RAS inhibitors

Abstract

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

Description

[0001] This application is a divisional application of the invention patent application with application date of January 9, 2023, application number 202380026429.5, and invention name “RAS inhibitor”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. application No. 63 / 298,098, filed on January 10, 2022, all of which are hereby incorporated by reference in their entirety. Background Art

[0004] The vast majority of small molecule drugs work by binding to functionally important pockets on target proteins, 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 engaging its substrate. The fact that many such drug / target interaction pairs are known may mislead some people into believing that small molecule regulators for most (if not all) proteins can be found, which provides a reasonable amount of time, effort and resources. But this is far from the case. Currently, it is estimated that only about 10% of all human proteins 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 difficult to treat or difficult to handle for the above-mentioned small molecule drug discovery. Such targets are often referred to as "undruggable". These undruggable targets include a huge and largely untapped reservoir of medically important human proteins. Therefore, there is great interest in discovering new molecular modalities that can regulate the functions of such undruggable targets.

[0005] It is well established in the literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play a crucial role in a variety of human cancers and are therefore suitable targets for anticancer therapy. In fact, in the United States, approximately 30% of all human cancers are caused by mutations in Ras proteins, many of which are lethal. Ras protein dysregulation caused by activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancers. For example, activating mutations at codon 12 in Ras proteins act by inhibiting GTPase activating protein (GAP) dependency and intrinsic GTP hydrolysis rate, significantly biasing the Ras mutant protein population toward the "on" (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP and can be activated even in the presence of low concentrations of this nucleotide. Mutations at codon 13 (eg, G13C) and codon 61 (eg, Q61K) in Ras also cause oncogenic activity in some cancers.

[0006] Despite extensive drug discovery efforts targeting Ras over the past few decades, only two agents targeting the K-Ras G12C mutant (sotorasib and adagrasib) have been approved in the U.S. Additional efforts are needed to discover additional drugs for cancers driven by various Ras mutations. Summary of the Invention

[0007] Ras inhibitors are provided herein. 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 protein (presenting protein) (e.g., cyclophilin A) that is widely expressed in cells. More specifically, in some embodiments, the Ras inhibitors described herein induce new binding pockets in Ras by driving the formation of a high-affinity ternary complex or conjugate between the Ras protein and the widely expressed cytoplasmic chaperone protein cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way in which the compounds of the present invention and the complexes or conjugates formed therefrom exert an inhibitory effect on Ras is to spatially block the interaction sites between Ras and downstream effector molecules such as RAF and PI3K required to propagate oncogenic signals.

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

[0009]

[0010] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0011] L 1 Not present or a joint;

[0012] W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynyl ketone or alkynyl sulfone;

[0013] R 1 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;

[0014] R 2 is optionally substituted C1-C6 alkyl; and

[0015] R 3 is an optionally substituted C1-C6 alkyl group or an optionally substituted C1-C3 heteroalkyl group.

[0016] Also provided are pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Also provided are pharmaceutical compositions comprising a compound of Table 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] Specifically contain, any limitation discussed about one embodiment of the present invention is applicable to any other embodiment of the present invention.In addition, any compound of the present invention or composition all can be used in any method of the present invention, and any method of the present invention all can be used for producing or utilizing any compound of the present invention or composition.

[0021] Definitions and Chemical Terms

[0022] In this application, unless the context clearly indicates otherwise, (i) the terms "a" and "an" mean "one or more"; (ii) the term "or" is used to mean "and / or" unless it is clearly indicated that the term means that the alternatives are unique or that the alternatives are mutually exclusive, however, the definition supported by this disclosure refers to the unique alternative and "and / or"; (iii) the terms "comprising" and "including" are understood to cover the listed components or steps, whether presented alone or in combination with one or more additional components or steps; and (iv) when a range is provided, the endpoints are included.

[0023] 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 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or lower percentages in either direction (greater than or less than) of the value, unless otherwise specified or otherwise apparent from the context (e.g., when the numeral will exceed 100% of the possible value).

[0024] As used herein, in the context of describing adjacent atoms, the term "adjacent" refers to divalent atoms that are directly connected via a covalent bond.

[0025] As used herein, "compounds of the present invention" and similar terms, whether explicitly indicated or not, refer to the Ras inhibitors described herein, including compounds of Formula I and its subformulas, such as the compounds of Table 1, as well as their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers.

[0026] The term "wild-type" refers to an entity having a structure or activity as found in nature in a "normal" (as opposed to mutated, diseased, altered, etc.) state or situation. Those skilled in the art will appreciate that wild-type genes and polypeptides typically exist in a variety of different forms (e.g., alleles).

[0027] It will be appreciated by those skilled in the art that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., wherein one or more atoms are substituted with different isotopes of said atoms, e.g., hydrogen is substituted with deuterium). Unless otherwise indicated or clear from the context, depicted structures are understood to represent any such isomeric or isotopic forms, either individually or in combination.

[0028] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are encompassed. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis methods. 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 have been described and can be separated in the form of isomer mixtures or in separated isomeric forms.

[0029] In some embodiments, one or more compounds described 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 one single bond with an adjacent double bond and 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 proton-transfer tautomeric forms include 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 of 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 derived from interconversion of acetals.

[0030] Unless otherwise stated, structures depicted 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 invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 33 P.35 S. 18 F. 36 Cl, 123 I and 125 I. Isotope-labeled compounds (e.g. 3 H and 14 C) can be used in compound or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are useful because of their ease of preparation and detectability. In addition, heavier isotopes, such as deuterium (i.e., 2 H) substitutions may provide certain therapeutic benefits due to enhanced 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 is replaced, or one or more carbon atoms are replaced 13 C or 14 C-enriched carbon substitutes. 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.

[0031] Non-limiting examples of moieties that may contain one or more deuterium substitutions in the compounds of the present invention, wherein any position "R" may be deuterium (D), include

[0032] Additional examples include, for example, the following:

[0033]

[0034] and similar R 1 Deuterated part of the type, where R 1 The definition of is found herein (e.g., in compounds of Formula I, Ia, II-5, II-5a, II-6, II-6a, II-6b, and II-6c). Deuteration of moieties within the substituent W in the compounds of the invention is also contemplated, wherein W is defined herein (see, e.g., Formulas I and II and subformulae thereof, and specific examples of W described herein, e.g., ). In addition, deuteration of available positions in any of the A moieties of the compounds of the formulae described herein is also contemplated, e.g.

[0035] In addition, deuterated substitutions can also occur at the linker positions of the compounds of the present invention, for example

[0036]

[0037] In another embodiment, silylation substitutions are also contemplated, for example in the following linker:

[0038]

[0039] As is known in the art, many chemical entities can assume a variety of different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including any solid form. In some embodiments, the compounds described or depicted herein can be provided in hydrate form or in solvate form.

[0040] Throughout this specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. Specifically, it is intended that the present disclosure include every individual subcombination of the 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. In addition, when a compound includes multiple positions, and substituents are disclosed in groups or in ranges at said positions, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., species and subclasses) containing every individual subcombination of members at each position.

[0041] The term "optionally substituted X" (e.g., "optionally substituted alkyl") is intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). It is not intended that the feature "X" (e.g., alkyl) itself is optional. As described herein, certain subject compounds may contain one or more "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," 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 portion, the heteroaryl portion, or both may be optionally substituted. Combinations of substituents contemplated by the present disclosure are preferably those that result in stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that allow its production, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0042] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group may independently be deuterium; halogen; -(CH2); 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R°; -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°; -(CH2) 0-4 Ph, which may be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which may be substituted by R°; -CH=CHPh, which may be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by R°; 4-8 membered saturated or unsaturated heterocycloalkyl (e.g. pyridyl); 3-8 membered saturated or unsaturated cycloalkyl (e.g. cyclopropyl, cyclobutyl or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 -C(O)-N(R°)2;-(CH2) 0-4 -C(O)-N(R°)-S(O)2-R°; -C(NCN)NR°2; -(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°; -(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR°2; -P( O)2R°; -P(O)R°2; -P(O)(OR°)2; -OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°; -SiR°3; -(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene) C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1Ph, -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 independently occurring R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0043] Suitable monovalent substituents on R° (or the ring formed by two independent R° together with their intervening atoms) may independently be halogen, -(CH2) 0-2 R ● 、-(halogen R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● 、-(CH2) 0-2 CH(OR ● )2、-O(halogen 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) 0-2 NR ● 2. -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、-(C 1-4 linear or branched alkylene)C(O)OR ● or -SSR ● , where each R ● unsubstituted or, in the case of "halo" being preceded by "halo", substituted only by one or more halogens, and independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0044] 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 R * is selected at each independent occurrence from hydrogen; C 1-6 an aliphatic group which may be substituted as defined below; or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 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- 3O-, where R * is selected at each independent occurrence from hydrogen; C 1-6 an aliphatic group which may be substituted as defined below; or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0045] R * Suitable substituents on the aliphatic group include halogen, -R ● 、-(halogen R ● ), -OH, -OR ● 、-O(halogen R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● unsubstituted or, when preceded by "halo," substituted only by one or more halogens, and independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0046] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen; C 1-6 an aliphatic group which may be substituted as defined below; unsubstituted -OPh; or an unsubstituted 3-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independently occurring Together with its intervening atoms, it forms a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0047] Suitable substituents on the aliphatic group are independently halogen, -R ● 、-(halogen R ● ), -OH, -OR ● 、-O(halogen R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● unsubstituted or, when preceded by "halo," substituted only by one or more halogens, and independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0048] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0049] As used herein, the term "alkoxy" refers to -O-C1-C 20 Alkyl groups, wherein the alkoxy group is attached to the remainder of the compound through an oxygen atom.

[0050] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon radical containing 1 to 20 (e.g., 1 to 10 or 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-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0051] The term "alkylene" as used herein means a saturated divalent hydrocarbon group obtained from a straight-chain or branched saturated hydrocarbon by removing two hydrogen atoms, and examples thereof are methylene, ethylene, isopropylene, and the like. The term "C x -C y"Alkylene" means an alkylene group having between x and y carbons. Exemplary x values ​​are 1, 2, 3, 4, 5, and 6, and exemplary y values ​​are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., 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.

[0052] Unless otherwise specified, the term "alkenyl" as used herein refers to a monovalent straight or branched chain group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and examples thereof are ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl includes cis and trans isomers. Unless otherwise specified, the term "alkenylene" as used herein refers to a divalent straight or branched chain group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0053] The term "alkynyl" as used herein refers to a monovalent straight or branched chain group having 2 to 20 carbons (eg, 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and examples thereof are ethynyl and 1-propynyl.

[0054] As used herein, the term "alkynyl sulfone" refers to a wherein R is any chemically feasible substituent described herein.

[0055] The term "amino" as used herein means For example -NH2 and -N(CH3)2.

[0056] The term "aminoalkyl" as used herein denotes an alkyl moiety in which one or more carbon atoms are substituted with one or more amino moieties.

[0057] As used 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 the side chain, amino group, or acid group (e.g., side chain). As used herein, the term "amino acid" refers in the broadest sense to any compound or substance that can be incorporated into a polypeptide chain, for example, via the formation of one or more peptide bonds. In some embodiments, an amino acid has a 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.

[0058] As used herein, term "aryl" refers to a monovalent monocyclic, bicyclic or polycyclic system formed by carbon atoms, wherein the ring connected to the side-joining group is an aromatic ring. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl and anthracenyl. The aromatic ring can be connected to its side-joining group at any heteroatom or carbocyclic atom producing a stable structure and unless otherwise specified, any ring atoms may be optionally substituted.

[0059] As used herein, the term "CO" refers to a bond. For example, a portion of the term -N(C(O)-(CO-C5 alkylene-H)- includes -N(C(O)-(CO alkylene-H)-, which is also represented as -N(C(O)-H)-.

[0060] As used herein, the terms "carbocycle" and "carbocyclyl" refer to a monovalent, optionally substituted C3-C 12 Monocyclic, bicyclic or tricyclic structure, it can be a bridged ring, a fused ring or a spirocycle, wherein all rings are formed by carbon atoms and at least one ring is a non-aromatic ring.Carbocyclic ring structure includes cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, dihydroindenyl, decahydronaphthyl etc.Carbocyclic ring can be connected to its side group at any ring atom producing a stable structure and unless otherwise specified, any ring atom can be optionally substituted.

[0061] The term "carbonyl" as used herein refers to a C(O) group, which may also be represented as C=O.

[0062] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or the unprotonated counterpart.

[0063] The term "cyano" as used herein refers to a -CN group.

[0064] The term "cycloalkyl" as used herein refers to a monovalent saturated cyclic hydrocarbon group which, unless otherwise specified, may be a bridged ring, a fused ring, or a spiro ring having three to eight ring carbons, and examples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0065] The term "cycloalkenyl" as used herein refers to a monovalent, non-aromatic, saturated cyclic hydrocarbon group which, unless otherwise specifically stated, may be bridged, fused, or spiro having three to eight ring carbons and containing one or more carbon-carbon double bonds.

[0066] As used herein, the term "diastereomers" refers to stereoisomers that are not mirror images of one another and are not superimposable on one another.

[0067] The term "enantiomer" as used herein 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 up to 10% of the other enantiomer), preferably at least 90% and more preferably at least 98% (as determined by standard methods in the art).

[0068] The term "guanidino" refers to a group having the following structure: wherein each R is independently any chemically feasible substituent described herein.

[0069] The term "guanidinoalkylalkyl" as used herein refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more guanidino moieties.

[0070] The term "haloacetyl" as used herein refers to an acetyl group in which at least one hydrogen is replaced by a halogen.

[0071] The term "haloalkyl" as used herein denotes an alkyl moiety in which one or more carbon atoms are substituted with one or more halogen moieties which may be the same or different.

[0072] The term "halogen" as used herein denotes a halogen selected from bromine, chlorine, iodine or fluorine.

[0073] As used herein, the term "heteroalkyl" refers to an "alkyl" as defined herein in which at least one carbon atom is replaced by a heteroatom (eg, O, N, or S atom). The heteroatom may be present in the middle or at the terminal end of the group.

[0074] As used herein, the term "heteroaryl" refers to a monovalent, monocyclic or polycyclic structure containing at least one fully aromatic ring: that is, they contain 4n+2 π electrons within the monocyclic or polycyclic ring system and 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 in which any of the above heteroaromatic rings are fused to one or more aromatic or carbocyclic rings (e.g., 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 specifically stated, any ring atom can be optionally substituted. In some embodiments, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents.

[0075] As used herein, the term "heterocycloalkyl" refers to a monovalent, monocyclic, bicyclic or polycyclic ring system in which at least one ring is a non-aromatic ring and wherein the non-aromatic ring contains one, two, three or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, which may be bridged, fused or spirocyclic. 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 with a bridged polycyclic structure in which one or more carbon atoms or heteroatoms bridge non-adjacent members of the monocyclic ring, such as quinuclidine. The term "heterocycloalkyl" includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocycles are fused to one or more aromatic rings, carbocyclic rings, heteroaromatic rings or heterocycles, such as aryl rings, cyclohexane rings, cyclohexene rings, cyclopentane rings, cyclopentene rings, pyridine rings or pyrrolidine rings. Examples of heterocycloalkyls are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine and decahydronaphthyridinyl. The heterocycloalkyl ring can be connected to its side group at any ring atom that produces a stable structure and unless otherwise specified, any ring atom can be optionally substituted.

[0076] The term "hydroxy" as used herein refers to an -OH group.

[0077] The term "hydroxyalkyl," as used herein, refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more -OH moieties.

[0078] 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 in stereoisomeric form, for example, in double bond isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures depicted herein and therefore the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compounds in the form of chiral salt complexes, or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0079] 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 produces a compound that achieves an IC50 of 2 uM or less in the Ras-RAF disruption assay protocol provided in the following examples and provided herein:

[0080] The purpose of this biochemical assay is to measure the ability of a test compound to promote the formation of a ternary complex between nucleotide-loaded Ras isoforms and cyclophilin A; the resulting ternary complex disrupts the binding to BRAF. RBD Binding of the construct inhibits Ras signaling through RAF effectors.

[0081] Unlabeled 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 present in the plate wells were diluents starting from a final concentration of 30 μM and undergoing 10-point 3-fold serial dilutions. After incubation at 25 ° C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay sample wells to reach final concentrations of 10 nM and 50 nM, respectively, and the reaction was 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 compounds that cause a decrease in the TR-FRET ratio relative to the DMSO control wells.

[0082] This assay can also be used to assess selectivity. In some embodiments, the compounds of the invention are selective for one or more specific Ras mutants (e.g., K-Ras G13C) over other Ras mutants (e.g., K-Ras G12C) or wild type compared to those known in the art.

[0083] In some embodiments, the linker comprises 20 or fewer linear atoms. In some embodiments, the linker comprises 15 or fewer linear atoms. In some embodiments, the linker comprises 10 or fewer linear atoms. In some embodiments, the molecular weight of the linker is less than 500 g / mol. In some embodiments, the molecular weight of the linker is less than 400 g / mol. In some embodiments, the molecular weight of the linker is less than 300 g / mol. In some embodiments, the molecular weight of the linker is less than 200 g / mol. In some embodiments, the molecular weight of the linker is less than 100 g / mol. In some embodiments, the molecular weight of the linker is less than 50 g / mol.

[0084] As used herein, a "monovalent organic moiety" is less than 500 kDa. In some embodiments, a "monovalent organic moiety" is less than 400 kDa. In some embodiments, a "monovalent organic moiety" is less than 300 kDa. In some embodiments, a "monovalent organic moiety" is less than 200 kDa. In some embodiments, a "monovalent organic moiety" is less than 100 kDa. In some embodiments, a "monovalent organic moiety" is less than 50 kDa. In some embodiments, a "monovalent organic moiety" is less than 25 kDa. In some embodiments, a "monovalent organic moiety" is less than 20 kDa. In some embodiments, a "monovalent organic moiety" is less than 15 kDa. In some embodiments, a "monovalent organic moiety" is less than 10 kDa. In some embodiments, a "monovalent organic moiety" is less than 1 kDa. In some embodiments, a "monovalent organic moiety" is less than 500 g / mol. In some embodiments, a "monovalent organic moiety" is within a range between 500 g / mol and 500 kDa.

[0085] As used herein, the term "stereoisomer" refers to all possible different isomeric and conformational forms that a compound (e.g., a compound of any formula described herein) may have, particularly all possible stereochemical and conformational 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 included within the scope of the present invention.

[0086] The term "sulfonyl" as used herein refers to a -S(O)2- group.

[0087] The term "thiocarbonyl" as used herein refers to a -C(S)- group.

[0088] As used herein, the term "vinyl ketone" refers to a group comprising a carbonyl group directly attached to a carbon-carbon double bond.

[0089] The term "vinyl sulfone" as used herein refers to a group comprising a sulfonyl group directly attached to a carbon-carbon double bond.

[0090] As used herein, the term "alkynone" refers to a wherein R is any chemically feasible substituent described herein.

[0091] Those of ordinary skill in the art reading this disclosure will understand that certain compounds described herein may be provided or utilized in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, 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 that compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of that compound rather than a racemic mixture of that compound; a particular salt of a compound may be considered a different form from another salt of that compound; a preparation containing one conformational isomer of a double bond ((Z) or (E)) may be considered a different form from a preparation containing another conformational isomer of that double bond ((E) or (Z)); a preparation having one or more isotopes of an atom that differ from the isotopes present in a reference preparation may be considered to be in a different form. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1A The compound A of the present invention showed the effect of KRAS G13C Selective covalent modification.

[0093] Figure 1B The compound B of the present invention showed the effect of KRAS G13C Compound X is a KRAS from WO 2021 / 091982. G12C Inhibitor A647.

[0094] Figure 2 The use of compound A (a compound of the present invention) to inhibit KRAS G13C (NSCLC CDX KRAS G13C / WT Single-dose PK / PD in vivo inhibition of PD-L1 / PD-L2 binding in vivo model).

[0095] Figure 3 demonstrated the use of Compound A (a compound of the present invention) in NSCLC CDX KRAS G13C / WT Tumor regression in the model.

[0096] Figure 4 demonstrated the use of Compound A (a compound of the present invention) in NSCLC PDX KRAS G13C / WT Tumor regression in the model. DETAILED DESCRIPTION

[0097] Compound

[0098] Ras inhibitors are provided herein. 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 protein (presenting protein) (e.g., cyclophilin A) that is widely expressed in cells. More specifically, in some embodiments, the Ras inhibitors described herein induce new binding pockets in Ras by driving the formation of a high-affinity triple complex between the Ras protein and the widely expressed cytoplasmic chaperone protein cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way in which the compounds of the present invention and the complexes or conjugates formed therefrom exert an inhibitory effect on Ras is to spatially block the interaction sites between Ras and downstream effector molecules, such as RAF, required for propagating oncogenic signals.

