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene,

[0338] where X a 、R 14 or L 2 At least one of exists.

[0339] In some embodiments, the linker is or comprises a cyclic group. In some embodiments, the linker has a structure of Formula IIb:

[0340]

[0341] Where o is 0 or 1;

[0342] X b is C(O) or SO2;

[0343] R 15 is hydrogen or an optionally substituted C1-C6 alkyl group;

[0344] Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and

[0345] L 3 is absent, -C(O)-, -SO2-, optionally substituted C1-C4 alkylene, or optionally substituted C1-C4 heteroalkylene.

[0346] In some embodiments, the linker is absent.

[0347] In some embodiments, W is hydrogen. In some embodiments, W is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine, or optionally substituted phenyl. In some embodiments, W is optionally substituted amino. In some embodiments, W is optionally substituted amide. In some embodiments, W is optionally substituted C1-C4 alkoxy. In some embodiments, W is optionally substituted C1-C4 alkyl. In some embodiments, W is optionally substituted C1-C4 hydroxyalkyl. In some embodiments, W is optionally substituted C1-C4 aminoalkyl. In some embodiments, W is optionally substituted C1-C4 haloalkyl. In some embodiments, W is optionally substituted C1-C4 guanidinoalkyl. In some embodiments, W is optionally substituted 3- to 11-membered heterocycloalkyl optionally substituted by C0-C4 alkyl. In some embodiments, W is optionally substituted 3- to 10-membered cycloalkyl. In some embodiments, W is an optionally substituted 3- to 10-membered heteroaryl. In some embodiments, W is an optionally substituted 6- to 10-membered aryl.

[0348] In some embodiments, the compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or atropisomer thereof.

[0349] Table 1: Certain compounds of the present invention

[0350]

[0351] Note that some compounds are shown with flat or wedge-shaped bonds. In some cases, the relative stereochemistry of stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. The present invention encompasses all stereoisomers of the compounds listed above. In certain embodiments, atropisomers of the compounds listed above are contemplated.

[0352] In some embodiments, the compounds of the present invention have improved oral bioavailability (F%) compared to what is known in the art. Methods for measuring oral bioavailability are known in the art, and one such method is provided below:

[0353] Oral bioavailability can be determined in BALB / c mice. After intravenous (IV) bolus and oral gavage (PO) administration of the test compound, whole blood samples of approximately 30 μL were collected at designated time points into tubes containing K2EDTA. Blood samples were centrifuged at 4600 rpm for approximately 5 minutes at 4°C, and plasma samples were stored at -80°C prior to bioanalysis. Plasma samples were extracted by protein precipitation and analyzed by tandem mass spectrometry (LC MS / MS), for example, on an API 5500 system using electrospray positive ionization.

[0354] All PK parameters were derived from plasma concentration data over time by non-compartmental analysis using WinNonlin. Bioavailability (F%, also known as %F) was estimated using the following formula:

[0355]

[0356] AUC inf,PO The area under the plasma concentration over time from time zero to infinity following PO administration.

[0357] AUC inf,IV The area under the plasma concentration over time from time zero to infinity following IV administration.

[0358] dose IV Total dose for IV administration

[0359] dose PO Total dose for PO administration

[0360] Generally speaking, F% (or %F) values exceeding 30% are preferred, with values exceeding 50% being more preferred.

[0361] In some embodiments, the compounds of the invention are selective for one or more specific Ras mutants relative to other Ras mutants or wild type, as compared to those known in the art. Methods for measuring such selectivity are known in the art, such as Ras-Raf binding assays, protocols for which are provided in the Examples below. Thus, in some embodiments, the compounds of the invention are selective for KRAS relative to other Ras mutants or relative to wild type. G12C In some embodiments, the compounds of the present invention are selective for KRAS relative to other Ras mutants or relative to wild type. G12D In some embodiments, the compounds of the present invention are selective for KRAS relative to other Ras mutants or relative to wild type. G12V In some embodiments, the compounds of the present invention are selective for KRAS relative to other Ras mutants or relative to wild type. G12D In some embodiments, the compounds of the present invention are selective for NRAS relative to other Ras mutants or relative to wild type. Q61K In some embodiments, the compounds of the present invention are selective for KRAS relative to other Ras mutants and wild type. G12D and KRAS G12V Selective. The compounds of the present invention may also exhibit higher selectivity for other RAS mutants disclosed herein or combinations thereof. In some embodiments, the compounds of the present invention exhibit an IC50 value of less than 30 nm in the above-mentioned Ras-Raf binding assay against one or more Ras mutants described herein.

[0362] In some embodiments, the compounds of the present invention are more effective against one or more specific Ras mutants relative to other Ras mutants or wild type compared to what is known in the art. Methods for measuring such potency are known in the art, such as the pERK assay, a protocol for which is provided in the Examples below. Thus, in some embodiments, the compounds of the present invention exhibit greater potency with respect to KRAS than is known in the art. G12D In some embodiments, the compounds of the present invention exhibit greater efficacy with respect to KRAS than is known in the art. G12V In some embodiments, the compounds of the present invention exhibit greater efficacy with respect to KRAS than is known in the art. G12C In some embodiments, the compounds of the present invention exhibit greater efficacy with respect to KRAS than is known in the art. G12D and KRAS G12V Compounds of the invention may also exhibit greater potency with respect to other RAS mutants disclosed herein, or combinations thereof.

[0363] In some embodiments, the compounds of the invention exhibit a greater deleterious effect on cell viability with respect to one or more specific Ras mutants relative to other Ras mutants or wild type than is known in the art. Methods of measuring cell viability are known in the art, such as Cell viability assay, a protocol of which is provided in the Examples below. Thus, in some embodiments, the compounds of the present invention exhibit enhanced activity with respect to KRAS compared to that known in the art. G12D In some embodiments, the compounds of the present invention exhibit greater reduction in cell viability with respect to KRAS than is known in the art. G12V In some embodiments, the compounds of the present invention exhibit greater reduction in cell viability with respect to KRAS than is known in the art. G12C In some embodiments, the compounds of the present invention exhibit greater reduction in cell viability with respect to KRAS than is known in the art. G12D and KRAS G12V Compounds of the invention may also exhibit greater reduction in cell viability with respect to other RAS mutants disclosed herein, or combinations thereof.

[0364] In some embodiments, the compounds of the present invention may exhibit greater metabolic stability, permeability, or solubility, or a combination thereof, than is known in the art. Methods for measuring such properties are known in the art. In some embodiments, the compounds of the present invention may exhibit improvements in any one or a combination of the following properties, as compared to those known in the art: selectivity, potency, cell viability, metabolic stability, permeability, or solubility.

[0365] In some embodiments, the compounds of the invention are or function as prodrugs, such as with respect to administration to a cell or to a subject in need thereof.

[0366] Also provided is a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0367] Further provided is a method of treating cancer in a subject in need thereof, 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 G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L, or a combination thereof. In some embodiments, the cancer comprises a Ras mutation, such as N-Ras G12D, N-RasQ61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P, or a combination thereof. Additional Ras mutations are described herein.

[0368] Further provided is a method of treating a Ras protein-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0369] Further provided is a method for inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Q61K, or K-Ras Q61L. The Ras protein can be, for example, N-Ras G12D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P. Other Ras proteins are described herein. The cell can be a cancer cell, such as a pancreatic cancer cell, a colorectal cancer cell, a lung cancer cell (e.g., a non-small cell lung cancer cell), an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid adenocarcinoma cell, a myelodysplastic syndrome cell, a melanoma cell, or a squamous cell lung cancer cell. Other cancer types are described herein. The cell can be in vivo or in vitro.

[0370] With respect to the compounds of the present invention, one stereoisomer may exhibit better inhibition than another stereoisomer. For example, one atropisomer may exhibit inhibition while another atropisomer may exhibit little or no inhibition.

[0371] In some embodiments, the methods or uses described herein further comprise administering another anticancer therapy. In some embodiments, the other anticancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the other anticancer therapy is a SHP2 inhibitor. Other additional anticancer therapies are described herein.

[0372] Synthesis method

[0373] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0374] The compounds of the present invention can be prepared by methods known to those skilled in the art, such as those disclosed in WO 2021 / 091956 and WO2022 / 060836 in combination with known synthetic organic chemistry techniques, and the respective disclosures of the patents are incorporated herein by reference. For example, the compounds of the present invention can be synthesized using the methods described in the schemes below, together with synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. These methods include, but are not limited to, those described in the schemes below.

[0375] Scheme 1. General Synthesis of Macrocyclic Ester

[0376]

[0377] The general synthesis of macrocyclic esters is outlined in Scheme 1. Appropriately substituted indolylboronic acid esters (1) can be prepared starting from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and an appropriately substituted boronic acid in four steps involving palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation.

[0378] Methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (3) can be prepared by coupling (S)-2-amino-3-(4-bromothiazol-2-yl)propanoic acid (2) with (S)-hexahydropyridazine-3-carboxylic acid methyl ester.

[0379] The final macrocyclic ester can be prepared by coupling methyl-amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (3) with an appropriately substituted indolyl boronate (1) in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps to afford the appropriately protected macrocyclic intermediate (5). Deprotection and coupling with an appropriately substituted carboxylic acid (or other coupling partner) can yield the macrocyclic product. Additional deprotection or functionalization steps may be required to yield the final compound 6.

[0380] Furthermore, with reference to Scheme 1, the thiazole may be replaced by an alternative optionally substituted 5- to 6-membered heteroarylene or an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene (e.g., morpholino), or an optionally substituted 6-membered arylene (e.g., phenyl).

[0381] Scheme 2. Alternative general synthesis of macrocyclic esters

[0382]

[0383] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. Appropriately substituted and protected indolyl boronates (7) can be coupled with (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Subsequent coupling with (S)-hexahydropyridazine-3-methyl carboxylate, followed by hydrolysis and macrolactonization can yield the iodinated intermediate (11). Subsequent palladium-mediated borylation and coupling with an appropriately substituted iodoaryl or iodoheteroaryl intermediate in the presence of a Pd catalyst can produce the appropriately protected macrocyclic intermediate. Alkylation, deprotection, and coupling with an appropriately substituted carboxylic acid (or other coupling partner) produce the macrocyclic product. Additional deprotection or functionalization steps may be required to produce the final compound 6.

[0384] Furthermore, with reference to Scheme 2, the thiazole may be replaced by an alternative optionally substituted 5- to 6-membered heteroarylene or an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene (e.g., morpholino), or an optionally substituted 6-membered arylene (e.g., phenyl).

[0385] The compounds of Table 1 herein were prepared using the methods disclosed herein or using the methods described herein in combination with the knowledge of one skilled in the art.

[0386] Pharmaceutical compositions and methods of use

[0387] Pharmaceutical compositions and methods of administration

[0388] The compounds of the present invention are Ras inhibitors and can be used to treat cancer. Therefore, one embodiment of the present invention provides a pharmaceutical composition containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and a method for preparing such a composition using the compound of the present invention.

[0389] As used herein, the term "pharmaceutical composition" refers to a compound, such as a compound of the present invention or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient.

[0390] In some embodiments, the compound is present in a pharmaceutical composition in a unit dose amount suitable for administration in a treatment regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition can be specifically formulated for administration in solid or liquid form, including those suitable for oral administration, such as a drench (aqueous or non-aqueous solution or suspension), tablet (e.g., those targeted for buccal, sublingual, and systemic absorption), bolus, powder, granules, paste for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as, for example, a sterile solution or suspension or a sustained release formulation; topical application, such as in the form of a cream, ointment, or controlled release patch or a spray applied to the skin, lungs, or oral cavity; intravaginal or rectal administration, such as in the form of a pessary, cream, or foam; sublingual; ophthalmic; transdermal; or nasal, transpulmonary, and to other mucosal surfaces.

[0391] As used herein, "pharmaceutically acceptable excipient" refers to any inactive ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in a subject. Typical excipients include, for example, anti-adhesive agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coating agents, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Excipients include, but are not limited to, butylated optionally substituted hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, cross-linked povidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with a variety of agents and materials that can be used as excipients. See, e.g., Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0392] Unless expressly stated to the contrary, whether or not expressly stated, the compounds described herein can be provided or used in salt form (e.g., pharmaceutically acceptable salt form). As used herein, the term "pharmaceutically acceptable salt" refers to salts of compounds described herein that are suitable for use in contact with the tissues of humans and other animals without excessive toxicity, irritation, allergic reactions, etc., and that conform to a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, 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 describe pharmaceutically acceptable salts. Salts can be prepared in situ during the final separation and purification of the compounds described herein or prepared separately by reacting the free base group with a suitable organic acid.

[0393] The compounds of the present invention may have an ionizable group so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts relating to inorganic or organic acids, or in the case of an acidic form of the compounds of the present invention, the salts may be prepared by inorganic or organic bases. In some embodiments, the compound is prepared into a pharmaceutically acceptable salt or is used in the form of a pharmaceutically acceptable salt, which is prepared into an addition product of a pharmaceutically acceptable acid or base. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid or tartaric acid for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc. for forming alkaline salts. The method for preparing suitable salts is well known in the art.

[0394] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, 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, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0395] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, a "subject" refers to a person at any stage of development. In some embodiments, a "subject" refers to a human patient. In some embodiments, a "subject" refers to a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, or pig). In some embodiments, the subject includes, but is not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, the subject can be a transgenic animal, a genetically engineered animal, or a clone.

