Macrocyclic ras inhibitors as anticancer agents and pharmaceutical compositions thereof

Abstract

The present disclosure is characterized by macrocyclic compounds capable of inhibiting Ras protein, as well as their pharmaceutical components and protein complexes, and their use in cancer treatment.

Description

Prior technology

[0001] The vast majority of small molecule drugs work by binding to functionally important pockets on the target protein, thereby regulating the activity of the protein. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thereby preventing the enzyme from engaging its substrate. In fact, many such drug / target interaction pairs are known, which may be misleading to believe that small molecule modulators against most, if not all, proteins can be discovered providing a reasonable amount of time, effort and resources. But this is far from the case. Currently, it is estimated that only about 10% of all human proteins can be targeted by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The remaining 90% are currently considered refractory or refractory to the aforementioned small molecule drug discovery. Such targets are often referred to as "undruggable". Such undruggable targets include the vast and often untapped reservoir of medically important human proteins. Therefore, there is great interest in discovering novel molecular modalities that can modulate the function of such undruggable targets.

[0002] It is well established in the literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play critical roles in a variety of human cancers and are therefore suitable targets for anticancer therapy. In fact, about 30 percent of all human cancers in the United States are caused by mutations in the Ras protein, and many of these cancers are fatal. Ras protein dysregulation caused by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations of Ras are often found in human cancers. For example, an activating mutation at codon 12 in the Ras protein significantly biased the population of Ras muteins toward the "on" (GTP-bound) state by inhibiting the GTPase-activating protein (GAP)-dependent and intrinsic GTP hydrolysis rate (Ras (ON)), leading to oncogenic MAPK signaling to function. Notably, Ras exhibits picomolar affinity for GTP, enabling Ras activation even in the presence of low concentrations of this nucleotide. Mutations in Ras at codons 13 (eg G13D) and 61 (eg Q61K) also result in oncogenic activity in some cancers.

[0003] Despite extensive drug discovery efforts targeting Ras over the past few decades, no drugs that directly target the "on" form of Ras have been approved. More efforts are needed to discover additional medicines for cancers driven by various Ras mutations.

Content of invention

[0004] Provided herein are Ras inhibitors. Such Ras inhibitors target, ie selectively bind to or inhibit, Ras(ON) (eg, selectively relative to the GDP-bound inactive state of Ras). The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g. Ras), and cytoplasmic chaperones (presentation proteins) that are ubiquitously expressed in cells (such as cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described herein activate in Ras by driving the formation of a high-affinity ternary complex between the Ras protein and the ubiquitously expressed cytoplasmic chaperone cyclophilin A (CYPA). Induces new binding pockets. Without being bound by theory, the inventors believe that one way in which the compounds of the invention and the complexes they form exert their inhibitory effect on Ras is by sterically blocking the relationship between Ras and downstream effector molecules such as RAF and PI3K that are required to propagate oncogenic signaling. interaction sites between them.

[0005] Accordingly, in some embodiments, the disclosure features a compound of formula Ia, or a pharmaceutically acceptable salt thereof: Formula Ia wherein A is an optionally substituted 3 to 6 membered cycloalkylene Group, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C2-C4 Alkylene or optionally substituted C2-C4 alkenylene; Y is ,,,,,, or; W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3 to 10 membered heterocycloalkyl, optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; X1 and X4 are each independently CH2 or NH; R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 15 membered cycloalkyl, optionally substituted Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; and R10 is hydrogen, hydroxyl, optionally substituted C1-C3 alkyl or optionally substituted C1-C6 heteroalkyl. In some embodiments, R10 is hydrogen.

[0006] There is also provided a pharmaceutical composition comprising a compound of formula Ia or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] There is also provided a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, there is provided a method of treating Ras protein-related disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0009] A method for inhibiting Ras protein in cells is further provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0010] In particular, any limitations discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention, with due consideration. Additionally, any compound or composition of the invention can be used in any method of the invention, and any method of the invention can be used to make or utilize any compound or composition of the invention. Definitions and Chemical Terms

[0011] In this application, unless otherwise clear from the context, (i) the term "a (one)" means "one or more"; (ii) the term "or" is used to mean "and / or ”, unless expressly indicated that the term means that the alternatives are the only ones or that the alternatives are mutually exclusive, however, the definition supported by this disclosure means the only alternatives and “and / or”; (iii) the term “comprises” and "comprising" should be understood to encompass the listed components or steps, whether presented alone or in combination with one or more additional components or steps; and (iv) where a range is provided , the endpoint is included.

[0012] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error of the apparatus or method used to determine the value. In certain embodiments, the term "about" refers to a value 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 unless Otherwise stated or otherwise evident from the context (for example when the number would exceed 100% of the possible value).

[0013] As used herein, the term "adjacent" in the context of describing adjacent atoms refers to divalent atoms that are directly linked by a covalent bond.

[0014] As used herein, "compounds of the present invention" and similar terms, whether expressly indicated or not, all refer to the Ras inhibitors described herein, including compounds of formula Ia or formula Ib and sub-formulas thereof, as well as 1a or the compound of Table 1b, and salts (such as pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers) and tautomers thereof.

[0015] The term "wild-type" refers to an entity having a structure or activity found in nature in a "normal" (as opposed to mutant, diseased, altered, etc.) state or situation. Those skilled in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (eg, alleles).

[0016] Those skilled in the art will appreciate that certain compounds described herein may be present in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) ) or in isotopic form (for example wherein one or more atoms are substituted by a different isotope of the atom, such as hydrogen by deuterium). Unless otherwise indicated or clear from context, depicted structures are understood to represent any such isomeric or isotopic forms, individually or in combination.

[0017] The compounds described herein may be asymmetric (eg, have one or more stereocenters). Unless otherwise indicated, all stereoisomers such as enantiomers and diastereomers are contemplated. Compounds of the disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthetic methods. Many geometric isomers of alkenes, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are contemplated by this disclosure. Cis and trans geometric isomers of the compounds of the disclosure have been described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0018] In some embodiments, one or more compounds depicted 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 for an adjacent double bond with concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation state having the same empirical formula and overall charge as the reference form. Examples of moieties with prototropic tautomeric forms are keto-enol pairs, amido-imidic acid pairs, lactam-lactamic acid pairs, amido-imidic acid pairs, enamine-imidic acid pairs For cyclic forms, in which protons can occupy two or more positions in the heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-triazole, 2H-triazole and 4H- 1 ,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms are obtained by interconversion of acetals.

[0019] Unless otherwise specified, structures depicted herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I. Isotopically labeled compounds (eg, compounds labeled with 3H and 14C) can be used in compound or substrate tissue distribution analysis. Tritiated (ie, 3H) and carbon-14 (ie, 14C) isotopes are useful for their ease of preparation and detection. In addition, substitution with heavier isotopes, such as deuterium (ie, 2H), may confer certain therapeutic benefits due to enhanced metabolic stability (eg, increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by a 13C or 14C enriched carbon. Positron emitting isotopes such as 15O, 13N, 11C and 18F can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared 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.

[0020] As is known in the art, many chemical entities may exist in various solid forms, such as amorphous or crystalline forms (eg, polymorphs, hydrates, solvates). In some embodiments, the compounds of the invention can be used in any such form, including any solid form. In some embodiments, compounds described or depicted herein may be provided in hydrated or solvated form.

[0021] Throughout this specification, substituents of compounds of the disclosure are disclosed as groups or as ranges. In particular, the disclosure is intended to include each individual subgroup of members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl individually. Furthermore, where a compound includes multiple positions, and at those positions substituents are disclosed in groups or in ranges, unless otherwise indicated, the disclosure is intended to encompass every single position containing a member at each position. Individual compounds and groups of compounds (eg, classes and subclasses) in different subgroups.

[0022] The term "optionally substituted X" (eg, "optionally substituted alkyl") is intended to be equivalent to "X, wherein X is optionally substituted" (eg, "alkyl, wherein the alkyl is optionally superseded"). It is not intended to imply that the feature "X" (eg, alkyl) itself is optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent, such as any of the substituents or groups described herein replacement. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be selected from a specified group When more than one substituent is substituted, the substituents at each position may be the same or different. For example, in the term "optionally substituted C1-C6 alkyl-C2-C9 heteroaryl", the alkyl moiety, the heteroaryl moiety, or both are optionally substituted. Combinations of substituents contemplated by this disclosure are preferably those that result in stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially stable when subjected to conditions that permit its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein. do not change.

[0023] Suitable monovalent substituents on substitutable carbon atoms of "optionally substituted" groups may be independently deuterium; halogen; -(CH2)0-4R°; -(CH2)0-4OR°;- O(CH2)0-4Ro; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0 -4Ph, which may be substituted by R°; -(CH2)0-4O(CH2)0-1Ph, which may be substituted by R°; -CH=CHPh, which may be substituted by R°; -(CH2)0-4O (CH2) 0-1-pyridyl, which may be substituted by R°; 4-11 membered saturated or unsaturated heterocycloalkyl (eg 4-8 membered saturated or unsaturated heterocycloalkyl (eg pyridyl)), It may be further optionally substituted (eg, substituted with methyl); 3-8 membered saturated or unsaturated cycloalkyl (eg, cyclopropyl, cyclobutyl or cyclopentyl); -NO2; -CN; -N3; -(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0- 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(R° )N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4-C(O)-N(Ro )2; -(CH2)0-4-C(O)-N(Ro)-S(O)2-Ro; -C(NCN)NR°2; -(CH2)0-4C(O)SR° ;-(CH2)0-4C(O)OSiR°3;-(CH2)0-4OC(O)R°;-OC(O)(CH2)0-4SR°;-SC(S)SR°;- (CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -(CH2)0-4OC (O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°) R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R° ;-S(O)2NR°2;-(CH2)0-4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°; -N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -P(O) (OR°)2;-OP(O)R°2;-OP(O)(OR°)2;-OP(O)(OR°)R°;-SiR°3;-(C1-4 linear Or branched chain alkyl) O-N (R °) 2; or - (C1-4 straight chain or branched chain alkyl) C (O) O-N (R °) 2, wherein each R ° can be as follows Definitions Substituted and independently hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2-(5-6 membered heteroaryl ring), or with 0-4 A 3-6 membered saturated, partially unsaturated or aryl ring of a heteroatom independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independently existing R° formed together with its intervening atom have 0-4 A 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring of heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0024] Suitable monovalent substituents on R ° (or the ring formed by two independently existing R ° and its intervening atom) can be independently halogen, -(CH ) 0-2R , -(halogen R ), -(CH2)0-2OH, -(CH2)0-2OR●, -(CH2)0-2CH(OR●)2, -O(halogen R●), -CN, -N3, -(CH2 )0-2C(O)R●, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR●, -(CH2)0-2SR●, -(CH2)0- 2SH, -(CH2)0-2NH2, -(CH2)0-2NHR , -(CH2)0-2NR 2, -NO2, -SiR 3, -OSiR 3, -C(O)SR , -(C1-4 straight chain or branched chain alkylene)C(O)OR● or -SSR●, wherein each R● is unsubstituted or preceded by "halogen" only through one or more substituted by halogen, and independently selected from C1-4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, or 5-6 with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur saturated, partially unsaturated or aryl rings. Suitable divalent substituents on saturated carbon atoms of R° include =O and =S.

[0025] Suitable divalent substituents on the saturated carbon atoms of the "optionally substituted" group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O) OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O- or -S(C(R*2))2-3S-, where R*, at each independent occurrence, is selected from hydrogen; a C1-6 aliphatic group, which may be substituted as defined below; or an untreated group having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Substituted 5-6 membered saturated, partially unsaturated or aryl rings. Suitable divalent substituents bonded to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR*2)2-3O-, where R*, at each independent occurrence, is selected from hydrogen; C1-6 aliphatic group, which may be substituted as defined below; or unsubstituted 5-6 membered saturated, partially unsaturated or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur Aryl ring.

[0026] Suitable substituents on the aliphatic group of R* include halogen, -R, -(halogen R), -OH, -OR, -O (halogen R), -CN, - C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2 or -NO2, wherein each R● is unsubstituted or preceded by "halo" One or more halogen substituted, and independently C1-4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph or 5 with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur -6 membered saturated, partially unsaturated or aryl ring.

[0027] Suitable substituents on substitutable nitrogens of "optionally substituted" groups include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C( O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, -C(S)NR†2, -C( NH)NR†2 or -N(R†)S(O)2R†; wherein each R† is independently hydrogen; a C1-6 aliphatic group which may be substituted as defined below; unsubstituted- OPh; or an unsubstituted 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independently R† together with its 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.

[0028] Suitable substituents on the aliphatic group of R† are independently halogen, -R, -(halo R), -OH, -OR, -O(halo R), -CN , -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2 or -NO2, where each R is unsubstituted or preceded by "halo" Only substituted by one or more halogens, and independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur 5-6 membered saturated, partially unsaturated or aryl ring. Suitable divalent substituents on saturated carbon atoms of R† include =O and =S.

[0029] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0030] As used herein, the term "alkoxy" refers to an -O-C1-C20 alkyl group, wherein the alkoxy group is attached to the rest of the compound through an oxygen atom.

[0031] As used herein, the term "alkyl" refers to a saturated, linear or branched monovalent hydrocarbon group containing 1 to 20 (eg, 1 to 10 or 1 to 6) carbons. In some embodiments, the alkyl group is unbranched (ie, linear); in some embodiments, the alkyl group is branched. Alkyl groups such as, but not limited to, methyl, ethyl, n- and isopropyl, n-butyl, second-, iso-, and third-butyl, and neopentyl.

[0032] As used herein, the term "alkylene" refers to 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 , isopropyl and similar groups. The term "Cx-Cy 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 (eg C1-C6, C1-C10, C2-C20, C2-C6, C2-C10 or C2-C20 alkylene). In some embodiments, the alkylene group can be further substituted with 1, 2, 3 or 4 substituents as defined herein.

[0033] Unless otherwise specifically stated, otherwise, as used herein, the term "alkenyl" refers to a compound having 2 to 20 carbons (eg, 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds. The monovalent linear or branched chain groups and examples thereof are vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. Alkenyl includes both cis and trans isomers. As used herein, unless specifically stated otherwise, the term "alkenylene" refers to a bis having 2 to 20 carbons (eg, 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds. Valence straight chain or branched chain group.

[0034] As used herein, the term "alkynyl" means a monovalent straight chain having 2 to 20 carbons (eg, 2 to 4, 2 to 6, or 2 to 10 carbons) containing carbon-carbon double bonds or There are branched groups and examples thereof are ethynyl and 1-propynyl.

[0035] As used herein, the term "alkynyl" means a group comprising the structure wherein R is any chemically feasible substituent described herein.

[0036] As used herein, the term "amino" means -N(R†)2, such as -NH2 and -N(CH3)2.

[0037] As used herein, the term "aminoalkyl" means an alkyl moiety having one or more carbon atoms substituted with one or more amine moieties.

[0038] As described herein, the term "amino acid" refers to a molecule having a side chain, an amine group, and an acid group (such as -CO2H or -SO3H), wherein the amino acid is Acid groups (eg, side chains) are attached to the parent molecular group. As used herein, the term "amino acid" in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, eg, via the formation of one or more peptide bonds. In some embodiments, the amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any 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, glutamic acid, glycine, histidine, optionally substituted Hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine amino acid, serine, taurine, threonine, tryptophan, tyrosine and valine.

[0039] As used herein, the term "aryl" denotes a monovalent monocyclic, bicyclic or polycyclic ring system formed of carbon atoms, wherein the ring attached to the pendant group is an aromatic ring. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl and anthracenyl. An aromatic ring may be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure and unless specifically stated otherwise, any ring atom may be optionally substituted.

[0040] As used herein, the term "C0" means a bond. For example, a portion of the term -N(C(O)-(C0-C5alkylene-H)- includes -N(C(O)-(C0alkylene-H)-, which is also represented as- N(C(O)-H)-.

[0041] As used herein, the terms "carbocycle" and "carbocyclyl" refer to monovalent, optionally substituted C3-C12 monocyclic, bicyclic or tricyclic structures which may be bridged rings, fused rings or A spiro ring in which all rings are formed from carbon atoms and at least one ring system is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclyl are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fenyl, indenyl, dihydroindene group, decahydronaphthyl group and similar groups. A carbocycle may be attached to its pendant group at any ring atom that results in a stable structure and unless specifically stated otherwise, any ring atom may be optionally substituted.