[0099] Without being bound by theory, the inventors assume that the covalent and non-covalent interactions of the compounds of the present invention with Ras and chaperone proteins (e.g., cyclophilin A) can contribute to the inhibition of Ras activity. In some embodiments, the compounds of the present invention form covalent adducts with the side chains of Ras proteins (e.g., the sulfhydryl side chains of cysteine ​​at positions 12 or 13 of mutant Ras proteins). Covalent adducts can also be formed with other side chains of Ras. Additionally or alternatively, non-covalent interactions can play a role: for example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bond interactions and combinations thereof can contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors. Therefore, the compounds of the present invention can inhibit a variety of Ras proteins (e.g., K-Ras, N-Ras, H-Ras, and mutants thereof mutated at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, as well as other mutants described herein).

[0100] Methods of determining covalent adduct formation are known in the art.One method of determining covalent adduct formation is to perform a "cross-linking" assay, such as that performed under these conditions.

[0101] Note: The following protocol describes a procedure for monitoring the cross-linking of K-Ras G12C (GMP-PNP) with compounds of the invention. This protocol can also be implemented by substituting other Ras proteins or nucleotides such as G13C.

[0102] The purpose of this biochemical assay is to measure the ability of a test compound to covalently label a nucleotide-loaded K-Ras isoform. A 5 μM stock solution of K-Ras (1-169) G12C loaded with GMP-PNP is diluted 10-fold to a final concentration of 0.5 μM in an assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCl, 1 mM MgCl2, 1 mM BME, 5 μM cyclophilin A, and 2 μM test compound; the final sample volume is 100 μL.

[0103] The samples were incubated at 25°C for up to 24 hours, after which they were quenched by adding 10 μL of 5% formic acid. The quenched samples were centrifuged at 15,000 rpm for 15 minutes in a benchtop centrifuge, after which a 10 μL aliquot was injected onto a reverse-phase C4 column and eluted into the mass spectrometer using an increasing acetonitrile gradient as the mobile phase. Raw data were analyzed using Waters MassLynx MS software, where % binding was calculated from the deconvoluted protein peaks of labeled and unlabeled K-Ras.

[0104] Therefore, provided herein is a compound having a structure of Formula I or a pharmaceutically acceptable salt thereof:

[0105]

[0106] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0107] L 1 Not present or a joint;

[0108] W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynyl ketone or alkynyl sulfone;

[0109] R 1 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;

[0110] R 2 is optionally substituted C1-C6 alkyl; and

[0111] R 3 is an optionally substituted C1-C6 alkyl group or an optionally substituted C1-C3 heteroalkyl group.

[0112] In some embodiments, W is a crosslinking group comprising a vinyl ketone, a vinyl sulfone, or an alkynyl ketone.

[0113] In some embodiments, provided herein is a compound having the structure of Formula Ia or a pharmaceutically acceptable salt thereof:

[0114]

[0115] In some embodiments of the compounds of the invention, A is optionally substituted thiazole-diyl, optionally substituted oxazole-diyl, optionally substituted morpholine-diyl, optionally substituted pyrrolidine-diyl, optionally substituted pyridine-diyl, optionally substituted azetidine-diyl, optionally substituted pyrazine-diyl, optionally substituted pyrimidine-diyl, optionally substituted piperidine-diyl, optionally substituted oxadiazole-diyl, optionally substituted thiadiazole-diyl, optionally substituted triazole-diyl, optionally substituted thiomorpholine-diyl, or optionally substituted phenylene.

[0116] In some embodiments, the present disclosure provides a compound of structural formula II-1 or a pharmaceutically acceptable salt thereof:

[0117]

[0118] In some embodiments, provided are compounds having the structure of Formula II-2 or pharmaceutically acceptable salts thereof:

[0119]

[0120] where R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0121] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0122] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0123] In some embodiments, the compounds of the present invention have the structure of Formula II-3, or a pharmaceutically acceptable salt thereof:

[0124]

[0125] In some embodiments, the compounds of the present invention have the structure of Formula II-4, or a pharmaceutically acceptable salt thereof:

[0126]

[0127] In some embodiments, the compounds of the present invention have the structure of Formula II-4b, or a pharmaceutically acceptable salt thereof:

[0128]

[0129] In some embodiments of the compounds of the present invention, R 2 yes:

[0130] In some embodiments of the compounds of the present invention, R 3 is an optionally substituted C1-C6 alkyl. 3 yes:

[0131] In some embodiments of the compounds of the present invention, R 3 is an optionally substituted C1-C3 heteroalkyl. 3 yes:

[0132] In some embodiments of the compounds of the present invention, A is an optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is:

[0133] In some embodiments of the compounds of the present invention, A is optionally substituted phenylene. In some embodiments, A is:

[0134] In some embodiments of the compounds of the present invention, A is an optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is selected from the following or stereoisomers thereof:

[0135]

[0136] In some embodiments, A is selected from the following or stereoisomers thereof:

[0137] In some embodiments of the compounds of the present invention, the linker is a structure of Formula III:

[0138] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2

[0139] Formula III,

[0140] where A 1 is the bond between the linker and CH(R 3 )); A 2 is the bond between W and the linker; 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 ; each R N is independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3- to 14-membered heteroalkyl, 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 optionally substituted C1-C 10 alkylene, optionally substituted C2-C 10 alkenylene, optionally substituted C2-C 10 alkynylene, optionally substituted 3- to 14-membered heteroalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C 10 polyethylene glycol, or optionally substituted C1-C 10 heteroalkylene, or the chemical bond connecting A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h [[ID=--]] 3 ) i -(C 2 ) j -(B 4 ) k –A 2 to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 .

[0141] In some embodiments of the compounds of the present invention, the linker is or comprises a cyclic moiety. In some embodiments, the linker has a structure of Formula IIIa:

[0142]

[0143] Where o is 0 or 1;

[0144] R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene;

[0145] X 1 absent, optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene;

[0146] Cy is optionally substituted 3 to 8 membered cycloalkylene, optionally substituted 3 to 12 membered heterocycloalkylene, optionally substituted 6-10 membered arylene, or optionally substituted 5 to 10 membered heteroarylene; and

[0147] L 2 is absent, -SO2-, -NH-, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted 3- to 6-membered heterocycloalkylene.

[0148] In some embodiments, the linker is selected from the following or stereoisomers thereof:

[0149]

[0150]

[0151] In some embodiments, the linker is selected from the following or stereoisomers thereof:

[0152]

[0153]

[0154] In some embodiments, the compounds of the present invention have the structure of Formula II-5, or a pharmaceutically acceptable salt thereof:

[0155]

[0156] Among them, Cy 1 is optionally substituted spirocyclic 8- to 11-membered heterocycloalkylene or optionally substituted bicyclic 7- to 9-membered heterocycloalkylene; and

[0157] wherein W comprises vinyl ketone or vinyl sulfone.

[0158] In some embodiments, Cy 1 is an optionally substituted spirocyclic 10- to 11-membered heterocycloalkylene.

[0159] In some embodiments, the compounds of the present invention have the structure of Formula II-5a:

[0160]

[0161] where X 2 It is O, C (R 11 )2、NR 12 , S or SO2.

[0162] r is 1 or 2;

[0163] Each t is independently 0, 1, or 2;

[0164] R 11 and R 12 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, or optionally substituted 3- to 5-membered cycloalkyl; and

[0165] Each R 13 is independently -CH3.

[0166] In some embodiments, the compounds of the present invention have the structure of Formula II-5b:

[0167]

[0168] where X 2 It is O, C (R 11 )2、NR 12 , S or SO2.

[0169] r is 1 or 2;

[0170] s and t are each independently 0, 1 or 2;

[0171] R 11 and R 12 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, optionally substituted 3 to 6 membered heterocycloalkyl, or optionally substituted 3 to 5 membered cycloalkyl; and

[0172] Each R 13 are independently -CH3, F, or two R attached to the same atom 13 Together with the atoms to which they are attached, they form an optionally substituted C3-C6 cycloalkyl group, or two R13 Together with the atoms to which it is attached, it forms an optionally substituted 3- to 6-membered heterocycloalkyl.

[0173] In some embodiments, R 13 It is -CH3.

[0174] In some embodiments, the sum of s and t is 1. In some embodiments, the sum of s and t is 2. In some embodiments, s is 0 and t is 1. In some embodiments, the sum of s and t is 0.

[0175] In some embodiments, the compounds of the present invention have the structure of Formula II-5c:

[0176]

[0177] In some embodiments, the compounds of the present invention have the structure of Formula II-5d:

[0178] In some embodiments, the compounds of the present invention have the structure of Formula II-5e:

[0179]

[0180]

[0181] In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, X 2 Is O. In some embodiments, X 2 Is S. In some embodiments, X 2 It's SO2.

[0182] In some embodiments, X 2 It is NR 12 In some embodiments, R 12 Selected from the following or their stereoisomers:

[0183] -CH3, Or -H. In some embodiments, R 12 Selected from the following or their stereoisomers:

[0184] In some embodiments, X 2 It is C(R 11 )2. In some embodiments, each R 11 It's hydrogen.

[0185] In some embodiments of the compounds of the present invention, W is a crosslinking group comprising a vinyl ketone. In some embodiments, W has a structure of Formula IVa:

[0186]

[0187] where R 8a 、R 8b and R 8c W is independently hydrogen, -CN, halogen, or -C1-C3 alkyl optionally substituted with one or more substituents independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or a 4- to 7-membered saturated heterocycloalkyl. In some embodiments, W is selected from the following or stereoisomers thereof:

[0188] In some embodiments, W is selected from the following or stereoisomers thereof:

[0189] In some embodiments of the compounds of the present invention, W is a cross-linking group comprising a vinyl sulfone. In some embodiments, W has a structure of Formula IVc:

[0190]

[0191] where R 10a 、R 10b and R 10c W is independently hydrogen, -CN, or -C1-C3 alkyl optionally substituted by one or more substituents independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or a 4- to 7-membered saturated heterocycloalkyl. In some embodiments, W is:

[0192]

[0193] In some embodiments of the compounds of the present invention, W is a cross-linking group comprising an alkynone. In some embodiments, W has the structure of Formula IVb:

[0194]

[0195] where R 9 W is hydrogen, -C1-C3 alkyl optionally substituted by one or more substituents independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or 4 to 7 membered saturated cycloalkyl, or 4 to 7 membered saturated heterocycloalkyl. In some embodiments, W is selected from:

[0196]

[0197] In some embodiments, the compounds of the present invention have the structure of Formula II-6:

[0198]

[0199] where Q 1 It is CH2, NR N or O;

[0200] Q 2 CO, NR N or O; and

[0201] Z is optionally substituted 3- to 6-membered heterocycloalkylene or optionally substituted 5- to 10-membered heteroarylene; or

[0202] where Q 1 -Q 2 -Z is optionally substituted 9- to 10-membered spirocyclic heterocycloalkylene.

[0203] In some embodiments, the compounds of the present invention have the structure of Formula II-6a:

[0204]

[0205] where R 14 is fluorine, hydrogen or C1-C3 alkyl; and

[0206] u is 0 or 1.

[0207] In some embodiments, R 14 is fluoro and u is 1. In some embodiments, R 14 is hydrogen and u is 0.

[0208] In some embodiments, the compounds of the present invention have the structure of Formula II-6b:

[0209]

[0210] In some embodiments, the compounds of the present invention have the structure of Formula II-6c:

[0211]

[0212] 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. In some embodiments, the compound is a compound selected from A1 to A209 of Table 1. In some embodiments, the compound is a compound selected from A210 to A368 of Table 1.

[0213] Table 1: Certain compounds of the present invention

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286] In some embodiments, the compound of the present invention is a compound selected from Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of the present invention is a compound selected from Table 2, or a pharmaceutically acceptable salt or atropisomer thereof.

[0287] In some embodiments, the compound of the present invention is not a compound selected from Table 2. In some embodiments, the compound of the present invention is not a compound selected from Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of the present invention is not a compound selected from Table 2, or a pharmaceutically acceptable salt or atropisomer thereof.

[0288] Table 2: Some compounds

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491] It should be noted that some compounds show bonds that are flat or wedge-shaped. In some cases, the relative stereochemistry of stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. In some cases, a single example number corresponds to a mixture of stereoisomers. The present invention encompasses all stereoisomers of the compounds in the above table. In certain embodiments, atropisomers of the compounds in the above table are contemplated. Parentheses should be ignored.

[0492] Also provided is a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0493] Further provided is a conjugate or a salt thereof comprising a structure of Formula V:

[0494] MLP

[0495] Formula V,

[0496] Where L is the linker;

[0497] P is a monovalent organic moiety; and

[0498] M has the structure of Formula VIa:

[0499]

[0500] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0501] R 2 is an optionally substituted C1-C6 alkyl group;

[0502] R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;

[0503] X 2 It is O, C (R 11 )2、NR 12 , S or SO2;

[0504] r is 1 or 2;

[0505] Each t is independently 0, 1, or 2;

[0506] R 11 and R 12are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, or optionally substituted 3- to 5-membered cycloalkyl;

[0507] Each R 13 are independently -CH3; and

[0508] R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0509] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0510] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0511] Further provided is a conjugate or a salt thereof comprising a structure of Formula V:

[0512] MLP

[0513] Formula V,

[0514] Where L is the linker;

[0515] P is a monovalent organic moiety; and

[0516] M has the structure of Formula VIb:

[0517]

[0518] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0519] R 2 is an optionally substituted C1-C6 alkyl group;

[0520] R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;

[0521] R 14 is fluorine, hydrogen or C1-C3 alkyl;

[0522] u is 0 or 1; and

[0523] R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0524] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0525] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0526] Further provided is a conjugate or a salt thereof comprising a structure of Formula V:

[0527] MLP

[0528] Formula V,

[0529] Where L is the linker;

[0530] P is a monovalent organic moiety; and

[0531] M has the structure of Formula VIc:

[0532]

[0533] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0534] R 2 is an optionally substituted C1-C6 alkyl group;

[0535] R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; and

[0536] R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0537] R4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0538] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0539] Further provided is a conjugate or a salt thereof comprising a structure of Formula V:

[0540] MLP

[0541] Formula V,

[0542] Where L is the linker;

[0543] P is a monovalent organic moiety; and

[0544] M has the structure of Formula VId:

[0545]

[0546] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0547] R 2 is an optionally substituted C1-C6 alkyl group;

[0548] R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; and

[0549] R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0550] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0551] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0552] In some embodiments of the conjugates of the invention, the monovalent organic moiety is a protein. In some embodiments, the protein is a Ras protein. In some embodiments, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. In some embodiments of the conjugates of the invention, the linker is bound to the monovalent organic moiety via a bond to a sulfhydryl group of an amino acid residue of the monovalent organic moiety.

[0553] The compounds of the present invention are also suitable for use in antibody-drug conjugates and degrader applications.

[0554] Further provided is a method for 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 may, for example, be 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 G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras mutations are described herein.

[0555] 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.

[0556] Further provided is a method for inhibiting Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. The cell may be a cancer cell, such as a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid adenocarcinoma cell, a myelodysplastic syndrome cell, or a squamous cell lung cancer cell. Other cancer types are described herein. The cell may be in vivo or in vitro.

[0557] Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula I. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula Ia. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula II-1. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula II-2. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula II-3. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula II-4. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula II-5. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula II-5a. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula II-6. Further provided is a method for treating K-Ras G13C mutant cancer using a compound of Formula II-6a. Further provided is a method of treating K-Ras G13C mutant cancer using a compound of formula II-6b. Further provided is a method of treating K-Ras G13C mutant cancer using a compound of formula II-6c.

[0558] Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula I. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula Ia. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula II-1. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula II-2. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula II-3. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula II-4. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula II-5. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula II-5a. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula II-6. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of Formula II-6a. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of formula II-6b. Further provided is a method for treating K-Ras G12C mutant cancer using a compound of formula II-6c.

[0559] For compounds of the present invention, one stereoisomer may exhibit a superior inhibitory effect over another stereoisomer. For example, one atropisomer may exhibit an inhibitory effect, while another atropisomer may exhibit little or no inhibitory effect.

[0560] In some embodiments, the methods or uses described herein further comprise administering an additional anticancer therapy. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, 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 additional anticancer therapy is a SHP2 inhibitor. Other additional anticancer therapies are described herein.

[0561] Synthesis method

[0562] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic techniques.

[0563] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described in the following schemes, as well as synthetic methods known in the field of synthetic organic chemistry or modifications thereof as understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following schemes.

[0564] Scheme 1. General synthesis of macrocyclic esters

[0565]

[0566] The general synthesis of macrocyclic esters is outlined in Scheme 1. Appropriately substituted aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ols (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 a three-step process involving palladium-mediated coupling, alkylation, and deprotection. Amino-hexahydropyridazine-3-carboxylic acid methyl ester-boronic acid esters (2) can be prepared in a three-step process involving protection, iridium catalyst-mediated borylation, and coupling with (S)-hexahydropyridazine-3-carboxylic acid methyl ester.

[0567] Appropriately substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (or alternative amino acid derivatives) (4) can be prepared by coupling methyl-L-valine ester with protected (S)-pyrrolidine-3-carboxylic acid, followed by deprotection, coupling with a carboxylic acid containing an appropriately substituted Michael acceptor, and hydrolysis steps.

[0568] The final macrocyclic ester can be prepared by coupling amino-hexahydropyridazine-3-carboxylic acid methyl ester-boronate (2) with aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (1) in the presence of Pd catalyst, followed by hydrolysis and macrolactonization steps to obtain the appropriately protected macrocyclic intermediate (5). Deprotection and coupling with the appropriately substituted intermediate 4 yield the macrocyclic product. Additional deprotection and / or functionalization steps may be required to prepare the final compound.

[0569] Scheme 2. Alternative general synthesis of macrocyclic esters

[0570]

[0571] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. An appropriately protected bromo-indolyl (6) is coupled with a boronate (3) 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 produce the iodine intermediate (7). Coupling with an appropriately substituted boronate and alkylation in the presence of a Pd catalyst can yield the fully protected macrocycle (5). Additional deprotection or functionalization steps are required to prepare the final compound.

[0572] In addition, it will be appreciated by those skilled in the art that the compounds of the present disclosure can be synthesized using the methods described in the following examples, as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof. These methods include, but are not limited to, the methods described in the following examples. For example, one skilled in the art will be able to install the desired -BLW group of a compound of formula (I), wherein B, L, and W are as defined herein, into a macrocyclic ester, including by using the methods exemplified in the Examples section herein.

[0573] The compounds of Table 1 herein are prepared using the methods disclosed herein, or using the methods disclosed herein in combination with the knowledge of those skilled in the art. The compounds of Table 2 can be prepared using the methods disclosed herein, or using the methods disclosed herein in combination with the knowledge of those skilled in the art.

[0574] Scheme 3. General synthesis of macrocyclic esters

[0575]

[0576] An alternative general synthesis of macrocyclic esters is outlined in Scheme 3. Appropriately substituted indolylboronic acid esters (8) 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 a four-step process involving palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation.

[0577] Methyl (S)-2-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10) can be prepared by coupling (S)-2-amino-3-(4-bromothiazol-2-yl)propanoic acid (9) with methyl (S)-hexahydropyridazine-3-carboxylate.

[0578] The final macrocyclic ester can be prepared by coupling amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (10) with an appropriately substituted indolyl boronate (8) in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps to afford the appropriately protected macrocyclic intermediate (11). Deprotection and coupling with an appropriately substituted intermediate 4 can yield the macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 13 or 14.

[0579] Scheme 4. General Synthesis of Macrocyclic Esters

[0580]

[0581] An alternative general synthesis of macrocyclic esters is outlined in Scheme 4. Appropriately substituted morpholine or alternative heterocyclic intermediates (15) can be coupled via palladium-mediated coupling with appropriately protected intermediates 1. Subsequent ester hydrolysis and coupling with piperazoic esters afford intermediates 16.

[0582] Macrocyclic esters can be prepared by hydrolysis, deprotection and macrocyclization steps. Subsequent deprotection and coupling with intermediate 4 (or analogs) yield the appropriately substituted final macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 17.

[0583] Scheme 5. General Synthesis of Macrocyclic Esters

[0584]

[0585] An alternative general synthesis of macrocyclic esters is outlined in Scheme 5. Appropriately substituted macrocycles (20) can be prepared starting from appropriately protected boronate esters 18 and bromoindolyl intermediates (19) via palladium-mediated coupling, hydrolysis, coupling with piperazolyl esters, hydrolysis, deprotection, and macrocyclization steps. Subsequent coupling with appropriately substituted protected amino acids, followed by palladium-mediated coupling, affords intermediates 21. Additional deprotection and derivatization steps, including alkylation, may be required.

[0586] The final macrocyclic ester can be prepared by coupling intermediate (22) with an appropriately substituted carboxylic acid intermediate (23). Additional deprotection or functionalization steps may be required to prepare the final compound (24).

[0587] In addition, the compounds of the present disclosure can be synthesized using the methods described in the following examples, as well as synthetic methods known in the art of synthetic organic chemistry, or modifications of such methods as would be appreciated by those skilled in the art. These methods include, but are not limited to, those described in the following examples. For example, one skilled in the art will be able to install the desired -BLW group of a compound of formula (I), wherein B, L, and W are as defined herein, into a macrocyclic ester, including by using the methods exemplified in the Examples section herein.