[0396] As used herein, the term "dosage form" refers to a physical 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 compound. In some embodiments, such an amount is a unit dose amount (or its entire portion) suitable for administration according to a dosage regimen that has been determined to be relevant to the desired or beneficial results when administered to a relevant group (i.e., using a therapeutic dosage regimen). It is understood by those skilled in the art that the total amount of the therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms. As used herein, the term "dosage regimen" refers to a group of unit doses (usually more than one) that are typically administered separately to a subject in separate time periods. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosage regimen that may involve one or more doses. In some embodiments, the dosage regimen includes multiple doses, each of which is separated by a time period of the same length; in some embodiments, the dosage regimen includes multiple doses and at least two different time periods separating individual doses. In some embodiments, all doses within the dosage regimen have the same unit dose amount. In some embodiments, different doses within the dosage regimen have different amounts. In some embodiments, a dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount that is the same as the first dose amount. In some embodiments, a dosing regimen is associated with a desired or beneficial outcome when administered in a relevant population (i.e., is a therapeutic dosing regimen).

[0397] A "therapeutic regimen" refers to a regimen of dosages whose administration in the relevant population is associated with desired or beneficial therapeutic outcomes.

[0398] The term "treatment" (as well as "treat" or "treating") broadly refers to any administration of a substance (e.g., a compound of the present invention) that partially or completely alleviates, ameliorates, alleviates, suppresses, delays the onset of, reduces the severity of, or reduces the incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject who does not show signs of the relevant disease, disorder, or condition, or to a subject who shows only early signs of the disease, disorder, or condition. Alternatively or additionally, in some embodiments, treatment may be administered to a subject who shows one or more established signs of the relevant disease, disorder, or condition. In some embodiments, treatment may be treatment of a subject who has been diagnosed with the relevant disease, disorder, or condition. In some embodiments, treatment may be treatment of a subject who is known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, or condition.

[0399] The term "therapeutically effective amount" means an amount sufficient to treat the disease, disorder or illness when administered to a population suffering from or susceptible to the disease, disorder or illness according to a therapeutic dosing regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity of one or more symptoms of the disease, disorder or illness or delays its onset. Those of ordinary skill in the art will understand that the term "therapeutically effective amount" does not actually require successful treatment in a particular individual. On the contrary, a therapeutically effective amount can be an amount that provides a specific desired pharmacological response in a large number of subjects when administered to a patient in need of such treatment. In particular, it should be understood that a particular subject may actually be "refractory" to a "therapeutically effective amount". In some embodiments, reference to a therapeutically effective amount may refer to an amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder or illness) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount can be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount can be formulated or administered in multiple doses, for example, as part of a dosing regimen.

[0400] In order to be used as the treatment of a subject, the compound of the present invention or a pharmaceutically acceptable salt thereof can be formulated into a medicine or veterinary composition. Depending on the subject to be treated, the mode of administration and the desired type of treatment (e.g., prevention / prophylaxis or treatment), the compound or its pharmaceutically acceptable salt is formulated in a manner consistent with these parameters. An overview of such technology can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0401] The composition can be prepared according to conventional mixing, granulation or coating methods, respectively, and the pharmaceutical composition of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the compound of the present invention or its pharmaceutically acceptable salt by weight or volume. In some embodiments, the compound described herein or its pharmaceutically acceptable salt can be present in an amount of 1%-95% by weight of the total weight of the composition (such as a pharmaceutical composition).

[0402] Composition can be suitable for intra-articular, oral, parenteral (such as intravenous, intramuscular), per rectum, percutaneous, subcutaneous, through surface, through dermal, sublingual, per nasal, per vaginal, intracapsular, intraurethral, intrathecal, epidural, through ear or through eye administration or by injection, suction or with the dosage form of nose, urogenital, reproduction or oral mucosa direct contact provide.Therefore, pharmaceutical composition can be in such as tablet, capsule, pill, powder, granule, suspension, emulsion, solution, comprise the gel of hydrogel, paste, ointment, emulsifiable paste, plaster, drench medicine, osmotic delivery device, suppository, enema, injection, implant, spray, be suitable for the preparation sent by iontophoresis or the form of aerosol.Composition can be prepared according to conventional medicine practice.

[0403] As used herein, the term "administering" refers to administering 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 performed by any appropriate route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous.

[0404] The formulation can be suitable for systemic administration or prepared in a manner suitable for topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or can be prepared for transdermal, transmucosal, or oral administration. The formulation will typically include a diluent and, in some cases, an adjuvant, a buffer, a preservative, etc. The compound or its pharmaceutically acceptable salt can also be administered in a liposomal composition or in a microemulsion.

[0405] For injection, the preparation can be prepared into a liquid solution or suspension form in a conventional manner, or into a solid form suitable for dissolving or suspending in a liquid before injection, or into an emulsion. Suitable excipients include, for example, water, saline, glucose, glycerol, etc. Such compositions can also contain a certain amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitan monolaurate, etc.

[0406] Various sustained-release systems for drugs have also been designed. See, for example, U.S. Pat. No. 5,624,677.

[0407] Systemic administration can also include relatively non-invasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or pharmaceutically acceptable salts thereof. As understood in the art, suitable forms include syrups, capsules, and tablets.

[0408] Each compound as described herein or its pharmaceutically acceptable salt can be formulated in a variety of ways known in the art. For example, the first and second doses of the combination therapy can be formulated together or separately. Other modes of combination therapy are described herein.

[0409] Individual or individually formulated agents can be packaged together into a medicine box. Non-limiting examples include, but are not limited to, medicine boxes containing, for example, two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The medicine box may include optional components that help administer a unit dose to the subject, such as a vial for reconstitution of the powder form, a syringe for injection, a custom IV delivery system, an inhaler, etc. In addition, the unit dose medicine box may contain instructions for preparing and administering the composition. The medicine box may be manufactured into a unit dose for a single use by a subject, for multiple use by a specific subject (with a constant dose or wherein the efficacy of an individual compound or its pharmaceutically acceptable salt may change with the progress of therapy); or the medicine box may contain multiple doses suitable for administration to multiple subjects ("batch packaging"). The medicine box components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0410] Formulations for oral use include tablets containing one or more active ingredients in admixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch (including potato starch), calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrants (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, cross-linked sodium carboxymethyl cellulose, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavorings, plasticizers, wetting agents, buffers, and the like.

[0411] Two or more compounds can be mixed together in a tablet, capsule or other vehicle, or can be separated. In one example, the first compound is contained inside the tablet, and the second compound is outside, so that most of the second compound is released before the first compound is released.

[0412] Formulations for oral use can also be provided as chewable tablets; or hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules, and pellets can be prepared in a conventional manner using, for example, a mixer, fluidized bed apparatus, or spray drying apparatus using the ingredients mentioned above under tablets and capsules.

[0413] Dissolution or diffusion controlled release can be achieved by coating the tablets, capsules, pellets or granules of the compound, or by incorporating the compound or its pharmaceutically acceptable salt into a suitable matrix. The controlled release coating can include one or more of the coating materials mentioned above or, for example, shellac, beeswax, glucose wax (glycowax), castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethylacrylate, methacrylate hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, tristearin, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0414] Liquid forms in which the compounds of the invention or pharmaceutically acceptable salts thereof and compositions can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0415] Typically, when administered to a person, the oral dose of any one of the compound of the present invention or its pharmaceutically acceptable salt will depend on the properties of the compound, and can be easily determined by those skilled in the art. Dosage can be, for example, from about 0.001 mg to about 2000 mg per day, from about 1 mg to about 1000 mg per day, from about 5 mg to about 500 mg per day, from about 100 mg to about 1500 mg per day, from about 500 mg to about 1500 mg per day, from about 500 mg to about 2000 mg per day, or any range available therein. In some embodiments, the daily dose range of oral administration can be, for example, in the range of from about 0.001 mg to about 2000 mg / kg human body weight, administered in single doses or divided doses. On the other hand, it may be necessary to use a dosage exceeding these limits in some cases.

[0416] In some embodiments, the pharmaceutical composition may also include another compound with antiproliferative activity. Depending on the mode of administration, the compound or its pharmaceutically acceptable salt will be formulated into a suitable composition to allow for easy delivery. Each compound or its pharmaceutically acceptable salt of the combination therapy can be formulated in a variety of ways known in the art. For example, the first and second doses of the combination therapy can be formulated together or separately. Ideally, the first and second doses are formulated together so that the doses are administered simultaneously or nearly simultaneously.

[0417] It will 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 concurrently with, before, or after one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutics or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agents or procedures with the desired therapeutic effect to be achieved. It will also be understood that the therapies used may achieve the desired effect for the same condition, or they may achieve different effects (e.g., control any adverse effects).

[0418] Administration of each drug in the combination therapy as described herein can independently be from once to four times daily for one day to one year, and may even continue for the lifetime of the subject. Chronic, long-term administration may be indicated.

[0419] How to use

[0420] In some embodiments, the present invention discloses a method of treating a disease or condition characterized by aberrant Ras activity due to a Ras mutant. In some embodiments, the disease or condition is cancer.

[0421] Therefore, a method for treating cancer in a subject in need is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendix cancer, melanoma, acute myeloid leukemia, small intestinal cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary site, endometrial cancer, esophagogastric cancer, gastrointestinal neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendix cancer, endometrial cancer, or melanoma. A method for treating a Ras protein-related disorder in a subject in need is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0422] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and 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, and the like. 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, tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcomas. Other cancers include, for example:

[0423] Cardiac cancers, such as sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas;

[0424] Lung cancer, such as bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, and mesothelioma;

[0425] Gastrointestinal cancers, such as: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0426] Genitourinary tract cancers, such as: kidney cancer (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma);

[0427] Liver cancer, such as liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma;

[0428] Biliary tract cancer, such as gallbladder cancer, ampullary cancer, and bile duct cancer;

[0429] Bone cancers, such as osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;

[0430] Cancers of the nervous system, such as: skull cancer (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibromas, neurofibromatosis type 1, meningioma, glioma, sarcoma);

[0431] Gynecological cancers, such as: uterine cancer (endometrial cancer, uterine carcinoma, uterine corpus endometrial cancer), cervical cancer (cervical cancer, preneoplastic cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube cancer (carcinoma);

[0432] Blood cancers, such as: myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders (e.g., myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0433] Skin cancers, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis; and

[0434] Adrenal gland cancer, such as neuroblastoma.

[0435] In some embodiments, the Ras protein is wild-type. WT ). Thus, in some embodiments, the compounds of the present invention are used to treat a patient with a disease comprising Ras WT (e.g., K-Ras WT 、H-Ras WT or N-Ras WTIn some embodiments, the Ras protein is a Ras amplified protein (e.g., K-Ras amp ). Thus, in some embodiments, the compounds of the present invention are used to treat a patient with a disease comprising Ras amp (K-Ras amp 、H-Ras amp or N-Ras amp In some embodiments, the cancer comprises a Ras mutation, such as a Ras mutation described herein. In some embodiments, the mutation is selected from:

[0436] (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;

[0437] (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and

[0438] (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;

[0439] Or a combination of any of the foregoing. In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit more than one Ras mutant. For example, the compound may inhibit both K-Ras G12D and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12C and K-Ras G13C. In some embodiments, the compound can inhibit both K-Ras G12D and K-Ras G12V. In some embodiments, the compound can inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the mutation is selected from the group consisting of G12A, G12C, G12D, G12E, G12F, G12H, G12I, G12K, G12L, G12M, G12N, G12P, G12Q, G12R, G12S, G12T, G12V, G12W, and G12Y of K-Ras, N-Ras, or H-Ras, or a combination thereof. In some embodiments, the mutation is selected from the group consisting of G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y of K-Ras, N-Ras, or H-Ras, or a combination thereof. In some embodiments, the compound inhibits wild-type K-Ras, wild-type H-Ras, or wild-type N-Ras, and optionally further inhibits a mutant Ras protein containing a mutation as described herein. In some embodiments, the cancer is non-small cell lung cancer, and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C. In some embodiments, the cancer is colorectal cancer, and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation comprises an N-Ras mutation, such as N-Ras G12D. In some embodiments, the cancer is non-small cell lung cancer, and the Ras protein is K-Ras. amp .

[0440] In addition, 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 more than one Ras mutant. For example, the compound may inhibit both K-Ras G12C and K-Ras G13C. The compound may inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the present invention inhibit Ras in addition to inhibiting one or more additional Ras mutations. WT (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 in addition to inhibiting one or more additional Ras mutations. amp (e.g., K-, H-, or N-Ras amp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H-, or N-Ras amp and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K-, H-, or N-Ras amp and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0441] Methods for detecting Ras mutations are known in the art. Such means include, but are not limited to, direct sequencing and utilizing highly sensitive diagnostic assays (using CE-IVD marking), such as described in Domagala et al., Pol J Pathol 3: 145-164 (2012), incorporated herein by reference in its entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See also, for example, WO 2020 / 106640.

[0442] 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 already specified, the compound may also inhibit Ras WT (e.g., K-, H-, or N-Ras WT ) or Ras amp (e.g., K-, H-, or N-Ras amp ).

[0443] In some embodiments, the cancer comprises a Ras mutation and STK11 LOF , KEAP1, EPHA5 or NF1 mutations or a combination thereof. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation, STK11 LOF In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and a STK11 LOF 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-Ras G13C Ras mutation and 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 ).

[0444] Also provided is a method for inhibiting Ras protein in a cell, comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof can inhibit more than one type of Ras protein in the cell. Also provided is a method for inhibiting RAF-Ras binding, comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. The cell can be a cancer cell. The cancer cell can be of any cancer type described herein. The cell can be in vivo or in vitro.

[0445] Combination therapy

[0446] The methods of the present invention may include the compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-drug treatments or therapeutic agents). When administered alone, the dosage of one or more additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced from the standard dose. For example, the dosage may be determined empirically from drug combinations and permutations, or the dosage may be inferred by isoradiometric analysis (e.g., Black et al., Neurology 65: S3-S6 (2005)).

[0447] The compounds of the present invention may be administered before, after, or in parallel with one or more of such additional therapies. When combined, the dose of the compound of the present invention and the dose of one or more additional therapies (e.g., non-drug therapies or therapeutic agents) provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The compounds of the present invention and another therapy (such as an anticancer agent) may be administered together, such as in the form of a single pharmaceutical composition, or administered separately, and when administered separately, this may be performed simultaneously or sequentially. The time of such sequential administration may be close or distant.