[0042] As used herein, the term "carbonyl" means a C(O) group, which can also be expressed as C=O.

[0043] As used herein, the term "carboxy" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or the unprotonated counterpart.

[0044] As used herein, the term "cyano" means a -CN group.

[0045] As used herein, the term "cycloalkyl" means a monovalent saturated cyclic hydrocarbon group, which may be a bridged ring, fused ring or spiro ring having three to eight ring carbons unless otherwise specified, and which Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloheptyl.

[0046] As used herein, the term "cycloalkenyl" means a monovalent, non-aromatic saturated cyclic hydrocarbon group, which may have from three to eight ring carbons and contain one or more carbon-carbon Double bond bridged ring, fused ring or spiro ring.

[0047] As used herein, the term "diastereomer" means stereoisomers that are not mirror images of each other and are not superimposable.

[0048] As used herein, the term "enantiomer" means having at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), less Each individual optically active form of a compound of the invention is preferably at least 90% and more preferably at least 98% in optical purity or enantiomer excess (as determined by methods standard in the art).

[0049] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen has been replaced with a halogen.

[0050] As used herein, the term "haloalkyl" means an alkyl moiety in which one or more carbon atoms are substituted with one or more halo moieties, which may be the same or different.

[0051] As used herein, the term "halogen" means a halogen selected from bromine, chlorine, iodine or fluorine.

[0052] 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, an O, N, or S atom). Heteroatoms can be present either centrally or terminally in the group.

[0053] As used herein, the term "heteroaryl" denotes a monovalent, monocyclic or polycyclic structure containing at least one fully aromatic ring: that is, it contains 4n+2 within the monocyclic or polycyclic system π electrons and contains at least one heteroatom selected from N, O or S in the aromatic ring. Exemplary unsubstituted heteroaryls have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9 )carbon. The term "heteroaryl" includes bicyclic, tricyclic and tetracyclic groups in which any of the aforementioned heteroaromatic rings is fused with one or more aromatic or carbocyclic rings, such as phenyl rings or cyclohexane rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolyl, and 4- Azaindolyl. A heteroaryl ring may be attached to its pendant group at any ring atom that results in a stable structure and unless specifically stated otherwise, any ring atom may be optionally substituted. In a certain embodiment, the heteroaryl is substituted with 1, 2, 3 or 4 substituents.

[0054] As used herein, the term "heterocycloalkyl" means at least one ring system non-aromatic ring and wherein the non-aromatic ring contains one, two, three or four independently selected from nitrogen, oxygen and Monovalent, monocyclic, bicyclic or polycyclic ring systems of heteroatoms grouped by sulfur, which may be bridged, fused or spiro rings. 5-membered rings have zero to two double bonds, and 6- and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocycloalkyl 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 a) carbon. The term "heterocycloalkyl" also refers to heterocyclic compounds having bridged polycyclic ring structures in which one or more carbon or heteroatoms bridge nonadjacent members of a monocyclic ring, eg, quinuclidinyl. The term "heterocycloalkyl" includes any of the aforementioned heterocycles with one or more aromatic rings, carbocycles, heteroaromatic rings or heterocyclic rings, such as aryl rings, cyclohexane rings, cyclohexene rings, cyclopentene rings, Alkane ring, cyclopentene ring, pyridine ring or pyrrolidine ring fused bicyclic, tricyclic and tetracyclic groups. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridinyl and decahydronaphthyridinyl. A heterocycloalkyl ring may be attached to its pendant group at any ring atom that results in a stable structure and unless specifically stated otherwise, any ring atom may be optionally substituted.

[0055] As used herein, the term "hydroxyl," means an -OH group.

[0056] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more -OH moieties.

[0057] As used herein, the term "isomer" means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the present invention . It is recognized that the compounds of the present invention may possess one or more chiral centers or double bonds, and therefore, in stereoisomeric forms, such as double bond isomers (i.e., E / Z geometric isomers ) or diastereomers (eg, enantiomers (ie, (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures depicted herein and thus the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereomerically pure (e.g. geometrically pure, enantiomerically pure or diastereomerically pure) ) forms as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomers and stereoisomer mixtures of the compounds of the present invention can typically be obtained by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, and the compound as a chiral salt. Crystallization of the complex form or resolution of the compound into its component enantiomers or stereoisomers by crystallization in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents and catalases by well-known asymmetric synthesis methods.

[0058] As used herein, the term "stereoisomer" refers to a compound (such as a compound of any of the formulas described herein) that may have all possible different isomeric and configurational forms, particularly those of the basic molecular structure. All possible stereochemical and conformational isomeric forms, all diastereoisomers, enantiomers or configurational isomers, including atropisomers. Some of the compounds of the present invention may exist in different tautomeric forms and all such tautomeric forms are included within the scope of the present invention.

[0059] As used herein, the term "sulfonyl" means a -S(O)2- group.

[0060] As used herein, the term "thiocarbonyl" refers to a -C(S)- group.

[0061] Those skilled in the art will appreciate upon reading this disclosure that certain compounds described herein may be provided or utilized in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, Isomeric forms (eg, 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, preparations of a single stereoisomer of a compound can be considered as different forms of the compound rather than a racemic mixture of the compound; A different form of another salt; preparations containing one conformational isomer ((Z) or (E)) with a double bond may be considered as identical to the other conformational isomer containing the double bond ((E) ) or (Z)) in different forms; preparations whose isotopes of one or more atoms differ from the isotopes present in the reference preparation may be considered to be in different forms.

Implementation

[0064] CROSS-REFERENCE TO RELATED APPLICATIONS

[0065] This application claims U.S. Application No. 63 / 078,802 filed September 15, 2020; U.S. Application No. 63 / 129,231 filed December 22, 2020; filed May 5, 2021 Priority benefit of U.S. Application No. 63 / 184,412, filed May 25, 2021, and U.S. Application No. 63 / 192,775, filed May 25, 2021, all of which are hereby incorporated by reference in their entirety. compound

[0066] Provided herein are Ras inhibitors. Such Ras inhibitors target, ie selectively bind to, or inhibit Ras(ON) (eg, selectively relative to the GDP-bound, inactive state of Ras). As used herein, the term "RAS(ON) inhibitor" refers to targeting, i.e., selectively binding to or inhibiting the active GTP-bound state of RAS (e.g., selectively relative to the inactive GDP-bound state of RAS). sex) inhibitors. Inhibiting the GTP-bound active state of RAS includes, for example, inhibiting oncogenic signaling from the GTP-bound active state of RAS. In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the GTP-bound active state of RAS. In certain embodiments, RAS(ON) inhibitors also bind to or inhibit the GDP-bound, inactive state of RAS (eg, have a lower affinity or inhibition constant than the GTP-bound, active state of RAS). In some embodiments, the RAS(ON) inhibitor has a molecular weight between 800 and 1100 Da, inclusive. Thus, for example, the term "KRAS(ON) inhibitor" refers to any inhibitor that binds to KRAS in the GTP-bound "ON" position. A "KRAS G12C(ON) inhibitor" is a KRAS inhibitor that selectively binds to or targets the G12C mutant form of KRAS. Non-limiting examples of RAS(ON) inhibitors are provided in WO 2021091982, WO 2021091967, WO 2021091956 and WO 2020132597, some of which are KRASG12C(ON) inhibitors.

[0067] As used herein, the term "RAS (OFF) inhibitor" refers to a drug that targets, i.e. selectively binds to or inhibits, the GDP-bound inactive state of RAS (e.g., relative to the GTP-bound activity of RAS). state is selective) inhibitors. Inhibiting the GDP-bound inactive state of RAS includes, for example, sequestering the inactive state by inhibiting the exchange of GDP to GTP, thereby inhibiting RAS from assuming an active conformation. In certain embodiments, a RAS(OFF) inhibitor can also bind to or inhibit the GTP-bound, active state of RAS (eg, has a lower affinity or inhibition constant than the GDP-bound, inactive state of RAS). In some embodiments, the RAS(OFF) inhibitor has a molecular weight of less than 700 Da. In some embodiments, the RAS(OFF) inhibitor has a molecular weight of less than 700 Da. Thus, for example, the term "KRAS(OFF) inhibitor" refers to any inhibitor that binds to KRAS in the "OFF" position bound by GDP. A "KRAS G12C(OFF) inhibitor" is a KRAS inhibitor that selectively binds to or targets the G12C mutant form of KRAS. KRASG12C(OFF) inhibitors are known in the art and non-limiting examples include adagrasib and sotorasib. Additional KRAS(OFF) inhibitors are provided herein. The term "inhibitor" means a compound or agent (eg, peptide, antibody) that prevents a biomolecule (eg, protein) from completing or initiating a reaction. Inhibitors can inhibit a reaction by competitive, anti-competitive or non-competitive means. The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g. Ras), and cytoplasmic chaperones (presentation proteins) that are ubiquitously expressed in cells (such as cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described herein activate in Ras by driving the formation of a high-affinity ternary complex between the Ras protein and the ubiquitously expressed cytoplasmic chaperone cyclophilin A (CYPA). Induces new binding pockets. Without being bound by theory, the inventors believe that one way in which the compounds of the invention and the complexes they form exert their inhibitory effect on Ras is by sterically blocking the interaction between Ras and downstream effector molecules, such as RAF, required for the propagation of oncogenic signaling. interaction site.

[0068] Without being bound by theory, the inventors hypothesize that non-covalent interactions of the compounds of the invention with Ras and chaperone proteins (eg, cyclophilin A) may contribute to the inhibition of Ras activity. For example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, and combinations thereof, can contribute to the ability of the compounds of the invention to form complexes and act as Ras inhibitors. Therefore, the compounds of the present invention can inhibit various Ras proteins (such as wild-type Ras or Rasamp, or K-Ras, N-Ras, H-Ras and mutants thereof at positions 12, 13 and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, and other mutants described herein, and combinations of Ras proteins).

[0069] Therefore, this paper provides a compound having a structure of formula Ia or a pharmaceutically acceptable salt thereof: Formula Ia wherein A is an optionally substituted 3 to 6 membered cycloalkylene group, an optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylylene, optionally substituted 5-6 membered heteroarylylene, optionally substituted C2-C4alkylene or optionally substituted C2-C4 alkenyl; Y is ,,,,,, or; W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3 to 10 membered hetero Cycloalkyl, optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; X1 and X4 are each independently CH2 or NH; R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered Cycloalkenyl, optionally substituted 3 to 15 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; and R2 is hydrogen, optionally Substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R10 is hydrogen, hydroxyl, optionally substituted C1-C3 alkyl or optionally Case substituted C1-C6 heteroalkyl.

[0070] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ia-2: Formula Ia-2 wherein A is an optionally substituted 3 to 6 membered cycloalkylene, optionally Optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 membered aryl or optionally substituted 5 to 6 membered heteroaryl; Y is ,,,, or; W is hydrogen , C1-C4 alkyl, optionally substituted 3 to 10 membered heterocycloalkyl, optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted Substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted Optionally substituted 3 to 7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; and R10 is hydrogen or optionally substituted C1-C6 heteroaryl alkyl. In some embodiments, R10 is hydrogen.

[0071] In some embodiments, R1 is an optionally substituted 6 to 10 membered aryl or an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R1 is optionally substituted phenyl or optionally substituted pyridine.

[0072] In some embodiments, A is optionally substituted thiazole, optionally substituted triazole, optionally substituted N-morpholinyl, optionally substituted piperidinyl, optionally substituted pyridine or optionally substituted phenyl. In some embodiments, A is an optionally substituted thiazole, an optionally substituted triazole, an optionally substituted N-morpholinyl, or a phenyl. In some embodiments, A is not optionally substituted phenyl or benzimidazole. In some embodiments, A is not hydroxyphenyl.

[0073] In some embodiments, Y is -NHC(O)- or -NHC(O)NH-.

[0074] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIa: formula IIa, wherein a is 0 or 1.

[0075] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IIa-1: formula IIa-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0076] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IIa-2: Formula IIa-2.

[0077] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IIa-3: formula IIa-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0078] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IIa-4: Formula IIa-4.

[0079] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IIa-5: formula IIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is H. In some embodiments, X3 is N, m is 1 and R11 is H.

[0080] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IIa-6: Formula IIa-6.

[0081] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IIa-7: Formula IIa-7.

[0082] In some embodiments (eg, embodiments having any of Formula IIa-6 or IIa-7), R6 is methyl.

[0083] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IIa-8 or formula IIa-9: formula IIa-8, formula IIa-9.

[0084] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa: formula IIIa, wherein a is 0 or 1.

[0085] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IIIa-1: formula IIIa-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0086] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IIIa-2: Formula IIIa-2.

[0087] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IIIa-3: formula IIIa-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0088] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IIIa-4: Formula IIIa-4.

[0089] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IIIa-5: formula IIIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1 and R11 is H.

[0090] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IIIa-6: Formula IIIa-6.

[0091] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIIa-7: Formula IIIa-7.

[0092] In some embodiments (eg, embodiments having any of Formula Ilia-6 or Ilia-7), R6 is methyl.

[0093] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IIIa-8 or formula IIIa-9: formula IIIa-8, formula IIIa-9.

[0094] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa: formula IVa, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1.

[0095] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IVa-1: formula IVa-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0096] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IVa-2: Formula IVa-2.

[0097] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IVa-3: formula IVa-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0098] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IVa-4: Formula IVa-4.

[0099] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IVa-5: formula IVa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0100] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IVa-6: Formula IVa-6.

[0101] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IVa-7: Formula IVa-7.

[0102] In some embodiments (eg, embodiments having any of Formulas IVa-6 or IVa-7), R6 is methyl.

[0103] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula IVa-8 or formula IVa-9: formula IVa-8, formula IVa-9.

[0104] In some embodiments (e.g., of formula IVa, IVa-1, IVa-2, IVa-3, IVa-4, IVa-5, IVa-6, IVa-7, IVa-8, or IVa-9 In any embodiment), R9 is a methyl group.

[0105] In some embodiments, Y is -NHS(O)2- or -NHS(O)2NH-.

[0106] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Va: Formula Va, wherein a is 0 or 1.

[0107] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula Va-1: formula Va-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0108] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Va-2: Formula Va-2.

[0109] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula Va-3: formula Va-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0110] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Va-4: Formula Va-4.

[0111] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula Va-5: formula Va-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0112] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula VIa: Formula VIa, wherein a is 0 or 1.

[0113] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula VIa-1: formula VIa-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0114] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula VIa-2: Formula VIa-2.

[0115] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula VIa-3: formula VIa-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0116] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula VIa-4: Formula VIa-4.

[0117] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIa-5: formula VIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0118] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula VIIa: Formula VIIa, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1.

[0119] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula VIIa-1: formula VIIa-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0120] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula VIIa-2:.

[0121] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula VIIa-3: formula VIIa-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, visual Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0122] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula VIIa-4: Formula VIIa-4.

[0123] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula VIIa-5: formula VIIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0124] In some embodiments (eg, embodiments having any of Formula Vila, Vila-1, Vila-2, Vila-3, Vila-4, or Vila-5), R9 is methyl.

[0125] In some embodiments, Y is -NHS(O)- or -NHS(O)NH-.

[0126] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula VIIIa: Formula VIIIa, wherein a is 0 or 1.

[0127] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula VIIIa-1: formula VIIIa-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0128] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula VIIIa-2: Formula VIIIa-2.

[0129] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula VIIIa-3: formula VIIIa-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, visual Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0130] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula VIIIa-4: Formula VIIIa-4.

[0131] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula VIIIa-5: formula VIIIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0132] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IXa: Formula IXa, wherein a is 0 or 1.

[0133] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa-1: formula IXa-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0134] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula IXa-2: Formula IXa-2.

[0135] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa-3: formula IXa-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0136] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula IXa-4: Formula IXa-4.

[0137] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IXa-5: formula IXa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0138] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Xa: Formula Xa, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1.

[0139] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula Xa-1: formula Xa-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

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

[0141] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula Xa-3: formula Xa-3, wherein R4 and R5 are each independently selected from halogen, cyano, hydroxyl, Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl (eg, optionally substituted 3 to 6 membered heterocycloalkyl), optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0142] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula Xa-4: Formula Xa-4.