[0588] Pharmaceutical compositions and methods of use

[0589] Pharmaceutical compositions and methods of administration

[0590] 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.

[0591] 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.

[0592] In some embodiments, the compound is present in the pharmaceutical composition in an amount suitable for administration in a unit dose in a treatment regimen, and the compound shows a statistically significant likelihood 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 administration in the following ways: oral administration, such as liquids (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as, for example, sterile solutions or suspensions, or sustained-release formulations; topical administration, such as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or oral cavity; intravaginal or rectal administration, such as pessaries, creams, or foams; sublingual administration; ophthalmic administration; transdermal administration; or nasal, pulmonary, and other mucosal surfaces.

[0593] As used herein, "pharmaceutically acceptable excipient" refers to any inactive ingredient that is non-toxic and non-inflammatory in a subject (e.g., a vehicle capable of suspending or dissolving an active compound). Typical excipients include, for example, antiadherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (pigments), softeners, 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 for hydration. Excipients include, but are not limited to, optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, cross-linked polyvinylpyrrolidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, 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 includes at least two different pharmaceutically acceptable excipients.

[0594] Unless expressly stated to the contrary, the compounds described herein, whether or not expressly stated, may be provided or utilized in the form of a salt, such as a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds described herein that are suitable for use in contact with human tissues without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (P.H. Stahl and C.G. Wermuth eds.), Wiley-VCH, 2008. The salts may be prepared in situ during the final isolation and purification of the compounds described herein, or may be separated by reacting the free base group with a suitable organic acid.

[0595] The compounds of the present invention may have ionizable groups, so that they can be prepared into pharmaceutically acceptable salt forms. These salts may be acid addition salts involving inorganic or organic acids, or in the case where the compounds of the present invention are in acid form, the salts may be prepared from inorganic or organic bases. In some embodiments, the compound is prepared as a pharmaceutically acceptable salt form or used in a pharmaceutically acceptable salt form, which is prepared as an addition product of a pharmaceutically acceptable acid or base. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid or tartaric acid, for forming acid addition salts; and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc., for forming basic salts. Methods for preparing appropriate salts are well known in the art.

[0596] 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-ethyl Alkanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0597] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, a "subject" refers to a human being 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 insects. In some embodiments, the subject may be a transgenic animal, a genetically engineered animal, or a clone.

[0598] 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, this amount is the amount of a unit dose (or an integral portion thereof) suitable for administration according to a dosing regimen, which is determined to be associated with a desired or beneficial outcome when administered to a relevant population (i.e., according to a therapeutic dosing regimen). It will be 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 a variety of dosage forms.

[0599] As used herein, the term "dosage regimen" refers to a group of unit doses (usually more than one unit dose) administered individually to a subject, the unit doses typically being spaced apart for a certain period of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosing regimen that may involve one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each of which is spaced apart by a time period of the same length; in some embodiments, the dosing regimen comprises multiple doses and at least two different time periods for separating individual doses. In some embodiments, all doses within the dosing regimen are the same unit dose amount. In some embodiments, the different doses within the dosing regimen are different amounts. In some embodiments, the dosing regimen comprises a first dose of the amount of a first dose, followed by one or more additional doses of the amount of a second dose different from the amount of the first dose. In some embodiments, the dosing regimen comprises a first dose of the amount of a first dose, followed by one or more additional doses of the amount of a second dose identical to the amount of the first dose. In some embodiments, the dosing regimen is associated with desired or beneficial results when applied to a relevant population (i.e., a therapeutic dosing regimen).

[0600] A "therapeutic regimen" refers to a regimen of dosages whose administration is associated with desired or beneficial therapeutic results in the relevant population.

[0601] The term "treatment" ("treatment / treat / treating") in its broadest sense refers to any administration of a substance (e.g., a compound of the present invention) that partially or completely alleviates, ameliorates, alleviates, inhibits one or more symptoms, features, or causes of a particular disease, disorder, or condition; delays its onset; reduces its severity; or reduces its occurrence. In some embodiments, this treatment may be applied to a subject who does not show signs of the relevant disease, disorder, or condition or a subject who only shows early signs of the disease, disorder, or condition. Alternatively or additionally, in some embodiments, treatment may be applied to a subject who shows one or more established signs of the relevant disease, disorder, or condition. In some embodiments, treatment may be used for a subject diagnosed with a relevant disease, disorder, or condition. In some embodiments, treatment may be used for a subject known to have one or more susceptibility factors that are statistically associated with an increased risk of developing a relevant disease, disorder, or condition.

[0602] The term "therapeutically effective amount" means an amount sufficient to treat a disease, disorder or condition when administered to a population suffering from or susceptible to the disease, disorder or condition according to a therapeutic 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 condition or delays its onset. It will be understood by those skilled in the art that the term "therapeutically effective amount" does not actually require the desired successful treatment to be achieved in a particular individual. In fact, a therapeutically effective amount may be an amount that provides a specific desired pharmacological response in a considerable number of subjects when administered to a patient in need of such treatment. It is particularly important to understand that a particular subject may actually be "refractory" to the "therapeutically effective amount." In some embodiments, the therapeutically effective amount mentioned may refer to an amount as measured in one or more specific tissues (e.g., tissues affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). It will be understood by those skilled in the art that in some embodiments, a therapeutically effective amount may be formulated as a single dose or administered in a single dose. In some embodiments, a therapeutically effective amount can be formulated as multiple doses, for example, formulated as part of a dosing regimen, or administered as multiple doses.

[0603] For use as a treatment for a subject, the compound of the present invention or a pharmaceutically acceptable salt thereof can be formulated as a pharmaceutical composition or a veterinary composition. Depending on the subject to be treated, the mode of administration, and the desired type of treatment, such as prevention, control, or treatment, the compound or a pharmaceutically acceptable salt thereof is formulated in a manner consistent with these parameters. An overview of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0604] The compositions can be prepared according to conventional mixing, granulation or coating methods, respectively, and the pharmaceutical compositions of the present invention may 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 a pharmaceutically acceptable salt thereof by weight or volume. In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof may be present in an amount of 1-95% by weight of the total amount of the composition, such as a pharmaceutical composition.

[0605] The composition can be provided in the dosage form suitable for following application: intra-articular, oral, parenteral (such as intravenous, intramuscular), rectum, skin, subcutaneous, surface, transdermal, sublingual, nasal, vaginal, intracapsular, intraurethral, ​​intrathecal, epidural, ear or eye application, or by injection, suction or direct contact with nose, urogenital, genitalia or oral mucosa. Therefore, the pharmaceutical composition can be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, medicinal liquids, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, preparations suitable for iontophoresis delivery or aerosols. The composition can be prepared according to conventional medical practice.

[0606] 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 intrabronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intracapsular, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous administration.

[0607] The preparation can be prepared in a manner suitable for systemic administration or surface or topical administration. Systemic preparations include preparations designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or can be prepared for transdermal, transmucosal or oral administration. The preparation will typically include a diluent, and in some cases, adjuvants, buffers, preservatives, etc. The compound or its pharmaceutically acceptable salt can also be administered in liposome compositions or in microemulsion form.

[0608] For injection, the formulation can be prepared in conventional forms, such as liquid solutions or suspensions, or solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in the form of emulsions. Suitable excipients include, for example, water, physiological saline, dextrose, glycerol, and the like. Such compositions may also contain a certain amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, and the like, for example, sodium acetate, sorbitan monolaurate, and the like.

[0609] Various sustained-release drug systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0610] Systemic administration can also include relatively non-invasive methods, such as using suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or pharmaceutically acceptable salts thereof. It will be appreciated in the art that suitable forms include syrups, capsules, and tablets.

[0611] 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 agent and the second agent in the combination therapy can be formulated together or separately. Other modalities of combination therapy are also described herein.

[0612] Individual or separately formulated medicaments can be packaged together in a kit form. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, a suppository or a liquid in a vial, two topical creams, etc. The kit may include optional components that help to administer a unit dose to a subject, such as vials, syringes for injection, custom IV delivery systems, inhalers, etc., to reconstitute the powder form. In addition, the unit dose kit may contain instructions for the preparation and administration of the composition. The kit may be manufactured as a disposable unit dose for a subject, for multiple uses for a specific subject (at a constant dose, or wherein the efficacy of an individual compound or its pharmaceutically acceptable salt may vary with treatment progress); or the kit may contain multiple doses suitable for administration to multiple subjects ("whole package"). The kit components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0613] Formulations for oral use include tablets containing the active ingredient 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, starches 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, starches including potato starch, cross-linked sodium carboxymethylcellulose, 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 carboxymethylcellulose, 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, humectants, buffers, and the like.

[0614] Two or more compounds can be mixed together in a tablet, capsule or other vehicle, or can be separated. In one example, a first compound is contained on the inside of a tablet, and a second compound is on the outside, so that the majority of the second compound is released before the first compound is released.

[0615] Formulations for oral use may also be provided in the form of chewable tablets, or in the form of 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 in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and granules may be prepared using the ingredients mentioned above for tablets and capsules in a conventional manner, using, for example, a mixer, a fluidized bed apparatus, or a spray drying apparatus.

[0616] Dissolution or diffusion controlled release can be achieved by appropriately coating tablets, capsules, granules or granular preparations 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 above-mentioned coating materials, such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted 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.

[0617] Liquid forms for oral administration that may incorporate the compounds of the invention, or pharmaceutically acceptable salts thereof, and compositions include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0618] In general, when administered to humans, the oral dosage of any compound of the present invention or a pharmaceutically acceptable salt thereof will depend on the properties of the compound and can be readily determined by one skilled in the art. The 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 derived therefrom.

[0619] In some embodiments, the pharmaceutical composition may also include an additional compound with antiproliferative activity. Depending on the mode of administration, the compound or its pharmaceutically acceptable salt will be formulated into a suitable composition for delivery. Each compound or its pharmaceutically acceptable salt in the combination therapy can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in the combination therapy can be formulated together or separately. Ideally, the first agent and the second agent are formulated together so that the agents are administered simultaneously or nearly simultaneously.

[0620] It will be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, that is, they can be formulated with or administered concurrently with, before, or after the administration of one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutics or procedures) used in a combination regimen should 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 employed may achieve the desired effect for the same condition, or they may achieve different effects (e.g., control any adverse effects).

[0621] As described herein, administration of each drug in the combination therapy can independently be from once to four times daily for a period of one day to one year, and may even be continued for the lifetime of the subject. Chronic, long-term administration may be required.

[0622] How to use

[0623] In some embodiments, the present invention discloses a method for treating a disease or condition characterized by aberrant Ras activity caused by a Ras mutant. In some embodiments, the disease or condition is cancer.

[0624] Thus, a method for treating cancer in a subject in need thereof is also provided, 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, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendix cancer, endometrial cancer, or melanoma. Also provided is a method for 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, or a pharmaceutical composition comprising such a compound or salt.

[0625] 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, the following tumor types: astrocyte, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example:

[0626] Heart, such as: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas;

[0627] Lung, for example: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma;

[0628] Gastrointestinal, for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0629] Genitourinary tract, for example: kidney (adenocarcinoma, Wilm's tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[0630] Liver, for example: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0631] Biliary tract, such as gallbladder cancer, ampullary cancer, and bile duct cancer;

[0632] Bone, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor;

[0633] Nervous system, for example: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, neurofibromatosis type 1, meningiomas, gliomas, sarcomas);

[0634] Gynecology, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, cervical precancerous atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma);

[0635] Hematopoietic system, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders (e.g., myelofibrosis and myeloproliferative neoplasms), multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0636] Skin, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and

[0637] Adrenal glands, e.g. neuroblastoma.

[0638] In some embodiments, the Ras protein is wild-type (Ras WT ). Thus, in some embodiments, the compounds of the present invention are used to treat a 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:

[0639] (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;

[0640] (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

[0641] (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;

[0642] Or a combination of any of the foregoing. In some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of: G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer comprises an N-Ras mutation selected from the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit 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 WT and one or more additional Ras mutations (e.g., K-, H-, or N-Ras WT and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H, or N-Ras WT and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Ras WTand N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T). In some embodiments, the compounds of the invention inhibit Ras amp and one or more additional Ras mutations (e.g., K-, H-, or N-Ras amp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H, or N-Ras amp and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Ras amp and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0643] Methods for detecting Ras mutations are known in the art. Such methods include, but are not limited to, direct sequencing and the use of highly sensitive diagnostic assays (using CE-IVD marking), such as Domagala et al., Pol J Pathol 3: 145-164 (2012), which are incorporated herein by reference in their entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreenPyro. See also, for example, WO 2020 / 106640.

[0644] In some embodiments, the cancer is non-small cell lung cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is colorectal cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is pancreatic cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12D or K-Ras G12V. In some embodiments, the cancer is pancreatic cancer and the Ras mutation comprises an N-Ras mutation, such as N-Ras G12D. In some embodiments, the cancer is melanoma and the Ras mutation comprises an N-Ras mutation, such as N-Ras Q61R or N-Ras Q61K. In some embodiments, the cancer is non-small cell lung cancer and the Ras protein is K-Ras. amp In any of the foregoing, if not specifically stated, the compound may also inhibit Ras WT (e.g. K-, H- or N-Ras WT ) or Ras amp (e.g. K-, H- or N-Ras amp ).

[0645] In some embodiments, the cancer comprises a 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 G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and 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 G12C or 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, ovarian cancer, bile duct cancer or mucinous appendix 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 ).

[0646] 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. 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 may be a cancer cell. The cancer cell may be any type of cancer described herein. The cell may be in vivo or in vitro.

[0647] Combination therapy

[0648] The methods of the present invention may include the use of a compound of the present invention alone or in combination with one or more additional therapies (e.g., non-drug therapies or therapeutic agents). When administered alone, the dosage of one or more of the additional therapies (e.g., non-drug therapies or therapeutic agents) may be reduced relative to the standard dosage. For example, the dosage may be determined empirically based on the drug combination and permutation or may be inferred by isobolographic analysis (e.g., Black et al., Neurology 65: S3-S6 (2005)).

[0649] The compounds of the present invention may be administered before, after, or simultaneously with the administration of one or more of these additional therapies. When combined, the dose of the compound of the present invention and the dose of the 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 the additional therapy, e.g., an anticancer agent, may be administered together, e.g., in a single pharmaceutical composition, or separately, and when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close in time or distant in time.

[0650] In some embodiments, the additional therapy is the administration of a side effect limiting agent (e.g., an agent intended to reduce the occurrence or severity of a therapeutic side effect). 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 granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0651] In some embodiments, the one or more additional therapies include non-drug treatments (such as surgery or radiotherapy). In some embodiments, the one or more additional therapies include therapeutic agents (such as compounds or biological preparations as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors or autophagy inhibitors). In some embodiments, the one or more additional therapies include non-drug treatments (such as surgery or radiotherapy) and therapeutic agents (such as compounds or biological preparations as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors or autophagy inhibitors). In other embodiments, the one or more additional therapies include two therapeutic agents. In other embodiments, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0652] In this Combination Therapies section, all references are incorporated by reference with respect to the agents described, whether or not expressly stated as such.

[0653] Non-drug therapies

[0654] 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 acceptor transfer (ACT) therapy.

[0655] In some embodiments, the compounds of the present invention can be used as postoperative adjuvant therapy. In some embodiments, the compounds of the present invention can be used as preoperative neoadjuvant therapy.

[0656] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative disorders, such as cancer, in subjects, such as mammals (e.g., humans). The technology of administering radiation therapy is known in the art. Radiation therapy can be administered via one of several methods or a combination of methods, including but not limited to external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and persistent or transient interstitial brachytherapy. As used herein, the term "brachytherapy" refers to a radiation therapy delivered by a spatially confined radioactive material inserted into or near a tumor or other proliferative tissue disease site in the body. 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 Lu radioisotopes). Suitable radioactive sources used as cell conditioning agents of the present invention include solids and liquids. 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 a solution of any radionuclide, such as a solution of I-125 or I-131, or the radioactive fluid can be prepared using a slurry of a suitable fluid containing small particles of a solid radionuclide, such as Au-198 or Y-90. In addition, the radionuclide can be embedded in a gel or radioactive microspheres.

[0657] In some embodiments, the compounds of the present invention can sensitize abnormal cells to radiation therapy, thereby killing or inhibiting the growth of such cells. Therefore, the present invention also relates to a method for sensitizing abnormal cells in a mammal to radiation therapy, comprising administering to the mammal an amount of a compound of the present invention effective to sensitize the abnormal cells to radiation therapy. The amount of compound in this method can be determined according to the methods used to determine 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.

[0658] In some embodiments, the non-drug treatment is T cell acceptor transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell can be modified to express a chimeric antigen receptor (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 T cells are amplified and genetically modified, the source of T cells is obtained from the subject. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue and tumor. In certain embodiments of the present invention, a variety of T cell lines available in the art can be used. In some embodiments, the T cell is an autologous T cell. Before or after T cells are genetically modified to express a desired protein (e.g., a CAR), the T cells can be activated and expanded, typically using methods as described, for example, in the following U.S. Patents: 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0659] therapeutic agents

[0660] The therapeutic agent can be a compound used to treat cancer or its related symptoms. The compounds of the present invention can be combined with a second, third or fourth therapeutic agent or more therapeutic agents. The compounds of the present invention can be combined with one or more therapeutic agents and one or more non-drug therapies.

[0661] For example, the therapeutic agent may be a steroid. Steroids are known in the art. Therefore, 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, and the like. isone), cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide), fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate

[00145] The present invention also includes but is not limited to: tabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, 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.

[0662] 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. Pat. Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, as well as U.S. Pat. International patent applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089 and WO00 / 02871.

[0663] The therapeutic agent may be a biological agent (e.g., a cytokine (e.g., interferon or interleukin, such as IL-2)) for treating cancer or its associated symptoms. Biological agents are known in the art. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that excites the target to stimulate an anti-cancer response or antagonizes an antigen that is important for cancer. Antibody-drug conjugates are also included.

[0664] The therapeutic agent may be a T cell checkpoint inhibitor. Such checkpoint inhibitors are known in the art. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is 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 (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, 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 the checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0665] The therapeutic agent can be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab). Other anti-TIGIT antibodies are known in the art.

[0666] The therapeutic agent can be an agent for treating cancer or its related symptoms (e.g., a cytotoxic agent, a non-peptide small molecule, or other compounds useful for treating cancer or its related symptoms, collectively referred to as "anti-cancer agents"). Anti-cancer agents can be, for example, chemotherapeutic agents or targeted therapeutic agents. Such agents are known in the art.

[0667] 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 urea, 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, the one or more additional therapies include two or more anticancer agents. The two or more anticancer agents can be used in a mixture for combined administration or separate administration. Suitable dosing regimens for combining anticancer agents are known in the art and are described in, for example, Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0668] 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 altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trimethylolmelamine; polyacetyl groups (especially bullatacin and bullatacinone); camptothecins; thecin (including its synthetic analogue, 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 CB1-TM1); eleutherobin; pancratistatin; sarcodictin A. A); spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, e.g., calicheamicin γll and calicheamicin ωll (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins, e.g., dynemicin A; bisphosphonates, e.g., clodronate; esperamicin; neocarzinostatin chromophores; chromophore and related chromophores, enediyne antibiotic chromophores, aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycin s), dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamicin (doxorubicin), morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinyl-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU);Folic acid analogs, such as denopterin, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone propionate, propionate, epitiostanol, mepitiostane, testolactone; antiadreners such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; 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; phenamet; and pirarubicin.losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes, such as T-2 toxin, verracurin A, roridin A, and roridin B. A) and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as (paclitaxel), (Nanoparticulate formulation of albumin-engineered paclitaxel without polyoxyethylene hydrogenated castor oil) and (docetaxel); chloranbucil; tamoxifen (Nolvadex TM ); raloxifene; aromatase-inhibiting 4(5)-imidazoles; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene Flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamicins; capecitabine (e.g., ); and pharmaceutically acceptable salts of any one of the foregoing.

[0669] Additional non-limiting examples of anticancer agents include trastuzumab bevacizumab Cetuximab (cetuximabv) Rituximab ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, anti-tumor agents (e.g., cell cycle nonspecific anti-tumor agents and other anti-tumor agents described herein), anti-tumorigenic herbal remedies, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximinesulfoximine), CBV (chemotherapy), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, lanigadote aniquidar), larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A), sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0670] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin / actinomycin D), daunomycin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycins, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and eliminates cells that cannot synthesize asparagine themselves), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., methylchlorambucil, cyclophosphamide and analogs, melphalan, and chlorambucil), ethyleneimine, and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors, such as abemaciclib, ribociclib, palbociclib, seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU), and the like),and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites (e.g., folic acid analogs), pyrimidine analogs (e.g., fluorouracil, azathiouracil, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid), acid, vorinostat, belinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., ), PI3K inhibitors such as PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), (PI3Kδ and γ inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; 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 leuprorelin); olide and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38 MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN163L), 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.

[0671] In some embodiments, the anticancer agent is selected from the group consisting of mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Sorafenib or any analog or derivative variant thereof.