[0448] In some embodiments, another therapy is the administration of a side effect limiting agent (e.g., an agent intended to reduce the occurrence or lessen the severity of a side effect of treatment. For example, in some embodiments, the compounds of the present invention may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or a pharmaceutically acceptable salt thereof.

[0449] In some embodiments, one or more additional therapies include non-drug treatments (such as surgery or radiotherapy). In some embodiments, one or more additional therapies include therapeutic agents (such as compounds or biological agents as anti-angiogenic agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors or autophagy inhibitors). In some embodiments, one or more additional therapies include non-drug treatments (such as surgery or radiotherapy) and therapeutic agents (such as compounds or biological agents as anti-angiogenic agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors or autophagy inhibitors). In other embodiments, one or more additional therapies include two therapeutic agents. In other embodiments, one or more additional therapies include three therapeutic agents. In some embodiments, one or more additional therapies include four or more therapeutic agents.

[0450] In this Combination Therapies section, all references are incorporated herein by reference to the described agents, or pharmaceutically acceptable salts, solvates, isomers (eg, stereoisomers), prodrugs, or tautomers thereof, whether or not expressly so stated.

[0451] Non-drug therapies

[0452] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (eg, surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0453] In some embodiments, the compounds of the present invention may be used as adjuvant therapy after surgery. In some embodiments, the compounds of the present invention may be used as neoadjuvant therapy before surgery.

[0454] In a subject (e.g., a mammal (e.g., a human)), radiotherapy can be used to inhibit abnormal cell growth or treat hyperproliferative disorders, such as cancer. The technology for administering radiotherapy is known in the art. Radiotherapy can be administered by one of several methods or a combination of methods, including but not limited to external beam radiation therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to a radiotherapy delivered by inserting a spatially confined radioactive material into a tumor or other proliferative tissue disease site in the body or near it. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Radioactive sources suitable for use as cell regulators of the present invention include both solid and liquid. As non-limiting examples, 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 radiation. The radioactive material can also be a fluid made from any solution of one or more radionuclides (e.g., a solution of I-125 or I-131), or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of a solid radionuclide (such as Au-198 or Y-90). In addition, one or more radionuclides can be contained in a gel or radioactive microspheres.

[0455] In some embodiments, the compounds of the present invention can make abnormal cells more sensitive to radiation therapy to kill such cells or inhibit their growth. Therefore, the present invention also relates to a method for sensitizing abnormal cells in a mammal to radiation therapy, the method comprising administering to the mammal an amount of a compound of the present invention that is effective to sensitize the abnormal cells to radiation therapy. The amount of the compound in this method can be determined according to the means for determining the effective amount of such compounds described herein. In some embodiments, the compounds of the present invention can be used as an adjuvant therapy after radiation therapy or as a neoadjuvant therapy before radiation therapy.

[0456] In some embodiments, non-drug treatment is T cell adoptive transfer (ACT) therapy. In some embodiments, T cells are activated T cells. T cells can be modified to express chimeric antigen receptors (CAR). CAR-modified T (CAR-T) cells can be produced by any method known in the art. For example, CAR-T cells can be produced by introducing a suitable expression vector encoding CAR into T cells. Before the amplification and genetic modification of T cells, T cell sources are obtained from the subject. T cells can be obtained from many sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue at the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art can be used. In some embodiments, T cells are autologous T cells. Before or after genetically modifying T cells to express a desired protein (e.g., a CAR), T cells can generally be activated and expanded using methods such as those described in, for example, 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.

[0457] therapeutic agents

[0458] A therapeutic agent can be a compound used to treat cancer or symptoms associated therewith.

[0459] For example, the therapeutic agent may be a steroid. Thus, in some embodiments, the one or more additional therapies include a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazole, chloramphenicol ... cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetate acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medroxyprogesterone, meprednisone, methylprednisolone, mometasone furoatefuroate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0460] Other examples of therapeutic agents that can be used in combination therapy with the compounds of the present invention include compounds described in 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 Application 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.

[0461] The therapeutic agent may be a biological agent (e.g., a cytokine (e.g., interferon or interleukin, such as IL-2)) used to treat cancer or symptoms associated therewith. In some embodiments, the biological agent is an immunoglobulin-based biological agent that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof). Antibody-drug conjugates are also included.

[0462] The therapeutic agent may be a T cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, a humanized antibody or a 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 an inhibitor or antagonist of PD-1 (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-L1 (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-L2 (e.g., an inhibitory antibody or Fc fusion or a small molecule inhibitor) (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, or a combination thereof. 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 Checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9 and KW-6002.

[0463] The therapeutic agent can be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0464] The therapeutic agent can be an agent that treats cancer or symptoms associated therewith (e.g., a cytotoxic agent, a non-peptide small molecule, or other compound useful for treating cancer or symptoms associated therewith, collectively referred to as an "anti-cancer agent"). The anti-cancer agent can be, for example, a chemotherapeutic agent or a targeted therapy agent.

[0465] Anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogen, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, one or more additional therapies include two or more anticancer agents. Two or more anticancer agents can be used in the form of a mixture to be administered in combination or separately. Suitable dosing regimens for combining anticancer agents are known in the art and are described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18: 233a (1999) and Douillard et al., Lancet 355 (9209): 1041-1047 (2000).

[0466] Other non-limiting examples of anticancer agents include (Imatinib Mesylate); (carfilzomib); (bortezomib); Casodex (bicalutamide); (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; polyacetyl groups (especially bratacin); camptothecins (including the synthetic analogues topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycin (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including its synthetic analogues KW-2189 and CB-1065); 1-TM1); eleutherobin; hyoscyamine; stoloniferol A; spongestatin; nitrogen mustards such as chlorambucil, naphthiazolin, cholephosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitroureas such as carmustine ustine), chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins such as calicheamicin γll and calicheamicin ωll (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins such as dynemicin A; bisphosphonates such as clodronate; esperamicin;New carcinostatisin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, actinomycin C, calicheamicin, carabicin, caminomycin, carminomycin, carmomycin, chromomycin, dactinomycin, daunorubicin, detoximum iodine, daunorubicin ... detorubicin), 6-diazo-5-oxo-L-norleucine, adriamicin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptozocin, streptozocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil Uracil (5-FU); folic acid analogs such as dimethylfolate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as cyclocytidine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, propionate), epithioandrostol, mepitiostane, testolactone; antiadreners such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; acetylglucuronolactone; aldophosphamide glycosides; aminolevulinic acid; and eniluracil.amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate acetate; epothilones such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; methambucil; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanamine; tricholomanic acid; triazoline quinone; 2,2',2"-trichlorotriethylamine; trichothecenes such as T-2 toxin, verrucosporin A, baculosporin A, and serpentin; carbamates; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; pipobroman; garcitocin; arabinoside ("cytarabine"); cyclophosphamide; thiotepa; taxanes, such as (Pacitaxel), (Cremophor-free albumin-engineered nanoparticle formulation of paclitaxel) and (docetaxel); chlorambucil; tamoxifen (Nolvadex TM ); raloxifene; aromatase-inhibiting 4(5)-imidazoles; 4-hydroxytamoxifen, trioxifene; keoxifene; LY 117018; onapristone; toremifene Flutamide, nilutamide, bicamide, leuprolide, goserelin; nitrogen mustard; gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); dihydroxyanthraquinone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamicin; capecitabine (e.g., ); and pharmaceutically acceptable salts of any one of the above.

[0467] Other non-limiting examples of anticancer agents include trastuzumab (Herc ), bevacizumab Cetuximab Rituximab ABVD, avicine, abagovomab, acridinium carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, avocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agents (e.g., cell cycle nonspecific antineoplastic agents and other antineoplastic agents described herein), antineoplastic herbal remedies, apaziquone, atiprimod, azathiopurines, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, diosmin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, scutellarin, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferrugol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolecarbazole, irofulven, laniquidar, lalostat larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, StanfordV, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatinium tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0468] 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), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycins, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and takes away cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative / Antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and mechlorethamine phenylbutyrate), 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, dinacilib, dapoxetine ... clib), P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites such as folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, cytoxan ... statin 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 hydroxamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array520), DNA binding agents (e.g., ), PI3K inhibitors (such as PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), PI3Kδ and γ inhibitors (e.g., CAL-130)), copanlisib, alpelisib, and idelalisib; multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogens), and hormone agonists, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprorelin, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38 MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 1631), Aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), AKT inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra), TM ), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR 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.

[0469] In some embodiments, the anticancer agent is selected from dichloromethane, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Sorafenib or any analogues or derivatives thereof.

[0470] In some embodiments, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab and pertuzumab Small molecule tyrosine kinase inhibitors, such as gefitinib Erlotinib Pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; ), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, and JNJ-26483327.

[0471] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005; and AP26113. Other examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0472] In some embodiments, the anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., a SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, or BBP-398, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof) , SOS1 inhibitors (e.g., BI-1701963, BI-3406, SDR5, BAY-293 or RMC-5845, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs or tautomers thereof), Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors or mTOR inhibitors (e.g., mTORC1 inhibitors or mTORC2 inhibitors). In some embodiments, the anticancer agent is JAB-3312.

[0473] In some embodiments, the anticancer agent is an SOS1 inhibitor. In some embodiments, the SOS1 inhibitor is selected from those disclosed in WO2021173524, WO 2021130731, WO 2021127429, WO 2021092115, WO 2021105960, WO2021074227, WO 2020180768, WO 2020180770, WO 2020173935, WO 2020146470, WO2019201848, WO 2019122129, WO 2018172250 and WO 2018115380, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof.

[0474] In some embodiments, the anticancer agent is another Ras inhibitor or Ras vaccine, or another therapeutic modality designed to directly or indirectly reduce the oncogenic activity of Ras. In some embodiments, the anticancer agent is another Ras inhibitor. In some embodiments, the Ras inhibitor targets Ras in its active or GTP-bound state. In some embodiments, the Ras inhibitor targets Ras in its inactive or GDP-bound state. In some embodiments, the Ras inhibitor is an inhibitor such as K-Ras G12C, such as AMG 510 (sotolanib), MRTX1257, MRTX849 (adalanib), JNJ-74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-3312, JAB-21000, JAB-21822, ERAS-3490, BI 1823911, D-1553, D3S-001, HBI-2438, HS-10370, MK-1084, YL-15293, GFH925 (IBI351), RMC-6291 or GDC-6036, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof. In some embodiments, the Ras inhibitor is an inhibitor of K-Ras G12D, such as MRTX1133, MRTX282, JAB-22000, ERAS-4, HRS-4642, BI-2852, ASP3082, TH-Z827, TH-7835 or KD-8, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof. In some embodiments, the Ras inhibitor is a K-Ras G12V inhibitor, such as JAB-23000, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the KRAS (off) inhibitor is a pan-RAS (off) inhibitor. In specific embodiments, the pan-RAS (off) inhibitor is JAB-23400. In some embodiments, the Ras inhibitor is RMC-6236, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the Ras inhibitor is selected from the group consisting of Ras (on) inhibitors disclosed in the following documents, which are incorporated herein by reference in their entirety, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers thereof: WO 2023060253, WO 2022 / 060836, WO 2022 / 235864, WO 2022 / 235 / 870, WO 2021091982, WO 2021091967, WO2021091956 and WO2020132597. Other examples of Ras inhibitors that can be combined with the Ras inhibitors of the present invention are provided in the following patents, which are incorporated herein by reference in their entirety: WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023040989, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO2023030517, WO 2023030495, WO 2023030385, WO 2023025116, WO 2023020523, WO2023020521, WO 2023020519, WO 2023020518, WO 2023020347, WO 2023018812, WO2023018810, WO 2023018809, WO 2023018699, WO 2023014979, WO 2023014006, WO2023004102, WO 2023003417, WO 2023001141, WO 2023001123, WO 2022271658, WO2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO 2022265974, WO2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO 2022237815, WO2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO 2022223037, WO2022221739, WO 2022221528, WO 2022221386, WO 2022216762 (e.g., compound 44 or compound 66a), WO 2022192794, WO 2022192790, WO 2022188729, WO 2022187411, WO 2022184178, WO 2022173870, WO 2022173678, WO 2022135346, WO2022133731, WO 2022133038, WO2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO 2022109487, WO2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, WO2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2020050890, WO2020047192, WO 2020035031, WO 2020028706, WO 2019241157、WO 2019232419、WO2019217691、WO 2019217307、WO 2019215203、WO 2019213526、WO2019213516、WO2019155399、WO 2019150305、WO 2019110751、WO 2019099524、WO 2019051291、WO2018218070、WO 2018217651、WO 2018218071、WO 2018218069、WO 2018206539、WO2018143315、WO 2018140600、WO 2018140599、WO 2018140598、WO 2018140514、WO2018140513、WO 2018140512、WO 2018119183、WO 2018112420, WO 2018068017, WO2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659 and WO2013155223, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug or tautomer thereof.

[0475] In some embodiments, the therapeutic agent that can be combined with the compounds of the present invention is an inhibitor of the MAP kinase (MAPK) pathway (or "MAPK inhibitor"). MAPK inhibitors include, but are not limited to, one or more of the MAPK inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758–1784. For example, the MAPK inhibitor can be selected from one or more of 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, PLoS One. 2014 Nov 25;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). The MAPK inhibitor may be PLX8394, LXH254, GDC-5573, or LY3009120.

[0476] In some embodiments, the anticancer agent is a disruptor or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway. PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758–1784. For example, the PI3K / AKT inhibitor may be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0477] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0478] In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors and immunotherapy. In some embodiments, the therapeutic agent can be a pan-RTK inhibitor, such as afatinib.