[0143] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has a structure of formula Xa-5: formula Xa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or R6 and R7 and 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 R7 and R8 are combined with the atoms to which they are attached to form an optionally substituted Substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl. In some embodiments, X3 is N. In some embodiments, m is 1. In some embodiments, R11 is hydrogen. In some embodiments, X3 is N, m is 1, and R11 is H.

[0144] In some embodiments (eg, embodiments having any of Formulas Xa, Xa-1, Xa-2, Xa-3, Xa-4, or Xa-5), R9 is methyl.

[0145] In some embodiments of any of the aspects described herein, a is zero. In some embodiments of any of the above, a is 0.

[0146] In some embodiments of any of the aspects described herein, R2 is optionally substituted C1-C6 alkyl. In some embodiments, R2 is selected from -CH2CH3 or -CH2CF3.

[0147] In some embodiments of any of the aspects described herein, W is C1-C4 alkyl. In some embodiments, W is: or.

[0148] In some embodiments of any of the aspects described herein, W is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted Cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine, or optionally substituted phenyl.

[0149] In some embodiments of any of the aspects described herein, W is optionally substituted 3 to 10 membered heterocycloalkyl, optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0150] In some embodiments of any of the aspects described herein, W is an optionally substituted 3 to 10 membered heterocycloalkyl. In some embodiments, W is selected from the following or stereoisomers thereof:,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,or. In some embodiments, W is selected from the following or stereoisomers thereof: ,,,,,,,, or.

[0151] In some embodiments of any of the aspects described herein, W is an optionally substituted 3 to 10 membered cycloalkyl. In some embodiments, W is selected from the following or stereoisomers thereof:,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,or. In some embodiments, W is selected from the following or stereoisomers thereof: ,,,,, or.

[0152] In some embodiments of any of the aspects described herein, W is an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, W is selected from the following or stereoisomers thereof: ,,,,,,,,,,,, or.

[0153] In some embodiments of any of the aspects described herein, W is an optionally substituted 6 to 10 membered aryl. In some embodiments, W is optionally substituted phenyl.

[0154] In some embodiments of any of the aspects described herein, W is an optionally substituted C1-C3 heteroalkyl. In some embodiments, W is selected from the following or stereoisomers thereof: , or.

[0155] In some embodiments, the compound of the present invention is selected from Table 1a or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of the present invention is selected from Table 1a or a pharmaceutically acceptable salt or atropisomer thereof. Table 1a: Certain compounds of the invention instance number structure A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12 A13 A14 A15 A16 A17 A18 A19 A20 A21 A22 A23 A24 A25 A26 A27 A28 A29 A30 A31 A32 A33 A34 A35 A36 A37 A38 A39 A40 A41 A42 A43 A44 A45 A46 A47 A48 A49 A50 A51 A52 A53 A54 A55 A56 A57 A58 A59 A60 A61 A62 A63 A64 A65 A66 A67 A68 A69 A70 A71 A72 A73 A74 A75 A76 A77 A78 A79 A80 A81 A82 A83 A84 A85 A86 A87 A88 A89 A90 A91 A92 A93 A94 A95 A96 A97 A98 A99 A100 A101 A102 A103 A104 A105 A106 A107 A108 A109 A110 A111 A112 A113 A114 A115 A116 A117 A118 A119 A120 A121 A122 A123 A124 A125 A126 A127 A128 A129 A130 A131 A132 A133 A134 A135 A136 A137 A138 A139 A140 A141 A142 A143 A144 A145 A146 A147 A148 A149 A150 A151 A152 A153 A154 A155 A156 A157 A158 A159 A160 A161 A162 A163 A164 A165 A166 A167 A168 A169 A170 A171 A172 A173 A174 A175 A176 A177 A178 A179 A180 A181 A182 A183 A184 A185 A186 A187 A188 A189 A190 A191 A192 A193 A194 A195 A196 A197 A198 A199 A200 A201 A202 A203 A204 A205 A206 A207 A208 A209 A210 A211 A212 A213 A214 A215 A216 A217 A218 A219 A220 A221 A222 A223 A224 A225 A226 A227 A228 A229 A230 A231 A232 A233 A234 A235 A236 A237 A238 A239 A240 A241 A242 A243 A244 A245 A246 A247 A248 A249 A250 A251 A252 A253 A254 A255 A256 A257 A258 A259 A260 A261 A262 A263 A264 A265 A266 A267 A268 A269 A270 A271 A272 A273 A274 A275 A276 A277 A278 A279 A280 A281 A282 A283 A284 A285 A286 A287 A288 A289 A290 A291 A292 A293 A294 A295 A296 A297 A298 A299 A300 A301 A302 A303 A304 A305 A306 A307 A308 A309 A310 A311 A312 A313 A314 A315 A316 A317 A318 A319 A320 A321 A322 A323 A324 A325 A326 A327 A328 A329 A330 A331 A332 A333 A334 A335 A336 A337 A338 A339 A340 A341 A342 A343 A344 A345 A346 A347 A348 A349 A350 A351 A352 A353

[0156] It should be noted that bonds in some compounds are shown as flat or wedge-shaped lines. In some cases, the relative stereochemistry of stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. All stereoisomers of the compounds of the above table are included in the present invention. In certain embodiments, atropisomers of the compounds of the above table are contemplated. Any compound shown in parentheses indicates that the compound is a diastereomer, and the absolute stereochemistry of such diastereomers may not be known.

[0157] In some embodiments, the compound of the present invention is selected from the compound of Table 1b or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compounds of the present invention are selected from the compounds of Table 1b or pharmaceutically acceptable salts or atropisomers thereof. Table 1b: Certain compounds of the invention instance number structure A354 A355 A356 A357 A358 A359 A360 A361 A362 A363 A364 A365 A366 A367 A368 A369 A370 A371 A372 A373 A374 A375 A376 A377 A378 A379 A380 A381 A382 A383 A384 A385 A386 A387 A388 A389 A390 A391 A392 A393 A394 A395 A396 A397 A398 A399 A400 A401 A402 A403 A404 A405 A406 A407 A408 A409 A410 A411 A412 A413 A414 A415 A416 A417 A418 A419 A420 A421 A422 A423 A424 A425 A426 A427 A428 A429 A430 A431 A432 A433 A434 A435 A436 A437 A438 A439 A440 A441 A442 A443 A444 A445 A446 A447 A448 A449 A450 A451 A452 A453 A454 A455 A456 A457 A458 A459 A460 A461 A462 A463 A464 A465 A466 A467 A468 A469 A470 A471 A472 A473 A474 A475 A476 A477 A478 A479 A480 A481 A482 A483 A484 A485 A486 A487 A488 A489 A490 A491 A492 A493 A494 A495 A496 A497 A498 A499 A500 A501 A502 A503 A504 A505 A506 A507 A508 A509 A510 A511 A512 A513 A514 A515 A516 A517 A518 A519 A520 A521 A522 A523 A524 A525 A526 A527 A528 A529 A530 A531 A532 A533 A534 A535 A536 A537 A538 A539 A540 A541 A542 A543 A544 A545 A546 A547 A548 A549 A550 A551 A552 A553 A554 A555 A556 A557 A558 A559 A560 A561 A562 A563 A564 A565 A566 A567 A568 A569 A570 A571 A572 A573 A574 A575 A576 A577 A578 A579 A580 A581 A582 A583 A584 A585 A586 A587 A588 A589 A590 A591 A592 A593 A594 A595 A596 A597 A598 A599 A600 A601 A602 A603 A604 A605 A606 A607 A608

[0158] It should be noted that bonds in some compounds are shown as flat or wedge-shaped lines. In some cases, the relative stereochemistry of stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. All stereoisomers of the compounds of the above table are included in the present invention. In certain embodiments, atropisomers of the compounds of the above table are contemplated. Any compound shown in parentheses indicates that the compound is a diastereomer, and the absolute stereochemistry of such diastereomers may not be known.

[0159] In some embodiments, the compound of the present invention is selected from the compounds of Table 2 or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the present invention are selected from the compounds in Table 2 or pharmaceutically acceptable salts or atropisomers thereof.

[0160] In some embodiments, the compound of the 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. Table 2: Certain Compounds instance number structure B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15 B16 B17 B18 B19 B20 B21 B22 B23 B24 B25

[0161] In some embodiments, the compound of the present invention is selected from the compounds in Table 3 (eg, C1-C20 or C1-C21) or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the present invention are selected from the compounds in Table 3 (eg C1-C20 or C1-C21) or their pharmaceutically acceptable salts or atropisomers.

[0162] In some embodiments, the compound of the invention is not a compound selected from Table 3 (eg, C1-C20 or C1-C21). In some embodiments, the compound of the present invention is not a compound selected from Table 3 (eg, C1-C20 or C1-C21 ) or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of the present invention is not a compound selected from Table 3 (eg, C1-C20 or C1-C21 ) or a pharmaceutically acceptable salt or atropisomer thereof. Table 3: Some Compounds instance number structure C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21

[0163] In some embodiments, compounds of the present invention have improved oral bioavailability (%F) compared to compounds known in the art. Methods of measuring oral bioavailability are known in the art, and one such method is provided below: Oral bioavailability can be determined in BALB / c mice. Following intravenous (IV) bolus and oral gavage (PO) administration of test compounds, approximately 30 µL whole blood samples were collected into tubes containing K2EDTA at indicated time points. Blood samples were centrifuged at 4600 rpm for approximately 5 minutes at 4°C and plasma samples were stored at -80°C pending bioanalysis. Protein samples are extracted by protein precipitation and analyzed by tandem mass spectrometry (LC MS / MS), eg on an API 5500 system, using electrospray positive ionization.

[0164] All PK parameters were obtained from plasma concentration over time data using non-compartmental analysis using WinNonlin. Bioavailability (F%, also expressed as %F) was estimated using the following formula: AUCinf,PO is the area under the plasma concentration curve from time zero to an infinite time after PO administration AUCinf,IV is the area from time zero to IV The area under the plasma concentration curve within an infinite time after administration DoseIV is the total dose of IV administration DosePO is the total dose of PO administration Generally speaking, the F% (or %F) value is better than 30%, and the value of more than 50% is more good.

[0165] In some embodiments, compounds of the invention are selective for one or more particular Ras mutants relative to other Ras mutants or wild-type compared to compounds known in the art. Methods to measure such selectivity are known in the art, such as the Ras-Raf binding assay, the protocol of which is provided in the Examples below. Thus, in some embodiments, compounds of the invention are selective for KRASG12C relative to other Ras mutants or relative to wild type. In some embodiments, the compounds of the invention are selective for KRASG12D relative to other Ras mutants or relative to wild type. In some embodiments, the compounds of the invention are selective for KRASG12V relative to other Ras mutants or relative to wild type. In some embodiments, the compounds of the invention are selective for KRASG12D relative to other Ras mutants or relative to wild type. In some embodiments, the compounds of the invention are selective for NRASQ61K relative to other Ras mutants or relative to wild type. In some embodiments, compounds of the invention are selective for KRASG12D and KRASG12V relative to other Ras mutants and wild type. Compounds of the invention may also exhibit higher selectivity for other RAS mutants disclosed herein or combinations thereof. In some embodiments, compounds of the invention exhibit an IC50 value of less than 30 nm in the Ras-Raf binding assay described above against one or more Ras mutants described herein.

[0166] In some embodiments, compounds of the invention are more potent against one or more specific Ras mutants than other Ras mutants or wild type compared to compounds known in the art. Methods of measuring such potencies are known in the art, such as the pERK assay, the protocol provided in the Examples below. Thus, in some embodiments, compounds of the invention exhibit greater potency against KRASG12D than compounds known in the art. In some embodiments, compounds of the invention exhibit greater potency against KRASG12V than compounds known in the art. In some embodiments, compounds of the invention exhibit higher potency against KRASG12C than compounds known in the art. In some embodiments, compounds of the invention exhibit higher potency against KRASG12D and KRASG12V than compounds known in the art. Compounds of the invention may also exhibit higher potency against other RAS mutants disclosed herein or combinations thereof.

[0167] In some embodiments, the compounds of the present invention exhibit a higher effect on cell viability against one or more specific Ras mutants relative to other Ras mutants or wild type compared to compounds known in the art. Harmful effect. Methods of measuring cell viability are known in the art, such as the CellTiter-Glo® cell viability assay, the protocol of which is provided in the Examples below. Thus, in some embodiments, compounds of the invention exhibit a greater reduction in cell viability against KRASG12D compared to compounds known in the art. In some embodiments, compounds of the invention exhibit a greater reduction in cell viability against KRASG12V compared to compounds known in the art. In some embodiments, compounds of the invention exhibit a greater reduction in cell viability against KRASG12C compared to compounds known in the art. In some embodiments, compounds of the invention exhibit greater reductions in cell viability against KRASG12D and KRASG12V compared to compounds known in the art. Compounds of the invention may also exhibit greater reductions in cell viability against other RAS mutants disclosed herein or combinations thereof.

[0168] In some embodiments, compounds of the invention may exhibit increased metabolic stability, permeability or solubility, or a combination thereof, relative to compounds known in the art. Methods for measuring such properties are known in the art. In some embodiments, compounds of the invention may exhibit improvements in any one or combination of the following properties compared to compounds known in the art: selectivity, potency, cell viability, metabolic stability, permeability or solubility.

[0169] In some embodiments, compounds of the invention are or are used as prodrugs, such as for administration to a cell or an individual in need thereof.

[0170] There is also provided a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0171] There is further provided a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The cancer may eg be pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myelogenous leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome or squamous cell lung cancer. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Ras Q61R, K-Ras Q61K or K-Ras Q61L, or a combination thereof. In some embodiments, the cancer comprises a Ras mutation, such as N-Ras G12D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P, or a combination thereof. Other Ras mutations are also described herein.

[0172] It further provides a method for treating Ras protein-related disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0173] There is further provided a method of inhibiting Ras protein in a cell, the method comprising contacting the cell with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, K-Ras Q61H, K-Ras Q61R, K-Ras Ras Q61K or K-Ras Q61L. The Ras protein can be, for example, N-Ras G12D, N-Ras Q61R, N-Ras Q61K, N-Ras Q61L, N-Ras Q61H, or N-Ras Q61P. Other Ras proteins are also described herein. The cells may be cancer cells such as pancreatic cancer cells, colorectal cancer cells, lung cancer cells (e.g. non-small cell lung cancer cells), acute myeloid leukemia cells, multiple myeloma cells, thyroid adenocarcinoma cells, myelodysplastic syndrome cells , myeloma cells or squamous cell lung cancer cells. Other cancer types are also described herein. The cells may be in vivo or in vitro.

[0174] For the compounds of the present invention, one stereoisomer may exhibit a superior inhibitory effect than the other stereoisomer. For example, one atropisomer may exhibit inhibition while another atropisomer may exhibit little or no inhibition.

[0175] In some embodiments, the methods or uses described herein further comprise administering an additional anti-cancer therapy. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, 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, PTEN inhibitors, AKT inhibitors, mTORC1 inhibitors, BRAF inhibitors, PD-L1 inhibitors, PD-1 inhibitors, CDK4 / 6 inhibitors, or combinations thereof. In some embodiments, the additional anticancer therapy is a SHP2 inhibitor. Other additional anticancer therapies are also described herein. resolve resolution

[0176] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic or enzymatic procedures.

[0177] 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, compounds of the present invention can be synthesized using the methods described in the following schemes, as well as synthetic methods known in the art of synthetic organic chemistry or modifications of such methods understood by those skilled in the art. Such methods include, but are not limited to, those described in the following schemes. Scheme 1. General Synthetic Method of Macrocyclic Ester

[0178] The general synthesis of macrocyclic esters is outlined in Scheme 1. Properly substituted indolyl boronate (1) can be protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol And suitably substituted boronic acid as the starting material, prepared in four steps, including palladium-mediated coupling, alkylation, deprotection and palladium-mediated borylation reaction.

[0179] amino-3-(4-bromothiazol-2-yl) propionyl) hexahydropyrazine-3-carboxylic acid methyl ester (3) can be obtained by making (S)-2-amino-3-( Prepared by coupling 4-bromothiazol-2-yl)propionic acid (2) with (S)-hexahydropyridazine-3-carboxylic acid methyl ester.