[0672] In some embodiments, the anticancer agent is a HER2 inhibitor. HER2 inhibitors are known in the art. 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 (CI1033), HKI-272, lapatinib (GW-572016; ), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.

[0673] In some embodiments, the anticancer agent is an ALK inhibitor. ALK inhibitors are known in the art. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005; and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0674] In some embodiments, the anticancer agent is an inhibitor of a receptor tyrosine kinase (RTK) / growth factor receptor downstream member (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) thereof. ), prodrugs or tautomers), 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.

[0675] In some embodiments, the anticancer agent is an SOS1 inhibitor. SOS1 inhibitors are known in the art. In some embodiments, the SOS1 inhibitor is selected from WO 2022146698, WO 2022081912, WO 2022058344, WO2022026465, WO 2022017519, WO 2021173524, WO 2021130731, WO 2021127429, WO2021092115, WO 2021105960, WO 2021074227, WO 2020180768, WO 2020180770, WO2020173935, WO 2020146470, WO 2019201848, WO 2019122129, WO 2018172250 and WO2018115380, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the compounds of the present invention are used in combination with an SOS1 inhibitor to treat K-Ras G13C cancer.

[0676] In some embodiments, the anticancer agent is an additional Ras inhibitor or Ras vaccine or another therapeutic modality designed to directly or indirectly reduce the oncogenic activity of Ras. Such agents are known in the art. In some embodiments, the anticancer agent is an additional Ras inhibitor. In some embodiments, the Ras inhibitor targets Ras in its active state or GTP-bound state. In some embodiments, the Ras inhibitor targets Ras in its inactive state or GDP-bound state. In some embodiments, the Ras inhibitor is an inhibitor of, for example, K-Ras G12C, such as AMG 510, MRTX1257, MRTX849, JNJ-74699157, LY3499446, or ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21822, JAB-21000, IBI351, ERAS-3490, RMC-6291, or GDC-6036. In some embodiments, the Ras inhibitor is an inhibitor of K-Ras G12D, such as MRTX1133 or JAB-22000. In some embodiments, the Ras inhibitor is a K-Ras G12V inhibitor, such as JAB-23000. In some embodiments, the Ras inhibitor is RMC-6236. In some embodiments, the Ras inhibitor is selected from the Ras(ON) inhibitors (i.e., Ras in its GTP-bound state) 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 2021091982, WO 2021091967, WO 2021091956, and WO2020132597. Other examples of Ras inhibitors are known in the art, for example in the following documents, which are incorporated herein by reference in their entirety: WO 2022271658, WO 2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO 2022265974, WO 2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO 2022237815, WO 2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO 2022223037, WO 2022221739, WO 2022221528、WO 2022221386、WO2022216762、WO 2022192794、WO 2022192790、WO 2022188729、WO2022187411, WO2022184178, WO 2022173870, WO 2022173678, WO 2022135346, WO 2022133731, WO2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO2022109487, WO 2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO 2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO2021175199, WO 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO2019232419, WO2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO2019051291, WO 2018218070, WO 2018217651, WO 2018218071, WO 2018218069, WO2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO2018068017, WO 2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO2014143659 and WO 2013155223.

[0677] In some embodiments, the therapeutic agent that can be combined with the compounds of the present invention is a MAP kinase (MAPK) pathway inhibitor (or "MAPK inhibitor"). Such agents are known in the art. 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, described in 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.

[0678] 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. Such agents are known in the art. 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.

[0679] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist. Such agents are known in the art.

[0680] 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, additional therapeutic agents include FGFR inhibitors, PARP inhibitors, BET inhibitors, PRMT5i inhibitors, MAT2A inhibitors, VEGF inhibitors and HDAC inhibitors. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0681] IGF-1R inhibitors are known in the art and include linsitinib or a pharmaceutically acceptable salt thereof.

[0682] EGFR inhibitors are known in the art and include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Useful antibody inhibitors of EGFR include cetuximab panitumumab Zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by the natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include 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 binding specificity thereto.

[0683] 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. Patent No. 5,747,498; WO96 / 30347; EP 0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP 837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP 682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12): 1599-1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0684] MEK inhibitors are known in the art and include, but are not limited to, pimasetinib, selumetinib, cobimetinib, trametinib and bimetinib In some embodiments, the MEK inhibitor targets a MEK mutation selected from the group consisting of: 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.

[0685] PI3K inhibitors are known in the art and 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]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ- 235 or NVP-BEZ235, 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); PIK 75 (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]-methylene-(Z)-ylidene]-thiazolidine-2,4-dione (available from Axon Medchem); 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.

[0686] AKT inhibitors are known in the art and 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 Suppl):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).

[0687] mTOR inhibitors are known in the art and include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including temsirolimus. Everolimus ( WO94 / 09010); deforolimus (also known as deforolimus or AP23573); rapalogs, such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-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; U.S. Pat. No. 5,877,657; Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, as well as derivatives disclosed in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO2018204416, WO2019212990, and WO2019212991), such as RMC-5552, which has the structure:

[0688]

[0689] BRAF inhibitors that can be used in combination with the compounds of the present invention are known in the art and include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF may comprise a Class 3 BRAF mutation. In some embodiments, the Class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0690] MCL-1 inhibitors are known in the art and include, but are not limited to, AMG-176, MIK665, and S63845. The myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance to not only traditional chemotherapy but also targeted therapeutics including BCL-2 inhibitors such as ABT-263.

[0691] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor. SHP2 is known in the art. 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. Stimulation with, for example, cytokines or growth factors that act through receptor tyrosine kinases (RTKs) results in exposure of the catalytic site, leading to enzymatic activation of SHP2.

[0692] SHP2 is involved in signaling via the RAS-mitogen-activated protein kinase (MAPK), i.e., JAK-STAT or phosphoinositide 3-kinase-AKT pathway. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental diseases, such as Noonan Syndrome and Leopard Syndrome, as well as in 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 particularly interesting target for the development of novel therapies for various diseases, including cancer. The combination of SHP2 inhibitors (e.g., RMC-4550 or SHP099) with RAS pathway inhibitors (e.g., MEK inhibitors) has been shown to inhibit the proliferation of multiple cancer cell lines (e.g., pancreatic, lung, ovarian, 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 various malignancies.

[0693] Comprehensive practical examples of SHP2 suppression in this area: Chen et al., MolPharmacol.2006, 70, 562; Sarver et al., J.Med.Chem.2017, 62, 179 3; 20222084008, WO 2022135568, WO 2021176072, WO 2021171261, WO2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO2021143680, WO 2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO2020156242, WO 2020108590, WO 2020104635, WO 2020094104, WO 2020094018, WO2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO 2020033828, WO2020033286, WO 2020022323, WO 2019233810, WO 2019213318, WO 2019183367, WO2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO2019158019, WO2019152454, WO 2019051469, WO 2019051084, WO 2018218133, WO 2018172984, WO2018160731, WO 2018136265, WO 2018136264, WO 2018130928, WO 2018129402, WO2018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO 2017211303, WO2017210134, WO 2017156397, WO 2017100279, WO 2017079723、WO 2017078499、WO2016203406、WO 2016203405、WO 2016203404、WO 2016196591、WO 2016191328、WO2015107495、WO 2015107494、WO 2015107493, WO 2014176488, WO 2014113584, US20210085677, US 10858359, US 10934302, US 10954243, US 10988466, US 11001561, US11033547, US 11034705 or US 11044675, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, each of which is incorporated herein by reference.

[0694] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, such as a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor 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:

[0695] or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RMC-4630, which has the structure:

[0696] 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:

[0697]

[0698] 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,

[0699]

[0700] 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

[0701]

[0702] or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is ERAS-601. In some embodiments, the SHP2 inhibitor is BBP-398.

[0703] In some embodiments, the additional 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 additional 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, a Ras inhibitor of the present invention is used in combination with a SHP2 inhibitor and a Ras inhibitor that inhibits multiple Ras isoforms and / or mutants (e.g., RMC-6236). In some embodiments, the cancer is lung cancer, and the treatment comprises administering a Ras inhibitor of the present invention in combination with a second or third therapeutic agent, such as a SHP2 inhibitor and a Ras inhibitor that inhibits multiple Ras isoforms and / or mutants. In some embodiments, the cancer is colorectal cancer, and the treatment comprises administering a Ras inhibitor of the present invention in combination with a second or third therapeutic agent, such as a SHP2 inhibitor and a Ras inhibitor that inhibits multiple Ras isoforms and / or mutants. In some embodiments, a Ras inhibitor of the present invention is used in combination with an immunotherapy, optionally in combination with a chemotherapeutic agent.

[0704] Proteasome inhibitors are known in the art and include, but are not limited to, carfilzomib. Bortezomib and oprozomib.

[0705] 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. Other immunotherapies are known in the art.

[0706] Immunomodulatory drugs (IMiDs) are a class of immunomodulatory drugs (drugs that regulate immune responses) that contain an imide group. IMiDs include thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0707] Exemplary anti-PD-1 antibodies and methods of use thereof are described in Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168A1), and elsewhere herein.

[0708] FGFR inhibitors are known in the art, such as pemigatinib and erdafitinib, including FGFR2 inhibitors and FGFR4 inhibitors. See, for example, Cancers (Basel), 2021 Jun; 13(12):2968.

[0709] BET inhibitors are known in the art, such as romidepsin, panobinostat, and belinostat. See, for example, British J. Cancer 124: 1478 (2021).

[0710] PRMT5i inhibitors are known in the art, such as PF-0693999, PJ-68, and MRTX1719. See, for example, Biomed. Pharmacotherapy 144: 112252 (2021).

[0711] MAT2A inhibitors are known in the art, such as AG-270 and IDE397. See, for example, Exp Opin Ther Patents (2022) DOI: 10.1080 / 13543776.2022.2119127.

[0712] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as those described in U.S. Pat. No. 6,111,090, U.S. Pat. No. 8,586,023, WO2010 / 003118, and WO2011 / 090754; or such as those described in U.S. Pat. No. 7,025,962, EP 1947183, U.S. Patent No. 7,812,135; U.S. Patent No. 8,388,967; U.S. Patent No. 8,591,886; U.S. Patent No. 7,618,632, EP1866339 and 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.

[0713] 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 are known in the art and include, but are not limited to, chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof prepared by in vitro synthesis. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally can be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth. In some embodiments, the one or more additional therapies include anti-angiogenic agents.

[0714] 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 useful COX-II inhibitors include alecoxib, valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, 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 MMP-1 inhibitory activity. More preferred are inhibitors that selectively inhibit MMP-2 or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors include AG-3340, RO 32-3555, and RS13-0830.

[0715] 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 to VEGF receptors), VEGF inhibitors, EGFR inhibitors (e.g., antibodies or antigen binding regions that specifically bind to EGFR), e.g. (panitumumab), erlotinib Anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind to Angl and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind to Tie2 kinase). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., antibodies or antigen binding regions that specifically bind, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM disintegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), anti-eph receptor or anti-dextrin antibodies or anti- The present invention relates to a novel PDGF-BB antagonist comprising a pro-binding region (U.S. Pat. Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and members of their patent families), and an anti-PDGF-BB antagonist (e.g., an antibody or antigen binding region that specifically binds to a PDGF-BB ligand), and an antibody or antigen binding region that specifically binds to a PDGF-BB ligand, and a PDGFR kinase inhibitor (e.g., an antibody or antigen binding region that specifically binds to a PDGFR kinase). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptaniboctasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US 5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DAC anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA);KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); maspin (Sosei, Japan); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); second-generation α5β3 integrin MAb (Applied Molecular Evolution, USA and Medlmmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived antiangiogenic agents (XOMA, USA); PI 88 (Progen, Australia); cilengitide (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA);AVE8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthorrhizol (Yonsei University, South Korea); gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX478 (ProlX, USA); METASTATIN (EntreMed, USA); troponin I (Harvard University, USA); SU6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); atiprimod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); angiogenesis vaccine (EntreMed, USA);Urokinase plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); angustin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); drug delivery system, intraocular 2-methoxyestradiol; anginex (Maastricht University, Netherlands, and University of Minnesota, USA); ABT 510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-α inhibitor; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, α5β (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada);BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine (Genaera, USA); RPI 4610 (Sirna, USA); heparinase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thrombin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0716] Other examples of therapeutic agents that can be used in combination with the compounds of the present 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 the receptor c-Met. Such agents are known in the art.

[0717] 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 are known in the art and include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil TM ), bafilomycin A1 (bafilomycin A1), 5-amino-4-imidazolecarboxamide riboside (AICAR), soft spongy acid, autophagy inhibitory algae toxins that inhibit type 2A or type 1 protein phosphatase, cAMP analogs and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside and vincristine. In addition, antisense or siRNA that inhibits the expression of proteins including but not limited to ATG5 (involved in autophagy) can also be used. In some embodiments, the one or more additional therapies include autophagy inhibitors.

[0718] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-tumor agent, which is known in the art. In some embodiments, the one or more additional therapies include an anti-tumor agent. Non-limiting examples of anti-tumor agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, amifostine, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabineocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta), etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphatephosphate), formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human alpha-fetoprotein, ibandronic acid acid), idarubicin, imiquimod, interferon alpha, natural interferon alpha, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-n3, consensus interferon-1, natural interferon alpha, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, interferon alpha, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide metoclopramide), mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguanidine, dibromodulcitol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, new erythropoiesis-stimulating protein, NSC 631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alfa-2b, pentosan polysulfatesodium), pentostatin, picibanil, birubicin, rabbit anti-thymocyte polyclonal antibody, pegylated interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, etidronate rhenium Re 186, RII isotretinoinamide, rituximab, romurtide, samarium 153Sm lexidronam), sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131), trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, native tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, spalfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (NewYorkUniversity), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or valspodar.

[0719] 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; ipilumumab; MEDI4736 MSB0010718C; AMP 224; adalimumab ado-trastuzumab emtansine Aflibercept Alemtuzumab basiliximab belimumab basiliximab Belimumab brentuximab vedotin canakinumab Certolizumab pegol Daclizumab daratumumab denosumab Eculizumab efalizumab gemtuzumab ozogamicin Golimumab Ibritumomab tiuxetan infliximab Motavizumab Natalizumab obinutuzumab Ofatumumab Omalizumab palivizumab Pertuzumab Pertuzumab Ranibizumab Raxibacumab tocilizumab Tositumomab; Tositumomab-i-131; Tositumomab and Tositumomab-i-131 ustekinumab AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0720] Depending on the disorder being treated, the compounds described herein may be used in combination with the agents disclosed herein or other suitable agents. Therefore, in some embodiments, one or more compounds of the present disclosure will be co-administered with other therapies described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with the second agent. This combination may include administering two agents simultaneously in the same dosage form, administering them simultaneously in independent dosage forms, and administering them separately. That is, the compounds described herein and any agent described herein may be formulated together into the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any therapy described herein may be administered simultaneously, wherein the two agents are present in independent formulations. In another alternative, the compounds of the present disclosure may be administered first and then any therapy described herein, or vice versa. In some embodiments of the separate administration scheme, the compounds of the present invention and any therapy described herein are administered a few minutes apart, a few hours apart, or a few days apart.

[0721] In some embodiments of any 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 either order. The first therapeutic agent can be administered immediately, at most 1 hour, at most 2 hours, at most 3 hours, at most 4 hours, at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, 14 hours, at most 16 hours, at most 17 hours, at most 18 hours, at most 19 hours, at most 20 hours, at most 21 hours, at most 22 hours, at most 23 hours, at most 24 hours, or at most 1-7 days, 1-14 days, 1-21 days, or 1-30 days before or after administration of the one or more additional therapies.

[0722] 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.

[0723] Since one aspect of the present invention encompasses treating diseases or their associated symptoms with a combination of pharmaceutically active compounds that can be administered separately, the present invention also relates to combining independent pharmaceutical compositions in the form of a kit. The kit may comprise two independent pharmaceutical compositions: a compound of the present invention and one or more additional therapies. The kit may comprise a container for accommodating the independent compositions, such as a sub-bottle or a sub-foil package. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for use of the independent components. The kit form is particularly advantageous when the independent components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosing intervals, or when a prescribing health care provider wishes to adjust the individual components in the combination.

[0724] Numbered implementation plan

[0725] 1. A compound having a structure of Formula I, or a pharmaceutically acceptable salt thereof:

[0726]

[0727] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0728] L 1 Not present or a joint;

[0729] W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynyl ketone or alkynyl sulfone;

[0730] R 1 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;

[0731] R 2 is optionally substituted C1-C6 alkyl; and

[0732] R 3 is an optionally substituted C1-C6 alkyl group or an optionally substituted C1-C3 heteroalkyl group.

[0733] 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazole-diyl, optionally substituted oxazole-diyl, optionally substituted morpholine-diyl, optionally substituted pyrrolidine-diyl, optionally substituted pyridine-diyl, optionally substituted azetidine-diyl, optionally substituted pyrazine-diyl, optionally substituted pyrimidine-diyl, optionally substituted piperidine-diyl, optionally substituted oxadiazole-diyl, optionally substituted thiadiazole-diyl, optionally substituted triazole-diyl, optionally substituted thiomorpholine-diyl, or optionally substituted phenylene.

[0734] 3. The compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure of formula II-1:

[0735]

[0736] 4. The compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure of formula II-2:

[0737]

[0738] where R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0739] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0740] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0741] 5. The compound according to embodiment 4, or a pharmaceutically acceptable salt thereof, having the structure of formula II-3:

[0742]

[0743] 6. The compound according to embodiment 4, or a pharmaceutically acceptable salt thereof, having the structure of formula II-4:

[0744]

[0745] 7. The compound according to embodiment 4, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-4b:

[0746]

[0747] 8. A compound as described in any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

[0748] 9. A compound as described in any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C1-C6 alkyl group.

[0749] 10. The compound according to embodiment 9, or a pharmaceutically acceptable salt thereof, wherein R 3 yes:

[0750] 11. A compound as described in any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted C1-C3 heteroalkyl.

[0751] 12. The compound according to embodiment 11, or a pharmaceutically acceptable salt thereof, wherein R 3 yes:

[0752] 13. The compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 5- to 10-membered heteroarylene.

[0753] 14. The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, wherein A is:

[0754]

[0755] 15. The compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted phenylene.

[0756] 16. The compound of embodiment 15, or a pharmaceutically acceptable salt thereof, wherein A is:

[0757]

[0758] 17. The compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene.

[0759] 18. The compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein A is:

[0760]

[0761] 19. The compound according to embodiment 17 or a pharmaceutically acceptable salt thereof, wherein A is:

[0762]

[0763] 20. The compound of any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the linker is a structure of Formula III:

[0764] A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2

[0765] Formula III,

[0766] Among them A 1 The linker and CH(R 3 ) between the key; A 2 is the bond between W and the linker; 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 ; Each R N are independently hydrogen, optionally substituted C 1– C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-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 optionally substituted C1-C 10 Alkylene, optionally substituted C2-C10 Alkenylene, optionally substituted C2-C 10 Alkynylene, 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 bond connecting A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - and -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 chemical bond.

[0767] 21. The compound according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the linker is or comprises a cyclic moiety.

[0768] 22. The compound according to embodiment 21, or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of formula IIIa:

[0769]

[0770] where o is 0 or 1;

[0771] R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene or optionally substituted 3- to 8-membered heterocycloalkylene;

[0772] X 1 is absent, is optionally substituted C1-C4 alkylene, O, NCH3 or optionally substituted C1-C4 heteroalkylene;

[0773] Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 12-membered heterocycloalkylene, optionally substituted 6-10-membered arylene or optionally substituted 5- to 10-membered heteroarylene; and

[0774] L 2 is absent, is -SO2-, -NH-, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted 3- to 6-membered heterocycloalkylene.

[0775] 23. The compound of embodiment 22, or a pharmaceutically acceptable salt thereof, wherein the linker is selected from the following or a stereoisomer thereof:

[0776]

[0777]

[0778]

[0779] 24. The compound of embodiment 22, or a pharmaceutically acceptable salt thereof, wherein the linker is selected from the following or a stereoisomer thereof:

[0780]

[0781]

[0782] 25. The compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein the compound is not a compound of Table 2.

[0783] 26. The compound of any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-5:

[0784]

[0785] Among them, Cy 1 is optionally substituted spirocyclic 8- to 11-membered heterocycloalkylene or optionally substituted bicyclic 7- to 9-membered heterocycloalkylene; and

[0786] wherein W comprises vinyl ketone or vinyl sulfone.

[0787] 27. The compound of embodiment 26, or a pharmaceutically acceptable salt thereof, wherein Cy 1 is an optionally substituted spirocyclic 10- to 11-membered heterocycloalkylene.

[0788] 28. The compound according to embodiment 27, or a pharmaceutically acceptable salt thereof, has the structure of Formula II-5a:

[0789]

[0790] where X 2 It is O, C (R 11 )2、NR 12 , S or SO2.

[0791] r is 1 or 2;

[0792] Each t is independently 0, 1, or 2;

[0793] R 11 and R 12 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, or optionally substituted 3- to 5-membered cycloalkyl; and

[0794] Each R 13 is independently -CH3.