[0479] IGF-1R inhibitors include linsitinib or a pharmaceutically acceptable salt thereof.

[0480] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Available EGFR antibody inhibitors include cetuximab (Erb ), panitumumab Zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation 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 No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0481] Small molecule EGFR antagonists 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 of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96 / 33980; U.S. Pat. No. 5,747,498; WO96 / 30347; EP0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP 837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP 682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO 99 / 35132; WO99 / 07701; and WO92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12): 1599-1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0482] MEK inhibitors include but are not limited to pamosenterib, selumetinib, and cometinib. trametinib and bemetinib In some embodiments, the MEK inhibitor targets a MEK mutation selected from the group consisting of a class I MEK1 mutation: D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from the group consisting of ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0483] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thiopheno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO06 / 122806); (S)-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-chromen-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinopyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem); Medchem); PIK75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl(Z)-ylidene]-thiazolidine-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (available 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.

[0484] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1) (Barnett et al., Biochem. J. 2005, 385(Pt. 2):399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2):399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05 / 011700); indole-3-methanol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12):3493S-3498S); perifosine (e.g., interferes 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).

[0485] mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancer; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including temsirolimus. Everolimus ( WO94 / 09010); remdaformolimus (also known as deforolimus or AP23573); rapamycin analogs (rapalogs), such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropionic acid]-rapamycin (also known as CC1779); 40-epi(tetrazolyl)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 16-pentynyloxy-32(S)-dihydrorapamycin; derivatives disclosed in WO05 / 005434 ; derivatives disclosed in U.S. Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a dual steric inhibitor (see, e.g., WO2018204416, WO2019212990, and WO2019212991), such as RMC-5552, which has the following structure:

[0486]

[0487] BRAF inhibitors that can be used in combination with the compounds of the present invention include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF may comprise three types of BRAF mutations. In some embodiments, the three types of 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.

[0488] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the major anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance not only to traditional chemotherapy but also to targeted therapeutics including BCL-2 inhibitors (such as ABT-263).

[0489] In some embodiments, the other therapeutic agent is a SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, autoinhibitory conformation stabilized by a binding network involving residues from the N-SH2 and PTP domains. For example, stimulation by cytokines or growth factors that act through receptor tyrosine kinases (RTKs) exposes the catalytic site, leading to enzymatic activation of SHP2.

[0490] SHP2 participates in signal transduction through the RAS-mitogen-activated protein kinase (MAPK), 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) and human cancers (such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancers). Some of these mutations destabilize the autoinhibitory conformation of SHP2 and promote its autoactivation or enhanced growth factor-driven activation. Therefore, SHP2 represents a highly attractive target for the development of novel therapies for the treatment of various diseases, including cancer. The combination of SHP2 inhibitors (such as RMC-4550 or SHP099) with RAS pathway inhibitors (such as MEK inhibitors) has been shown to inhibit the proliferation of multiple cancer cell lines (such as pancreatic cancer, lung cancer, ovarian cancer, and breast cancer) in vitro. Therefore, combination therapy involving SHP2 inhibitors and RAS pathway inhibitors may be a general strategy for preventing tumor resistance in a wide range of malignancies.

[0491] Comprehensive practical examples of SHP2 suppression in this area: Chen et al. MolPharmacol.2006,70,562; Sarver et al., J.Med.Chem.2017,6 2,1793; 2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO20222084008, WO 2022135568, WO 2021176072, WO 2021171261, WO 2021149817, WO2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO 2021143680, WO2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO 2021088945, WO2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO 2021033153, WO2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO 2020259679, WO2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO 2020177653, WO2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO 2020156242, WO2020108590, WO 2020104635, WO 2020094104, WO 2020094018, WO 2020081848, WO2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO2020065452、WO2020063760、WO 2020061103、WO 2020061101、WO 2020033828、WO 2020033286、WO2020022323、WO 2019233810、WO 2019213318、WO 2019183367、WO 2019183364、WO2019182960、WO 2019167000、WO 2019165073、WO 2019158019、WO 2019152454、WO2019051469、WO 2019051084、WO 2018218133、WO 2018172984、WO 2018160731、WO2018136265、WO 2018136264、WO 2018130928、WO 2018129402、WO 2018081091、WO2018057884、WO 2018013597、WO 2017216706、WO 2017211303、WO 2017210134、WO2017156397、WO 2017100279、WO 2017079723、WO 2017078499、WO 2016203406、WO2016203405、WO 2016203404、WO 2016196591、WO 2016191328、WO 2015107495、WO2015107494、WO 2015107493、WO 2014176488、WO 2014113584、CN 115677661、CN115677660、CN 115611869、CN 115521305、CN 115490697、CN 115466273、CN 115394612、CN115304613、CN 115304612、CN 115300513、CN 115197225、CN 114957162、CN 114920759、CN114716448、CN 114671879、CN 114539223、CN 114524772、CN 114213417、CN 114195799、CN114163457、CN 113896710、CN 113248521、CN 113248449、CN 113135924、CN 113024508、CN112920131、CN 112823796、CN 112409334、CN 112402385、CN112174935, 111848599, CN111704611, CN 111393459, CN 111265529, CN 110143949, CN 108113848, US 11179397, US20210085677, US 10858359, US 10934302, US 10954243, US 10988466, US 11001561, US11033547, US 11034705 or US 11044675, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs or tautomers thereof, each of which is incorporated herein by reference.

[0492] In some embodiments, the SHP2 inhibitor binds in the active site. In some embodiments, the SHP2 inhibitor is a mixed irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, such as a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor that targets a cysteine residue (C333) located 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, which has the structure

[0493] or a pharmaceutically acceptable salt, solvate, isomer (eg, stereoisomer), prodrug, or tautomer thereof.

[0494] In some embodiments, the SHP2 inhibitor is RMC-4550, which has the structure

[0495]

[0496] or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RMC-4630, which has the structure:

[0497]

[0498] or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is JAB-3068, which has the structure

[0499]

[0500] or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is JAB-3312. In some embodiments, the SHP2 inhibitor is the following compound,

[0501]

[0502] or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RLY-1971, which has the structure

[0503]

[0504] Or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is ERAS-601 or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is BBP-398 or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is SH3809. In some embodiments, the SHP2 inhibitor is PF-07284892 or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.

[0505] In some embodiments, the other therapeutic agent is selected from the group consisting of: a MEK inhibitor, a HER2 inhibitor, a SHP2 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an SOS1 inhibitor, and a PD-L1 inhibitor. In some embodiments, the other therapeutic agent is selected from the group consisting of: a MEK inhibitor, a SHP2 inhibitor, and a PD-L1 inhibitor. See, for example, Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575: 217 (2019). In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PD-L1 inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PD-L1 inhibitor and an SHP2 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer and treatment comprises administering a Ras inhibitor of the invention in combination with a second or third therapeutic agent.

[0506] Proteasome inhibitors include but are not limited to carfilzomib Bortezomib and oprozomib.

[0507] 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, anti-PD-L1, anti-CTLA4, anti-LAG1, and anti-OX40 agents).

[0508] Immunomodulatory drugs (IMiDs) are a class of immunomodulatory drugs (drugs that modulate immune responses) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0509] Exemplary anti-PD-1 antibodies and methods of use thereof are described by Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO 06 / 121168 A1) and elsewhere herein.

[0510] 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. Pat. No. 6,111,090, U.S. Pat. No. 8,586,023, WO2010 / 003118, and WO2011 / 090754; or, for example, U.S. Pat. No. 7,025,962, EP 1947183, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, U.S. Pat. No. 7,618,632, EP 1866339 and the anti-GITR antibodies described in WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451 and WO2011 / 051726.

[0511] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof synthesized in vitro. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally can act to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or inhibit cell growth. In some embodiments, one or more additional therapies include anti-angiogenic agents.

[0512] Anti-angiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib and bevacizumab. Examples of available 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, and U.S. Pat. Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those 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 RS13-0830.

[0513] Other exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind to VEGF (e.g., 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 thereto), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto) (such as (panitumumab), erlotinib ), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind to them or their receptors (e.g., Tie2 / Tek)), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind to them). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., specific binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM disintegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), specific binding anti-eph receptors or anti-liver receptors. PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands) and antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US 5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Celgene, USA, US 5712291); 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, EP0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); metastasis inhibitor (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); MAb α5β3 integrin second generation (Applied Molecular Evolution, USA and Medlmmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived antiangiogenic agents (XOMA, USA); PI 88 (Progen, Australia); Cilengitide (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan);AS1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); endostatin (Boston Children's Hospital, USA); ATN161 (Attenuon, USA); 2-methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthorrhizol (Yonsei Pharmaceuticals, USA) University, South Korea); gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California at San Diego, USA); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); orthoguanidine (Dimensional Pharmaceuticals, USA); motopramide C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); atiprimod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); University, USA); AE 941 (Aeterna, Canada); angiogenesis vaccine (EntreMed, USA); urokinase plasminogen activator inhibitor (Dendreon, USA);oglufanide (pINN) (Melmotte, USA); HIF-lα inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South) Korea); GW2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin) Brewery, Japan); intraocular 2-methoxyestradiol drug delivery system; anginex (Maastricht University, Netherlands and University of Minnesota, USA); ABT 510 (Abbott, USA); AAL 993 (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); CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada);BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG13925 (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); heparanase inhibitor (InSight, Israel); KL3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland and Schering AG, Germany); 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).

[0514] Other examples of therapeutic agents that can be used in combination with the compounds of the invention include agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding regions that specifically bind to its receptor c-Met.

[0515] 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 ribonucleoside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNA that inhibits the expression of proteins including but not limited to ATG5 (which is related to autophagy) can also be used. In some embodiments, one or more additional therapies include an autophagy inhibitor.

[0516] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-neoplastic agent.In some embodiments, the one or more additional therapies include an anti-neoplastic agent. Non-limiting examples of anti-neoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, bromuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine octadecyl phosphate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, deoxyfluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta beta), etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab ozogamicinzogamicin), 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, interferon alphacon-1, natural interferon alpha, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, iobenzylguanidine, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, interferon-alpha, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone tone), miltefosine, mirimostim, mismatched double-stranded RNA, mitoguanidine, dibromodulcitol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC 631570Octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit anti-thymocyte polyclonal antibody, peginterferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium etidronate186. RII retinamide, rituximab, romurtide, samarium lexidronam (153Sm), sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin , thyroid-stimulating hormone alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diazocone, EL532 (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 PharmaceuticalDevelopment), HER-2 and Fc MAbs (Medarex), idiotype 105AD7 MAbs (CRC Technology), idiotype CEA MAbs (Trilex), LYM-1-iodine 131 MAbs (Techniclone), polymorphic epithelial mucin-yttrium 90 MAbs (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, fospartate, SRL 172 (SR Pharma), SU5416 (SUGEN), TA 077 (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.

[0517] Additional examples of therapeutic agents that can be used in combination with the compounds of the present invention include ipilimumab Tremelimumab; 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; ipilimumab; MEDI4736 MSB0010718C; AMP 224; adalimumab Ado-trastuzumab emtansine (K ); aflibercept Alemtuzumab basiliximab belimumab Basiliximab Belimumab brentuximab vedotin canakinumab Certolizumab pegol Daclizumab daratumumab denosumab Eculizumab efalizumab gemtuzumab ozogamicin Golimumab Titan-Eretumomab infliximab Motavizumab Natalizumab Obinutuzumab Ofatumumab Omalizumab palivizumab Pertuzumab Pertuzumab Ranibizumab Raxibacumab tocilizumab Tositumomab; Tositumomab-i-131; Tositumomab and Tositumomab-i-131 ustekinumab AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0518] The compounds described herein can be used in combination with agents disclosed herein or other suitable agents according to the illness being treated. Therefore, in some embodiments, one or more compounds of the present disclosure will be co-administered with other therapies as described herein. When used in combination therapy, the compounds described herein can be administered simultaneously or separately with the second agent. This combined administration can include the simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. In other words, the compounds described herein and any one of the agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any one of the therapies described herein can be administered simultaneously, with the two agents being present in separate preparations. In another alternative, the compounds of the present disclosure can be administered, and subsequently any one of the therapies described herein, or vice versa. In some embodiments of the separate administration scheme, the compounds of the present invention and any one of the therapies described herein are administered a few minutes apart, a few hours apart, or a few days apart.

[0519] In some embodiments of any one of the methods described herein, the first therapy (e.g., a compound of the present invention) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent can be administered immediately before or after one or more additional therapies 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, 1-14, 1-21, or 1-30 days.

[0520] The present invention also provides a kit comprising (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the invention), and (b) a package insert with instructions for performing any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the invention), (b) one or more additional therapies (e.g., non-drug therapies or therapeutic agents), and (c) a package insert with instructions for performing any of the methods described herein.

[0521] Since one aspect of the present invention encompasses treating a disease or the symptoms associated therewith 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 can include two separate pharmaceutical compositions: a compound of the present invention, and one or more other therapies. The kit can include a container for accommodating a separate composition, such as a separate bottle or a separate foil packet. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit can include instructions for use of separate components. When separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when a prescribing healthcare professional needs to titrate the individual components of the combination, the kit form is particularly advantageous.

[0522] Example

[0523] The present disclosure is further illustrated by the following examples and synthesis examples, which should not be considered as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are therefore not intended to limit the scope of the present disclosure. It should also be understood that, without departing from the spirit of the present disclosure or the scope of the appended claims, various other embodiments, modifications, and equivalents thereof that can be conceived by those skilled in the art can be turned to.