[0180] The final macrocyclic ester can be prepared by: amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyrazine-3-carboxylic acid methyl ester (3) and suitably substituted The indolylboronate (1) was coupled in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps to yield the appropriately protected macrocyclic intermediate (5). Deprotection and coupling with an appropriately substituted carboxylic acid (or other coupling partner) can yield macrocyclic products. Additional deprotection or functionalization steps may be required to prepare final compound 6.

[0181] Additionally, for Scheme 1, thiazole can be alternatively optionally substituted 5 to 6 membered heteroaryl or optionally substituted 3 to 6 membered cycloalkylene, optionally substituted 3 to 6 membered Replacement with heterocycloalkylene (eg N-morpholinyl) or optionally substituted 6-membered arylylene (eg phenyl). Scheme 2. Alternative general synthesis of macrocyclic esters

[0182] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. Coupling of appropriately substituted and protected indolylboronate (7) with (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid in the presence of Pd catalyst followed by iodination , Deprotection and ester hydrolysis. Subsequent coupling with (S)-methylhexahydropyridazine-3-carboxylate, followed by hydrolysis and macrolide, yields the iodo intermediate (11). Subsequent palladium-mediated borylation and coupling with appropriately substituted iodoaryl or iodoheteroaryl intermediates in the presence of a Pd catalyst can afford appropriately protected macrocyclic intermediates. Alkylation, deprotection and coupling with an appropriately substituted carboxylic acid (or other coupling partner) yields the macrocyclic product. Additional deprotection or functionalization steps may be required to prepare final compound 6.

[0183] Additionally, for Scheme 2, thiazole may be substituted with optionally substituted 5 to 6 membered heteroaryl or optionally substituted 3 to 6 membered cycloalkylene, optionally substituted 3 to 6 membered Replacement with a membered heterocycloalkylene (eg N-morpholinyl) or an optionally substituted 6-membered arylylene (eg phenyl).

[0184] The compounds of Table 1a or Table 1b herein are prepared using the methods disclosed herein or using the methods described herein combined with the knowledge of those skilled in the art. Pharmaceutical composition and method of use Pharmaceutical composition and method of administration

[0185] The compounds involved in the present invention are Ras inhibitors and can be used to treat cancer. Accordingly, one embodiment of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and methods of using the compound of the present invention to prepare such compositions.

[0186] 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.

[0187] In some embodiments, a compound that exhibits a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to a relevant population is present in the pharmaceutical composition in an amount suitable for its unit dosage to be administered in a therapeutic regimen . In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for oral administration, such as liquid solutions (aqueous or non-aqueous solutions or suspensions), lozenges (such as intended for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes for administration to the tongue; parenteral administration, for example by subcutaneous, intramuscular, intravenous or epidural injection, Such as, for example, sterile solutions or suspensions, or sustained release formulations; topical administration, such as creams, ointments, or controlled release patches or sprays for application to the skin, lungs or mouth; intravaginal or rectal administration, such as Pessary, cream, or foam; sublingual administration; ocular administration; transdermal administration; or nasal, pulmonary, and other mucosal surfaces.

[0188] As used herein, a "pharmaceutically acceptable excipient" refers to any inactive ingredient (eg, a vehicle capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in the subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film formers Or coating agent, flavoring agent, aromatic agent, glidant (flow enhancer), lubricant, preservative, printing ink, absorbent, suspending or dispersing agent, sweetener or water of hydration. Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, cross-linked methylcellulose, cross-linked polyvinylpyrrolidone , citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, stearin Magnesium Acid, Maltitol, Mannitol, Methionine, Methylcellulose, Methylparaben, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinylpyrrolidone, Povidone, Pregel Starch, Propylparaben, Retinyl Palmitate, Shellac, Silicon Dioxide, Sodium Carboxymethylcellulose, Sodium Citrate, Sodium Starch Glycolate, Sorbitol, Starch (Corn Starch), Hardened Fatty acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol. Those skilled in the art are familiar with a wide variety of reagents and materials that can be used as excipients. See, for example, Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; we , Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition includes at least two different pharmaceutically acceptable excipients.

[0189] Unless expressly stated to the contrary, the compounds described herein, whether expressly stated or not, may be provided or used in salt form, eg, as a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" means, within the scope of sound medical judgment, suitable for use in contact with human tissues without undue toxicity, irritation, allergic reaction and the like, and with reasonable efficacy. Salts of compounds described herein commensurate with the risk / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (eds. P.H. Stahl and C.G. Wermuth), Wiley- VCH, 2008. Such salts can be prepared in situ during the final isolation and purification of the compounds described herein, or isolated by reacting the free basic group with a suitable organic acid.

[0190] The compounds of the present invention may have ionizable groups and thus can be prepared in the form of pharmaceutically acceptable salts. The salts may be acid addition salts involving inorganic or organic acids, or, where the compounds of the invention are in the acid form, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used in the form of pharmaceutically acceptable salts, and the pharmaceutically acceptable salt forms are used as pharmaceutically acceptable Preparation of addition products of acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric or tartaric acids for the formation of acid addition salts; and potassium hydroxide, hydrogen Sodium oxide, ammonium hydroxide, caffeine, various amines and the like are used to form base salts. Methods for preparing appropriate salts are recognized in the art.

[0191] Representative acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, Butyrate, Camphorate, Camphorsulfonate, Citrate, Cyclopentanepropionate, Digluconate, Lauryl Sulfate, Ethanesulfonate, Fumarate, Glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxy-ethanesulfonate , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotine , nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate , propionate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, valerate and similar salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, Tetraethylammonium, Methylamine, Dimethylamine, Trimethylamine, Triethylamine, Ethylamine and the like.

[0192] As used herein, the term "individual" refers to any member of the animal kingdom. In some embodiments, an "individual" refers to a human being at any stage of development. In some embodiments, "individual" refers to a human patient. In some embodiments, "individual" refers to a non-human animal. In some embodiments, the non-human animal is a mammal (eg, a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, or pig). In some embodiments, individuals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or insects. In some embodiments, an individual may be a transgenic animal, a genetically engineered animal, or a purebred.

[0193] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (eg, a compound of the invention) for administration to a subject. Each unit contains a predetermined amount of compound. In some embodiments, the amount is that amount (or an integral fraction thereof) of a unit dose suitable for administration according to a dosage regimen determined to be desirable or beneficial when administered to a relevant population (i.e., according to a therapeutic dosage regimen). The results are relevant. Those skilled in the art will appreciate that the total amount of therapeutic composition or compound administered to a particular individual is at the discretion of one or more attending physicians and may involve the administration of multiple dosage forms. As used herein, the term "dosage regimen" refers to the individual administration of a group of unit doses (typically more than one unit dose) to an individual, typically at intervals of time. In some embodiments, a given therapeutic compound (eg, a compound of the invention) has a recommended dosage regimen, which may involve one or more doses. In some embodiments, the dosage regimen comprises multiple doses that are each separated from each other by a time period of the same length; in some embodiments, the dosage regimen comprises multiple doses with at least two different time periods separating individual doses. In some embodiments, all doses within a dosage regimen are in the same unit dose amount. In some embodiments, different doses within a dosage regimen are different amounts. In some embodiments, a dosage regimen comprises a first dose in an amount of a first dose followed by one or more additional doses in an amount of a second dose different from the first dose. In some embodiments, the dosage regimen comprises a first dose in the amount of a first dose followed by one or more additional doses in the amount of a second dose that is the same amount as the first dose. In some embodiments, the dosage regimen is associated with a desired or beneficial outcome when administered to a relevant population (ie, is a therapeutic dosage regimen).

[0194] "Treatment regimen" means a dosage regimen associated with a desired or beneficial therapeutic outcome when administered in a relevant population.

[0195] The term "treatment" ("treatment / treat / treating") in its broadest sense refers to the partial or complete alleviation, amelioration, alleviation, suppression of one or more of the symptoms, characteristics or causes of a particular disease, disorder or disorder ; delaying its onset; reducing its severity; or any administration of a substance (such as a compound of the invention) that reduces its occurrence. In some embodiments, such treatment may be administered to individuals who exhibit no signs of the relevant disease, disorder or disorder or who exhibit only early signs of the disease, disorder or disorder. Alternatively or additionally, in some embodiments, treatment may be administered to an individual exhibiting one or more established signs of an associated disease, disorder, or disorder. In some embodiments, treatment is for individuals diagnosed with a relevant disease, disorder or condition. In some embodiments, treatment may be used in individuals known to have one or more predisposing factors that are statistically associated with an increased risk of developing an associated disease, disorder or disorder.

[0196] The term "therapeutically effective amount" means an amount sufficient to treat a disease, disorder or disorder when administered according to a therapeutic dosage regimen to a population suffering from or susceptible to the disease, disorder or disorder. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity or delays the onset of one or more symptoms of the disease, disorder or disorder. Those skilled in the art will understand that the term "therapeutically effective amount" need not actually achieve the desired successful treatment in a particular individual. In fact, a therapeutically effective amount is that amount which, when administered to a patient in need of such treatment, provides a particular desired pharmacological response in a substantial number of individuals. It is particularly important to understand that a particular individual may actually be "therapeutically effective" and "refractory". In some embodiments, reference to a therapeutically effective amount may refer to, for example, one or more specific tissues (e.g., tissues affected by a disease, disorder, or disorder) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). ) is the quantity measured in . Those skilled in the art will appreciate that, in some embodiments, a therapeutically effective amount may be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated in multiple doses, eg, formulated as part of a dosage regimen, or administered in multiple doses.

[0197] For use in the treatment of individuals, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated in the form of pharmaceutical or veterinary compositions. Depending on the individual to be treated, the mode of administration and the type of treatment desired, eg prophylaxis, prophylaxis or therapy, the compounds or pharmaceutically acceptable salts thereof are formulated in a manner consistent with these parameters. An overview of such technologies 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 incorporated herein by reference.

[0198] Compositions can be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical composition of the present invention can contain about 0.1% to about 99%, about 5% to about 90% or about 1% to about 20% of a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is present in an amount ranging from 1-95% by weight of the total composition, such as a pharmaceutical composition.

[0199] The composition may be provided in a dosage form suitable for administration: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, subcutaneous, topical, transdermal, sublingual, nasal , vaginal, intracapsular, intraurethral, ​​intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with nasal, urogenital, genital, or oral mucosa. Thus, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, drops, osmotic Delivery device, suppository, enema, injection, implant, spray, formulation suitable for iontophoretic delivery, or aerosol. The compositions can be formulated according to customary medical practice.

[0200] As used herein, the term "administering" refers to administering a composition (eg, a compound or formulation comprising a compound as described herein) to an individual or system. Administration to an animal subject (eg, to a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, Intraperitoneal, intrathecal, intravenous, intrathecal, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous administration.

[0201] The formulations may be prepared in a manner suitable for systemic administration or for topical or localized administration. Systemic formulations include those designed for injection (eg, intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal or oral administration. Formulations will generally include diluents, and in some cases, adjuvants, buffers, preservatives and the like. The compounds, or pharmaceutically acceptable salts thereof, can also be administered in liposomal formulations or in the form of microemulsions.

[0202] For injection, the formulations can be prepared in conventional forms, either as liquid solutions or suspensions, or solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol and the like. The compositions may also contain amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like, such as sodium acetate, sorbitan monolaurate, and the like.

[0203] Various sustained release drug systems have also been devised. See, eg, US Patent No. 5,624,677.

[0204] Systemic administration can also include relatively noninvasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for a compound of the invention, or a pharmaceutically acceptable salt thereof. As will be appreciated in the art, suitable forms include syrups, capsules and lozenges.

[0205] Each compound described herein, or a pharmaceutically acceptable salt thereof, can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in a combination therapy can be formulated together or separately. Other modes of combination therapy are also described herein.

[0206] Individually or separately formulated medicaments may be packaged together in kit form. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, suppositories or liquids in vials, two topical creams, and the like. The kit may include optional components to facilitate administration of the unit dose to the individual, such as vials for reconstitution of the powder form, syringes for injection, custom IV delivery systems, inhalers, and the like. Additionally, unit dosage kits can contain instructions for the preparation and administration of the compositions. The kit may be manufactured as a single unit dose for one individual, for multiple uses in a given individual (at a constant dose, or where the potency of the individual compounds or pharmaceutically acceptable salts thereof may progress with the treatment). may vary); or the kit may contain multiple doses suitable for administration to multiple individuals ("monolithic package"). The kit components can be assembled in cartons, blister packs, bottles, tubes and the like.

[0207] Formulations for oral use include lozenges containing the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients. Such excipients may be, for example, inert diluents or fillers such as sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate , calcium sulfate or sodium phosphate); granulating agents and disintegrants (such as cellulose derivatives, including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginate or alginic acid) Binders (such as sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, formazan cellulose, optionally substituted hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants and antiadhesives (such as stearic acid magnesium, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil or talc). Other pharmaceutically acceptable excipients may be coloring agents, flavoring agents, plasticizers, humectants, buffers and the like.

[0208] Two or more compounds may be mixed together in a tablet, capsule or other vehicle, or may be separated. In one example, the first compound is contained on the inside of the lozenge and the second compound is on the outside such that a substantial portion of the second compound is released before the release of the first compound.

[0209] Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin); or provided in soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules and pellets can be prepared in a customary manner using the ingredients mentioned above for tablets and capsules, for example using mixers, fluid bed apparatus or spray-drying equipment.

[0210] Dissolution or diffusion controlled release can be achieved by suitably coating the compound in tablet, capsule, pellet or granular formulations, or by incorporating the compound or a pharmaceutically acceptable salt thereof into an appropriate implemented in the matrix. The controlled release coating may comprise one or more of the coating substances mentioned above, for example shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, Glyceryl stearate, glyceryl palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene , polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogel, 1,3 butanediol, ethylene glycol methacrylate or poly ethylene glycol. In controlled release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate- Methyl methacrylate, polyvinyl chloride, polyethylene or halogenated fluorocarbons.

[0211] Liquid forms for oral administration that may incorporate the compounds of this invention, or pharmaceutically acceptable salts and compositions thereof, include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and preparations such as cottonseed oil. , sesame, coconut or peanut oil flavored emulsions, as well as elixirs and similar pharmaceutical vehicles.

[0212] In general, the oral dosage of any compound of the present invention, or a pharmaceutically acceptable salt thereof, when administered to humans will depend on the nature of the compound and can be readily determined by one skilled in the art. The dosage can be, for example, about 0.001 mg to about 2000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 100 mg to about 1500 mg per day, about 500 mg to about 1500 mg per day, From about 500 mg to about 2000 mg or any range derived therein. In some embodiments, daily dosages for oral administration may range, for example, from about 0.001 mg to about 2000 mg per kilogram of human body weight, administered in single or divided doses. On the other hand, it may be necessary in some cases to use doses outside these limits.

[0213] In some embodiments, the pharmaceutical composition may further comprise additional compounds having antiproliferative activity. Depending on the mode of administration, the compound, or a pharmaceutically acceptable salt thereof, will be formulated into a suitable composition for delivery. Each compound in the combination therapy, or a pharmaceutically acceptable salt thereof, can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in a combination therapy can be formulated together or separately. Desirably, the first and second agents are formulated together so that the agents are administered at or near the same time.

[0214] It is understood that the compounds and pharmaceutical compositions of the present invention may be formulated and used in combination therapy, that is, the compounds and pharmaceutical compositions may be formulated with one or more other desired therapeutic agents or medical procedures or concurrently with, prior to, or subsequent to the administration of the one or more other desired therapeutic agents or medical procedures. The particular combination of therapies (therapeutic agents or procedures) to be used in a combination regimen will take into account the compatibility of the desired therapeutic agents or procedures with the desired therapeutic effect to be achieved. It is also understood that the therapy employed may achieve the desired effect for the same disorder, or it may achieve a different effect (eg, control any adverse effects).

[0215] As described herein, the administration of each drug in the combination therapy can independently range from one to four times daily, for one day to one year, and even for the lifetime of the individual. Chronic / long-term administration is also applicable. Instructions

[0216] In some embodiments, the present invention discloses a method of treating a disease or condition characterized by aberrant Ras activity caused by a Ras mutant. In some embodiments, the disease or disorder is cancer.

[0217] Accordingly, there is also provided a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a compound comprising such a compound or salt. Pharmaceutical composition. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendix cancer, melanoma, acute myelogenous leukemia, small bowel 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, liver and gallbladder cancer or bladder cancer. In some embodiments, the cancer is appendix cancer, endometrial cancer or melanoma. Also provided is a method for treating Ras protein-related disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such a compound or salt thing.