[0795] 29. The compound of embodiment 27, or a pharmaceutically acceptable salt thereof, has the structure of Formula II-5b:

[0796]

[0797] where X 2 It is O, C (R 11 )2、NR 12 , S or SO2.

[0798] r is 1 or 2;

[0799] s and t are each independently 0, 1 or 2;

[0800] R 11 and R 12 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, optionally substituted 3 to 6 membered heterocycloalkyl, or optionally substituted 3 to 5 membered cycloalkyl; and

[0801] Each R 13 are independently -CH3, F, or two R attached to the same atom 13 Together with the atoms to which they are attached, they form an optionally substituted C3-C6 cycloalkyl group, or two R 13 Together with the atoms to which it is attached, it forms an optionally substituted 3- to 6-membered heterocycloalkyl.

[0802] 30. The compound according to embodiment 29, wherein R 13 It is -CH3.

[0803] 31. The compound of embodiment 29, wherein the sum of s and t is 1.

[0804] 32. The compound of embodiment 29, wherein the sum of s and t is 2.

[0805] 33. The compound of embodiment 29, wherein s is 0 and t is 1.

[0806] 34. The compound of embodiment 29, wherein the sum of s and t is 0.

[0807] 35. The compound of embodiment 28 or 29, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-5c:

[0808]

[0809] 36. The compound of embodiment 28 or 29, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-5d:

[0810]

[0811] 37. The compound of embodiment 28 or 29, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-5e:

[0812]

[0813] 38. The compound of embodiment 28 or 29, or a pharmaceutically acceptable salt thereof, wherein r is 1.

[0814] 39. The compound of embodiment 28 or 29, or a pharmaceutically acceptable salt thereof, wherein r is 2.

[0815] 40. The compound of any one of embodiments 28 to 39, or a pharmaceutically acceptable salt thereof, wherein X 2 It's O.

[0816] 41. A compound as described in any one of embodiments 28 to 39, or a pharmaceutically acceptable salt thereof, wherein X 2 It’s S.

[0817] 42. The compound of any one of embodiments 28 to 39, or a pharmaceutically acceptable salt thereof, wherein X 2 It's SO2.

[0818] 43. A compound as described in any one of embodiments 28 to 39, or a pharmaceutically acceptable salt thereof, wherein X 2 It is NR 12 .

[0819] 44. The compound of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from the following or their stereoisomers:

[0820] -CH3, or -H.

[0821] 45. The compound of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from the following or their stereoisomers:

[0822]

[0823] 46. ​​The compound of any one of embodiments 28 to 39, or a pharmaceutically acceptable salt thereof, wherein X 2 It is C(R 11 )2.

[0824] 47. The compound of embodiment 46, or a pharmaceutically acceptable salt thereof, wherein each R 11 It's hydrogen.

[0825] 48. The compound of any one of embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising a vinyl ketone.

[0826] 49. The compound of embodiment 48, or a pharmaceutically acceptable salt thereof, wherein W has the structure of Formula IVa:

[0827]

[0828] where R 8a 、R 8b and R 8c is independently hydrogen, -CN, halogen, or -C1-C3 alkyl optionally substituted with one or more substituents independently selected from -OH, -O-C1-C3 alkyl,

[0829] -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or a 4- to 7-membered saturated heterocycloalkyl.

[0830] 50. The compound of embodiment 49, or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or a stereoisomer thereof:

[0831]

[0832] 51. The compound of embodiment 49, or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or a stereoisomer thereof:

[0833]

[0834] 52. The compound of any one of embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising vinyl sulfone.

[0835] 53. The compound of embodiment 52, or a pharmaceutically acceptable salt thereof, wherein W has the structure of Formula IVc:

[0836]

[0837] where R 10a 、R 10b and R 10c are independently hydrogen, -CN, or -C1-C3 alkyl optionally substituted with one or more substituents independently selected from -OH, -O-C1-C3 alkyl,

[0838] -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or a 4- to 7-membered saturated heterocycloalkyl.

[0839] 54. The compound of embodiment 53, or a pharmaceutically acceptable salt thereof, wherein W is:

[0840]

[0841] 55. The compound of any one of embodiments 1 to 47, or a pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising an alkynone.

[0842] 56. The compound of embodiment 55, or a pharmaceutically acceptable salt thereof, wherein W has the structure of Formula IVb:

[0843]

[0844] where R 9 is hydrogen, -C1-C3 alkyl optionally substituted by one or more substituents independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or a 4- to 7-membered saturated cycloalkyl, or a 4- to 7-membered saturated heterocycloalkyl.

[0845] 57. The compound of embodiment 56, or a pharmaceutically acceptable salt thereof, wherein W is selected from:

[0846]

[0847] 58. The compound of embodiment 56 or 57, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-6:

[0848]

[0849] where Q 1 It is CH2, NR N or O;

[0850] Q 2 CO, NR N or O; and

[0851] Z is optionally substituted 3- to 6-membered heterocycloalkylene or optionally substituted 5- to 10-membered heteroarylene; or

[0852] where Q 1 -Q 2 -Z is optionally substituted 9- to 10-membered spirocyclic heterocycloalkylene.

[0853] 59. The compound of any one of embodiments 56 to 58, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-6a:

[0854]

[0855] where R 14 is fluorine, hydrogen or C1-C3 alkyl; and

[0856] u is 0 or 1.

[0857] 60. The compound of embodiment 59, or a pharmaceutically acceptable salt thereof, wherein R 14 is fluorine and u is 1.

[0858] 61. The compound of embodiment 59, or a pharmaceutically acceptable salt thereof, wherein R 14 is hydrogen and u is 0.

[0859] 62. The compound of any one of embodiments 56 to 59, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-6b:

[0860]

[0861] 63. The compound of any one of embodiments 56 to 59, or a pharmaceutically acceptable salt thereof, having the structure of Formula II-6c:

[0862]

[0863] 64. A compound or a pharmaceutically acceptable salt thereof selected from Table 1.

[0864] 65. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0865] 66. A conjugate or a salt thereof comprising a structure of Formula V:

[0866] MLP

[0867] Formula V,

[0868] Where L is the linker;

[0869] P is a monovalent organic moiety; and

[0870] M has the structure of Formula VIa:

[0871]

[0872] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0873] R 2 is an optionally substituted C1-C6 alkyl group;

[0874] R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;

[0875] X 2 It is O, C (R 11 )2、NR 12 , S or SO2;

[0876] r is 1 or 2;

[0877] Each t is independently 0, 1, or 2;

[0878] R 11 and R 12 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, or optionally substituted 3- to 5-membered cycloalkyl;

[0879] Each R 13 are independently -CH3; and

[0880] R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0881] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0882] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0883] 67. A conjugate or a salt thereof comprising a structure of Formula V:

[0884] MLP

[0885] Formula V,

[0886] Where L is the linker;

[0887] P is a monovalent organic moiety; and

[0888] M has the structure of Formula VIb:

[0889]

[0890] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0891] R 2 is an optionally substituted C1-C6 alkyl group;

[0892] R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;

[0893] R 14 is fluorine, hydrogen or C1-C3 alkyl;

[0894] u is 0 or 1; and

[0895] R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0896] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0897] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0898] 68. A conjugate or a salt thereof comprising a structure of Formula V:

[0899] MLP

[0900] Formula V,

[0901] Where L is the linker;

[0902] P is a monovalent organic moiety; and

[0903] M has the structure of Formula VIc:

[0904]

[0905] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0906] R 2 is an optionally substituted C1-C6 alkyl group;

[0907] R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; and

[0908] R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0909] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0910] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0911] 69. A conjugate or a salt thereof comprising a structure of Formula V:

[0912] MLP

[0913] Formula V,

[0914] Where L is the linker;

[0915] P is a monovalent organic moiety; and

[0916] M has the structure of Formula VId:

[0917]

[0918] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;

[0919] R 2 is an optionally substituted C1-C6 alkyl group;

[0920] R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; and

[0921] R 4 、R 5 and R 6 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 heterocycloalkyl; or

[0922] R 4 and R 5 together with the atoms to which it is attached, form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; or

[0923] R 4 and R 6 Together with the atoms to which it is attached, it forms an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl.

[0924] 70. The conjugate or salt thereof of any one of embodiments 66 to 69, wherein the monovalent organic moiety is a protein.

[0925] 71. The conjugate or salt thereof of embodiment 70, wherein the protein is Ras protein.

[0926] 72. The conjugate or salt thereof of embodiment 71, wherein the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C.

[0927] 73. The conjugate of embodiment 72, wherein the Ras protein is K-Ras G13C.

[0928] 74. The conjugate or salt thereof of any one of embodiments 66 to 73, wherein the linker is bound to the monovalent organic moiety via a bond to a sulfhydryl group of an amino acid residue of the monovalent organic moiety.

[0929] 75. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1 to 64, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 65.

[0930] 76. The method of embodiment 75, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, or endometrial cancer.

[0931] 77. The method of embodiment 75 or 76, wherein the cancer comprises a Ras mutation.

[0932] 78. The method of embodiment 77, wherein the Ras mutation is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C.

[0933] 79. The method of embodiment 78, wherein the Ras mutation is K-Ras G13C.

[0934] 80. 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 any one of embodiments 1 to 64, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 65.

[0935] 81. A method of inhibiting Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of any one of Embodiments 1 to 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 65.

[0936] 82. The method of embodiment 80 or 81, wherein the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C.

[0937] 83. The method of embodiment 82, wherein the Ras protein is K-Ras G13C.

[0938] 84. The method of any one of embodiments 81 to 83, wherein the cell is a cancer cell.

[0939] 85. The method of embodiment 84, wherein the cancer cell is a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, or an endometrial cancer cell.

[0940] 86. The method or use of any one of embodiments 75 to 85, wherein the method or use further comprises administering an additional anti-cancer therapy.

[0941] 87. The method of embodiment 86, wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

[0942] 88. The method of embodiment 86 or 87, wherein the additional anti-cancer therapy is a SHP2 inhibitor.

[0943] Example

[0944] The present disclosure will be further illustrated by the following examples and synthetic examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples provided are intended to illustrate certain embodiments and are not intended to limit the scope of the present disclosure. It should also be understood that various other embodiments, modifications thereof, and equivalents that may be conceivable to those skilled in the art may be resorted to without departing from the spirit of the present disclosure or the scope of the appended claims.

[0945] Chemical synthesis

[0946] The definitions used in the following examples and elsewhere herein are as follows:

[0947] CH2Cl2, DCM, methylene chloride, dichloromethane

[0948] CH3CN, MeCN, acetonitrile

[0949] CuI Copper(I) iodide

[0950] DIPEA Diisopropylethylamine

[0951] DMF N,N-dimethylformamide

[0952] EtOAc

[0953] h hour

[0954] H2O water

[0955] HCl

[0956] K3PO4 tripotassium phosphate

[0957] MeOH methanol

[0958] Na2SO4 sodium sulfate

[0959] NMP N-Methylpyrrolidone

[0960] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0961] instrument

[0962] Mass spectrometry data collection was performed using a Shimadzu LCMS-2020, Agilent 1260LC-6120 / 6125MSD, Shimadzu LCMS-2010EV, or Waters Acquity UPLC equipped with a QDa detector or SQ detector 2. The sample was injected into a C-18 reverse phase column in the liquid phase. The compound was eluted from the column using an acetonitrile gradient and fed into the mass analyzer. Initial data analysis was performed using an Agilent ChemStation, Shimadzu LabSolutions, or Waters MassLynx. NMR data were collected using a Bruker AVANCE III HD 400 MHz, Bruker Ascend 500 MHz, or Varian 400 MHz instrument, and raw data were analyzed using TopSpin or Mestrelab Mnova.

[0963] synthetic intermediates

[0964] Intermediate 1. Synthesis of 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylpropan-1-ol

[0965]

[0966] Step 1. To a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (65 g, 137 mmol, crude) in DCM (120 mL) was slowly added 1 M SnCl4 in DCM (137 mL, 137 mmol) at 0 ° C under N2 atmosphere. The mixture was stirred at 0 ° C for 30 minutes, and then a solution of 5-bromo-1H-indole (26.8 g, 137 mmol) in DCM (40 mL) was added dropwise. The mixture was stirred at 0 ° C for 45 minutes, then diluted with EtOAc (300 mL), washed with brine (100 mL × 4), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (55 g, 75% yield). LCMS (ESI): m / z [M+Na] C 29 H 32 Calculated value for BrNO2SiNa 556.1; experimental value 556.3.

[0967] Step 2. To a mixture of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (50 g, 93.6 mmol) in THF (100 mL) was added LiBH (6.1 g, 281 mmol) at 0°C under N atmosphere. The mixture was heated to 60°C and stirred for 20 hours, then MeOH (10 mL) and EtOAc (100 mL) were added, and the mixture was washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (50 mL), cooled to 10°C, and dihydropyridine (9.5 g, 37.4 mmol) and TsOH.HO (890 mg, 4.7 mmol) were added. The mixture was stirred at 10° C. for 2 hours, filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (41 g, 84% yield). LCMS (ESI): m / z [M+H] C 29 H 34 Calculated value of BrNOSi: 519.2; experimental value: 520.1; 1HNMR(400MHz, CDCl3)δ7.96(s,1H),7.75-7.68(m,5H),7.46-7.35(m,6H),7.23-7.1 9(m,2H),6.87(d,J=2.1Hz,1H),3.40(s,2H),2.72(s,2H),1.14(s,9H),0.89(s,6H).

[0968] Step 3. To a mixture of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (1.5 g, 2.9 mmol) and I (731 mg, 2.9 mmol) in THF (15 mL) was added AgOTf (888 mg, 3.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, then diluted with EtOAc (200 mL) and washed with saturated Na2S2O3 (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (900 mg, 72% yield) as a solid. 1 H NMR (400MHz, DMSO-d6) δ11.70 (s, 1H), 7.68 (d, J = 1.3Hz, 1H), 7.64-7.62 (m, 4H), 7.46-7.43 (m, 6H), 7.2 4-7.22(d,1H),7.14-7.12(dd,J=8.6,1.6Hz,1H),3.48(s,2H),2.63(s,2H),1.08(s,9H),0.88(s,6H).

[0969] Step 4. To a stirred mixture of HCOOH (66.3 g, 1.44 mol) in TEA (728 g, 7.2 mol) at 0°C under an Ar atmosphere was added (4S,5S)-2-chloro-2-methyl-1-(4-methylphenylsulfonyl)-4,5-diphenyl-1,3-diaza-2-rutheniumcyclopentaneisopropyltoluene (3.9 g, 6.0 mmol) in portions. The mixture was heated to 40°C and stirred for 15 minutes, then cooled to room temperature and 1-(3-bromopyridin-2-yl)ethanone (120 g, 600 mmol) was added in portions. The mixture was heated to 40°C and stirred for an additional 2 hours, then the solvent was concentrated under reduced pressure. Brine (2 L) was added to the residue, and the mixture was extracted with EtOAc (4×700 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give (1S)-1-(3-bromopyridin-2-yl)ethanol (100 g, 74% yield) as an oil. LCMS (ESI): m / z [M+H] Calcd. for C7H8BrNO 201.1; Found 201.9.

[0970] Step 5. To a stirred mixture of (1S)-1-(3-bromopyridin-2-yl)ethanol (100 g, 495 mmol) in DMF (1 L) was added a 60% dispersion of NaH in oil (14.25 g, 594 mmol) in portions at 0°C. The mixture was stirred at 0°C for 1 hour. MeI (140.5 g, 990 mmol) was added dropwise at 0°C, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was cooled to 0°C and saturated NH4Cl (5 L) was added. The mixture was extracted with EtOAc (3×1.5 L), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (90 g, 75% yield) as an oil. LCMS (ESI): m / z [M+H] CH 10 Calculated for BrNO 215.0; found 215.9.

[0971] Step 6. To a stirred mixture of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (90 g, 417 mmol) and Pd(dppf)Cl2 (30.5 g, 41.7 mmol) in toluene (900 mL) was added bis(pinacolato)diboron (127 g, 500 mmol) and KOAc (81.8 g, 833 mmol) in portions at room temperature under Ar atmosphere. The mixture was heated to 100°C and stirred for 3 hours. The filtrate was concentrated under reduced pressure and the residue was purified by Al2O3 column chromatography to give 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 g, 63% yield) as a semi-solid. LCMS (ESI): m / z [M+H] C 14 H 22 Calculated value for BNO3: 263.2; experimental value: 264.1.

[0972] Step 7. To a stirred mixture of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-iodo-1H-indole (140 g, 217 mmol) and 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 g, 380 mmol) in 1,4-dioxane (1.4 L) was added KCO (74.8 g, 541 mmol), Pd(dppf)Cl (15.9 g, 21.7 mmol) and H0 (280 mL) in portions at room temperature under an Ar atmosphere. The mixture was heated to 85° C. and stirred for 4 h, then cooled, H0 (5 L) was added, and the mixture was extracted with EtOAc (3×2 L). The combined organic layers were washed with brine (2×1 L), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indole (71 g, 45% yield) as a solid. LCMS (ESI): m / z [M+H] C 37 H 43 Calculated value for BrN2O2Si 654.2; experimental value 655.1.

[0973] Step 8. To a stirred mixture of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indole (71 g, 108 mmol) in DMF (0.8 L) was added CsCO (70.6 g, 217 mmol) and EtI (33.8 g, 217 mmol) in portions at 0° C. under N atmosphere. The mixture was warmed to room temperature and stirred for 16 h, then H O (4 L) was added and the mixture was extracted with EtOAc (3×1.5 L). The combined organic layers were washed with brine (2×1 L), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indole (66 g, 80% yield) as an oil. LCMS (ESI): m / z [M+H] C 39 H 47 Calculated value for BrN2O2Si: 682.3; experimental value: 683.3.

[0974] Step 9. To a stirred mixture of TBAF (172.6 g, 660 mmol) in THF (660 mL) was added 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indole (66 g, 97 mmol) in portions at room temperature under N2 atmosphere. The mixture was heated to 50 °C and stirred for 16 hours, cooled, diluted with H2O (5 L), and extracted with EtOAc (3 x 1.5 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylpropan-1-ol (30 g, 62% yield) as a solid. LCMS (ESI): m / z [M+H] C 23 H 29 Calculated for BrN2O2 444.1; experimental 445.1.

[0975] Intermediate 1. Alternative synthesis via the Fisher Indole Route.

[0976]

[0977] Step 1. To a mixture of i-PrMgCl (2M in THF, 0.5 L) was added 2.5M n-BuLi in hexanes (333 mL, 833 mmol) dropwise at -10°C under N2 atmosphere over 15 minutes. The mixture was stirred at -10°C for 30 minutes, followed by the addition of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (180 g, 833 mmol) in THF (0.5 L) at -10°C over 30 minutes. The resulting mixture was warmed to -5°C and stirred for 1 hour, followed by the addition of 3,3-dimethyloxane-2,6-dione (118 g, 833 mmol) in THF (1.2 L) at -5°C over 30 minutes. The mixture was warmed to 0°C and stirred for 1.5 hours, then quenched by adjusting the pH to approximately 5 with the addition of pre-cooled 4M HCl in 1,4-dioxane (0.6 L) at 0°C. The mixture was diluted with ice water (3 L) and extracted with EtOAc (3×2.5 L). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-2,2-dimethyl-5-oxopentanoic acid (87 g, 34% yield) as a solid. LCMS (ESI): m / z [M+H] C 15 H 21 The calculated value of NO4 is 279.2; the experimental value is 280.1.

[0978] Step 2. To a mixture of 5-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-2,2-dimethyl-5-oxopentanoic acid (78 g, 279 mmol) in EtOH (0.78 L) was added (4-bromophenyl)hydrazine hydrochloride (68.7 g, 307 mmol) in portions at room temperature under N2 atmosphere. The mixture was heated to 85 ° C and stirred for 2 hours, cooled to room temperature, and then a 4M HCl solution in 1,4-dioxane (69.8 mL, 279 mmol) was added dropwise. The mixture was heated to 85 ° C and stirred for an additional 3 hours, then concentrated under reduced pressure, and the residue was dissolved in TFA (0.78 L). The mixture was heated to 60 ° C and stirred for 1.5 hours, concentrated under reduced pressure, and the residue was adjusted to about pH 5 with saturated NaHCO3, then extracted with EtOAc (3×1.5 L). The combined organic layers were dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-(5-bromo-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indol-3-yl)-2,2-dimethylpropanoic acid and (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoic acid ethyl ester (78 g, crude). LCMS (ESI): m / z [M+H] C 21 H 23 Calculated value of BrN2O3 is 430.1 and C 23 H 27 Calculated for BrN2O3, 458.1; experimental values, 431.1 and 459.1.

[0979] Step 3. To a mixture of 3-(5-bromo-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indol-3-yl)-2,2-dimethylpropanoic acid and ethyl (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoate (198 g, 459 mmol) in DMF (1.8 L) was added CsCO (449 g, 1.38 mol) in portions at 0° C. under N atmosphere. EtI (215 g, 1.38 mmol) in DMF (200 mL) was then added dropwise at 0° C. The mixture was warmed to room temperature and stirred for 4 h, then diluted with brine (5 L) and extracted with EtOAc (3×2.5 L). The combined organic layers were washed with brine (2 x 1.5 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylpropanoate (160 g, 57% yield) as a solid. LCMS (ESI): m / z [M+H] C 25 H 31 Calculated value for BrN2O3: 486.2; experimental value: 487.2.