[0524] Chemical synthesis

[0525] Definitions used in the following examples and elsewhere herein are:

[0526] B2pin2 Bis(pinacolato)diboron

[0527] BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0528] CH2Cl2, DCM (Methylene chloride / Dichloromethane)

[0529] CH3CN, MeCN, acetonitrile

[0530] CuI Copper(I) iodide

[0531] DIPEA, DIEA diisopropylethylamine

[0532] DMF N,N-dimethylformamide

[0533] EA Ethyl acetate

[0534] EDCl N-ethyl-N'-carbodiimide hydrochloride

[0535] EtOAc

[0536] h hour

[0537] H2O water

[0538] HCl

[0539] HOBt Hydroxybenzotriazole

[0540] K3PO4 Potassium Phosphate (Tribasic)

[0541] MeOH methanol

[0542] Na2SO4 sodium sulfate

[0543] NMM N-Methylmorpholine

[0544] NMP N-Methylpyrrolidone

[0545] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0546] PE petroleum ether

[0547] rt room temperature

[0548] TFA trifluoroacetic acid

[0549] instrument

[0550] The mass spectrometry data collection adopts Shimadzu LCMS-2020, Agilent 1260LC-6120 / 6125MSD, Shimadzu LCMS-2010EV or Waters Acquity UPLC (equipped with QDa detector or SQ detector 2) to carry out. The sample is injected into the C-18 reverse phase with its liquid phase. The compound is eluted from the column and fed into the mass analyzer using an acetonitrile gradient. Initial data analysis adopts Agilent ChemStation, Shimadzu LabSolutions or Waters MassLynx to carry out. NMR data are collected using Bruker AVANCE III HD 400MHz, Bruker Ascend 500MHz instruments or Varian 400MHz, and raw data are analyzed using TopSpin or Mestrelab Mnova.

[0551] Example 1. Synthesis of compounds

[0552] The compounds of Table 1 and intermediates in their synthesis can be prepared by those skilled in the art of synthetic organic chemistry, such as by combining known techniques with the experimental procedures detailed in the Examples section of WO 2021 / 091956 and WO 2022 / 060836, each of which is incorporated herein by reference in its entirety. Additional synthetic preparations are provided below.

[0553] Example C: (1S,2S)-N-((7 3 S,9S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3,3-dimethyl-6,8-dioxo-7-yl)- 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 Synthesis of H-5-oxa-1(3,5)-indolo-7(3,1)-pyridazinocyclotridecan-9-yl)-2-methylcyclopropane-1-carboxamide

[0554]

[0555] Step 1. To a stirred solution of (S)-methyl hexahydropyridazine-3-carboxylate (1.47 g, 4.36 mmol) and NMM (43.6 mmol) in 20 mL of DCM was added (S)-2-((tert-butoxycarbonyl)amino)hex-5-enoic acid (1 g, 4.36 mmol) and EDCI (1.67 g, 8.72 mmol) / HOBT (0.87 mmol) in portions at 0 ° C. under air atmosphere. The resulting mixture was stirred at 25 ° C. under air atmosphere for 2 hours. The resulting mixture was washed with HO (3 x 20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC to give (S)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)hex-5-enoyl)hexahydropyridazine-3-carboxylate (782 mg, 50.44%) as a yellow oil. LCMS (ESI): C 17 H 30 m / z of N3O5[M+H] + Calculated value: 356.2; measured value: 356.0.

[0556] Step 2. To a stirred solution / mixture of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)hex-5-enoyl)hexahydropyridazine-3-carboxylate (500 mg) and DCM (10 mL) was added TFA (10 mL) at room temperature. The resulting mixture was concentrated under reduced pressure and used in the next step without further purification.

[0557] Step 3. To a stirred solution of (S)-1-((S)-2-aminohex-5-enoyl)hexahydropyridazine-3-carboxylic acid methyl ester (500 mg, 1.96 mmol) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (196.06 mg, 1.96 mmol) in 10 mL of DCM was added HATU (744.62 mg, 1.96 mmol) and DIPEA (2531.02 mg, 19.56 mmol) at room temperature. The resulting mixture was washed with H2O (3 x 100 mL). The residue was purified by silica gel column chromatography to give (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylic acid methyl ester (500 mg, 75.67%) as a white solid.

[0558] Step 4. To a stirred solution of (3S)-1-[(2S)-2-{[(1S,2S)-2-methylcyclopropyl]formamido}hex-5-enoyl]-1,2-diazinane-3-carboxylic acid methyl ester (500 mg, 1.48 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH (177.43 mg, 7.41 mmol) at room temperature. The mixture was acidified to pH 5 with 1 M HCl (aq). The aqueous layer was extracted with DCM (3 x 100 mL). The organic mixture was concentrated under reduced pressure to give 420 mg of crude product, which was used directly without further purification. LCMS (ESI): C 16 H 26 m / z of N3O4 [M+H] + Calculated value: 324.2; measured value: 324.3.

[0559] Step 5. To a stirred solution of (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylic acid (320 mg, 0.99 mmol) and (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (537.85 mg, 0.99 mmol) in 10 mL of DCM was added DCC (408.32 mg, 1.98 mmol) and DMAP (24.18 mg, 0.20 mmol) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (720 mg, 85.71%) as a white solid. LCMS (ESI): C 44 H 63 m / z[M+H] of BrN7O5 + Calculated value: 848.4; measured value: 848.5.

[0560] Step 6. To the reaction mixture of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (640 mg) was added at room temperature under nitrogen atmosphere. To a stirred solution of 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1161.14 mg, 7.54 mmol) in toluene (9 mL), dioxane (3 mL) and H2O (3 mL) was added K3PO4 (400 mg, 1.88 mmol) and Pd(dppf)Cl2 (122 mg, 0.15 mmol). The reaction was stirred at 70 ° C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(1-ethyl-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-vinyl-1H-indol-3-yl)-2,2-dimethylpropyl (S)-1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (500 mg, 83.31%). LCMS (ESI): C 46 H 66 m / z of N7O5[M+H] + Calculated value: 796.5; measured value: 796.5.

[0561] Step 7. To a stirred solution of (S)-3-(1-ethyl-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-vinyl-1H-indol-3-yl)-2,2-dimethylpropyl 1-((S)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)hex-5-enoyl)hexahydropyridazine-3-carboxylate (800 mg, 1.01 mmol) and titanium tetraisopropoxide (142.81 mg, 0.50 mmol) in 100 mL of DCM was added benzylene-bis(tricyclohexylphosphine)ruthenium dichloride (0.17 g, 0.20 mmol) portionwise at 25° C. under air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (1S,2S)-N-((7 3 S,9S,E)-11-ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3,3-dimethyl-6,8-dioxo-7-yl)- 1,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-5-oxa-1(3,5)-indolo-7(3,1)-pyridazinolcyclotridecan-12-en-9-yl)-2-methylcyclopropane-1-carboxamide (17 mg, 2.17%). LCMS (ESI): C 44 H 62 m / z of N7O5[M+H] + Calculated value: 768.5; measured value: 768.5.

[0562] Step 8. In a pressure tank, (1S,2S)-N-((7 3 S,9S,E)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3,3-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 To a solution of H-5-oxa-1(3,5)-indolo-7(3,1)-pyridazinolcyclotridec-12-en-9-yl)-2-methylcyclopropane-1-carboxamide (260 mg, 0.13 mmol) in 3 mL of MeOH was added Pd(OH)2 / C (20%, 0.26 g). The mixture was hydrogenated under 30 psi of H2 at room temperature for 1 hour, filtered through a fritted funnel and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1S,2S)-N-((7 3 S,9S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-3,3-dimethyl-6,8-dioxo-7-yl)- 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-5-oxa-1(3,5)-indolo-7(3,1)-pyridazinolcyclotridecan-9-yl)-2-methylcyclopropane-1-carboxamide (30 mg, 29.08%). LCMS (ESI): C 44 H 64m / z of N7O5[M+H] + Calculated value: 770.5; measured value: 770.6. 1 H NMR(300MHz,DMSO-d6)δ8.51–8.43(d,1H),8.01–7.93(m,1H),7.43–7.34(m,1H),7.28(s,1H),7.24–7.18(m,1H),7.03–6.95 (m,1H),5.48–5.38(m,1H),5.34–5.23(m,1H),4.40–4.28(m,1H),4.16–3.97(m,2H),3.95–3.81(m,1H),3.71–3.47(m,3H),3 .28–3.21(m,4H),3.00–2.79(m,4H),2.66–2.58(m,1H),2.48–2.43(m,4H),2.28–2.21(m,4H),1.92–1.76(m,3H),1.69–1.41 (m,7H),1.40–1.32(m,5H),1.18–1.06(m,3H),1.04–0.95(m,4H),0.88–0.72(m,4H),(s,4H),0.57(s,3H),0.47–0.36(m,1H).

[0563] Synthesis of (1S,2R)-2-(3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-((RS)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)cyclopropyl methanesulfonate

[0564]

[0565] Step 1. To a stirred solution of 3-(5-bromo-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropan-1-ol (15 g, 33.7 mol) in DCM (150 mL) and DMF (30 mL) was added imidazole (6.88 g, 101.1 mol) and TBDPSCl (13.89 g, 50.5 mol) at 20°C. The resulting solution was stirred at 60°C for 2 hours. The solution was diluted with DCM (300 mL) and H2O (300 mL). The layers were separated, and the organic layer was washed with H2O (100 mL×3), brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give 5-bromo-3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indole (19.8 g, 81% yield) as a colorless oil. LCMS (ESI): C 39 H 47 m / z[M+H] of BrN2O2Si + Calculated value: 683.3; measured value: 683.2.

[0566] Step 2. A solution of vinylboronic acid pinacol ester (10.4 g, 67.5 mmol), 5-bromo-3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indole (42 g, 61.4 mmol), DIPEA (15.87 g, 122.8 mmol), Pd2(dba)3 (5.62 g, 6.1 mmol) and P(t-Bu)3·HBF4 (3.56 g, 12.2 mmol) in anhydrous toluene (320 mL) was stirred at 95°C under N2 atmosphere for 2 hours. The solution was cooled and the precipitate was filtered. The filtrate was evaporated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give 3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-[(1E)-prop-1-en-1-yl]indole (37 g, 84% yield) as a green semi-oil. LCMS (ESI): C 47 H 61 m / z[M+H] of BN2O4Si + Calculated value: 757.5; measured value: 757.5.

[0567] Step 3. flame drying is equipped with a 100mL round-bottom flask with a stirring bar, and ZnEt2(1M solution in hexane, 39.8mL, 39.8mmol) and DCM(160mL) are loaded into the container. At-5°C, CH2I2(21.3g, 79.5mmol) is added dropwise to the reaction mixture by a syringe. The resulting mixture is stirred at-5°C for 1 hour, then 3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]indole (12g, 15.9mmol) is added dropwise to the flask as a solution in DCM(30mL). The reaction mixture is warmed to 20 DEG C and stirred vigorously for 16 hours. The reaction mixture is then quenched with saturated NH4Cl (aqueous solution), extracted with DCM (50x 2mL), and washed with brine (50x 2mL). The organic phase is collected, dried over Na2SO4, filtered and concentrated to give a residue. The residue is purified by silica gel chromatography to give 3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-[(1S, 2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]indole (10g, 77% yield) as a light yellow semisolid. LCMS (ESI): C 48 m / z[M+H] of H63BN2O4Si + Calculated value: 771.5; measured value: 771.4.

[0568] Step 4. To a solution of 3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]indole (12 g, 15.6 mmol) in THF (120 mL) and NaOH (12 mL) was added 30% H2O2 (6 mL) at 0°C. The reaction mixture was stirred at 20°C for 0.5 hours. The reaction mixture was quenched with saturated Na2S2O3 aqueous solution, extracted with EtOAc (20 x 3 mL), and washed with brine (30 mL x2). The organic phase was collected, dried over Na2SO4, and then concentrated to give a residue. The residue was purified by silica gel chromatography to give (1S,2R)-2-(3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl)cyclopropan-1-ol (10 g, 92% yield) as a light green semisolid. LCMS (ESI): C 42 H 52 m / z[M+H] of N2O3Si + Calculated value: 661.4; measured value: 661.3.

[0569] Step 5. To a solution of (1S,2R)-2-(3-{3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl)cyclopropan-1-ol (7.2 g, 10.9 mmol, 1.0 equiv) in DCM (72 mL) was added EtN (2.21 g, 21.8 mmol), DMAP (0.27 g, 2.18 mmol). Methanesulfonyl chloride (1.86 g, 16.4 mmol) was then added dropwise at 0 °C and the reaction mixture was stirred at 20 °C for 1 hour. The mixture was quenched with saturated NaHCO (aq), extracted with DCM (50 x 2 mL), and washed with brine (50 x 2 mL). The organic phase was collected, dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography to give (1S,2R)-2-(3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-((RS)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)cyclopropyl methanesulfonate as a light green semisolid (a mixture of two diastereomers, ratio 1:1.6, 6.8 g, 80% yield). LCMS (ESI): C 43 H54 m / z[M+H] of N2O5SSi + Calculated value: 739.4; measured value: 739.3.

[0570] Example A7: (1SR, 2RS, 3SR)-N-((2 1 RS,2 2 SR,7 3 RS,5RS)-1 2 -(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 Synthesis of H-9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododec-5-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0571]

[0572] Step 1. To a solution of tert-butyl N-[(3S)-2-oxooxetan-3-yl]carbamate (20 g, 0.107 mol) in MeCN (100 mL) was added N, 1-dimethylaniline (13 g, 0.11 mol) at 20 ° C. The resulting solution was stirred at 20 ° C for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (R) -3- (benzyl (methyl) amino) -2- ((tert-butoxycarbonyl) amino) propanoic acid (25 g, 65% yield) as a light yellow solid. LCMS (ESI): C 16 H 25 m / z of N2O4 [M+H] + Calculated value: 309.2; measured value: 309.2.