[0218] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein are useful in the treatment of various cancers, including tumors, such as Lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compounds of the present invention or their salts, pharmaceutical compositions comprising such compounds or salts, and methods include, but are not limited to, tumor types such as: astrocytic, breast, cervix, colon Carcinomas and sarcomas of the rectum, endometrium, esophagus, stomach, head and neck, hepatocytes, larynx, lung, oral cavity, ovary, prostate and thyroid. Other cancers include, for example: heart, e.g. sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung, e.g. bronchogenic carcinoma (squamous cell , undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal, e.g. esophageal (squamous carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor , vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine ( adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, eg: kidney (adenocarcinoma, Wilm's tumor (Wilms tumor), lymphoma , leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma) , sarcomas, mesenchymal cell carcinomas, fibromas, fibroadenomas, adenomatoid tumors, lipomas); liver, e.g. hepatocellular carcinoma (liver cell carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, Adenoma, hemangioma; Biliary tract, eg, gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone, eg, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma (Ewing's sarcoma) sarcoma), malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (exostoses of osteochondral), benign enchondroma, chondroblastoma, chondromyxoma fibroma, osteoid osteoma, and giant cell tumor; nervous system, e.g., skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, colloid neoplastic disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglia Cytoma, schwannomas, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, neurofibromatosis type 1, meningioma, glioma, sarcoma); gynecology, e.g. uterus (endometrial cancer , uterine cancer, endometrial cancer), cervix (cervical cancer, cervical precancerous atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granular-theca cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma tumor), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematopoietic system, e.g. blood (myelogenous leukemia (acute and chronic), acute leukemia, chronic lymphocytic leukemia, myeloproliferative disorders (such as myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's disease Lymphoma (malignant lymphoma); skin, eg, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid , psoriasis; and adrenal glands, eg, neuroblastoma.

[0219] In some embodiments, the Ras protein is wild-type (RasWT). Accordingly, in some embodiments, compounds of the invention are used in methods of treating a patient with a RasWT-containing cancer (eg, K-RasWT, H-RasWT, or N-RasWT). In some embodiments, the Ras protein is Ras amplified (eg, K-Rasamp). Accordingly, in some embodiments, compounds of the invention are used in a method of treating a patient with a Rasamp (K-Rasamp, H-Rasamp or N-Rasamp) containing cancer. In some embodiments, the cancer comprises a Ras mutation, such as a Ras mutation described herein. In some embodiments, the mutant line is selected from: (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; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C , K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R, and combinations thereof; (c) the following N-Ras mutants: Q61R, Q61K, G12D , Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, or any combination thereof; combination of one. 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, compounds of the invention inhibit more than one Ras mutation. For example, compounds can inhibit both K-Ras G12D and K-Ras G12C. In some embodiments, the compound inhibits both K-Ras G12V and K-Ras G12C. In some embodiments, the compound inhibits both K-Ras G12C and K-Ras G13C. In some embodiments, the compound inhibits both K-Ras G12D and K-Ras G12V. In some embodiments, the compound inhibits both K-Ras G12V and K-Ras G12S. In some embodiments, the mutation of K-Ras, N-Ras or H-Ras is selected from the group consisting of: G12A, G12C, G12D, G12E, G12F, G12H, G12I, G12K, G12L, G12M, G12N, G12P , G12Q, G12R, G12S, G12T, G12V, G12W, and G12Y, or combinations thereof. In some embodiments, the mutation of K-Ras, N-Ras, or H-Ras is selected from the group consisting of G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y, or combinations thereof . In some embodiments, the compounds inhibit wild-type K-Ras, wild-type H-Ras, or wild-type N-Ras, and optionally also inhibit mutant Ras proteins containing mutations as described herein. In some embodiments, the cancer is non-small cell lung cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C. In some embodiments, the cancer is colorectal cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C. In some embodiments, the cancer is pancreatic cancer and the Ras mutation comprises an N-Ras mutation, such as N-Ras G12D. In some embodiments, the cancer is non-small cell lung cancer and the Ras protein is K-Rasamp.

[0220] Additionally, 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, compounds of the invention inhibit multiple Ras mutants. For example, compounds can inhibit both K-Ras G12C and K-Ras G13C. Compounds can inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compound inhibits both K-Ras G12C and K-Ras G12D. In some embodiments, the compound inhibits both K-Ras G12V and K-Ras G12C. In some embodiments, the compound inhibits both K-Ras G12V and K-Ras G12S. In some embodiments, compounds of the invention inhibit RasWT as well as one or more additional Ras mutations (e.g., K-, H-, or N-RasWT and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S , A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K-, H- or N-RasWT and H-Ras Q61R, G13R, or K-, H- or N-RasWT and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T). In some embodiments, compounds of the invention inhibit Rasamp as well as one or more additional Ras mutations (e.g., K-, H-, or N-Rasamp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S , A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K-, H- or N-Rasamp and H-Ras Q61R, G13R, or K-, H- Or N-Rasamp and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T).

[0221] Methods for detecting Ras mutations are known in the art. Such approaches include, but are not limited to, direct sequencing and the use of high-sensitivity diagnostic assays (using CE-IVD markers), such as Domagala et al., Pol J Pathol 3: 145-164 (2012), which is incorporated herein by reference in its entirety Methods described in, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; See also eg WO 2020 / 106640.

[0222] 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-Rasamp. In any of the foregoing, if not specifically stated, the compound may also inhibit RasWT (eg, K-, H-, or N-RasWT) or Rasamp (eg, K-, H-, or N-Rasamp).

[0223] In some embodiments, the cancer comprises a Ras mutation and a STK11LOF, KEAP1, EPHA5, or NF1 mutation, or a combination thereof. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation, a STK11LOF mutation, and a KEAP1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and a STK11 LOF mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and a STK11 LOF mutation. In some embodiments, the cancer comprises a K-Ras G13C Ras mutation and a STK11LOF, KEAP1, EPHA5, or NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and comprises a K-Ras G12C mutation. In any of the foregoing, compounds may also inhibit RasWT (eg, K-, H-, or N-RasWT) or Rasamp (eg, K-, H-, or N-Rasamp).

[0224] Also provided is a method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt thereof can inhibit more than one type of Ras protein in a cell. Also provided is a method of inhibiting RAF-Ras binding comprising contacting the cell with an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. The cell can be a cancer cell. The cancer cells may be of any type of cancer described herein. The cells can be in vivo or in vitro. combination therapy

[0225] The methods of the invention may include the compounds of the invention alone or in combination with one or more additional therapies (eg, non-drug treatments or therapeutic agents). When administered alone, the dosage of one or more of these additional therapies (eg, non-drug treatments or therapeutic agents) may be reduced relative to the standard dosage. For example, doses can be determined empirically based on drug combinations and permutations or can be inferred by isoradiometric analysis (eg, Black et al., Neurology 65:S3-S6 (2005)).

[0226] The compounds of the invention may be administered before, after or concurrently with one or more of these additional therapies. When combined, the dose of the compound of the invention and the dose of the one or more additional therapies (eg, non-drug treatments or therapeutic agents) provide a therapeutic effect (eg, a synergistic or additive therapeutic effect). A compound of the invention and an additional therapy, such as an anticancer agent, can be administered together, such as in a single pharmaceutical composition, or separately, and when administered separately, the administration can occur simultaneously or sequentially. Such sequential administrations may be close or far apart in time.

[0227] In some embodiments, the additional therapy is the administration of a side effect limiting agent (eg, an agent intended to reduce the occurrence or severity of side effects of treatment). For example, in some embodiments, compounds of the invention may also be used in combination with therapeutic agents for the treatment of nausea. Examples of agents that may be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or Its pharmaceutically acceptable salt.

[0228] In some embodiments, the one or more additional therapies include non-drug treatments (eg, surgery or radiation therapy). In some embodiments, the one or more additional therapies include a therapeutic agent (eg, a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, anti-proliferative agent, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies include non-drug treatments such as surgery or radiation therapy and therapeutic agents such as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors or Compounds or biological agents of autophagy inhibitors). In other embodiments, the one or more additional therapies include two therapeutic agents. In yet 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.

[0229] In this combination therapy section, all references refer to the agent described, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. is incorporated by reference for all constituents, whether or not so expressly stated. non-drug therapy

[0230] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (eg, surgical resection of tumor tissue), and T cell recipient transfer (ACT) therapy.

[0231] In some embodiments, the compounds of the invention may be used as adjunctive therapy after surgery. In some embodiments, compounds of the invention may be used as preoperative neoadjuvant therapy.

[0232] Radiation therapy is useful for inhibiting abnormal cell growth or treating hyperproliferative disorders, such as cancer, in an individual, eg, a mammal (eg, a human). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implant radiation, stereotaxic radiosurgery, whole body radiation therapy, radiation therapy, and permanent or transient implant brachytherapy . As used herein, the term "brachytherapy" refers to radiation therapy delivered by insertion of spatially confined radioactive material in the body at or near the site of a tumor or other proliferative tissue disease. The term is intended, but not limited to, to include exposure to radioactive isotopes such as At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu radioactive isotopes). Suitable radioactive sources for use as cell conditioning agents of the present invention include solids and liquids. As a non-limiting example, the radioactive source may 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 hormones, beta particles, gamma radiation or other therapeutic rays. The radioactive material may also be a fluid made from any radionuclide solution, such as a solution of I-125 or I-131, or a radioactive fluid may be made using a suitable fluid containing small particles of a solid radionuclide such as Au-198 or Y-90. Fluid slurry preparation. In addition, radionuclides can be embedded in gels or radioactive microspheres.

[0233] In some embodiments, the compounds of the present invention can sensitize abnormal cells to radiation therapy for the purpose of killing or inhibiting the growth of such cells. Accordingly, the invention further relates to a method for sensitizing abnormal cells in a mammal to radiation therapy, the method comprising administering to the mammal an amount of a compound of the invention effective to sensitize the abnormal cells to radiation therapy . The amount of the compound in the method can be determined according to the manner used to determine the effective amount of the compound described herein. In some embodiments, compounds of the invention are useful as adjuvant therapy following radiation therapy or as neoadjuvant therapy prior to radiation therapy.

[0234] In some embodiments, the non-drug therapy is T cell recipient transfer (ACT) therapy. In some embodiments, the T cell line activates T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding CAR into T cells. A source of T cells is obtained from an individual prior to expansion and genetic modification of the T cells. 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 a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the invention, various T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Before or after T cells have been genetically modified to express a desired protein, such as a CAR, such T cells can generally be activated and expanded using methods such as those described in, for example, the following US 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; 6,867,041. therapeutic agent

[0235] A therapeutic agent may be a compound useful in the treatment of cancer or its associated symptoms.

[0236] For example, the therapeutic agent can be a steroid. Accordingly, in some embodiments, the one or more additional therapies include steroids. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone , cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone ( diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, Flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, flupermesolone acetate (fluperolone acetate), fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide ( halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrison (medrysone), meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone ( prednisolone), 25-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, Lime rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0237] Additional examples of therapeutic agents that may be used in combination therapy with the compounds of the present invention include compounds described in the following patents: U.S. Patent Nos. No. 5,770,599, No. 5,747,498, No. 5,990,141, No. 6,235,764 and No. 8,623,885, and international patent applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279 , WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089 and WO00 / 02871.

[0238] The therapeutic agent may be a biological agent (eg, an interleukin (eg, an interferon or an interleukin, such as IL-2)) for the treatment of cancer or a condition associated with it. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein or functional fragment thereof). Antibody-drug conjugates are also included.

[0239] The therapeutic agent can be a T cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (eg, a monospecific antibody, such as a monoclonal antibody). The antibody can be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (eg, an inhibitory antibody or a small molecule inhibitor) (eg, an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (eg, an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (eg, an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L2 inhibitor or antagonist (eg, an inhibitory antibody or Fc fusion or small molecule inhibitor) (eg, a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B Inhibitors or antagonists of -7 family ligands or combinations thereof (eg inhibitory antibodies or small molecule inhibitors). In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as avelumab (avelumab), durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene) or Preusser, M . et al. (2015) Nat. Rev. Neurol. The checkpoint inhibitors disclosed in, including but not limited to ipilimumab (ipilimumab), tremelimumab (tremelimumab), nivolumab, pembrolizumab anti, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9 and KW-6002.

[0240] The therapeutic agent may be an anti-TIGIT antibody such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab).

[0241] The therapeutic agent can be an agent that treats cancer or its related symptoms (eg, cytotoxic agents, non-peptide small molecules, or other compounds useful in the treatment of cancer or its related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapeutic or targeted therapeutic agents.

[0242] Anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folate analogs , pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination Complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogues . Other anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel ( doxetaxel). In some embodiments, the one or more additional therapies include two or more anticancer agents. The two or more anticancer agents may be used in a mixed solution for combined administration or separate administration. Suitable dosing regimens for combination anticancer agents are known in the art and described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355 (9209 ): 1041-1047 (2000).

[0243] Other non-limiting examples of anticancer agents include Gleevec® (Imatinib Mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib) ); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; Busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine amines; polyacetylenes (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin ( bryostatin ); callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycin (especially candocin 1 and candocin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin ; pancratistatin; sarcodictyn A; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholphosamide (cholophosphamide), estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, Xinen Novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine ( carmustine ), chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediynes Antibiotics (e.g., calicheamicin, such as calicheamicin γ11 and calicheamicin ω11 (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dannamycin ( dynemicin ), such as dynomycin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophore and related chromophores Alkyne antibiotic chromophore, aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, actinomycin Cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycin ), dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (adriamycin) (doxorubicin), N-morpholinodoxorubicin, cyano(N-morpholino)doxorubicin, 2-pyrrolinyl-doxorubicin, deoxydoxorubicin star, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (such as mitomycin C) , mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, tri-iron quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, netastatin ( zinostatin), zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folate analogs such as denopterin, pteropterin ), trimetrexate (trimetrexate); purine analogs, such as fludarabine (fludarabine), 6-mercaptopurine, thiamiprine, thioguanine (thioguanine); pyrimidine analogs, such as amcitabine ( ancitabine), azacitidine, 6-thiazopyrimidine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enoxa enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testosterone Testolactone; anti-epinephrines such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as frolinic acid; aceglucuronide (aceglatone); aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene (bisantrene); edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone, such as epothilon B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoid, Such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; Pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine ); PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes such as T-2 toxin, verracurin A), roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; tepa; taxoids such as Taxol® (paclitaxel), Abraxane® (polyoxyethylene hydrogenated castor oil-free, albumin-engineered nanoparticle formulation of paclitaxel), and Taxotere® (doxyne Taxel); chloranbucil; tamoxifen (Nolvadex™); raloxifene; aromatase-inhibiting 4(5)-imidazole; 4-hydroxytamoxifen fen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston®); nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine ; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); Ifosfamide; Mitoxantrone; Vincristine; Navelbine® (vinorelbine); Novantrone; Teniposide; Edatril edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (eg, CPT-11); topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids, such as retinoic acid; Esperamicins; Capecitabine (eg Xeloda®); acceptable salt.

[0244] Additional non-limiting examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®) , rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridine carboxamide, adelaide adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-amine Pyridine-2-carbaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastic agents (e.g., cell cycle non-specific antineoplastic agents, and others as described herein) antineoplastic agents), antineoplastic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine ), BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), sponge-induced cancer Calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod (imiquimod), indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, thiothrone ( 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 -tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, 2-chloroethylamine, troxacitabine , uramustine, vadimezan, vinflunine, ZD6126 and zosuquidar.