[0980] Step 4. To a mixture of ethyl 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylpropanoate (160 g, 328 mmol) in THF (1.6 L) was added LiBH (28.6 g, 1.3 mol) at 0° C. under N atmosphere. The mixture was heated to 60° C. for 16 hours, cooled, and quenched with pre-cooled (0° C.) aqueous NH4Cl solution (5 L). The mixture was extracted with EtOAc (3×2 L) and the combined organic layers were washed with brine (2×1 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give two atropisomers of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (as a single atropisomer) (60 g, 38% yield) and (40 g, 26% yield) as solids. LCMS (ESI): m / z [M+H] C 23 H 29 Calculated value for BrN2O2 444.1; experimental value 445.2.

[0981] Intermediate 2. Synthesis ((6 3 S,4S,Z)-1 1-ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 tert-Butyl H-8-oxa-2(4,2)-thiazol-1(5,3)-indol-6(1,3)-pyridazinylheterocycleundecyl-4-yl)carbamate

[0982]

[0983] Step 1. To a solution of (2S)-3-(4-bromo-1,3-thiazol-2-yl)-2-[(tert-butoxycarbonyl)amino]propanoic acid methyl ester (110 g, 301.2 mmol) in THF (500 mL) and H2O (200 mL) was added LiOH (21.64 g, 903.6 mmol) at room temperature. The resulting solution was stirred for 1 hour and then concentrated under reduced pressure. The resulting residue was adjusted to pH 6 with 1M HCl and then extracted with DCM (3x500 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (108 g, crude). LCMS (ESI) m / z: [M+H] C 11 H 15 Calculated for BrN2O4S: 351.00; found: 351.0.

[0984] Step 2. To a solution of (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (70 g, 199.3 mmol) in DCM (500 mL) was added (3S)-1,2-diazacyclohexane-3-methyl carboxylate bis(trifluoroacetic acid) salt (111.28 g, 298.96 mmol), NMM (219.12 mL, 1993.0 mmol), EDCI (76.41 g, 398.6 mmol) and HOBt (5.39 g, 39.89 mmol) at 0 ° C. The resulting solution was warmed to room temperature and stirred for 1 hour. The reactant was then quenched with H2O (500 mL) and extracted with EtOAc (3x500 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→50% EtOAc / petroleum ether) to give the desired product (88.1 g, 92.6% yield). LCMS (ESI) m / z: [M+H]C 17 H 25Calculated value for BrN4O5S: 477.08; experimental value 477.1.

[0985] Step 3. To a solution of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (60 g, 134.7 mmol) in toluene (500 mL) was added bis(pinacolato)diboron (51.31 g, 202.1 mmol), Pd(dppf)Cl2 (9.86 g, 13.48 mmol) and KOAc (26.44 g, 269.4 mmol) at room temperature. The reaction mixture was then heated to 90 ° C and stirred for 2 hours. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. Purification by silica gel chromatography (0→50% EtOAc / petroleum ether) gave the desired product (60.6 g, 94.0% yield). LCMS (ESI) m / z: [M+H] C 29 H 41 Calculated value of BN2O4: 493.32; experimental value 493.3.

[0986] Step 4. To a solution of (S)-3-(1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (30 g, 60.9 mmol) in toluene (600 mL), dioxane (200 mL) and H2O (200 mL) were added (S)-methyl 1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (43.62 g, 91.4 mmol), K3PO4 (32.23 g, 152.3 mmol) and Pd(dppf)Cl2 (8.91 g, 12.18 mmol) at room temperature. The resulting solution was heated to 70 ° C and stirred overnight. The reaction mixture was then cooled to room temperature and quenched with H2O (200mL). The resulting mixture was extracted with EtOAc (3x1000mL) and the combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 → 90% EtOAc / petroleum ether) to obtain the desired product (39.7g, 85.4% yield). LCMS (ESI) m / z: [M+H] C 40 H 54 Calculated value of N6O7S: 763.39; experimental value 763.3.

[0987] Step 5. To a solution of (S)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (39.7 g, 52.0 mmol) in THF (400 mL) and HO (100 mL) was added LiOH HO (3.74 g, 156.2 mmol) at room temperature. The resulting mixture was stirred for 1.5 hours and then concentrated under reduced pressure. The residue was acidified to pH 6 with 1 M HCl and extracted with DCM (3×1000 mL). The combined organic layers were dried over Na SO , filtered and concentrated under reduced pressure to give the desired product (37.9 g, crude). LCMS (ESI) m / z: [M+H] C 39 H 52 Calculated value of N6O7S: 749.37; experimental value 749.4.

[0988] Step 6. To a solution of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid (37.9 g, 50.6 mmol), HOBt (34.19 g, 253.0 mmol) and DIPEA (264.4 mL, 1518 mmol) in DCM (4 L) was added EDCI (271.63 g, 1416.9 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was then quenched with H2O and washed with 1M HCl (4x1 L). The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→70% EtOAc / petroleum ether) to give the desired product (30 g, 81.1% yield). LCMS (ESI) m / z: [M+H]C 39 H 50 Calculated value of N6O6S: 731.36; experimental value 731.3.

[0989] Intermediate 3. Synthesis of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine

[0990]

[0991] Step 1. Under argon atmosphere, to a stirred solution of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (80.00 g, 370.24 mmol, 1.00 equiv) and bis(pinacolato)diboron (141.03 g, 555.3 mmol, 1.50 equiv) in THF (320 mL) was added dtbpy (14.91 g, 55.5 mmol) and chloro(1,5-cyclooctadiene)iridium(I) dimer (7.46 g, 11.1 mmol). The resulting mixture was stirred at 75 ° C for 16 hours under argon atmosphere. The mixture was concentrated under reduced pressure. The resulting mixture was dissolved in EtOAc (200 mL) and the mixture was adjusted to pH 10 with water (600 mL) containing Na2CO3 (40 g) and NaOH (10 g) (mass 4: 1). The aqueous layer was extracted with EtOAc (800 mL). The aqueous phase was acidified with HCl (6N) to pH = 6 to precipitate the desired solid to give 5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-ylboronic acid (50 g, 52.0% yield) as a light yellow solid. LCMS (ESI): m / z [M+H] C8H 11 Calculated for BBrNO3: 259.0; experimental: 260.0.

[0992] Step 2. To a stirred solution of 5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-ylboronic acid (23.00 g, 88.5 mmol) in ACN (230 mL) was added NIS (49.78 g, 221.2 mmol) at room temperature under argon atmosphere. The resulting mixture was stirred at 80 ° C. under argon atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The resulting mixture was dissolved in DCM (2.1 L) and washed with Na2S2O3 (3x500 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (20 g, 66.0% yield). LCMS (ESI): m / z [M+H] calculated value for C8H9BrINO 340.9; found value 341.7.

[0993] Intermediate 4. Synthesis ((6 3 S,4S,Z)-11-ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-11 tert-Butyl H-8-oxa-2(4,2)-thiazol-1(5,3)-indol-6(1,3)-pyridazinylheterocycleundecyl-4-yl)carbamate

[0994]

[0995] Step 1. Into a 3L three-necked round-bottom flask purged and maintained with an argon inert atmosphere were placed 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (147 g, 429.8 mmol), benzyl piperazine-1-carboxylate (94.69 g, 429.8 mmol), Pd(OAc)2 (4.83 g, 21.4 mmol), BINAP (5.35 g, 8.6 mmol), Cs2CO3 (350.14 g, 1074.6 mmol), and toluene (1 L). The resulting solution was stirred overnight at 100°C in an oil bath. After the reaction was complete, the reaction mixture was cooled to 25°C. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column using ethyl acetate / hexane (1:1). The solvent was removed under reduced pressure to give (S)-benzyl 4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (135 g, 65.1% yield) as a dark yellow solid. LCMS (ESI): m / z [M+H] C 20 H 24 Calculated for BrN3O3 433.1; experimental 434.1.

[0996] Step 2. Into a 3 L three-necked round-bottom flask purged and maintained with an argon inert atmosphere was placed benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-yl]piperazine-1-carboxylate (135 g, 310.8 mmol), bis(pinacolato)diboron (86.82 g, 341.9 mmol), Pd(dppf)Cl2 (22.74 g, 31.0 mmol), KOAc (76.26 g, 777.5 mmol), and toluene (1 L). The resulting solution was stirred in an oil bath at 90° C. for 2 days. The reaction mixture was cooled to 25° C. The resulting mixture was concentrated under vacuum. The residue was applied to a neutral alumina column using ethyl acetate / hexane (1:3). The solvent was removed under reduced pressure to give benzyl (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperazine-1-carboxylate (167 g, crude) as a dark yellow solid. LCMS (ESI): m / z [M+H] C 26 H 36 Calculated value for BN3O5 481.3; experimental value 482.1.

[0997] Step 3. Into a 3 L three-necked round-bottom flask purged and maintained with an argon inert atmosphere were placed (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperazine-1-carboxylate (167 g, 346.9 mmol), 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-iodo-1H-indole (224.27 g, 346.9 mmol), Pd(dppf)Cl2 (25.38 g, 34.6 mmol), dioxane (600 mL), H2O (200 mL), K3PO4 (184.09 g, 867.2 mmol), and toluene (200 mL). The resulting solution was stirred in an oil bath at 70°C overnight. After the reaction is complete, the reaction mixture is cooled to 25 ° C. The resulting mixture is concentrated under vacuum. The residue is applied to a silica gel column using ethyl acetate / hexane (1: 1). The solvent is removed under reduced pressure to obtain (S) -4- (5- (5- bromo -3- (3- ((tert-butyldiphenylsilyl) oxy) -2,2- dimethylpropyl) -1H- indol -2- bases) -6- (1- methoxyethyl) pyridin-3-yl) piperazine -1- benzyl formate (146g, 48.1% yield) as a yellow solid. LCMS (ESI): m / z [M + H] C 49 H 57 Calculated value for BrN4O4Si 872.3; experimental value 873.3.

[0998] Step 4. To a stirred mixture of (S)-benzyl 4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (146 g, 167.0 mmol) and CsCO (163.28 g, 501.1 mmol) in DMF (1200 mL) was added CHI (52.11 g, 334.0 mmol) in multiple portions at 0° C. under N atmosphere. The final reaction mixture was stirred at 25° C. for 12 h. The desired product could be detected by LCMS. The resulting mixture was diluted with EA (1 L) and washed with brine (3×1.5 L). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to obtain (S)-benzyl 4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (143 g, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS (ESI): m / z [M+H] C 51 H61 Calculated value for BrN4O4Si: 900.4; experimental value: 901.4.

[0999] Step 5. To a stirred mixture of (S)-benzyl 4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (143 g, 158.5 mmol) in DMF (1250 mL) was added CsF (72.24 g, 475.5 mmol). The reaction mixture was then stirred at 60 °C under N2 atmosphere for 2 days. The desired product could be detected by LCMS. The resulting mixture was diluted with EA (1 L) and washed with brine (3x1 L). The organic phase was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 3) to give two atropisomers, (S)-benzyl 4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate A (38 g, 36% yield, RT = 1.677 min in 3 min LCMS (0.1% FA)) and B (34 g, 34% yield, RT = 1.578 min in 3 min LCMS (0.1% FA)), both as yellow solids. LCMS (ESI): m / z [M+H] C 35 H 43 Calculated value for BrN4O4 663.2; experimental value 662.2.

[1000] Step 6. Into a 500 mL three-necked round-bottom flask purged and maintained with a nitrogen inert atmosphere was placed benzyl (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate A (14 g, 21.1 mmol), bis(pinacolato)diboron (5.89 g, 23.21 mmol), Pd(dppf)Cl2 (1.54 g, 2.1 mmol), KOAc (5.18 g, 52.7 mmol), and toluene (150 mL). The resulting solution was stirred in an oil bath at 90° C. for 5 hours. The reaction mixture was cooled to 25° C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 3) to give (S)-benzyl 4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (12 g, 76.0% yield) as a yellow solid. LCMS (ESI): m / z [M+H] C 41 H 55 Calculated value for BN4O6: 710.4; experimental value: 711.3.

[1001] Step 7. Into a 250 mL round-bottom flask purged and maintained with an argon inert atmosphere were placed benzyl (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (10.8 g, 15.2 mmol), (3S)- 1-[(2S)-3-(4-bromo-1,3-thiazol-2-yl)-2-[(tert-butoxycarbonyl)amino]propionyl]-1,2-diazacyclohexane-3-carboxylic acid methyl ester (7.98g, 16.7mmol), Pd(dtbpf)Cl2(0.99g, 1.52mmol), K3PO4(8.06g, 37.9mmol), toluene (60mL), dioxane (20mL), H2O(20mL). The resulting solution was stirred at 70°C in an oil bath for 3 hours. The reaction mixture was cooled to 25°C. The resulting solution was extracted with EtOAc (2x50mL) and concentrated under reduced pressure. The residue was applied to a silica gel column using ethyl acetate / hexane (10:1). The solvent was removed to give (S)-methyl 1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (8 g, 50.9% yield) as a yellow solid. LCMS (ESI): m / z [M+H] C 52 H 68 Calculated value for N8O9S: 980.5; experimental value: 980.9.

[1002] Step 8. To a stirred mixture of (S)-methyl 1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (12 g, 12.23 mmol) in THF (100 mL) / HO (100 mL) was added LiOH (2.45 g, 61.1 mmol) under N atmosphere and the resulting mixture was stirred at 25° C. for 2 h. The desired product was detected by LCMS. THF was concentrated under reduced pressure. The pH of the aqueous phase was acidified to 5 with HCL (1 N) at 0° C. The aqueous layer was extracted with DCM (3 x 100 ml). The organic phase was concentrated under reduced pressure to give (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (10 g, 84.5% yield) as a light yellow solid. LCMS (ESI): m / z [M+H] C 51 H 66 Calculated value for N8O9S 966.5; experimental value 967.0.

[1003] Step 9. Into a 3 L round-bottom flask purged and maintained with a nitrogen inert atmosphere was placed (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (18 g, 18.61 mmol), ACN (1.8 L), DIEA (96.21 g, 744.4 mmol), EDCI (107.03 g, 558.3 ​​mmol), and HOBT (25.15 g, 186.1 mmol). The resulting solution was stirred at 25° C. overnight. After completion of the reaction, the mixture was concentrated under vacuum. The resulting solution was diluted with DCM (1 L). The resulting mixture was washed with HCl (3x1 L, 1 N aqueous). The resulting mixture was washed with water (3x1 L). The organic layer was then concentrated and the residue was applied to a silica gel column using ethyl acetate / hexane (1: 1). The solvent was removed under reduced pressure to obtain 4-(5-(6- methyl)- thiazolinone) as a light yellow solid. 3S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1-(4- ...2-(4-(tert-butoxycarbonyl)amino)-1-(tert-butoxycarbonyl)amino)-2-(tert-butoxycarbonyl)amino)-1-(tert-butoxycarbonyl)amino)-1-(tert-butoxycarbonyl) 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-Oxa-2(4,2)-thiazolin-1(5,3)-indol-6(1,3)-pyridazine heterocyclic undecylphan-1 2 -yl)-benzyl 6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (10.4 g, 54.8% yield). LCMS (ESI): m / z [M+H] C 51 H 64 Calculated value for N8O8S: 948.5; experimental value: 949.3.

[1004] Step 10. Into a 250 mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 4-(5-((6 3 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1-(4- ...2-(4-(tert-butoxycarbonyl)amino)-1-(tert-butoxycarbonyl)amino)-2-(tert-butoxycarbonyl)amino)-1-(tert-butoxycarbonyl)amino)-1-(tert-butoxycarbonyl) 1 -ethyl-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-Oxa-2(4,2)-thiazolin-1(5,3)-indol-6(1,3)-pyridazine heterocyclic undecylphan-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (10.40 g, 10.9 mmol), Pd(OH)2 / C (5 g, 46.9 mmol), MeOH (100 mL). The resulting solution was stirred at 25 ° C under 2 atm H2 atmosphere for 3 hours. The solid was filtered out and the filter cake was washed with MeOH (3x100 mL). The combined organic phase was then concentrated under reduced pressure to give ((6 3 S,4S,Z)-11-ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6-Hexahydro-1 1 tert-Butyl H-8-oxa-2(4,2)-thiazol-1(5,3)-indol-6(1,3)-pyridazinylheterocycloundecanoyl-4-yl)carbamate (8.5 g, 90.4% yield). LCMS (ESI): m / z [M+H] C 43 H 58 Calculated value for N8O6S 814.4; experimental value 815.3.

[1005] Step 11. Into a 1000 mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, ((6 3 S,4S,Z)-11-ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-2 (4,2)-thiazole-1 (5,3)-indole-6 (1,3)-pyridazine heterocycle undecyl-4-yl) carbamic acid tert-butyl ester (8.5g, 10.4mmol), MeOH (100mL), AcOH (1.88g, 31.2mmol) and stirred for 15 minutes. Then HCHO (1.88g, 23.15mmol, 37% aqueous solution) and NaBH3CN (788mg, 12.5mmol) were added at 25°C. The resulting solution was stirred at 25°C for 3 hours. The resulting mixture was quenched with 100mL of water and concentrated under reduced pressure to remove MeOH. The resulting solution was diluted with 300mL of DCM. The resulting mixture was washed with water (3x100mL). The solvent was removed to obtain ((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 tert-Butyl H-8-oxa-2(4,2)-thiazol-1(5,3)-indol-6(1,3)-pyridazinylheterocycloundecyl-4-yl)carbamate (8.2 g, 90.1% yield). LCMS (ESI): m / z [M+H] C44 H 60 Calculated value for N8O6S 828.4; experimental value 829.3.

[1006] Intermediate 5. Synthesis (6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-Oxa-1(5,3)-indole-6(1,3)-pyridazin-2(1,3)-benzeneheterocyclic undecylphane-5,7-dione

[1007]

[1008] Step 1. To a solution of (2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (100 g, 290 mmol) in DMF (1 L) was added NaHCO (48.8 g, 581.1 mmol) and MeI (61.9 g, 435.8 mmol) at room temperature. The reaction mixture was stirred for 16 hours and then quenched with H2O (1 L) and extracted with EtOAc (3x1 L). The combined organic layers were washed with brine (3x500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (13% EtOAc / petroleum ether) to give the final product (109 g, crude). LCMS (ESI) m / z [M+Na] C 15 H 20 Calculated for BrNO4: 380.05; experimental value: 380.0.

[1009] Step 2. To a stirred solution of (2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid methyl ester (108 g, 301.5 mmol) and bis(pinacolato)diboron (99.53 g, 391.93 mmol) in dioxane (3.2 L) was added KOAc (73.97 g, 753.70 mmol) and Pd(dppf)Cl2 (22.06 g, 30.15 mmol). The reaction mixture was heated to 90 ° C for 3 hours and then cooled to room temperature and extracted with EtOAc (2×3 L). The combined organic layers were washed with brine (3×800 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% EtOAc / petroleum ether) to give the product (96 g, 78.6% yield). LCMS (ESI) m / z [M+Na] C 21 H 32 Calculated value for BNO6: 428.22; experimental value: 428.1.

[1010] Step 3. To a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (94 g, 231.9 mmol) and 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate (75.19 g, 231.93 mmol) in dioxane (1.5 L) and H O (300 mL) was added K CO (64.11 g, 463.85 mmol) and Pd(DtBPF)Cl (15.12 g, 23.19 mmol). The reaction mixture was heated to 70° C. and stirred for 4 hours. The reaction mixture was extracted with EtOAc (2×2 L) and the combined organic layers were washed with brine (3×600 mL), dried over Na SO , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% EtOAc / petroleum ether) to give the product (130 g, crude). LCMS (ESI) m / z [M+H] C 30 H 38 Calculated value for N2O6: 523.28; experimental value: 523.1.

[1011] Step 4. To a solution of (2S)-3-(3-[3-[3-(acetyloxy)-2,2-dimethylpropyl]-1H-indol-5-yl]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid methyl ester (95.0 g, 181.8 mmol) and iodine (36.91 g, 145.41 mmol) in THF (1 L) was added AgOTf (70.0 g, 272.7 mmol) and NaHCO (22.9 g, 272.65 mmol) at -10 ° C. The reaction mixture was stirred at 0 ° C for 30 minutes and then quenched by adding saturated Na2S2O3 aqueous solution (100 mL). The resulting mixture was extracted with EtOAc (3x1 L) and the combined organic layers were washed with brine (3x500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / petroleum ether) to give (S)-methyl 3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (49.3 g, 41.8% yield). LCMS (ESI) m / z [M+H] C 30 H 37 Calculated value of IN2O6: 649.18; experimental value: 649.1.