[0573] Step 2. To a stirred solution of rac-(R)-3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (29 g, 0.09 mol) in MeOH (70 mL) and toluene (210 mL) was added (trimethylsilyl)diazomethane (21 g, 0.19 mol) at 20°C. The resulting solution was stirred at 20°C for 2 hours. Afterwards, it was quenched with HO (20 mL) and concentrated to dryness to give a residue. The residue was diluted with EtOAc (800 mL) and HO (100 mL). The organic layer was washed with HO (100 mL x 3), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give (R)-methyl 3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoate (23 g, 72% yield) as a light yellow oil. LCMS (ESI): C 16 H 25 m / z of N2O4 [M+H] + Calculated value: 323.2; measured value: 323.3.

[0574] Step 3. To a solution of rac-(R)-methyl 3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoate (7.1 g, 0.02 mol) in MeOH (50 mL) was added Pd / C (1 g, 14% wt) at 20°C. The resulting solution was stirred under H atmosphere (1 atm) at 20°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude desired product, methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(methylamino)propanoate (4 g, >90% purity) as a light yellow oil. This crude product was used in the next step without further purification.

[0575] Step 4. To a stirred solution of (3-{4-[5-(3-{3-[(tert-butyldimethylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-5-[(1S,2R)-2-(methylsulfonyloxy)cyclopropyl]indol-2-yl)-6-[(1S)-1-methoxyethyl]pyridin-3-yl]piperazin-1-yl}phenyl)methyl formate (3.28 g, 0.004 mol) and rac-(R)-methyl 3-(benzyl(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoate (4.55 g, 0.02 mol) in MeCN (5 mL) was added CsCO (3.81 g, 0.012 mol) at 20°C. The resulting solution was stirred at 400°C for 1 h. 80℃The mixture was stirred for 3 days under N2 atmosphere. The solution was diluted with EtOAc (600 mL) and H2O (100 mL). The organic layer was washed with H2O (50 mL × 3), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give the desired product 4-(5-(5-((1RS, 2SR)-2-(((RS)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)(methyl)amino)cyclopropyl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-((RS)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (1.8 g, 50% purity) as a light yellow solid. LCMS (ESI): C 54 H 80 m / z[M+H] of N6O8Si + Calculated value: 969.6; measured value: 969.4.

[0576] Step 5. To a stirred solution of benzyl 4-(5-(5-((1RS,2SR)-2-(((RS)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)(methyl)amino)cyclopropyl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-((RS)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (1.7 g, 0.002 mol) in THF (18 mL) and H2O (6 mL) was added LiOH (0.09 g, 0.004 mol) at 20°C and the resulting solution was stirred for 2 h. After adjusting the pH to 7 with 1N HCl at 5°C and concentrating, the residue was dissolved in DCM (200 ml), washed with H2O (20 mL) and brine (50 mL), dried over Na2SO4 and concentrated to give (RS)-3-(((1SR,2RS)-2-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.7 g, 50% purity) as a grey foam, which was used directly in the next step without further purification.

[0577] Step 6. To a stirred solution of (RS)-3-(((1SR,2RS)-2-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.9 g, 1.67 mmol) and (3S)-methyl 1,2-diazinane-3-carboxylate dihydrochloride (363 mg, 1.67 mmol) in DCM (16 mL) at 5°C was added DIPEA (1.08 g, 8.37 mmol) followed by T3P (1.28 g, 2.01 mmol) and stirred for 1 hour. The solution was diluted with DCM (300 mL) and H2O (50 mL).The organic layer was washed with H2O (30 mL x 3), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give the desired product, (S)-methyl 1-((RS)-3-(((1SR,2RS)-2-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate as a light yellow solid (two diastereomers separated, V-0173-03-P1: 590 mg, 30% yield; V-0173-03-P2: 470 mg, 23% yield). LCMS (ESI): C 59 H 88 m / z[M+H] of N8O9Si + Calculated value: 1081.6; Found: 541.4 [M / 2+H] +

[0578] Step 7. To a stirred solution of (S)-methyl 1-((RS)-3-(((1SR,2RS)-2-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (300 mg, 0.28 mmol) in MeOH (3 mL) at 20° C. was added NH F (410 mg, 11.2 mol). The resulting solution was stirred at 60° C. for 48 h. The solution was concentrated under reduced pressure to give a residue that was diluted with EtOAc (40 mL) and HO (20 mL). The organic layer was washed with H2O (20 mL x 3), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give (3S)-1-[(2S)-2-{[tert-butyl(formyl)-[[tert-butyl(formyl)-[[tert-butyl(3-hydroxy-1- ...

[0579] Step 8. To a stirred solution of (S)-methyl 1-((RS)-3-(((1SR,2RS)-2-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)cyclopropyl)(methyl)amino)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (300 mg, 0.31 mmol), HOBT (424.3 mg, 3.1 mmol) and DIPEA (1.62 g, 12.4 mmol) in DCM (30 mL) was added EDCI (1.81 g, 9.3 mmol). The reaction mixture was stirred at 35 °C for 5 h. The mixture was quenched with H2O (60 mL), and the obtained mixture was extracted with DCM (50 mL x 3). The organic phase was collected, dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography to give 4-(5-(2-[4-(4-oxo-2-yl)-1-oxo-3-yl)-4-nitro-1-oxo ... 1 RS,2 2 SR,73 S,5RS)-5-((tert-butoxycarbonyl)amino)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-benzyl 9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanocyclododec-12-yl)-6-((RS)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (50 mg, 16% yield). LCMS (ESI): C 52 H 70 m / z[M+H] of N8O8 + Calculated value: 935.5; measured value: 936.1.

[0580] Step 9. To 4-(5-((2 1 RS,2 2 SR,7 3 S,5RS)-5-((tert-butoxycarbonyl)amino)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 To a stirred solution of benzyl H-9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododecane-12-yl)-6-((RS)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (120 mg, 0.13 mmol) in EtOAc (2 mL) was added Pd / C (50% w / w, 60 mg). The reaction mixture was then stirred at 20 ° C. under H2 atmosphere (1 atm) for 6 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give ((2 1 RS,2 2 SR,7 3 S,5RS)-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-3,11,11-trimethyl-6,8-dioxo-7-yl)- 1 ,7 2 ,73 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 Tert-butyl H-9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropazocyclododec-5-yl)carbamate (90 mg, 70% purity) was used directly in the next step without further purification.

[0581] Step 10. Add ((2 1 RS,2 2 SR,7 3 S,5RS)-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-3,11,11-trimethyl-6,8-dioxo-7-yl)- 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 Tert-butyl H-9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododec-5-yl)carbamate (45 mg, 0.06 mmol), (1-ethoxycyclopropyloxy)trimethylsilane (586 mg, 3.37 mmol) and i To a solution of PrOH (2 mL) was added AcOH (5.1 mg, 0.08 mmol) and sodium cyanoborohydride (14.1 mg, 0.24 mmol). The reaction mixture was stirred at 60 ° C for 3 hours. The mixture was diluted in EtOAc (20 mL), washed with H2O (10 mL x 2) and brine (20 mL). The organic phase was collected, dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography to give (2 1 RS,2 2 SR,7 3 S,5RS)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1tert-Butyl H-9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododec-5-yl)carbamate (20 mg, 38% yield). LCMS (ESI): C 47 H 68 m / z[M+H] of N8O6 + Calculated value: 841.5; measured value: 841.2.

[0582] Step 11. Heat the mixture to ((2 1 RS,2 2 SR,7 3 S,5RS)-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 To a solution of tert-butyl H-9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododec-5-yl)carbamate (20 mg, 0.02 mmol) in DCM (0.5 mL) was added TFA (0.2 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated to dryness to give (2 1 RS,2 2 SR,7 3 S,5RS)-5-amino-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropacyclododecane-6,8-dione (20 mg TFA salt, purity 90%) was used directly in the next step without further purification.

[0583] Step 12. Add (2 1 RS,2 2 SR,7 3S,5RS)-5-amino-12-(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 A solution of H-9-oxa-3-aza-1(5,3)-indole-7(1,3)-pyridazine-2(1,2)-cyclopropanecyclododecane-6,8-dione (6.2 mg, 0.06 mmol) in DMF (0.5 mL) was added dropwise HATU (15.4 mg, 0.05 mmol) and DIPEA (34.9 mg, 0.30 mmol). The reaction mixture was stirred at 0 ° C for 0.5 hours. The mixture was diluted in EtOAc (30 mL), washed with H2O (20 mL x 2) and brine (20 mL). The organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give (1SR, 2RS, 3SR)-N-((2 1 RS,2 2 SR,7 3 RS,5RS)-1 2 -(5-(4-cyclopropylpiperazin-1-yl)-2-((RS)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-3,11,11-trimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-9-oxa-3-aza-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododec-5-yl)-2,3-dimethylcyclopropane-1-carboxamide (5.0 mg, 21% yield). LCMS (ESI): C 48 H 68 m / z of N8O5[M+H] + Calculated value: 837.5; measured value: 837.5. 1HNMR (400MHz, CD3OD) δ8.40(d,J=2.8,1H),7.95(s,1H),7.37–7.30(m,2H),7.09(d,J=8.4Hz,1H),6.67–6.63(m,1H),6.31 –6.24(m,1H),5.66–5.62(m,1H),4.48(d,J=13.2Hz,1H),4.19–4.12(m,2H),4.06–3.88(m,3H),3.77–3.75(m,1H),3.48–3. 40(m,1H),3.28–3.08(m,6H),2.93–2.70(m,8H),2.60–2.53(m,1H),2.35(s,3H),2.19–2.15(m,1H),1.93–1.90(m,1H),1.7 5–1.60(m,3H),1.40(d,J=6.4Hz,3H),1.30–1.19(m,4H),1.16–0.99(m,10H),0.81(s,3H),0.66(s,3H),0.56–0.45(m,4H).

[0584] Example A6: (1r, 2R, 3S)-N-((2 1 R,2 2 R,7 3 S,5S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 Synthesis of H-9-oxa-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropane-5-cyclododecane-2,3-dimethylcyclopropane-1-carboxamide

[0585]

[0586] Step 1. To a solution of 3-(5-bromo-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropyl acetate (10 g, 0.014 mol) and methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}hex-5-enoate (10.2 g, 0.042 mol) in MeCN (100 mL) was added tri-o-tolylphosphine (3.4 g, 0.011 mol), EtN (4.25 g, 0.042 mol) and Pd(OAc) (1.9 g, 0.008 mol) at 20 ° C. The solution was stirred under N at 90 ° C for 16 hours. The mixture was quenched with H O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to give a crude product, which was purified by silica gel chromatography to give (2S,5E)-6-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}-2-{[(tert-butoxy)carbonyl]amino}hex-5-enoic acid methyl ester (10 g, 75% yield) as a light yellow solid. LCMS (ESI): C 49 H 65 m / z[M+H] of N5O9 + Calculated value: 868.5; measured value: 868.5.

[0587] Step 2. To a solution of Et2Zn (92 mL, 92 mmol) in DCM (160 mL) was added TFA (10.5 g, 92 mmol) at 0°C. The solution was stirred at 0°C for 1 hour under N2. To this solution was added CH2I2 (24.6 g, 92 mmol) at 0°C, and the solution was stirred for 1 hour. To this solution was added (2S, 5E)-6-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}-2-{[(tert-butoxy)carbonyl]amino}hex-5-enoic acid methyl ester (8 g, 9.2 mmol) at 0°C. The solution was stirred at 20°C for 14 hours under N2. The mixture is quenched with saturated NaHCO and extracted with DCM (30mL x 3). The combined organic layer is washed with brine (20mL), dried over Na2SO4 and concentrated to give a crude product which is purified by silica gel chromatography to give (2S) -4- [(1R, 2R) -2- {3- [3- (acetyloxy) -2,2- dimethylpropyl] -1- ethyl -2- [5- (4- {3- [(formyloxy) methyl] phenyl} piperazine -1- bases) -2- [(1S) -1- methoxyethyl] pyridin-3-yl] indol-5-yl} cyclopropyl] -2- aminobutyric acid methyl ester (5.4g, 59% yield) as a light yellow solid. LCMS (ESI): C 45 H 59 m / z[M+H] of N5O7 + Calculated value: 782.4; measured value: 782.3.

[0588] Step 3. To a solution of (2S)-methyl 4-[(1R,2R)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}cyclopropyl]-2-aminobutanoate (5.5 g, 7 mmol) and NaHCO (2.9 g, 35 mmol) in THF / HO (1:1, 60 mL) was added (Boc)O (4.58 g, 21 mmol) at 20° C. and stirred for 1 hour. The mixture was quenched with HO (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to give a crude product, which was purified by silica gel chromatography to give (2S)-methyl 4-[(1R,2R)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}cyclopropyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate (5.4 g, 61% yield) as a yellow solid. LCMS (ESI): C 50 H 67 m / z[M+H] of N5O9 + Calculated value: 882.5; measured value: 882.4.

[0589] Step 4. To a solution of methyl (2S)-4-[(1R,2R)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl}cyclopropyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate (5.3 g, 0.006 mol) in THF / HO (5:1, 60 mL) was added LiOH (2.16 g, 0.09 mol) at 20° C. The solution was stirred at 20° C. for 16 h. The mixture was quenched with 1 M HCl and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to give (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoic acid (5.7 g, mixture of two isomers from LCMS, 70% purity) as a yellow solid. LCMS (ESI): C 47 H 63 m / z[M+H] of N5O8 + Calculated value: 826.4; measured value: 826.4.