[0245] 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), glycosides), antibiotics (such as dactinomycin / actinomycin D, daunomycin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, Plicamycin (mithramycin), mitomycin, enzymes such as L-asparaginase that systemically metabolize L-asparagine and remove amide cells), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g. methamethamine, 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 (such as busulfan ), nitrosoureas (such as carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic Antimetabolites (such as folate analogs), pyrimidine analogs (such as fluorouracil, aziridine, and cytarabine), purine analogs, and related inhibitors (such as mercaptopurine, thioguanine, pentostatin, and 2- Chlorodeoxyadenosine), aromatase inhibitors (such as anastrozole, exemestane, and letrozole), and platinum coordination complexes (such as cisplatin and carboplatin) , procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (eg, trichostatin, sodium butyrate, epidane (apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat) , mTOR inhibitors (such as vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5 ) inhibitors (e.g. Array 520), DNA binding agents (e.g. Zalypsis®), PI3K inhibitors such as PI3K delta inhibitors (e.g. GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g. CAL-130), Copanlisib, alpelisib, and idelalisib; multikinase inhibitors (such as TG02 and sorafenib), hormones (such as estrogens), and hormone agonists agents such as luteinizing hormone releasing hormone (LHRH) agonists (eg goserelin, leuprolide and triptorelin), BAFF neutralizing antibodies (eg LY2127399), IKK inhibitors , p38MAPK inhibitors, anti-IL-6 (such as CNT0328), telomerase inhibitors (such as GRN 163L), Aurora kinase inhibitors (such as MLN8237), cell surface monoclonal antibodies (such as anti-CD38 (HUMAX-CD38), anti- CS1 (e.g. elotuzumab), HSP90 inhibitors (e.g. 17 AAG and KOS 953), P13K / Akt inhibitors (e.g. perifosine), Akt inhibitors (e.g. GSK-2141795 ), PKC inhibitors (e.g. enzastaurin), FTIs (e.g. Zarnestra™), anti-CD138 (e.g. BT062), Torcl / 2-specific kinase inhibitors (e.g. INK128), ER / UPR targeting agents (e.g. such as MKC-3946), cFMS inhibitors such as ARRY-382, JAK1 / 2 inhibitors such as CYT387, PARP inhibitors such as olaparib and veliparib (ABT-888) and BCL-2 antagonists.

[0246] In some embodiments, the anticancer agent is selected from the group consisting of methamethine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafil Ni (sorafenib) or any of the aforementioned analogs or derivatives variants.

[0247] In some embodiments, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors such as gefitinib Iressa®, Erlotinib (Tarceva®), Pilitinib, CP-654577, CP-724714, Canertinib (CI 1033), HKI-272, Lapatinib Lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.

[0248] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005; and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0249] In some embodiments, the anticancer agent is an inhibitor of receptor tyrosine kinase (RTK) / growth factor receptor downstream members (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 pharmaceutically acceptable salts, solvates, isomers (such as stereoisomers ), prodrugs or tautomers), SOS1 inhibitors (such as BI-1701963, BI-3406, SDR5, BAY-293 or RMC-5845, or pharmaceutically acceptable salts, solvates, iso (e.g. stereoisomers), prodrugs or tautomers), Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors or mTOR inhibitors (e.g. mTORC1 inhibitor or mTORC2 inhibitor). In some embodiments, the anticancer agent is JAB-3312.

[0250] In some embodiments, the anticancer agent is a SOS1 inhibitor. In some embodiments, the SOS1 inhibitor is selected from WO 2021173524, WO 2021130731, WO 2021127429, WO 2021092115, WO 2021105960, WO 2021074227, WO 2020180768, WO 2020180770, WO 2020 173935, WO 2020146470, WO 2019201848, WO 2019122129, WO 2018172250 and those disclosed in WO 2018115380, or pharmaceutically acceptable salts, solvates, isomers (such as stereoisomers), prodrugs or tautomers thereof. In some embodiments, the anticancer agent is an additional Ras inhibitor or a Ras vaccine or another treatment modality designed to directly or indirectly reduce the oncogenic activity of Ras. In some embodiments, the anticancer agent is an additional Ras inhibitor. In some embodiments, the Ras inhibitor targets Ras in an active or GTP-bound state. In some embodiments, the Ras inhibitor targets Ras in an inactive or GDP-bound state. In some embodiments, the Ras inhibitor is such as a K-Ras G12C inhibitor, such as AMG 510 (sotoracib), MRTX1257, MRTX849 (adagracib), JNJ-74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21000, RMC-6291 or GDC-6036, or pharmaceutically acceptable salts, solvates, isomers (such as stereoisomers), former drug or tautomer. In some embodiments, the Ras inhibitor is a K-Ras G12D inhibitor, such as MRTX1133 or JAB-22000, or a pharmaceutically acceptable salt, solvate, isomer (such as a stereoisomer), or a pharmaceutically acceptable salt thereof. Prodrug or tautomer In some embodiments, the Ras inhibitor is a K-Ras G12V inhibitor, such as JAB-23000, or a pharmaceutically acceptable salt, solvate, isomer thereof (e.g. stereoisomers), prodrugs or tautomers. In some embodiments, the Ras inhibitor is RMC-6236, or a pharmaceutically acceptable salt, solvate, isomer (eg, stereoisomer), prodrug or tautomer thereof. In some embodiments, the Ras inhibitor is selected from the Ras(ON) inhibitors disclosed in the patents incorporated herein by reference in their entirety, or pharmaceutically acceptable salts, solvates, Isomers (eg stereoisomers), prodrugs or tautomers: WO 2021091982, WO 2021091967, WO 2021091956 and WO 2020132597. Further examples of Ras inhibitors that can be combined with the Ras inhibitors of the invention are provided in the following patents (which are incorporated herein by reference in their entirety): WO 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716 , WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2 021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019 217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018217651, WO 2018218071, WO 2018218069, WO 2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 20 18140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510 , WO 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2 017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659 and WO 2013155223, or pharmaceutically acceptable salts, solvates, isomers (such as stereoisomers), prodrugs or tautomers thereof.

[0251] In some embodiments, a therapeutic agent that can be combined with a compound of the invention is a MAP kinase (MAPK) pathway inhibitor (or "MAPK inhibitor"). MAPK inhibitors include but are not limited to one or more MAPK inhibitors described in Cancers (Basel) 2015 September; 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; ) (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. 25 Nov 2014; 9(11)) and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1; 17(5):989-1000). The MAPK inhibitor can be PLX8394, LXH254, GDC-5573 or LY3009120.

[0252] In some embodiments, the anticancer agent is a disruptor or a RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway inhibitor. PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) September 2015; 7(3): 1758-1784. For example, the PI3K / AKT inhibitor can be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103;

[0253] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0254] In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors and immunotherapy. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0255] IGF-1R inhibitors include linsitinib or a pharmaceutically acceptable salt thereof.

[0256] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and Matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block natural ligand activation of EGFR. 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 EGFR inhibition described in Yang et al., Cancer Res.1999, 59:1236-1243 agent. The EGFR inhibitor may 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 therefor.

[0257] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®) and lapatinib (TykerB®). See, eg, 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, 30 4( 5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). 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 ; US Patent No. 5,747,498; WO96 / 30347; EP 0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; 70; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; 4895;WO96 / 31510; wo98 / 14449; wo98 / 14450; wo98 / 14451; wo95 / 09847; wo97 / 19065; wo98 / 17662; US Patent No. 5,789,427; US Patent No. 5,650,415; US Patent No. 5,656,643; wo99 / 3 3; 5146; wo99 / 35132; WO99 / 07701; and WO92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family consists of HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3) and HER (ERBB4).

[0258] MEK inhibitors include, but are not limited to, pimasetinib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and bimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation selected from the group consisting of class I MEK1 mutations: D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from: ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0259] PI3K inhibitors include but are not limited to wortmannin; 17-hydroxy wortmannin 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 Pitilixi( pictilisib) or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl )-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in WO06 / 122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-(N-morpholino)thieno[3,2-d]pyrimidine- 6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H -l-benzopyran-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 (purchased from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2 -a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy -2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[l-[5-( 4-fluoro-2-hydroxyl-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione (available from Axon Medchem); TGX-221 (7 -Methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (available from Axon Medchem ); XL-765; and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI- 145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907 and AEZS-136.

[0260] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 ( Inhibition of Akl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (eg Jin et al., Br. J. Cancer 2004, 91:1808- 12); 1-H-imidazo[4,5-c]pyridyl compounds (eg WO 05 / 011700); indole-3-carbinol and derivatives thereof (eg US 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 (eg 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. People, Cancer Res. 2004, 64:4394-9).

[0261] mTOR inhibitors include but are not limited to ATP competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); Deforolimus (also known as deforolimus or AP23573); rapamycin analogs (rapalogs), such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapamycin (also known as CC1779); 40-table- (tetrazolyl)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 16-pentynyloxy-32(S)-dihydrorapamycin; described in WO05 / 005434 Derivatives disclosed in US Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842 and 5,256,790, and WO94 / 090101, WO92 / 05179, WO93 / 1111 30. WO94 Derivatives disclosed in / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (such as WO05 / 016252 ). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see eg WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552, which has the following structure.

[0262] BRAF inhibitors that may be used in combination with the compounds of the present invention include, for example, vemurafenib, dabrafenib and encorafenib. BRAF may comprise class 3 BRAF mutations. 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; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0263] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of 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.

[0264] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to various 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 configuration stabilized by a binding network involving residues from the N-SH2 and PTP domains. Stimulation with, for example, cytokines or growth factors acting through receptor tyrosine kinases (RTKs) results in exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0265] SHP2 is involved in signaling via the RAS-mitogen-activated protein kinase (MAPK), ie, JAK-STAT or phosphoinositide 3-kinase-AKT pathway. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental disorders, such as Noonan Syndrome and Leopard Syndrome, and human cancers, such as juvenile myelomonocytosis Leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, and cancers of the breast, lung, and colon. Some of these mutations destabilize the auto-inhibitory conformation of SHP2 and promote auto-activation or enhanced growth factor-driven activation of SHP2. Therefore, SHP2 represents a particularly interesting target for the development of novel therapies for the treatment of various diseases, including cancer. Combinations of SHP2 inhibitors (e.g. RMC-4550 or SHP099) and RAS pathway inhibitors (e.g. MEK inhibitors) have been shown to inhibit various cancer cell lines (e.g. pancreatic, lung, ovarian and breast) in vitro of proliferation. Therefore, combination therapy involving SHP2 inhibitors and RAS pathway inhibitors may be a general strategy for preventing tumor drug resistance in various malignancies.

[0266] Non-limiting examples of such SHP2 inhibitors known in the art include: Chen et al., Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem.2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications: WO 2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 20 21143701, WO 2021143680, WO2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO 2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 20210 43077, WO 2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO 2020156242, WO 2020 108590, WO 2020104635, WO 2020094104, WO 2020094018, WO 2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO 2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO 2020033828, WO 2020033286, WO 2020022323, WO 2019233810, WO 20 19213318, WO 2019183367, WO 2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO 2019158019, WO 2019152454 , WO 2019051469, WO 2019051084, WO 2018218133, WO 2018172984, WO 2018160731, WO 2018136265, WO 2018136264, WO 2018130928, WO 2018129402, WO 2 018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO 2017211303, WO 2017210134, WO 2017156397, WO 2017100279, WO 2017079723, WO 2017078499, WO 2016203406, WO 2016203405, WO 2016203404, WO 2016196591, WO 2016191328, WO 2015107495, WO 2015 107494, WO 2015107493, WO 2014176488, WO 2014113584, US 20210085677, US 10858359, US 10934302, US 10954243, US 10988466, US 11001561, US 11033547, US 11034705 or US 11044675, or pharmaceutically acceptable salts, solvates, isomers (such as stereoisomers), prodrugs or tautomers thereof, each Incorporated herein by reference.

[0267] 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, eg, 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 active site of the phosphatase. In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155, the structure of which is, or a pharmaceutically acceptable salt, solvate, isomer (eg, stereoisomer), prodrug or tautomer thereof.

[0268] In some embodiments, the SHP2 inhibitor is RMC-4550, having the following structure, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof structure. In some embodiments, the SHP2 inhibitor is RMC-4630, which has the following structure: , or a pharmaceutically acceptable salt, solvate, isomer (such as a stereoisomer), prodrug or tautomer thereof structure.

[0269] In some embodiments, the SHP2 inhibitor is JAB-3068, having the following structure, or a pharmaceutically acceptable salt, solvate, isomer (such as a stereoisomer), prodrug or mutual variants. In some embodiments, the SHP2 inhibitor is JAB-3312. In some embodiments, the SHP2 inhibitor is the following compound, or a pharmaceutically acceptable salt, solvate, isomer (eg, stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RLY-1971, which has the following structure, or a pharmaceutically acceptable salt, solvate, isomer (such as a stereoisomer), prodrug or tautomer thereof things. In some embodiments, the SHP2 inhibitor is ERAS-601, or a pharmaceutically acceptable salt, solvate, isomer (eg, stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is BBP-398, or a pharmaceutically acceptable salt, solvate, isomer (eg, stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is SH3809. In some embodiments, the SHP2 inhibitor is PF-07284892, or a pharmaceutically acceptable salt, solvate, isomer (eg, stereoisomer), prodrug, or tautomer thereof.

[0270] In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors agent. 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, eg, 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 inhibitors of the invention are used in combination with MEK inhibitors and SOS1 inhibitors. In some embodiments, the Ras inhibitors of the present invention are used in combination with PD-L1 inhibitors and SOS1 inhibitors. In some embodiments, the Ras inhibitors of the present invention are used in combination with PD-L1 inhibitors and SHP2 inhibitors. In some embodiments, the Ras inhibitors of the invention are used in combination with MEK inhibitors and SHP2 inhibitors. In some embodiments, the cancer is colorectal cancer and the treatment comprises administering a combination of a Ras inhibitor of the invention and a second or third therapeutic agent.

[0271] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0272] Immunotherapy includes, but is 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 agent, anti-PD-L1 agent, anti-CTLA4 agent, anti-LAG1 agent and anti-OX40 agent.

[0273] Immunomodulators (IMiDs) are a class of immunomodulatory drugs (drugs that modulate immune responses) that contain imide groups. IMiD drugs include thalidomide and its analogs (lenalidomide, pomalidomide and apremilast).

[0274] 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 / 121168 A1), and are also described elsewhere herein.

[0275] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (eg, bivalent anti-GITR antibodies), such as those described in U.S. Patent No. 6,111,090, U.S. Patent No. 8,586,023, WO2010 / 003118, and WO2011 / 090754 or such as US Patent No. 7,025,962, EP 1947183, US Patent No. 7,812,135; US Patent No. 8,388,967; US Patent No. 8,591,886; 54 , WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451 and WO2011 / 051726.

[0276] Another example of a therapeutic agent that may be used in combination with the compounds of this invention is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions, antibodies, antigen-binding domains, radionuclear species, and combinations and conjugates thereof synthesized in vitro. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally can be used to inhibit or stimulate their targets (such as receptor or enzyme activation or inhibition), and thereby promote cell death or make cells growth arrest. In some embodiments, the one or more additional therapies include anti-angiogenic agents.

[0277] Anti-angiogenic agents may 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 ( 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 US Patent Nos. 5,863,949 and 5,861,5 No. 10 in. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. More preferably compared to other matrix metalloproteases (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) are inhibitors that selectively inhibit MMP-2 or AMP-9. Some specific examples of MMP inhibitors are AG-3340, RO 32-3555 and RS 13-0830.

[0278] Other exemplary anti-angiogenic agents include kinase domain KDR (kinase domain receptor) inhibitors (such as antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (such as specific Antibodies or antigen binding domains that bind VEGF (e.g. bevacizumab or soluble VEGF receptor or its ligand binding domain), such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g. specifically bind to VEGF receptor Antibody or antigen-binding region of EGFR), EGFR inhibitors (such as antibodies or antigen-binding regions that specifically bind to EGFR), such as Vectibix® (panitumumab), Erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (such as antibodies or antigen-binding regions that specifically bind to Angl and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (such as antibodies or antigen-binding regions that specifically bind to Tie2 kinase district). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (such as specifically binding antibodies or antigen binding domains, or Soluble TWEAK receptor antagonists; see US6,727,225), ADAM disintegrin domains that antagonize the binding of integrins to their ligands (US 2002 / 0042368), specifically binding anti-eph receptor or anti-pterin antibodies or antigens Binding regions (U.S. Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and their patent family members), and anti-PDGF-BB antagonists (such as specifically binding antibodies or Antigen binding region), and an antibody or antigen binding region that specifically binds to PDGF-BB ligand, and a PDGFR kinase inhibitor (such as an antibody or antigen binding region that specifically binds to PDGFR kinase). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); Ilomastat (Arriva, USA, US5892112); Emaxanib (Pfizer, USA , US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); ) (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 Technologies (Ariad, USA); -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); Mitastatin (Metastatin) (EntreMed, USA); Serpin (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); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA); PI 88 (Progen, Australia); Lengitide (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA ); Endostatin (Boston Childrens Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Childrens 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); pegatanib (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); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); Motuporamine C (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); Kinase plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angusidine (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); Endo-2-methoxyestradiol; anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA ); tumor necrosis factor-α inhibitors; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA ); MAb, KDR (ImClone Systems, USA); MAb, α5β (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University , USA); CS 706 (Sankyo, Japan); Combretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); 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); (Genaera, USA); RPI 4610 (Sirna, USA); Heparanase 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); Protein-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); , USA); truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thromboplastin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA). .