[1012] Step 5. To a solution of methyl (2S)-3-(3-[3-[3-(acetyloxy)-2,2-dimethylpropyl]-2-iodo-1H-indol-5-yl]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (60 g, 92.5 mmol) in THF (600 mL) was added a solution of LiOH.HO (19.41 g, 462.5 mmol) in HO (460 mL). The resulting solution was stirred overnight and then the pH was adjusted to 6 with HCl (1 M). The resulting solution was extracted with EtOAc (2×500 mL) and the combined organic layers were washed with brine (2×500 mL), dried over NaSO, filtered and concentrated under reduced pressure to give the product (45 g, 82.1% yield). LCMS (ESI) m / z [M+Na] C 27 H 33 Calculated value for IN2O6: 615.13; experimental value: 615.1.

[1013] Step 6. To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl]phenyl]propanoic acid (30 g, 50.6 mmol) and (3S)-methyl 1,2-diazacyclohexane-3-carboxylate (10.9 g, 75.9 mmol) in DCM (400 mL) was added NMM (40.97 g, 405.08 mmol), HOBt (2.05 g, 15.19 mmol) and EDCI (19.41 g, 101.27 mmol). The reaction mixture was stirred overnight and then washed with saturated aqueous NH4Cl (2 x 200 mL) and brine (2 x 200 mL), and the mixture was filtered and concentrated under reduced pressure to give the product (14 g, 38.5% yield). LCMS (ESI) m / z [M+H] C 33 H 43 Calculated value for IN4O6: 718.23; experimental value: 719.4.

[1014] Step 7. To a solution of (S)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate (92 g, 128.0 mmol) in THF (920 mL) was added a solution of LiOH.HO (26.86 g, 640.10 mmol) in HO (640 mL) at 0°C. The reaction mixture was stirred for 2 h and then concentrated under reduced pressure to give the product (90 g, crude). LCMS (ESI) m / z [M+H] C 32 H 41 Calculated for IN4O6: 705.22; experimental: 705.1.

[1015] Step 8. To a solution of (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl]phenyl]propanoyl]-1,2-diazacyclohexane-3-carboxylic acid (90 g, 127.73 mmol) in DCM (10 L) was added HOBt (34.52 g, 255.46 mmol), DIPEA (330.17 g, 2554.62 mmol) and EDCI (367.29 g, 1915.96 mmol) at 0°C. The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The mixture was extracted with DCM (2 x 2 L) and the combined organic layers were washed with brine (3 x 1 L), dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / petroleum ether) to give the product (70 g, 79.8% yield). LCMS (ESI) m / z [M+H] C 32 H 39 Calculated for IN4O5: 687.21; experimental: 687.1.

[1016] Step 9. Charge (6 3 S,4S)-1 2 -iodo-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 tert-Butyl H-8-oxa-1(5,3)-indole-6(1,3)-pyridazin-2(1,3)-benzeneheterocycloundecane-4-yl)carbamate (22.0 g, 32.042 mmol), toluene (300.0 mL), Pd2(dba)3 (3.52 g, 3.845 mmol), S-Phos (3.95 g, 9.613 mmol) and KOAc (9.43 g, 96.127 mmol). 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26.66 g, 208.275 mmol) was added dropwise to the mixture under stirring at room temperature. The resulting solution was stirred at 60 ° C for 3 hours. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography to give the product as a solid (22 g, 90% yield). LCMS (ESI) m / z [M+H] C 38 H 51 Calculated value for BN4O7: 687.3; experimental value: 687.4.

[1017] Step 10. Under N2 atmosphere, ((6 3 S,4S)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6- 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 A mixture of tert-butyl H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecyl-4-yl)carbamate (2.0 g, 2.8 mmol), 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (0.60 g, 2.8 mmol), Pd(dppf)Cl2 (0.39 g, 0.5 mmol), and K3PO4 (1.2 g, 6.0 mmol) in dioxane (50 mL) and H2O (10 mL) was heated to 70°C and stirred for 2 hours. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the product as a solid (1.5 g, 74% yield). LCMS (ESI) m / z [M+H] C 40 H 49 Calculated value for N5O6: 695.4; experimental value: 696.5.

[1018] Step 11. Add ((6 3 S,4S)-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1To a solution of tert-butyl H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecyl-4-yl)carbamate (20 g, 28.7 mmol) and CsCO (18.7 g, 57.5 mmol) in DMF (150 mL) was added a solution of EtI (13.45 g, 86.22 mmol) in DMF (50 mL). The resulting mixture was stirred at 35 ° C. overnight and then diluted with H O (500 mL). The mixture was extracted with EtOAc (2 x 300 mL) and the combined organic layers were washed with brine (3 x 100 mL), dried over Na SO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (4.23 g, 18.8% yield) and the atropisomer (5.78 g, 25.7% yield) as a solid. LCMS (ESI) m / z [M+H] C 42 H 53 Calculated value for N5O6: 724.4; experimental value: 724.6.

[1019] Step 12. 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 A mixture of tert-butyl H-8-oxa-1(5,3)-indole-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecyl-4-yl)carbamate (1.3 g, 1.7 mmol) in TFA (10 mL) and DCM (20 mL) was stirred at 0° C. for 2 hours. The mixture was concentrated under reduced pressure to give the product as a solid (1.30 g, crude). LCMS (ESI) m / z [M+H] C 37 H 45 Calculated value for N5O4: 623.3; experimental value: 624.4.

[1020] Intermediate 6: Synthesis of (S)-3-(5-bromo-1-ethyl-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[1021]

[1022] Step 1. To a stirred solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (100 g, 224.517 mmol) and EtN (45.44 g, 449.034 mmol) in DCM (1 L) was added DMAP (2.74 g, 22.452 mmol) and AcO (27.50 g, 269.420 mmol) in multiple portions at 0 ° C under argon atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure and then diluted with EtOAc (1000 mL). The resulting mixture was washed with 1M HCl (500 mL), then with saturated NaHCO (500 mL) and brine (500 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with petroleum ether (500 mL) to give the product as a white solid (93.3 g, 85% yield). LCMS (ESI) m / z [M+H] C 25 H 31 Calculated value for BrN2O3: 487.16; experimental value: 489.2

[1023] Step 2. To a stirred solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (93.3 g, 191.409 mmol) and B2PIN2 (72.91 g, 287.113 mmol) in THF (370 mL) was added dtbpy (7.71 g, 28.711 mmol) and chloro(1,5-cyclooctadiene)iridium(I) dimer (6.43 g, 9.570 mmol) in portions at room temperature under argon atmosphere. The resulting mixture was stirred at 75 ° C overnight. The resulting mixture was concentrated under reduced pressure to give the product as an oil (190 g, crude). LCMS (ESI) m / z [M + H]; C 25 H 32 Calculated value for BBrN2O5: 531.17; Exp. value: 533.3

[1024] Step 3. To a stirred solution of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (110 g, 207.059 mmol) and chloramine-T trihydrate (349.96 g, 1242.354 mmol) in THF (550 mL) was added a solution of NaI (186.22 g, 1242.354 mmol) in HO (225 mL) in multiple portions at 0° C. under air atmosphere. The resulting mixture was stirred at 50° C. under argon atmosphere overnight. The resulting mixture was concentrated under reduced pressure and then washed with CHCl (500 mL). The resulting mixture was filtered and the filter cake was washed with CHCl (3×250 mL). The filtrate was extracted with CHCl (3×500 mL). The combined organic layers were washed with Na2S2O3 (500 mL), washed with brine (2 x 200 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

[1025] Intermediate 7: Synthesis of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[1026]

[1027] Step 1. To a stirred solution of 3-(5-bromo-1-ethyl-2-{5-iodo-2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropyl acetate (9 g, 14.674 mmol), (R)-octahydro-2H-pyrido[1,2-a]pyrazine (2.469 g, 17.609 mmol), CsCO (11.9523 g, 36.685 mmol) and BINAP (456.85 mg, 0.734 mmol) in toluene (63 mL) was added Pd(OAc) (329.44 mg, 1.467 mmol) in portions at room temperature under argon atmosphere. The resulting mixture was stirred at 100° C. for 6 h, then the mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (8% MeOH / DCM) to give the product as a solid (6 g, 65% yield). LCMS (ESI) m / z [M+H] C 33 H 45 Calculated value for BrN4O3: 625.28; experimental value: 627.4

[1028] Intermediate 8. Synthesis (6 3 S,4S)-4-amino-1 1 -ethyl-2 5 -(Fluoromethyl)-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-Oxa-1(5,3)-indole-6(1,3)-pyridazin-2(1,3)-benzeneheterocyclic undecylphane-5,7-dione

[1029]

[1030] Step 1. BAST (247.45 g, 1118.454 mmol) was added dropwise to a solution of (3-bromo-5-iodophenyl)methanol (175.0 g, 559.227 mmol) in DCM (2 L) at 0 ° C. The resulting mixture was stirred at room temperature for 16 hours. The reactant was quenched with saturated aqueous NaHCO at 0 ° C. The organic layer was washed with H2O (3x700 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% EtOAc / petroleum ether) to obtain the desired product (120 g, 68% yield).

[1031] Step 2. DMF (350.0 mL) and I (967.12 mg, 3.810 mmol) containing Zn powder (32.40 g, 495.358 mmol) were added to a 1000 mL three-necked round-bottom flask. To the mixture was added a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropionic acid methyl ester (27.0 g, 82.03 mmol) in DMF (10 mL). The mixture was heated to 30 ° C for 10 minutes. Then, a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropionic acid methyl ester (54.0 g, 164.07 mmol) in DMF (20 mL) was added to the mixture. The resulting mixture was stirred at room temperature for 30 minutes and filtered. At room temperature under argon atmosphere, the resulting solution is added to a mixture of 1-bromo-3-(fluoromethyl)-5-iodobenzene (60g, 190.522mmol), tri(furan-2-yl)phosphine (2.65g, 11.431mmol) and Pd(dba)(3.49g, 3.810mmol) in DMF (400mL) and the reaction mixture is heated to 60 DEG C for 10 minutes, then the oil bath is removed. The resulting mixture is stirred for approximately 1 hour until the temperature is cooled to 50 DEG C. The reactant is quenched with NH4Cl aqueous solution (3000mL) and the resulting mixture is extracted with EtOAc (3x1000mL). The combined organic layer is washed with brine (2x1000mL) and through anhydrous Na2SO4 drying. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (9% EtOAc / petroleum ether) to obtain the desired product (45g, 60% yield).

[1032] Step 3. A mixture of methyl (2S)-3-[3-bromo-5-(fluoromethyl)phenyl]-2-[(tert-butoxycarbonyl)amino]propanoate (75.28 g, 192.905 mmol), (S)-3-(1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (95 g, 192.905 mmol), Pd(dppf)Cl2 (14.11 g, 19.291 mmol) and K2CO3 (53.32 g, 385.810 mmol) in dioxane (900 mL) and H2O (180 mL) was stirred at 80°C for 2 h. The obtained mixture was concentrated under reduced pressure and then diluted with H o. The obtained mixture was extracted with EtOAc (3x1200mL) and the combined organic layer was washed with H o (3x500mL) and dried over anhydrous Na sO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / petroleum ether) to obtain the desired product (105g, 80% yield). LCMS (ESI) m / z: [M+H] C 39 H 50 Calculated value for FN3O6: 676.38; experimental value: 676.1.

[1033] Step 4. To a stirred solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5-(fluoromethyl)phenyl)propanoate (108 g, 159.801 mmol) in THF (500 mL) was added a solution of LiOH•HO (11.48 g, 479.403 mmol) in HO (500 mL) at 0°C. The resulting mixture was stirred at 0°C for 2 hours and then acidified to pH 6 with 1 M HCl(aq). The mixture was extracted with EtOAc (3 x 800 mL) and the combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the desired product (101 g, crude). LCMS (ESI) m / z: [M+H] C 38 H 48 Calculated value of FN3O6: 662.36; experimental value 662.1.

[1034] Step 5. To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5-(fluoromethyl)phenyl)propanoic acid (103 g, 155.633 mmol) and NMM (157.42 g, 1556.330 mmol) in DCM (1200 mL) at 0° C. was added methyl (3S)-1,2-diazacyclohexane-3-carboxylate (33.66 g, 233.449 mmol), HOBt (10.51 g, 77.816 mmol) and EDCI (59.67 g, 311.265 mmol) in portions. The resulting mixture was stirred at room temperature for 16 h. The organic layer was then washed with 0.5M HCl (2x1000mL) and brine (2x800mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / petroleum ether) to give the desired product (103g, 83% yield). LCMS (ESI) m / z: [M+H] C 44 H 58 Calculated value for FN5O7: 788.44; experimental value: 788.1.

[1035] Step 6. To a stirred solution of (S)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5-(fluoromethyl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate (103 g, 130.715 mmol) in THF (700 mL) at 0° C. was added a solution of LiOH·HO (27.43 g, 653.575 mmol) in HO (700 mL). The resulting mixture was stirred at 0° C. for 2 h and then neutralized to pH 6 with 1 M HCl. The resulting mixture was extracted with EtOAc (3 x 800 mL) and the combined organic layers were washed with brine (2 x 600 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired product (101 g, crude). LCMS (ESI) m / z: [M+H]C 43 H 56 Calculated value for FN5O7: 774.43; experimental value: 774.1.

[1036] Step 7. To a stirred solution of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5-(fluoromethyl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid (101 g, 130.50 mmol) in DCM (5500 mL) was added DIPEA (227.31 mL, 1305.0 mmol), HOBt (88.17 g, 652.499 mmol), and EDCI (375.26 g, 1957.498 mmol) at 0°C. The resulting mixture was stirred at room temperature overnight. The mixture was then washed with 0.5M HCl (2 x 2000 mL), brine (2 x 2000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / petroleum ether) to give the desired product (68 g, 65% yield). LCMS (ESI) m / z: [M+H]C 43 H 54 Calculated value of FN5O6: 756.42; experimental value 756.4.

[1037] Step 8. Add ((6 3 S,4S)-1 1 -ethyl-2 5 -(Fluoromethyl)-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 To a stirred solution of tert-butyl H-8-oxa-1(5,3)-indole-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecyl-4-yl)carbamate (350 mg, 0.403 mmol) in DCM (4 mL) was added TFA (1.50 mL). The resulting mixture was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure to give the desired product (600 mg, crude). LCMS (ESI) m / z: [M+H] C 38 H 46 Calculated value of FN5O4: 656.36; experimental value 656.4.

[1038] Intermediate 9. Synthesis of (3S)-1-((2S)-3-(5-bromo-3-((tert-butyldiphenylsilyl)oxy)-3,6-dihydropyridin-1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester

[1039]

[1040] Step 1. To a stirred solution of 3,5-dibromopyridine (48 g, 202.6 mmol, 1 eq) in ACN (480 mL) was added BnBr (51.9 g, 303.9 mmol, 1.5 eq) dropwise at room temperature. The resulting mixture was stirred at 60 ° C overnight and then concentrated under reduced pressure to give 1-benzyl-3,5-dibromopyridin-1-ium (76 g, crude) as a white solid. ESI-MS m / z = 325.9 [M] + ,327.9[M+2] + ,329.9[M+4] + MW calculated value: 325.9

[1041] Step 2. To a stirred mixture of 1-benzyl-3,5-dibromopyridin-1-ium (40 g, 121.9 mmol, 1.00 equiv) in DCM (400 mL) and EtOH (80 mL) was added NaBH(AcO)3 (129.2 g, 609.7 mmol, 5 equiv) in portions at 0 ° C. The resulting mixture was stirred at room temperature under an argon atmosphere for 4 hours, and then saturated brine (3x40 mL) was added. The aqueous phase was extracted with CHCl (4x50 mL), dried over anhydrous NaSO4 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 1-benzyl-3,5-dibromo-1,2,3,6-tetrahydropyridine (19.1 g, 47.4% yield) as a yellow oil. ESI-MS m / z=330.2[M+H] + ,332.2[M+H+2] + ,334.2[M+H+4] + MW calculated value: 328.9

[1042] Step 3. To a stirred mixture of 1-benzyl-3,5-dibromo-1,2,3,6-tetrahydropyridine (17.4 g, 52.6 mmol, 1.0 equiv) in ACN (87 mL) and H2O (87 mL) was added NaHCO3 (22.08 g, 262.800 mmol, 5 equiv) in portions at room temperature. The resulting mixture was stirred at 60 ° C under an argon atmosphere for 3 hours. The mixture was then diluted with brine (300 mL) and the aqueous layer was extracted with EtOAc (4x100 mL). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 1-benzyl-5-bromo-1,2,3,6-tetrahydropyridine-3-ol (10 g, 70.9% yield) as a yellow oil. ESI-MS m / z=268.1[M+H] + ; MW calculated value: 267.0.

[1043] Step 4. To a stirred mixture of imidazole (5.1 g, 74.6 mmol, 2 equiv) and 1-benzyl-5-bromo-1,2,3,6-tetrahydropyridine-3-ol (10 g, 37.3 mmol, 1.01 equiv) in DCM (100 mL) was added TBDPSCl (15.4 g, 55.9 mmol, 1.5 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature under an argon atmosphere and then concentrated under reduced pressure. The residue was purified by chromatography to give 1-benzyl-5-bromo-3-((tert-butyldiphenylsilyl)oxy)-1,2,3,6-tetrahydropyridine (18 g, 95.2% yield) as a yellow oil. ESI-MS m / z=506.4[M+H] + ; MW calculated value: 505.1.

[1044] Step 5. To a stirred solution of 1-benzyl-5-bromo-3-((tert-butyldiphenylsilyl)oxy)-1,2,3,6-tetrahydropyridine (11.7 g, 23.1 mmol, 1.0 equiv) in DCM (1.2 L) was added 2-chloroethyl chloroformate (13.2 g, 92.4 mmol, 4 equiv) at 0 ° C under an argon atmosphere. The resulting mixture was stirred at 40 ° C under an argon atmosphere for 4 hours and concentrated under reduced pressure. MeOH (1.2 L) was then added dropwise at room temperature under an argon atmosphere and stirred at 70 ° C under an argon atmosphere for 2 hours, and the resulting mixture was then concentrated under reduced pressure. The remaining residue was purified by chromatography to give 5-bromo-3-((tert-butyldiphenylsilyl)oxy)-1,2,3,6-tetrahydropyridine (6.2 g, 64.4% yield) as a yellow oil. ESI-MS m / z=416.2[M+H] + ; MW calculated value: 415.1.

[1045] Step 6. To a stirred solution of 5-bromo-3-((tert-butyldiphenylsilyl)oxy)-1,2,3,6-tetrahydropyridine (11.2 g, 26.9 mmol, 1.0 eq) in ACN (90 mL) and H2O (30 mL) was added (S)-tert-butyl(2-oxooxetan-3-yl)carbamate (6.1 g, 32.4 mmol, 1.2 eq) and Cs2CO3 (21.9 g, 67.5 mmol, 2.5 eq) at room temperature. The resulting mixture was stirred at 40°C for 4 h and concentrated under reduced pressure. The remaining residue was purified by chromatography to give (2S)-3-(5-bromo-3-((tert-butyldiphenylsilyl)oxy)-3,6-dihydropyridin-1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (11.2 g, 68.7% yield) as a white solid. ESI-MS m / z = 603.0 [M+H] + ; MW calculated value: 602.2.

[1046] Step 7. To a stirred solution of (2S)-3-(5-bromo-3-((tert-butyldiphenylsilyl)oxy)-3,6-dihydropyridin-1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (5.5 g, 9.2 mmol, 1 eq) in DCM (55 mL) was added DIEA (47.5 g, 367.1 mmol, 40 eq), (S)-methyl hexahydropyridazine-3-carboxylate (1.9 g, 13.8 mmol, 1.5 eq) and CIP (3.3 g, 11.9 mmol, 1.3 eq) at 0°C. The resulting mixture was stirred at 0°C for 2 hours. The mixture was then diluted with brine (500 mL) and the aqueous layer was extracted with DCM (3 x 400 mL). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by chromatography to give (3S)-methyl 1-((2S)-3-(5-bromo-3-((tert-butyldiphenylsilyl)oxy)-3,6-dihydropyridin-1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (2.2 g, 32.8% yield) as a white solid. ESI-MS m / z = 729.1 [M+H] + ; MW calculated value: 728.3.

[1047] Intermediate 10. Synthesis (6 3 S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-2 1 ,2 2 ,2 3 ,2 6 ,61 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Decahydrogen-1 1 H-8-Oxa-1(5,3)-indole-6(1,3)-pyridazin-2(5,1)-pyridine heterocycle undecylpyridine-5,7-dione

[1048]

[1049] Step 1. To a solution of (tert-butoxycarbonyl)-L-serine methyl ester (10 g, 45 mmol) in anhydrous MeCN (150 mL) was added DIPEA (17 g, 137 mmol). The reaction mixture was stirred at 45° C. for 2 hours to give the product in solution. LCMS (ESI) m / z [M+Na] C9H 15 Calculated value of NO4: 201.1; experimental value: 224.1.