[0590] Step 5. To a solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoic acid (5.5 g, 6.7 mmol) and (3S)-methyl 1,2-diazinane-3-carboxylate (1.9 g, 13.4 mmol) in DMF (55 mL) was added DIPEA (25.98 g, 0.2 mol) and HATU (3.8 g, 0.01 mol) at 0°C and stirred for 1 hour. The mixture is quenched with H2O (200mL) and extracted with EtOAc (100mL x 3). The combined organic layer is washed with brine (20mL), dried over Na2SO4 and concentrated to give a crude product, which is purified by silica gel chromatography to give (3S) -1- [(2S) -2- { [(tert-butoxy) carbonyl] amino} -4- [(1R, 2R) -2- { 1- ethyl -2- [5- (4- { 3- [(formyloxy) methyl] phenyl} piperazine -1- bases) -2- [(1S) -1- methoxyethyl] pyridin-3-yl] -3- (3- hydroxy -2,2- dimethylpropyl) indol -5- bases} cyclopropyl] butanoyl] -1,2- diazinane -3- carboxylic acid methyl ester (5g, 58% yield) as a yellow solid. LCMS (ESI): C 53 H 73 m / z[M+H] of N7O9 + Calculated value: 952.6; measured value: 952.4.

[0591] Step 6. To a solution of (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoyl]-1,2-diazinane-3-carboxylic acid methyl ester (2.5 g, 2.6 mmol) in THF / H2O (3:1, 24 mL) was added LiOH (0.19 g, 7.8 mmol) at 20°C. The solution was stirred at 20°C for 1 hour. The mixture was adjusted to pH 7 with 1N HCl and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give (3S)-1-[(2S,3R)-2-{[(1R,2R,3S)-2,3-dimethylcyclopropyl]formamido}-3-ethoxy-3-[(3R)-1-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}pyrrolidin-3-yl]propanoyl]-1,2-diazinane-3-carboxylic acid (2.5 g, 70% purity) as a yellow solid. LCMS (ESI): C 52 H 71 m / z [M+H] + calculated for N7O9: 938.5; found: 938.4.

[0592] Step 7. To a solution of (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(1R,2R)-2-{1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}cyclopropyl]butanoyl]-1,2-diazinane-3-carboxylic acid (2.5 g, 2.7 mmol) in DCM (250 mL) was added DIPEA (10.47 g, 81 mmol), HOBt (3.65 g, 27 mmol) and EDCI (15.5 g, 81 mmol) at 20° C. The solution was stirred at 45° C. under N for 16 h. The reaction mixture was purified by preparative HPLC to give 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-((tert-Butyloxycarbonyl)amino)-1-(4-(4-Butyloxy)-1 ... 1-ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-benzyl 9-oxa-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanocyclododec-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (120 mg, 4.8% yield). LCMS (ESI): C 52 H 69 m / z[M+H] of N7O8 + Calculated value: 920.5; measured value: 920.5.

[0593] Step 8. At 20°C, 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-((tert-Butyloxycarbonyl)amino)-1-(4-(4-Butyloxy)-1 ... 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 To a solution of H-9-oxa-1(5,3)-indole-7(1,3)-pyridazine-2(1,2)-cyclopropane and cyclododecane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (80 mg, 0.087 mmol) in DCM (3 mL) was added TFA (1 mL) and stirred for 1 hour. The mixture was quenched with saturated NaHCO and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (20 mL), dried over NaSO and concentrated to give 4-(5-(2- methylpropional)-1- hydroxy-4-oxo-2-nitropropane-3-yl)piperazine-1-carboxylic acid benzyl ester (80 mg, 0.087 mmol) in DCM (3 mL). 1 R,2 2 R,7 3 S,5S)-5-amino-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1H-9-oxa-1(5,3)-indole-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododecane-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (116 mg, purity>90%). LCMS (ESI): C 47 H 61 m / z[M+H] of N7O6 + Calculated value: 820.5; measured value: 820.4.

[0594] Step 9. To 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-amino-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-9-oxa-1(5,3)-indole-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododecane-1 2 To a solution of (1R, 2R, 3S)-2,3-dimethylcyclopropane-1-carboxylic acid (27 mg, 0.23 mmol) in DMF (2 mL) was added DIPEA (151 mg, 1.17 mmol) and HATU (66 mg, 0.17 mmol) and stirred for 1 hour. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by preparative TLC to give 4-(5-(2-nitro-4-oxo-2-nitro-1-yl)piperazine-1-carboxylic acid. 1 R,2 2 R,7 3 S,5S)-5-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1H-9-oxa-1(5,3)-indole-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododecane-1 2 -yl)-benzyl 6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (80 mg, 67% yield). LCMS (ESI): C 53 H 69 m / z of N7O7[M+H] + Calculated value: 916.5; measured value: 916.4.

[0595] Step 10. At 20°C, 4-(5-((2 1 R,2 2 R,7 3 S,5S)-5-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamido)-1 1 -ethyl-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-9-oxa-1(5,3)-indole-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododecane-1 2 To a solution of benzyl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (70 mg, 0.076 mmol) and paraformaldehyde (3.2 mg, 0.107 mmol) in MeOH (1 mL) was added Pd / C (23.2 mg, 50% w / w). The solution was stirred under H2 (1 atm) at 20 ° C for 16 hours. The mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by preparative TLC to give (1r,2R,3S)-N-((2 1 R,2 2 R,7 3 S,5S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7-yl)- 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1H-9-oxa-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododec-5-yl)-2,3-dimethylcyclopropane-1-carboxamide (40.5 mg, 64% yield). LCMS (ESI): C 46 m / z[M+H] of H65N7O5 + Calculated value: 796.5; measured value: 796.4. 1 H NMR (400MHz, MeOD) δ8.44(d,J=2.7Hz,1H),7.50(s,1H),7.38(d,J=2.8Hz,1H),7.31(d,J=8.5Hz,1H),7.16(d,J=8.1Hz,1H),5.71(d,J=7.2Hz,1H), 4.43(s,1H),4.08–3.97(m,3H),3.86–3.69(m,3H),3.36(d,J=4.3Hz,4H), 3.24(d,J=14.2Hz,1H),2.98(s,3H),2.88(s,1H),2.70(t,J=4.7Hz,4H),2 .41(s,3H),2.09(t,J=15.0Hz,2H),1.98(d,J=11.8Hz,1H),1.90(dd,J=11 .4,7.3Hz,3H),1.66(dd,J=23.0,8.7Hz,2H),1.52–1.45(m,1H),1.42(d,J =6.3Hz,3H),1.32(d,J=7.0Hz,2H),1.26(t,J=7.0Hz,5H),1.08(dd,J=9.0 ,4.2Hz,8H),0.92(s,3H),0.68–0.62(m,4H),0.51(dt,J=8.5,4.4Hz,1H).

[0596] Example A5: (1SR, 2RS, 3SR)-N-((2 1 RS,2 2 SR,7 3 RS,5RS)-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1Synthesis of H-3,9-dioxa-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropane-5-cyclododecane)-2,3-dimethylcyclopropane-1-carboxamide

[0597]

[0598] Step 1. To a stirred flask containing ethyl vinyl ether / DCM (375:225 mL) solution was added Pd(OAc)2 (3.07 g, 13.6 mmol) and 1,10-phenanthroline (2.47 g, 13.6 mmol) at 20 ° C. After stirring for 30 minutes under N2 atmosphere, (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-hydroxypropionic acid methyl ester (60 g, 273.7 mmol) was added to the solution and the resulting reaction mixture was stirred at 20 ° C. for 4 days. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography to obtain (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(vinyloxy)propionic acid methyl ester (30 g, 43% yield) as a colorless oil. LCMS (ESI): C 11 H 19 m / z of NO5 [M+H] + Calculated value: 246.1; Found: 268.1 [M+Na] + ;

[0599] Step 2. A solution of 3-(5-bromo-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropyl acetate (5.0 g, 10.26 mmol), methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(vinyloxy)propanoate (6.29 g, 25.65 mmol), Pd(OAc) (1.38 g, 6.2 mmol), tri-o-tolylphosphine (2.5 g, 8.21 mmol) and EtN (3.12 g, 30.78 mmol) in MeCN (50 mL) was stirred at 90° C. under N for 12 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give methyl (2S)-3-{[(E)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}vinyl]oxy}-2-{[(tert-butoxy)carbonyl]amino}propanoate (0.9 g, 14% yield) as a green semi-oil. LCMS (ESI): C 36 H 49 m / z[M+H] of N3O8 +Calculated value: 652.4; measured value: 652.4.

[0600] Step 3. is loaded into the flame-dried 100mL round-bottom flask equipped with stirring bar ZnEt(1M solution in hexane, 11.1mL, 11.1mmol) and DCM (13mL).CHI(5.91g, 22.1mmol) is added dropwise to the reaction mixture by syringe at-10 DEG C, and the reactant is stirred for 1 hour, then (2S)-3-{[(E)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl] pyridin-3-yl} indol-5-yl} vinyl] oxy}-2-{[(tert-butoxy) carbonyl] amino} methyl propionate (900mg, 1.38mmol) is added dropwise to the flask as a solution in DCM (5mL).Reaction mixture is warmed to 20 DEG C and vigorously stirred for 11 hours.Then the reaction mixture is concentrated to obtain residue. The residue was dissolved in EtOAc (50 mL) and washed with H2O (50 mL x 2). The organic phase was collected, dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by preparative HPLC to give (2S)-3-[(1R, 2S)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}cyclopropyloxy]-2-{[(tert-butoxy)carbonyl]amino}methyl propanoate (400 mg, 51% yield) as a yellow semisolid. LCMS (ESI): C 32 H 43 m / z[M+H] of N3O6 + Calculated value: 566.3; measured value: 566.3.

[0601] Step 4. To a solution of methyl (2S)-3-[(1R,2S)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}cyclopropyloxy]-2-aminopropanoate (0.73 g, 1.3 mmol) and (Boc)O (850 mg, 3.9 mmol) in THF (15 mL) and H2O (5 mL) was added NaHCO3 (330 mg, 3.9 mmol). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with H2O (20 mL) and EtOAc (20 mL), and the organic phase was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give methyl (2S)-3-[(1R,2S)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}cyclopropyloxy]-2-{[(tert-butoxy)carbonyl]amino}propanoate (0.9 g) as a green semi-solid. It was used directly in the next step without further purification.

[0602] Step 5. To a solution of methyl (2S)-3-[(1R,2S)-2-{3-[3-(acetyloxy)-2,2-dimethylpropyl]-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl}cyclopropyloxy]-2-{[(tert-butoxy)carbonyl]amino}propanoate (0.9 g, 1.57 mmol) in THF (10 mL) and H2O (2 mL) was added LiOH (0.16 g, 6.75 mmol), and the reaction mixture was stirred at 20°C for 12 hours. The mixture was poured into H2O (20 mL). 1N HCl was added to the mixture until pH 7 and the resulting mixture was extracted with EtOAc (20 mL x 3). The organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure to give (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropyloxy]propanoic acid (0.85 g, 90% yield). LCMS (ESI): C 34 H 47 m / z[M+H] of N3O7 + Calculated value: 610.3; measured value: 610.4.

[0603] Step 6. To a solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropyloxy]propanoic acid (700 mg, 1.15 mmol), (3S)-methyl 1,2-diazine-3-carboxylate (248.3 mg, 1.72 mmol) and DIPEA (445 m, 3.44 mmol) in DCM (7 mL) was added T3P (1.46 g, 2.30 mmol) at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The mixture was quenched with HO (50 mL) and the resulting mixture was extracted with DCM (50 ml x 3). The organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropyloxy]propanoyl]-1,2-diazinane-3-carboxylic acid methyl ester (0.45 g, 48% yield) as a light green solid. LCMS (ESI): C 40 H 57 m / z[M+H] of N5O8 + Calculated value: 736.4; measured value: 736.4.

[0604] Step 7. To a solution of (3S)-1-[(2S)-2-{[(tert-butyloxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropyloxy]propanoyl]-1,2-diazinane-3-carboxylic acid methyl ester (450 mg, 0.61 mmol) in THF (4.5 mL) and H2O (0.9 mL) was added LiOH (73 mg, 3.1 mmol), and the reaction mixture was incubated at 0°C for 2 hours. The mixture was poured into H2O (50 mL). 1N HCl was added to the mixture until pH 7 and the resulting mixture was extracted with EtOAc (50 ml x 3). The organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure to give (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropyloxy]propanoyl]-1,2-diazinane-3-carboxylic acid (440 mg, 90% yield) as a green semi-oil. LCMS (ESI): C 39 H 55 m / z[M+H] of N5O8 + Calculated value: 722.4; measured value: 722.4.

[0605] Step 8. To a stirred solution of (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(1R,2S)-2-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl]cyclopropyloxy]propanoyl]-1,2-diazinane-3-carboxylic acid (450 mg, 0.62 mmol), HOBT (842 mg, 6.2 mmol) and DIPEA (3.22 g, 24.9 mmol) in DCM (45 mL) was added EDCI (3.59 g, 18.6 mmol), and the reaction mixture was stirred at 20° C. for 12 h. The mixture was quenched with HO (60 mL) and the obtained mixture was extracted with DCM (50 mL×3). The organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography to give (2 1 RS,2 2 SR,7 3 RS,5RS)-1 1 -ethyl-1 2-(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 tert-Butyl H-3,9-dioxa-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododec-5-yl)carbamate (180 mg, 37% yield). LCMS (ESI): C 39 H 53 m / z[M+H] of N5O7 + Calculated value: 704.3; measured value: 704.4.

[0606] Step 9. To a solution of methyl (3S)-1-[(2S,3R)-2-{[(1R,2R,3S)-2,3-dimethylcyclopropyl]formamido}-3-ethoxy-3-[3-({1-ethyl-2-[5-(4-{3-[(formyloxy)methyl]phenyl}piperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)indol-5-yl}oxy)cyclobutyl]propanoyl]-1,2-diazinane-3-carboxylate (180 mg, 0.26 mmol) in DCM (10 mL) was added ZnBr (1.15 g, 5.11 mmol), and the reaction mixture was stirred at 20° C. for 12 h. The mixture was diluted with DCM (10 mL) and H O (10 mL). The organic phase was collected, dried over Na2SO4, filtered and concentrated under reduced pressure to give (2 1 RS,2 2 SR,7 3 RS,5RS)-5-amino-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-3,9-dioxa-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanecyclododecane-6,8-dione (170 mg, purity 90%). LCMS (ESI): C 34 H 45m / z of N5O5[M+H] + Calculated value: 604.3; measured value: 604.3.