[0279] Other examples of therapeutic agents that may be used in combination with the compounds of the present invention include agents (e.g., antibodies, antigen binding domains, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as hepatocyte growth factor (HGF, also Antagonists known as Scatter Factor), and antibodies or antigen binding domains that specifically bind the receptor c-Met.

[0280] Another example of a therapeutic agent that can be used in combination with the compounds of the invention is an autophagy inhibitor. Autophagy inhibitors include but are not limited to chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1 (bafilomycin A1), 5-amino-4-imidazolamide riboside (AICAR ), soft sponge acid, autophagy-inhibitory algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vincrin alkali. In addition, antisense RNA or siRNA that inhibit the expression of proteins, including but not limited to ATG5 (involved in autophagy), can also be used. In some embodiments, the one or more additional therapies include an autophagy inhibitor.

[0281] Another example of a therapeutic agent that may be used in combination with the compounds of the present invention is an antineoplastic agent. In some embodiments, the one or more additional therapies include antineoplastic agents. Non-limiting examples of antineoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, altretinoin, hexamethylmelamine , amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer , ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, Capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong - A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, Docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, Fluorouracil, HIT diclofenac, interferon α, daunomycin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine ), emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exixulin ( exisulind), fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, Gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, Glico Glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, imiquimod (imiquimod), interferon alpha, native interferon alpha, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-Nl, interferon alpha-n3, conjugated interferon-1, natural Interferon alpha, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, native interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguane , irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, Letrozole, interferon-alpha, leuprolide, levamisole + fluorouracil, liarazole, lobaplatin, lonidamine, lovastatin, Masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, Double-stranded RNA, mitoxantrone, dibromodulcitol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine ), nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoietin, NSC 631570 octreotide, oprelvekin, osaterone ), oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon α-2b, pentosan polysulfate sodium, spray Sistatin, picibanil, birubicin, rabbit anti-thymocyte polyclonal antibody, pegylated interferon α-2a, porfimer sodium, raloxifene ), raltitrexed, rasburiembodiment, etidronate rhenium Re 186, RII isotretinamide (retinamide), rituximab (rituximab), romotide (romourtide), lexiprazine Samarium (153 Sm) (samarium lexidronam), sargramostim, sizofiran, sobuzoxane, sonermin, strontium chloride-89, suramin ), tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide ), thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131 131), trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, natural tumor necrosis factor alpha, Ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, netrestat zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon ), decitabine (decitabine), desaminoglutethimide (dexaminoglutethimide), diaziquone (diaziquone), EL 532 (Elan), EM 800 (Endorecherche), eniluracil (eniluracil), etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat , IM 862 (Cytran), Interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira) , Cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), Idiotype 105AD7 MAb (CRC Technology), Idiotype CEA MAb (Trilex), LYM-1-Iodine 131 MAb (Techni clone), Polymorphic Epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitomomab, motexafin gadolinium, MX 6 ( Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat (prinomastat ), RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN) , TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine ( Biomira), Melanoma Vaccine (New York University), Melanoma Vaccine (Sloan Kettering Institute), Melanoma Tumor Lysate Vaccine (New York Medical College), Viral Melanoma Cell Lysate Vaccine (Royal Newcastle Hospital) Or valspodar.

[0282] Additional examples of therapeutic agents that may be used in combination with the compounds of the present invention include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, and Known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; (dacetuzumab); muromonab-CD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); ado-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab ( Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); certolizumab pegol (Cimzia®); daclizumab (Zenapax®); Anti-(daratumumab) (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); Gemtuzumab ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (infliximab) (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); Anti (ofatumumab) (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); Monoclonal antibodies (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); (tositumomab); tositumomab-i-131; tositumomab and tositumomab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0283] Depending on the condition being treated, the compounds described herein may be used in combination with the agents disclosed herein or other suitable agents. Accordingly, in some embodiments, one or more compounds of the disclosure will be co-administered with other therapies described herein. When used in combination therapy, the compounds described herein can be administered with the second agent simultaneously or separately. Such combination administration can include simultaneous administration of both agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any agent described herein can be formulated together in the same dosage form and administered at the same time. Alternatively, the compounds of the invention and any of the therapies described herein can be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, a compound of the disclosure may be administered first followed by any therapy described herein, or vice versa. In some embodiments of separate administration regimens, the compounds of the invention and any of the therapies described herein are administered minutes apart, or hours apart, or days apart.

[0284] In some embodiments of any of the methods described herein, the first therapy (eg, a compound of the invention) and the one or more additional therapies are administered simultaneously or sequentially in either order. The first therapeutic agent can be immediately before, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours after administration of the one or more additional therapies , up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours Hours, up to 23 hours, up to 24 hours, or up to 1-7 days, 1-14 days, 1-21 days, or 1-30 days.

[0285] The invention also features kits comprising (a) a pharmaceutical composition comprising an agent described herein (eg, a compound of the invention) and (b) with instructions for performing any of the methods described herein packaging insert. In some embodiments, the kit includes (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the invention), (b) one or more additional therapies (e.g., a non-drug treatment or therapeutic agent), and (c) A package insert with instructions for performing any of the methods described herein.

[0286] Since one aspect of the invention encompasses the treatment of a disease or its associated symptoms with combinations of pharmaceutically active compounds that may be administered separately, the invention further relates to combining individual pharmaceutical compositions in kit form. The kit may comprise two separate pharmaceutical compositions: a compound of the invention and one or more additional therapies. The kit may comprise containers for containing the individual components, such as dispensing bottles or dispensing foil packs. Additional examples of containers include syringes, boxes and bags. In some embodiments, the kit can include directions for the use of the individual components. When the individual components are preferably administered in different dosage forms (e.g., oral or parenteral), when administered at different dosage intervals, or when the prescribing healthcare practitioner wishes to adjust the individual components of the combination, This kit form is particularly advantageous. Example of numbering

[0287] [1] A compound or a pharmaceutically acceptable salt thereof having the structure of Formula Ia: Formula Ia wherein A is an optionally substituted 3 to 6 membered cycloalkylene, an optionally substituted 3 to 6 membered heterocycloalkylene, optionally substituted 6 membered arylylene, optionally substituted 5 to 6 membered heteroaryl, optionally substituted C2-C4 alkylene or optionally substituted Substituted C2-C4 alkenyl; Y is ,,,,,, or; W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3 to 10 members Heterocycloalkyl, optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; X1 and X4 are each independently CH2 or NH; R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3 to 15 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; R2 is hydrogen, optionally Substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R10 is hydrogen, hydroxyl, optionally substituted C1-C3 alkyl or optionally Case substituted C1-C6 heteroalkyl.

[288] [2] The compound of paragraph [1] or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted 6 to 10 membered aryl or an optionally substituted 5 to 10 membered heteroaryl .

[0289] [3] The compound of paragraph [2], or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted phenyl or optionally substituted pyridine.

[0290] [4] The compound according to any one of paragraphs [1] to [3], or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazole, optionally substituted triazole, optionally substituted Optionally substituted N-morpholinyl, optionally substituted piperidinyl, optionally substituted pyridine or optionally substituted phenyl.

[0291] [5] The compound according to any one of paragraphs [1] to [3] [or a pharmaceutically acceptable salt thereof, wherein A is not optionally substituted phenyl or benzimidazole.

[0292] [6] The compound of paragraph 5 or a pharmaceutically acceptable salt thereof, wherein A is not hydroxyphenyl.

[0293] [7] The compound according to any one of paragraphs [1] to [6], or a pharmaceutically acceptable salt thereof, wherein the compound is not a compound in Table 2.

[0294] [8] The compound according to any one of paragraphs [1] to [7], or a pharmaceutically acceptable salt thereof, wherein the compound is not a compound in Table 3.

[0295] [9] The compound according to any one of paragraphs [1] to [8], or a pharmaceutically acceptable salt thereof, wherein Y is -NHC(O)- or -NHC(O)NH-.

[0296]

[10] The compound of paragraph [9] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIa: formula IIa, wherein a is 0 or 1.

[0297]

[11] The compound of paragraph

[10] or a pharmaceutically acceptable salt thereof, which has the structure of formula II-1a: formula II-1a, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0298]

[12] The compound of paragraph

[11] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIa-2: Formula IIa-2.

[0299]

[13] The compound of paragraph

[12] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIa-3: formula IIa-3, wherein R4 and R5 are each independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl.

[0300]

[14] The compound of paragraph

[13] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IIa-4: Formula IIa-4.

[0301]

[15] The compound of paragraph

[14] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIa-5: formula IIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0302]

[16] The compound of paragraph

[15] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIa-6: Formula IIa-6.

[0303]

[17] The compound of paragraph

[15] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIa-7: Formula IIa-7.

[0304]

[18] The compound of paragraph

[16] or

[17] , wherein R6 is methyl.

[0305]

[19] The compound of paragraph

[15] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIa-8 or formula IIa-9: formula IIa-8, formula IIa-9.

[0306]

[20] The compound of paragraph [9] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa: formula IIIa, wherein a is 0 or 1.

[0307]

[21] The compound of paragraph

[20] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa-1: formula IIIa-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0308]

[22] The compound of paragraph

[21] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa-2: formula IIIa-2.

[0309]

[23] . The compound as in paragraph

[22] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa-3: formula IIIa-3, wherein R4 and R5 are each independently selected from halogen, cyanide radical, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0310]

[24] The compound of paragraph

[23] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa-4: Formula IIIa-4.

[0311]

[25] The compound of paragraph

[24] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa-5: formula IIIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0312]

[26] The compound of paragraph

[25] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa-6: formula IIIa-6.

[0313]

[27] The compound of paragraph

[25] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa-7: formula IIIa-7.

[0314]

[28] The compound of paragraph

[26] or

[27] , wherein R6 is methyl.

[0315]

[29] The compound of paragraph

[25] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIa-8 or formula IIIa-9: formula IIIa-8, formula IIIa-9.

[316]

[30] The compound of paragraph [9] or a pharmaceutically acceptable salt thereof, which has the structure of formula IVa: formula Iva, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1 .

[317]

[31] The compound of paragraph

[30] or a pharmaceutically acceptable salt thereof, which has the structure of formula IVa-1: formula IVa-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0318]

[32] The compound of paragraph

[31] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVa-2: Formula IVa-2.

[319]

[33] The compound of paragraph

[32] or a pharmaceutically acceptable salt thereof, which has the structure of formula IVa-3: formula IVa-3, wherein R4 and R5 are each independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl.

[0320]

[34] The compound of paragraph

[33] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVa-4: Formula IVa-4.

[0321]

[35] The compound of paragraph

[34] or a pharmaceutically acceptable salt thereof, which has the structure of formula IVa-5: formula IVa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0322]

[36] The compound of paragraph

[35] or a pharmaceutically acceptable salt thereof, which has a structure of formula IVa-6: formula IVa-6.

[0323]

[37] The compound of paragraph

[35] or a pharmaceutically acceptable salt thereof, which has the structure of formula IVa-7: formula IVa-7.

[0324]

[38] The compound of paragraph

[36] or

[37] , wherein R6 is methyl.

[0325]

[39] The compound of paragraph

[35] or a pharmaceutically acceptable salt thereof, which has the structure of formula IVa-8 or formula IVa-9: formula IVa-8, formula IVa-9.

[0326]

[40] The compound according to any one of paragraphs

[30] to

[39] , or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0327]

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

[0328]

[42] The compound of paragraph

[41] or a pharmaceutically acceptable salt thereof, which has the structure of formula Va: formula Va, wherein a is 0 or 1.

[0329]

[43] The compound of paragraph

[42] or a pharmaceutically acceptable salt thereof, which has the structure of formula Va-1: formula Va-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0330]

[44] The compound of paragraph

[43] or a pharmaceutically acceptable salt thereof, which has a structure of formula Va-2: formula Va-2.

[0331]

[45] The compound of paragraph

[44] or a pharmaceutically acceptable salt thereof, which has the structure of formula Va-3: formula Va-3, wherein R4 and R5 are each independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl.

[0332]

[46] The compound of paragraph

[45] or a pharmaceutically acceptable salt thereof, which has a structure of formula Va-4: formula Va-4.

[0333]

[47] The compound of paragraph

[46] or a pharmaceutically acceptable salt thereof, which has the structure of formula Va-5: formula Va-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0334]

[48] The compound of paragraph

[41] or a pharmaceutically acceptable salt thereof, which has the structure of formula VIa: formula VIa, wherein a is 0 or 1.

[0335]

[49] The compound of paragraph

[48] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIa-1: Formula VIa-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0336]

[50] The compound of paragraph

[49] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIa-2: Formula VIa-2.

[0337]

[51] The compound of paragraph

[50] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIa-3: Formula VIa-3, wherein R4 and R5 are each independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl.

[0338]

[52] The compound of paragraph

[51] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIa-4: Formula VIa-4.

[0339]

[53] The compound of paragraph

[52] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIa-5: Formula VIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0340]

[54] The compound of paragraph

[41] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIa: Formula VIIa, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1 .

[0341]

[55] The compound of paragraph

[54] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIa-1: Formula VIIa-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0342]

[56] The compound of paragraph

[55] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIa-2: Formula VIIa-2.

[0343]

[57] The compound of paragraph

[56] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIa-3: Formula VIIa-3, wherein R4 and R5 are each independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl.

[0344]

[58] The compound of paragraph

[57] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIa-4: Formula VIIa-4.

[0345]

[59] The compound of paragraph

[58] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIa-5: Formula VIIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0346]

[60] The compound according to any one of paragraphs

[54] to

[59] , or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0347]

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

[0348]

[62] The compound of paragraph

[61] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIa: Formula VIIIa, wherein a is 0 or 1.

[0349]

[63] The compound of paragraph

[62] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIa-1: Formula VIIIa-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0350]

[64] The compound of paragraph

[63] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIa-2: Formula VIIIa-2.

[65] The compound of paragraph

[64] or a pharmaceutically acceptable salt thereof, which has the structure of formula VIIIa-3: formula VIIIa-3, wherein R4 and R5 are each independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl.

[0352]

[66] The compound of paragraph

[65] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIa-4: Formula VIIIa-4.

[0353]

[67] The compound of paragraph

[66] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIa-5: Formula VIIIa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0354]

[68] The compound of paragraph

[61] or a pharmaceutically acceptable salt thereof, which has the structure of formula IXa: formula IXa, wherein a is 0 or 1.

[0355]

[69] The compound of paragraph

[68] or a pharmaceutically acceptable salt thereof, which has the structure of formula IXa-1: formula IXa-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0356]

[70] The compound of paragraph

[69] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IXa-2: Formula IXa-2.

[0357]

[71] The compound of paragraph

[70] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IXa-3: Formula IXa-3, wherein R4 and R5 are each independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl.

[0358]

[72] The compound of paragraph

[71] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula IXa-4: Formula IXa-4.

[0359]

[73] The compound of paragraph

[72] or a pharmaceutically acceptable salt thereof, which has the structure of formula IXa-5: formula IXa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0360]

[74] The compound of paragraph

[61] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xa: Formula Xa, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1 .

[0361]

[75] The compound of paragraph

[74] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xa-1: formula Xa-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0362]

[76] The compound of paragraph

[75] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xa-2: Formula Xa-2.

[0363]

[77] The compound of paragraph

[76] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xa-3: formula Xa-3, wherein R4 and R5 are each independently selected from halogen, cyano , hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 Cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl.

[0364]

[78] The compound of paragraph

[77] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xa-4: Formula Xa-4.

[0365]

[79] The compound of paragraph

[78] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xa-5: formula Xa-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0366]

[80] The compound of any one of paragraphs

[74] to

[79] , or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0367]

[81] The compound of any one of paragraphs

[10] to

[40] ,

[42] to

[60] or

[62] to

[80] , or a pharmaceutically acceptable salt thereof, wherein a is 0.