[1050] Step 2. To a solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (12 g, 60 mmol) in anhydrous MeCN (150 mL) was added DMAP (13 g, 90 mmol) and (Boc)O (26 g, 120 mmol) at 0 ° C. The reaction was stirred for 6 hours, then quenched with H2O (100 mL) and extracted with DCM (3x200 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (12.5 g, 65% yield) as a solid. LCMS (ESI) m / z [M+Na] C 14 H 23 Calculated value of NO6: 301.2; experimental value: 324.1.

[1051] Step 3. To a mixture of 5-bromo-1,2,3,6-tetrahydropyridine (8.0 g, 49 mmol) in MeOH (120 mL) was added methyl 2-{bis[(tert-butoxy)carbonyl]amino}prop-2-enoate (22 g, 74 mmol) under an Ar atmosphere. The mixture was stirred for 16 hours, then concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the product as an oil (12 g, 47% yield). LCMS (ESI) m / z [M+H] C 19 H 31 Calculated value for BrN2O6: 462.1; experimental value: 463.1.

[1052] Step 4. To a mixture of methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(5-bromo-3,6-dihydropyridin-1(2H)-yl)propanoate (14 g, 30 mmol) in dioxane (30 mL) and H2O (12 mL) was added LiOH (3.6 g, 151 mmol). The mixture was heated to 35 °C and stirred for 12 hours, then 1 M HCl was added and the pH was adjusted to about 3-4. The mixture was extracted with DCM (2x300 mL) and the combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the product as a solid (10 g, 85% yield). LCMS (ESI) m / z [M+H] C 13 H 21 Calculated for BrN2O4: 348.1; Found: 349.0.

[1053] Step 5. To a mixture of 3-(5-bromo-3,6-dihydropyridin-1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (10 g, 30 mmol), DIPEA (12 g, 93 mmol) and methyl (3S)-1,2-diazacyclohexane-3-carboxylate (5.4 g, 37 mmol) in DMF (100 mL) was added HATU (13 g, 34 mmol) at 0°C under Ar atmosphere. The mixture was stirred at 0°C for 2 hours, then H2O was added and the mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography to give the product (9.0 g, 55% yield) as a solid. LCMS (ESI) m / z [M+H] C 19 H 31 Calculated for BrN4O5: 474.1; found: 475.1.

[1054] Step 6. A mixture of methyl (3S)-1-(3-(5-bromo-3,6-dihydropyridin-1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (9.0 g, 18 mmol), KCO (4.5 g, 32 mmol), Pd(dppf)Cl.DCM (1.4 g, 2 mmol), 3-(1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl)-2,2-dimethylpropan-1-ol (9.8 g, 20 mmol) in dioxane (90 mL) and H0 (10 mL) was heated to 75° C. under Ar atmosphere and stirred for 2 h. H2O was added and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the product as a solid (4.0 g, 25% yield). LCMS (ESI) m / z [M+H] C 42 H 60 Calculated value of N6O7: 760.5; experimental value: 761.4.

[1055] Step 7. To a mixture of (3S)-methyl 1-(2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)propanoyl)hexahydropyridazine-3-carboxylate (4.1 g, 5.0 mmol) in THF (35 mL) at 0° C. was added LiOH (0.60 g, 27 mmol). The mixture was stirred at 0° C. for 1.5 hours, then 1 M HCl was added to adjust the pH to about 6-7 and the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to give the product as a solid (3.6 g, 80% yield). LCMS (ESI) m / z [M+H] C 41 H 58 Calculated value for N6O7: 746.4; experimental value: 747.4.

[1056] Step 8. To a mixture of (3S)-1-(2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)propanoyl)hexahydropyridazine-3-carboxylic acid (3.6 g, 5.0 mmol) and DIPEA (24 g, 190 mmol) in DCM (700 mL) was added EDCI HCl (28 g, 140 mmol) and HOBt (6.5 g, 50 mmol) under Ar atmosphere. The mixture was heated to 30° C. and stirred at 30° C. for 16 h, then concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and washed with H2O (2 x 200 mL), brine (200 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the product as a solid (1.45 g, 40% yield). LCMS (ESI) m / z [M+H] C 41 H 56 Calculated value for N6O6: 728.4; experimental value: 729.4.

[1057] Step 9. Add ((6 3 S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Decahydrogen-1 1 To a mixture of tert-butyl H-8-oxa-1(5,3)-indole-6(1,3)-pyridazin-2(5,1)-pyridinyl)undecylcarbamate (130 mg, 0.20 mmol) in DCM (1.0 mL) was added TFA (0.3 mL). The mixture was warmed to room temperature and stirred for 2 hours, then concentrated under reduced pressure to give the product, which was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] C 36 H 48 Calculated value for N6O4: 628.4; experimental value: 629.4.

[1058] Intermediate 11. Synthesis (6 3 S,4S)-4-amino-11 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Decahydrogen-1 1 H-8-Oxa-1(5,3)-indole-6(1,3)-pyridazin-2(5,1)-pyridine heterocycle undecylpyridine-5,7-dione

[1059]

[1060] Step 1. To a stirred solution of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (1 g, 1.598 mmol) and B2Pin2 (0.81 g, 3.196 mmol) in toluene (20 mL) was added KOAc (0.39 g, 3.995 mmol) and Pd(dppf)Cl2 (0.12 g, 0.16 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 2 hours. The mixture was then basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with DCM (3×40 mL) and the combined organic layers were washed with brine (3×40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% MeOH / DCM) to give the product as a solid (0.9 g, 83% yield). LCMS (ESI) m / z [M+H] C 39 H 57 Calculated value of BN4O5: 673.45; experimental value: 673.6

[1061] Step 2. To the mixture of 3-(1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (0.9 g, 1.338 mmol), (3S)-1-[(2S)-3-(3-bromo-5,6-dihydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]-2,2-dimethylpropyl acetate was added. To a stirred solution of methyl 4-[(tert-butyloxycarbonyl)amino]propionyl]-1,2-diazacyclohexane-3-carboxylate (1.02 g, 2.141 mmol), KCO (0.46 g, 3.345 mmol) and X-Phos (0.26 g, 0.535 mmol) in toluene (13.5 mL), dioxane (90 mL) and HO (4.5 mL) was added Pd(dba) (0.37 g, 0.401 mmol). The mixture was stirred at 70 ° C under a nitrogen atmosphere for 2 hours. The mixture was then basified to pH 8 with saturated NaHCO aqueous solution. The resulting mixture was extracted with DCM (3x100 mL) and the combined organic layers were washed with brine (3x100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% MeOH / DCM) to give the product as a solid (1.1 g, 87% yield). LCMS (ESI) m / z [M+H] C 52 H 76 Calculated value of N8O8: 941.59; experimental value: 941.8

[1062] Step 3. To a stirred solution of (S)-1-((S)-3-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester (1.1 g, 1.169 mmol) in THF (8 mL) was added dropwise a solution of LiOH (0.14 g, 5.845 mmol) in HO (8 mL) at 0°C under nitrogen atmosphere. The reaction mixture was stirred for 16 hours. The mixture was then acidified to pH 6 with concentrated HCl. The resulting mixture was extracted with DCM (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product as a solid (1.0 g, 96% yield), which was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] C 49 H72 Calculated value of N8O7: 885.56; experimental value: 885.5

[1063] Step 4. To a stirred solution of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)propanoyl)hexahydropyridazine-3-carboxylic acid (1.0 g, 1.13 mmol) and HOBt (0.76 g, 5.65 mmol) in DCM (100 mL) were added EDC•HCl (6.06 g, 31.64 mmol) and DIPEA (5.11 g, 39.55 mmol) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred for 16 hours.Then the mixture was alkalized to pH 8 with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with DCM (3x100mL) and the combined organic layer was washed with brine (3x100mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% MeOH / DCM) to obtain the product (650mg, 66% yield) in a solid state. LCMS (ESI) m / z [M+H] C 49 H 70 Calculated value of N8O6: 867.55; experimental value: 867.5

[1064] Step 5. Add ((6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Decahydrogen-1 1To a stirred solution of H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(5,1)-pyridine heterocycle undecyl-4-yl)carbamic acid tert-butyl ester (300 mg, 0.346 mmol) in DCM (3 mL) was added dropwise TFA (3 mL). The resulting mixture was stirred at 0 ° C for 1 hour. The mixture was then basified to pH 8 with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with DCM (3x50 mL) and the combined organic layers were washed with brine (3x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (260 mg, 98% yield) as a solid, which was used directly in the next step without further purification. LCMS (ESI) m / z [M + H] C 44 H 62 Calculated value of N8O4: 767.50; experimental value: 767.2

[1065] Intermediate 12. Synthesis (2 2 S,6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-Oxa-2(4,2)-morpholino-1(5,3)-indol-6(1,3)-pyridazineheterocyclic undecylenic-5,7-dione

[1066]

[1067] Step 1. TEMPO (715 mg, 4.6 mmol) and NaHCO (58 g, 690 mmol) were added to a solution of tert-butyl (2R)-2-(hydroxymethyl)morpholine-4-ylformate in EtOAc (1L) at room temperature. The mixture was cooled to -50 ° C., and then EtOAc (100 mL) containing TCCA (56 g, 241 mmol) was added dropwise over 30 minutes. The reaction mixture was warmed to 5 ° C. for 2 hours, then quenched with 10% Na2S2O3 (200 mL) and stirred for 20 minutes. The resulting mixture was filtered and the organic phase was separated. The aqueous phase was extracted with EtOAc (2x100 mL). The combined organic layer was washed with H2O (100 mL) and brine (100 mL), and then dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to obtain the product (50 g, crude) in an oily state.

[1068] Step 2. Tetramethylguanidine (35 g, 306 mmol) was added to a solution of (2R)-2-formylmorpholin-4-ylformic acid tert-butyl ester (49 g, 153 mmol) and 2-{[(benzyloxy)carbonyl]amino}-2-(dimethoxyphosphoryl)acetate (60 g, 183 mmol) in MeCN (300 mL) at 0-10 ° C. The reaction mixture was stirred at 10 ° C for 30 minutes and then warmed to room temperature for 2 hours. The reaction mixture was diluted with DCM (200 mL) and washed with 10% citric acid (200 mL) and 10% NaHCO3 aqueous solution (200 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give the product (36 g, 90% yield) as a solid. LCMS (ESI) m / z [M + Na] C 21 H 28 Calculated value of N2O4: 420.2; experimental value: 443.1

[1069] Step 3. To a solution of tert-butyl (S,Z)-2-(2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate (49 g, 0.12 mol) in MeOH (500 mL) was added (S,S)-Et-DUPHOS-Rh (500 mg, 0.7 mmol). The mixture was stirred at room temperature under an atmosphere of H (60 psi) for 48 h. The reaction was concentrated and purified by silica gel column chromatography to give the product as a solid (44 g, 90% yield). LCMS (ESI) m / z [M+Na] C 21 H 30 Calculated value of N2O7: 422.2; experimental value: 445.2.

[1070] Step 4. To a stirred solution of (S)-tert-butyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropyl)morpholine-4-carboxylate (2.2 g, 5.2 mmol) in EtOAc (2 mL) was added HCl / EtOAc (25 mL) at 15°C. The reaction was stirred at 15°C for 2 hours and then concentrated under reduced pressure to give the product as an oil (1.51 g, 90% yield). LCMS (ESI) m / z [M+H] C 16 H 22 Calculated value of N2O5: 322.1; experimental value: 323.2.

[1071] Step 5. To a solution of 3-(5-bromo-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-3-yl)-2,2-dimethylpropan-1-ol (100 g, 0.22 mol) and imidazole (30.6 g, 0.45 mol) in DCM (800 mL) was added TBSCl (50.7 g, 0.34 mol) in DCM (200 mL) at 0°C. The reaction was stirred at room temperature for 2 hours. The resulting solution was washed with H2O (3 x 300 mL) and brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (138 g, 90% yield) as a solid. LCMS (ESI) m / z [M+H] C 29 H 43 Calculated value for BrN2O2Si: 558.2; experimental value: 559.2.

[1072] Step 6. To a stirred solution of (S)-5-bromo-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (50 g, 89.3 mmol) in dioxane (500 mL) at 105° C. under N 2 atmosphere was added (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[( To the mixture was added methyl 2S)-morpholin-2-yl] propanoate (31.7 g, 98.2 mmol), RuPhos (16.7 g, 35.7 mmol), di-μ-chlorobis(2-amino-1,1-biphenyl-2-yl-C,N)dipalladium(II) (2.8 g, 4.4 mmol) and cesium carbonate (96 g, 295 mmol), followed by the addition of RuPhos-Pd-G2 (3.5 g, 4.4 mmol). The reaction mixture was stirred at 105 ° C under an N2 atmosphere for 6 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC chromatography to give the product (55 g, 73% yield) as a solid. LCMS (ESI) m / z [M + H] C 45 H 64 Calculated value of N4O7Si: 800.5; experimental value: 801.5.

[1073] Step 7. To a solution of methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2S)-4-(3-{3-[(tert-butyldimethylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl)morpholin-2-yl]propanoate (10 g, 12 mmol) in THF (270 mL) was added LiOH (1.3 g, 31 mmol) in HO (45 mL) at room temperature. The reaction was stirred at room temperature for 2 hours and then treated with 1N HCl at 0-5°C to adjust the pH to 4-5. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. The organic phase was then concentrated under reduced pressure to give the product as a solid (9.5 g, 97% yield). LCMS (ESI) m / z [M+H] C 44 H 62 Calculated value for N4O7Si: 786.4; experimental value: 787.4.

[1074] Step 8. To a stirred solution of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2S)-4-(3-{3-[(tert-butyldimethylsilyl)oxy]-2,2-dimethylpropyl}-1-ethyl-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}indol-5-yl)morpholin-2-yl]propanoic acid (10 g, 12.7 mmol) in DMF (150 mL) was added (S)-methyl hexahydropyridazine-3-carboxylate (2 g, 14 mmol), then cooled to 0° C., DIPEA (32.8 g, 254 mmol) was added, followed by HATU (9.7 g, 25.4 mmol) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 1 h. The resulting mixture was diluted with EtOAc (500 mL) and H 2 O (200 mL). The organic layer was separated and washed with H2O (2 x 100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the product. LCMS (ESI) m / z [M+H] C 50 H 72 Calculated value for N6O8Si: 912.5; experimental value: 913.4.

[1075] Step 9. To a solution of (S)-methyl 1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (8.5 g, 9 mmol) in THF (8 mL) was added a mixture of tetrabutylammonium fluoride (1 M in THF, 180 mL, 180 mmol) and AcOH (11 g, 200 mmol) at room temperature. The reaction mixture was stirred at 75 °C for 3 h. The resulting mixture was diluted with EtOAc (150 mL) and washed with HO (6 x 20 mL). The organic phase was concentrated under reduced pressure to give the product as a solid (7.4 g, 100% yield). LCMS (ESI) m / z [M+H] C 44 H 58 Calculated value for N6O8: 799.4; experimental value: 798.4.

[1076] Step 10. To a solution of (S)-methyl 1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (8 g, 10 mmol) in THF (200 mL) was added LiOH (600 mg, 25 mmol) in HO (30 mL). The reaction mixture was stirred at room temperature for 1 hour, then treated with 1N HCl at 0-5°C to adjust the pH to 4-5 and extracted with EtOAc (2 x 500 mL). The organic phase was washed with brine and concentrated under reduced pressure to give the product as a solid (8 g, crude). LCMS (ESI) m / z [M+H] C 43 H 56 Calculated value for N6O8: 784.4; experimental value: 785.4.

[1077] Step 11. To a stirred solution of (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid (8 g, 10.2 mmol) and DIPEA (59 g, 459 mmol) in DCM (800 mL) was added EDCI (88 g, 458 mmol) and HOBt (27.6 g, 204 mmol) at room temperature under argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the product as a solid (5 g, 66% yield); LCMS (ESI) m / z [M+H] C 43 H 54 Calculated value for N6O7: 766.4; experimental value: 767.4.

[1078] Step 12. At room temperature under H2 atmosphere, 2 S,6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 To a solution of H-8-oxa-2(4,2)-morpholino-1(5,3)-indole-6(1,3)-pyridazineheterocycleundecyl-4-yl)benzylcarbamate (400mg, 0.5mmol) in MeOH (20mL) was added Pd / C (200mg) and ammonium acetate (834mg, 16mmol) and the mixture was stirred for 2 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was dissolved in DCM (20mL) and washed with H2O (5mLx2), then concentrated under reduced pressure to give the product (320mg, 97% yield) in a solid state. LCMS (ESI) m / z[M+H]C 35 H 48 Calculated value for N6O5: 632.4; experimental value: 633.3.

[1079] Intermediate 13. Synthesis ((6 3 S,4S)-1 2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Decahydrogen-1 1 tert-Butyl H-8-oxa-1(5,3)-indole-6(1,3)-pyridazin-2(5,1)-pyridinylheterocycleundecylphan-4-yl)carbamate

[1080]

[1081] Step 1. To the reaction mixture was added 3-(5-bromo-2-(2-(methoxymethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (100 g, 200.3 mmol, 1 equiv) and (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-[(tert-butoxycarbonyl)amino]-3-[(tert-butoxycarbonyl)amino] ... To a stirred solution of [1,6-dihydro-2H-pyridin-1-yl]propanoyl]-1,2-diazacyclohexane-3-carboxylic acid methyl ester (132.3 g, 300.4 mmol, 1.5 equiv) in dioxane (1000 mL) was added Pd(dppf)Cl2 (14.65 g, 20.025 mmol, 0.1 equiv) and K3PO4 (106.27 g, 500.630 mmol, 2.5 equiv) in HO (200 mL) in multiple portions. The resulting mixture was stirred at 80 ° C under argon atmosphere for 2 hours. The resulting mixture was then extracted with DCM / MeOH (5 / 1; 3×1000 mL). The combined organic layers were washed with brine (2×1000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (180 g, crude) was used directly in the next step without further purification. ESI-MS m / z = 815.1 [M+H] + ; MW calculated value: 814.4.

[1082] Step 2. To a stirred solution of (S)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3-(5-(3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)propanoyl)hexahydropyridazine-3-carboxylate (180 g, 220.9 mmol, 1 eq) in THF (1500 mL) was added LiOH.HO (46.4 g, 1104.4 mmol, 5 eq) in HO (300 mL) dropwise at 0° C. and stirred at 25° C. under N atmosphere for 2 h. The mixture was acidified to pH = 6 with HCl (1 N). The resulting mixture was extracted with DCM / MeOH (5 / 1; 3 x 1500 ml). The combined organic layers were washed with brine (3 x 1000 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (180 g, crude) was used directly in the next step without further purification. ESI-MS m / z = 801.3 [M+H] + ; MW calculated value: 800.4.

[1083] Step 3. To the (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(5-(3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)propanoyl)hexahydrobenzoate was added at 0°C under nitrogen atmosphere. To a stirred solution of hydropyridazine-3-carboxylic acid (200g, 249.7mmol, 1 equivalent) and DIEA (968.2g, 7491.4mmol, 30 equivalents) in DCM (20 L) was added HOBT (168.7g, 1248.6mmol, 5 equivalents) and EDCI (1340.37g, 6991.964mmol, 28 equivalents) in multiple portions. The resulting mixture was stirred at 25 ° C under a nitrogen atmosphere for 16 hours. The mixture was acidified to pH 6-7 with HCl (1N). The resulting mixtur...

Claims

1. A compound having a structure of Formula I, or a pharmaceutically acceptable salt thereof: wherein A is optionally substituted 3 to 6 membered heterocycloalkylene, optionally substituted 3 to 6 membered cycloalkylene, optionally substituted 6 membered arylene, or optionally substituted 5 to 10 membered heteroarylene; L 1 Not present or a joint; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynyl ketone or alkynyl sulfone; R 1 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R 2 is an optionally substituted C1-C6 alkyl; and R 3 is an optionally substituted C1-C6 alkyl group or an optionally substituted C1-C3 heteroalkyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazole-diyl, optionally substituted oxazole-diyl, optionally substituted morpholine-diyl, optionally substituted pyrrolidine-diyl, optionally substituted pyridine-diyl, optionally substituted azetidine-diyl, optionally substituted pyrazine-diyl, optionally substituted pyrimidine-diyl, optionally substituted piperidine-diyl, optionally substituted oxadiazole-diyl, optionally substituted thiadiazole-diyl, optionally substituted triazole-diyl, optionally substituted thiomorpholine-diyl, or optionally substituted phenylene.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 yes:

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C1-C6 alkyl group.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 5- to 10-membered heteroarylene.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted phenylene group.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the linker is a structure of Formula III: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 Formula III, Among them A 1 The linker and CH(R 3 ) between the keys; A 2 is the bond between W and the linker; 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 ; Each R N are independently hydrogen, optionally substituted C 1– C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-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 connected to A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -with-(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 chemical bonds.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the linker has a structure of Formula IIIa: Where o is 0 or 1; R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X 1 absent, optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene; Cy is optionally substituted 3 to 8 membered cycloalkylene, optionally substituted 3 to 12 membered heterocycloalkylene, optionally substituted 6-10 membered arylene, or optionally substituted 5 to 10 membered heteroarylene; and L 2 is absent, -SO2-, -NH-, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted 3- to 6-membered heterocycloalkylene.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is not a compound of Table 2.

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