[0607] Step 10. Add (2 1 RS,2 2 SR,7 3 RS,5RS)-5-amino-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 To a solution of H-3,9-dioxa-1(5,3)-indole-7(1,3)-pyridazine-2(1,2)-cyclopropanecyclododecane-6,8-dione (170 mg, 0.28 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (63 mg, 0.56 mmol) in DMF (1.7 mL) were added HATU (129.3 mg, 0.34 mmol) and DIPEA (361 mg, 2.8 mmol) dropwise. The reaction mixture was stirred at 0 ° C for 0.5 hours. The mixture was diluted in EtOAc (30 mL), washed with water (20 mL x 2) and brine (20 mL). The organic phase was collected, dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography to give (1SR,2RS,3SR)-N-((2 1 RS,2 2 SR,7 3 RS,5RS)-1 1 -ethyl-1 2 -(2-((RS)-1-methoxyethyl)pyridin-3-yl)-11,11-dimethyl-6,8-dioxo-7 1 ,7 2 ,7 3 ,7 4 ,7 5 ,7 6 -Hexahydro-1 1 H-3,9-dioxa-1(5,3)-indolo-7(1,3)-pyridazin-2(1,2)-cyclopropanocyclododec-5-yl)-2,3-dimethylcyclopropane-1-carboxamide (5.8 mg, 2.6% yield). LCMS (ESI): C 40 H 53m / z of N5O6 [M+H] + Calculated value: 700.3; measured value: 700.4. 1 H NMR (400MHz, CD3OD) δ8.72(dd,J=4.8,1.6Hz,1H),7.88–7.86(m,1H),7.71(s,1H),7.52(dd,J=8.0,4.8Hz,1H),7.32(d,J=8.4Hz,1H),6.88(d,J =8.0Hz,1H),5.70(dd,J=7.6,5.6Hz,1H),4.47(d,J=12.4Hz,1H),4.47(q,J=6.0Hz,1H),4.14–4.02(m,2H),3.95–3.89(m,1H),3.84–3.80(m,2H ),3.72–3.67(m,1H),3.59–3.56(m,1H),3.36–3.33(m,1H),3.14(s,3H) ,2.99–2.96(m,1H),2.86–2.80(m,1H),2.51–2.48(m,1H),2.28–2.21(m ,2H),1.98–1.93(m,1H),1.81–1.64(m,2H),1.45(d,J=6.0Hz,3H),1.32 –1.29(m,2H),1.23–1.18(m,2H),1.13–1.04(m,10H),0.72–0.71(m,6H).

[0608] In vitro and in vivo experiments:

[0609] The following assays can be performed to evaluate various properties of the compounds of the invention: Compounds A1-A6 herein exhibit (i) a pERK (Capan-1, K-Ras G12V) IC50 of less than 8 μM; (ii) a MOA (G13C) IC50 of less than 30 μM; or (iii) both (i) and (ii).

[0610] Potency assay: pERK

[0611] The purpose of this assay is to measure the ability of a test compound to inhibit K-Ras in cells. Activated K-Ras induces an increase in ERK phosphorylation at threonine 202 and tyrosine 204 (pERK). This procedure measures the decrease in cellular pERK in response to a test compound. The procedure described below in NCI-H358 cells is applicable to K-Ras G12C.

[0612] NOTE: This protocol can be performed with alternative cell lines to characterize inhibitors of other RAS variants, including, for example, AsPC-1 (K-Ras G12D), Capan-1 (K-Ras G12V), NCI-H1355 (K-Ras G13C), Hs 766T (K-Ras Q61H), NCI-H2347, or KU-19-19 (N-Ras Q61R), or SK-MEL-30 (N-Ras Q61K).

[0613] NCI-H358 cells were grown and maintained using ATCC recommended media and procedures. The day before compound addition, cells were plated in 384-well cell culture plates (40 μl / well) and grown overnight in a 37°C, 5% CO2 incubator. Test compounds were prepared in 10,3-fold dilutions in DMSO with a high concentration of 10 mM. On the day of the assay, the cells were quantified using an Echo 550 liquid handler. 40 nl of test compound was added to each well of the cell culture plate. Test compound concentrations were tested in duplicate. Following compound addition, the plate was shaken at 300 rpm for 15 seconds, centrifuged, and the cells were incubated at 37°C, 5% CO₂ for 4 hours. Following incubation, the culture medium was removed and the cells were washed once with phosphate-buffered saline.

[0614] In some experiments, cellular pERK levels were determined using the AlphaLISA SureFire Ultra p-ERK1 / 2 assay kit (PerkinElmer). Cells were lysed in 25 μl of lysis buffer and shaken at 600 RPM at room temperature. The lysate (10 μl) was transferred to a 384-well Opti-plate (PerkinElmer) and 5 μl of the receptor mixture was added. After incubation for 2 hours in the dark, 5 μl of the donor mixture was added, the plate was sealed and incubated for 2 hours at room temperature. The signal was read on an Envision plate reader (PerkinElmer) using a standard AlphaLISA setup. a) Raw data analysis was performed in Excel (Microsoft) and Prism (GraphPad). The signal was plotted against the logarithm of the compound concentration and the IC was determined by fitting a 4-parameter sigmoidal concentration response model or b) using Genedata Screener (Genedata). 50 Normalized signals were plotted against the logarithm of the compound concentration and IC50s were determined by fitting a 4-parameter sigmoidal concentration-response model.

[0615] In other experiments, cell pERK was determined by intracellular Western blotting (In-Cell Western). After compound treatment, cells were washed twice with 200 μl tris-buffered saline (TBS) and fixed with 150 μl of 4% paraformaldehyde in TBS for 15 minutes. Fixed cells were washed 4 times for 5 minutes with TBS (TBST) containing 0.1% Triton X-100, and then blocked with 100 μl Odyssey blocking buffer (LI-COR) for 60 minutes at room temperature. The first antibody (pERK, CST-4370, Cell Signaling Technology) was diluted 1: 200 in blocking buffer, and 50 μl was added to each well and incubated overnight at 4°C. Cells were washed 4 times with TBST for 5 minutes. Secondary antibody (IR-800CW rabbit, LI-COR, 1:800 dilution) and DNA stain DRAQ5 (LI-COR, 1:2000 dilution) were added and incubated at room temperature for 1-2 hours. The cells were washed 4 times with TBST for 5 minutes. The plates were scanned on a Li-COR Odyssey CLx imager. Raw data were analyzed in Excel (Microsoft) and Prism (GraphPad). The signal was plotted against the logarithm of the compound concentration and the IC was determined by fitting a 4-parameter sigmoidal concentration response model. 50 .

[0616] The compounds of the present invention have an inhibitory effect on the Ras binding domain of B-Raf (BRAF RBD ) disruption of the interaction with K-Ras (also known as MOA assay)

[0617] NOTE – The following protocol describes the methods used to monitor the effects of compounds of the invention on K-Ras G12C (GMP-PNP) and BRAF RBD This protocol can also be performed using other Ras proteins or nucleotide substitutions.

[0618] The purpose of this biochemical assay is to measure the ability of a test compound to induce the formation of a ternary complex between nucleotide-loaded K-Ras isoforms and cyclophilin A; the resulting ternary complex disrupts the binding of BRAF to RBD The binding of the construct to the K-Ras agonist inhibits K-Ras signaling through RAF effectors. Data are reported as IC50 values.

[0619] Untagged cyclophilin A, His6-K-Ras-GMPPNP and GST-BRAF were mixed in an assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween 20, 0.1% BSA, 100 mM NaCl and 5 mM MgCl2.RBD The compounds were combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. Compounds were present in the wells of the culture plate in a 10-point, 3-fold dilution series starting at a final concentration of 30 μM. After incubation at 25°C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reactions were incubated for an additional 1.5 hours. TR-FRET signals were read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote disruption of the K-Ras:RAF complex were identified as those that triggered a decrease in the TR-FRET ratio relative to the DMSO control wells.

[0620] Determination of cell viability in RAS mutant cancer cell lines

[0621] plan: Cell viability assay

[0622] NOTE - The following protocol describes a procedure for monitoring cell viability of KRAS mutant cancer cell lines in response to compounds of the present invention. Other RAS isoforms can be employed, but the number of cells to be plated will vary depending on the cell line used.

[0623] The purpose of the word cell assay is to The effect of test compounds on the proliferation of three human cancer cell lines (NCI-H358 (KRAS G12C), AsPC-1 (KRAS G12D), Capan-1 (KRAS G12V)) over a 5-day treatment period was determined by quantifying the amount of ATP present at the endpoint using the TRIzOL® 2.0 reagent (Promega).

[0624] Cells were seeded at 250 cells / well in 40 μl of growth medium in a 384-well assay plate and incubated overnight at 37°C in a humidified atmosphere of 5% CO2. On the day of the assay, test compounds were prepared in 9,3-fold dilutions in DMSO, with a high concentration of 1 or 10 mM where appropriate. An Echo 550 liquid handler was used. Test compound (40 nl) was dispensed directly into each well of the cell culture plate. The plate was shaken at 300 rpm for 15 seconds, centrifuged, and incubated at 37°C in a humidified atmosphere of 5% CO2 for 5 days. On day 5, the assay plate and its contents were equilibrated to room temperature for approximately 30 minutes. 2.0 reagent (25 μl) and the plate contents were mixed on an orbital shaker for 2 minutes and then incubated at room temperature for 10 minutes. Luminescence was measured using a PerkinElmer Enspire. Data were normalized by: (sample signal / average DMSO)*100. A four-parameter logistic fit was used to fit the data.

[0625] Although the invention has been described with reference to specific embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any variations, uses, or modifications of the invention which generally follow from the principles of the invention and which come within known or customary practice in the art to which the invention pertains and which departures from the basic characteristics set forth herein are applicable.

[0626] All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. A compound having a structure of Formula Ia or a pharmaceutically acceptable salt thereof: where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene; G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-, where C is bound to -C(R 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bound to -C(R 7 R 8 )-, optionally substituted C1-C4 heteroalkylene or 3 to 8 membered heteroarylene; swIp (switch I / P-loop) is an organic moiety that non-covalently binds to residues 12 or 13 of the switch I binding pocket and the P-loop of Ras protein; X 1 is an optionally substituted C1-C2 alkylene, NR, O or S(O) n ; X 2 is O or NH; X 3 N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH or N; Y 2 、Y 3 、Y 4 and Y 7 are independently C or N; Y 5 is CH, CH2 or N; Y 6 is C(O), CH, CH2 or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R 1 and R 2 are combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 Combined with the carbon atoms to which they are attached, they form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- 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’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, halogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl; R 10a is hydrogen or halogen; R 16 is hydrogen or C1-C3 alkyl; and in i. The compound is not or ii. When W is cyclopropyl, then the compound does not have formula X, wherein formula X is: where R 1X is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2X is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; and Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2 or -NHS(O)2NH-.

2. A compound having a structure of Formula Ib or a pharmaceutically acceptable salt thereof: where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene; B does not exist, is -NH-, -N(CH3)-, -O-, -CH(R 9 )-or>C=CR 9 R 9’ , where the carbon is bound to -N(R 11 )C(O)-, an optionally substituted 3- to 6-membered cycloalkylene group, an optionally substituted 3- to 6-membered heterocycloalkylene group, an optionally substituted 6-membered arylene group, or a 5- to 6-membered heteroarylene group; G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-, where C is bound to -C(R 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bound to -C(R 7 R 8 )-, optionally substituted C1-C4 heteroalkylene or 3 to 8 membered heteroarylene; L does not exist or is a linker; W is hydrogen, cyano, optionally substituted amino, optionally substituted amido, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 3- to 10-membered heteroaryl; Z is -C(O)- or -S(O)2-; X 1 is an optionally substituted C1-C2 alkylene, NR, O or S(O) n ; X 2 is O or NH; X 3 N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH or N; Y 2 、Y 3 、Y 4 and Y 7 are independently C or N; Y 5 is CH, CH2 or N; Y 6 is C(O), CH, CH2 or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R 1 and R 2 are combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 R is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 Combined with the carbon atoms to which they are attached, they form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- 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’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or an optionally substituted C1-C6 alkyl group; R 10 is hydrogen, halogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl; R 10a is hydrogen or halogen; R 11 is hydrogen or C1-C3 alkyl; R 16 is hydrogen or C1-C3 alkyl; and in: i. The compound is not or ii. When W is cyclopropyl, then the compound does not have formula X, wherein formula X is: where R 1X is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2X is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; and Y is -NHC(O)-, -NHC(O)NH-, -NHC(O)NCH3-, -NHC(O)O-, -NHS(O)-, -NHS(O)NH-, -NHS(O)2 or -NHS(O)2NH-.

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

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ic: where Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R 10 is hydrogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Id: Where B does not exist, is -CH(R 9 )-, wherein the carbon is bound to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R 10 is hydrogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ie: Where B does not exist, is -CH(R 9 )-, wherein the carbon is bound to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R 3 Does not exist, or R 2 and R 3 are combined with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R 10 is hydrogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula If: B does not exist, is -CH(R 9 )-, wherein the carbon is bound to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is a C1-C6 alkyl group or a 3- to 6-membered cycloalkyl group; R 7 is a C1-C3 alkyl group; R 8 is a C1-C3 alkyl group; and R 9 is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group.

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

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

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ig: B does not exist, is -CH(R 9 )-, wherein the carbon is bound to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 2 is a C1-C6 alkyl group or a 3- to 6-membered cycloalkyl group; R 7 is a C1-C3 alkyl group; R 8 is a C1-C3 alkyl group; R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; X e N, CH or CR 17 ; X f N or CH; R 12 is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; and R 17 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl.

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