[0368]

[82] The compound of any one of paragraphs

[10] to

[40] ,

[42] to

[60] or

[62] to

[80] , or a pharmaceutically acceptable salt thereof, wherein a is 1.

[0369]

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

[82] , or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted C1-C6 alkyl.

[0370]

[84] The compound of paragraph

[83] , or a pharmaceutically acceptable salt thereof, wherein R2 is selected from -CH2CH3 or -CH2CF3.

[0371]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is a C1-C4 alkyl group.

[0372]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted cyclopropyl, optionally substituted cyclobutyl optionally substituted cyclopentyl or optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine or optionally substituted phenyl.

[0373]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 10 membered heterocycloalkyl, optionally A substituted 3 to 10 membered cycloalkyl, an optionally substituted 6 to 10 membered aryl or an optionally substituted 5 to 10 membered heteroaryl.

[0374]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 10 membered heterocycloalkyl.

[0375]

[89] The compound of paragraph

[88] or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or stereoisomers thereof: ,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,or.

[0376]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 10 membered cycloalkyl group.

[0377]

[91] The compound of paragraph

[90] or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or stereoisomers thereof: ,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,or.

[0378]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 5 to 10 membered heteroaryl.

[0379]

[93] The compound of paragraph

[92] or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or stereoisomers thereof: ,,,,,,,,,,, or.

[0380]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 6 to 10 membered aryl group.

[0381]

[95] The compound of paragraph

[94] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted phenyl group.

[0382]

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

[84] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted C1-C3 heteroalkyl group.

[0383]

[97] The compound of paragraph

[96] , or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or stereoisomers thereof: , or.

[0384]

[98] The compound of paragraph

[85] , or a pharmaceutically acceptable salt thereof, wherein W is selected from the following: or.

[0385]

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

[0386]

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

[0387]

[101] A compound or a pharmaceutically acceptable salt thereof having the structure of Formula Ib: Formula Ib wherein A is an optionally substituted 3 to 6 membered cycloalkylene, an optionally substituted 3 to 6 membered heterocycloalkylene, optionally substituted 6 membered arylylene, optionally substituted 5 to 6 membered heteroaryl, optionally substituted C2-C4 alkylene or optionally substituted Substituted C2-C4 alkenyl; Y is ,,,,,, or; W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3 to 10 members Heterocycloalkyl, optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; or W is -R14C(= O) R15, wherein R14 is 3 to 10 membered cycloalkylene and R15 is selected from optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; X1 and X4 are each independently CH2, CH(CH3) or NH; R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally Optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 15 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl Or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl , optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl ; R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3 to 7 and R12 and R13 are each independently selected from F or CH3 or the combination of R12 and R13 and the atoms they are connected to form a 3-membered cycloalkyl group.

[0388]

[102] The compound of paragraph

[101] , or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl .

[0389]

[103] The compound of paragraph

[102] , or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted phenyl or optionally substituted pyridine.

[0390]

[104] The compound of any one of paragraphs

[101] to

[103] , or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazole, optionally substituted triazole, optionally Optionally substituted N-morpholinyl, optionally substituted piperidinyl, optionally substituted pyridine or optionally substituted phenyl.

[0391]

[105] The compound of any one of paragraphs

[101] to

[103] , or a pharmaceutically acceptable salt thereof, wherein A is not optionally substituted phenyl or benzimidazole.

[0392]

[106] The compound of paragraph

[105] , or a pharmaceutically acceptable salt thereof, wherein A is other than hydroxyphenyl.

[0393]

[107] The compound according to any one of paragraphs

[101] to

[106] , or a pharmaceutically acceptable salt thereof, wherein the compound is not a compound in Table 2.

[0394]

[108] The compound according to any one of paragraphs

[101] to

[107] , or a pharmaceutically acceptable salt thereof, wherein the compound is not a compound in Table 3.

[0395]

[109] The compound of any one of paragraphs

[101] to

[108] , or a pharmaceutically acceptable salt thereof, wherein Y is -NHC(O)- or -NHC(O)NH-.

[0396]

[110] The compound of paragraph

[109] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIb: formula IIb, wherein a is 0 or 1.

[0397]

[111] The compound of paragraph

[110] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIb-1: formula IIb-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0398]

[112] The compound of paragraph

[111] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula IIb-2: Formula IIb-2.

[0399]

[113] The compound of paragraph

[112] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIb-3: formula IIb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0400] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula IIb-3, wherein W is an optionally substituted 3 to 10 membered heterocycloalkyl, an optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; or W is -R14C(=O)R15, wherein R14 is 3 to 10 cycloalkyl and R15 is selected from optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; R2 is hydrogen , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted Substituted 3 to 7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; R4 and R5 are each independently selected from halogen, cyano, hydroxyl, optionally Optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl , optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heterocycloalkyl Aryl; and R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl.

[0401]

[114] The compound of paragraph

[113] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIb-4: Formula IIb-4.

[0402] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula IIb-4, wherein W is an optionally substituted 3 to 10 membered heterocycloalkyl, an optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; or W is -R14C(=O)R15, wherein R14 is 3 to 10 cycloalkyl and R15 is selected from optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; R2 is hydrogen , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted Substituted 3 to 7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; R5 is selected from halogen, cyano, hydroxyl, optionally substituted Amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; and R10 is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3 to 7 members Heterocycloalkyl.

[0403]

[115] The compound of paragraph

[114] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIb-5: formula IIb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0404]

[116] The compound of paragraph

[115] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula IIb-6: Formula IIb-6.

[0405]

[117] The compound of paragraph

[115] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IIb-7: Formula IIb-7.

[0406]

[118] The compound of paragraph

[116] or

[117] , wherein R6 is methyl.

[0407]

[119] The compound of paragraph

[115] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIb-8 or formula IIb-9: formula IIb-8, formula IIb-9.

[0408]

[120] The compound of paragraph

[109] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb: formula IIIb, wherein a is 0 or 1.

[0409]

[121] The compound of paragraph

[120] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb-1: formula IIIb-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0410]

[122] The compound of paragraph

[121] , or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb-2: Formula IIIb-2.

[0411]

[123] The compound of paragraph

[122] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb-3: formula IIIb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0412]

[124] The compound of paragraph

[123] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb-4: Formula IIIb-4.

[0413]

[125] The compound of paragraph

[124] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb-5: formula IIIb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0414]

[126] The compound of paragraph

[125] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb-6: Formula IIIb-6.

[0415]

[127] The compound of paragraph

[125] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb-7: formula IIIb-7.

[0416]

[128] The compound of paragraph

[126] or

[127] , wherein R6 is methyl.

[0417]

[129] The compound of paragraph

[125] or a pharmaceutically acceptable salt thereof, which has the structure of formula IIIb-8 or formula IIIb-9: formula IIIb-8, formula IIIb-9.

[0418]

[130] The compound of paragraph

[109] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVb: Formula IVb, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1 .

[0419]

[131] The compound of paragraph

[130] or a pharmaceutically acceptable salt thereof, which has the structure of formula IVb-1: formula IVb-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0420]

[132] The compound of paragraph

[131] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVb-2: Formula IVb-2.

[0421]

[133] The compound of paragraph

[132] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVb-3: Formula IVb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0422]

[134] The compound of paragraph

[133] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVb-4: Formula IVb-4.

[0423]

[135] The compound of paragraph

[134] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVb-5: Formula IVb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0424]

[136] The compound of paragraph

[135] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVb-6: Formula IVb-6.

[0425]

[137] The compound of paragraph

[135] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IVb-7: Formula IVb-7.

[0426]

[138] The compound of paragraph

[136] or

[137] , wherein R6 is methyl.

[0427]

[139] The compound of paragraph

[135] or a pharmaceutically acceptable salt thereof, which has the structure of formula IVb-8 or formula IVb-9: formula IVb-8, formula IVb-9.

[0428]

[140] The compound of any one of paragraphs

[130] to

[139] , or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0429]

[141] The compound of any one of paragraphs

[101] to

[108] , or a pharmaceutically acceptable salt thereof, wherein Y is -NHS(O)2- or -NHS(O)2NH-.

[0430]

[142] The compound of paragraph

[141] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula Vb: Formula Vb, wherein a is 0 or 1.

[0431]

[143] The compound of paragraph

[142] or a pharmaceutically acceptable salt thereof, which has the structure of formula Vb-1: formula Vb-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0432]

[144] The compound of paragraph

[143] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula Vb-2: Formula Vb-2.

[0433]

[145] The compound of paragraph

[144] or a pharmaceutically acceptable salt thereof, which has the structure of formula Vb-3: formula Vb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0434]

[146] The compound of paragraph

[145] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula Vb-4: Formula Vb-4.

[0435]

[147] The compound of paragraph

[146] or a pharmaceutically acceptable salt thereof, which has the structure of formula Vb-5: formula Vb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0436]

[148] The compound of paragraph

[141] or a pharmaceutically acceptable salt thereof, which has the structure of formula VIb: formula VIb, wherein a is 0 or 1.

[0437]

[149] The compound of paragraph

[148] or a pharmaceutically acceptable salt thereof, which has the structure of formula VIb-1: formula VIb-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0438]

[150] The compound of paragraph

[149] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIb-2: Formula VIb-2.

[0439]

[151] The compound of paragraph

[150] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIb-3: Formula VIb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0440]

[152] The compound of paragraph

[151] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIb-4: Formula VIb-4.

[0441]

[153] The compound of paragraph

[152] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIb-5: Formula VIb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0442]

[154] The compound of paragraph

[141] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIb: Formula VIIb, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1 .

[0443]

[155] The compound of paragraph

[154] or a pharmaceutically acceptable salt thereof, which has the structure of formula VIIb-1: formula VIIb-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0444]

[156] The compound of paragraph

[155] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIb-2: Formula VIIb-2.

[0445]

[157] The compound of paragraph

[156] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIb-3: Formula VIIb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0446]

[158] The compound of paragraph

[157] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIb-4: Formula VIIb-4.

[0447]

[159] The compound of paragraph

[158] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIb-5: Formula VIIb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0448]

[160] The compound of any one of paragraphs

[154] to

[159] , or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0449]

[161] The compound of any one of paragraphs

[101] to

[108] , or a pharmaceutically acceptable salt thereof, wherein Y is -NHS(O)- or -NHS(O)NH-.

[0450]

[162] The compound of paragraph

[161] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIb: Formula VIIIb, wherein a is 0 or 1.

[0451]

[163] The compound of paragraph

[162] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIb-1: Formula VIIIb-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0452]

[164] The compound of paragraph

[163] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIb-2: Formula VIIIb-2.

[0453]

[165] The compound of paragraph

[164] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIb-3: Formula VIIIb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0454]

[166] The compound of paragraph

[165] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIb-4: Formula VIIIb-4.

[0455]

[167] The compound of paragraph

[166] or a pharmaceutically acceptable salt thereof, which has the structure of Formula VIIIb-5: Formula VIIIb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0456]

[168] The compound of paragraph

[161] or a pharmaceutically acceptable salt thereof, which has the structure of formula IXb: formula IXb, wherein a is 0 or 1.

[0457]

[169] . The compound of paragraph

[168] or a pharmaceutically acceptable salt thereof, which has the structure of formula IXb-1: formula IXb-1, wherein X2 is N or CH; each R3 is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted Substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted and n is an integer of 1-4.

[0458]

[170] The compound of paragraph

[169] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula IXb-2: ​​Formula IXb-2.

[0459]

[171] The compound of paragraph

[170] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IXb-3: Formula IXb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0460]

[172] The compound of paragraph

[171] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula IXb-4: Formula IXb-4.

[0461]

[173] The compound of paragraph

[172] or a pharmaceutically acceptable salt thereof, which has the structure of Formula IXb-5: Formula IXb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0462]

[174] The compound of paragraph

[161] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xb: Formula Xb, wherein R9 is H or C1-C6 alkyl; and a is 0 or 1 .

[0463]

[175] The compound of paragraph

[174] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xb-1: formula Xb-1, wherein X2 is N or CH; each R3 is independently selected from Halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted substituted 5-10 membered heteroaryl; and n is an integer of 1-4.

[0464]

[176] The compound of paragraph

[175] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula Xb-2: ​​Formula Xb-2.

[0465]

[177] The compound of paragraph

[176] or a pharmaceutically acceptable salt thereof, which has the structure of Formula Xb-3: Formula Xb-3, wherein R4 and R5 are each independently selected from hydrogen, halogen, Cyano, hydroxyl, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, R4 and R5 are not hydrogen.

[0466]

[178] The compound of paragraph

[177] , or a pharmaceutically acceptable salt thereof, which has the structure of Formula Xb-4: Formula Xb-4.

[0467]

[179] The compound of paragraph

[178] or a pharmaceutically acceptable salt thereof, which has the structure of formula Xb-5: formula Xb-5, wherein X3 is N or CH; m is 1 or 2; R6, R7, R8 and R11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, Optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl or R6 and R7 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R8 are combined with the atoms to which they are attached Form an optionally substituted 3 to 8 membered heterocycloalkyl; or R7 and R11 combine with the atoms to which they are attached to form an optionally substituted 4 to 8 membered heterocycloalkyl.

[0468]

[180] The compound of any one of paragraphs

[174] to

[179] , or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0469]

[181] The compound of any one of paragraphs

[110] to

[140] ,

[142] to

[160] or

[162] to

[180] , or a pharmaceutically acceptable salt thereof, wherein a is 0.

[0470]

[182] The compound of any one of paragraphs

[110] to

[140] ,

[142] to

[160] or

[162] to

[180] , or a pharmaceutically acceptable salt thereof, wherein a is 1.

[0471]

[183] ​​The compound according to any one of paragraphs

[101] to

[182] , or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted C1-C6 alkyl.

[0472]

[184] The compound of paragraph

[183] , or a pharmaceutically acceptable salt thereof, wherein R2 is selected from -CH2CH3 or -CH2CF3.

[0473]

[185] The compound of any one of paragraphs

[101] to

[184] , or a pharmaceutically acceptable salt thereof, wherein R10 is hydrogen.

[0474]

[186] The compound according to any one of paragraphs

[101] to

[184] , or a pharmaceutically acceptable salt thereof, wherein R10 is hydroxyl, optionally substituted C1-C6 alkoxy, optionally Substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 7 membered heterocycloalkyl.

[0475]

[187] The compound of paragraph

[186] , or a pharmaceutically acceptable salt thereof, wherein R10 is optionally substituted ethoxy.

[0476]

[188] The compound of paragraph

[186] , or a pharmaceutically acceptable salt thereof, wherein R10 is selected from the group consisting of the following or stereoisomers thereof: ,,,,,,,,,,,,,, ,,,,,,,,,,or.

[0477]

[189] The compound of any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is a C1-C4 alkyl group.

[0478]

[190] The compound according to any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted cyclopropyl, optionally substituted cyclobutyl optionally substituted cyclopentyl or optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine or optionally substituted phenyl.

[0479]

[191] The compound of any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 10 membered heterocycloalkyl, optionally A substituted 3 to 10 membered cycloalkyl, an optionally substituted 6 to 10 membered aryl or an optionally substituted 5 to 10 membered heteroaryl.

[0480]

[192] The compound of any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 10 membered heterocycloalkyl.

[0481]

[193] The compound of paragraph

[192] , or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or stereoisomers thereof: ,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,or.

[0482]

[194] The compound of any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 10 membered cycloalkyl group.

[0483]

[195] The compound of paragraph

[194] , or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or stereoisomers thereof: ,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,or.

[0484]

[196] The compound of any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 5 to 10 membered heteroaryl.

[0485]

[197] The compound of paragraph

[196] , or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or stereoisomers thereof: ,,,,,,,,,,, or.

[0486]

[198] The compound of any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 6 to 10 membered aryl group.

[0487]

[199] The compound of paragraph

[198] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted phenyl.

[0488]

[200] The compound of any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted C1-C3 heteroalkyl group.

[0489]

[201] The compound of paragraph

[200] , or a pharmaceutically acceptable salt thereof, wherein W is selected from the following or stereoisomers thereof: ,,, or.

[0490]

[202] The compound of paragraph

[189] , or a pharmaceutically acceptable salt thereof, wherein W is selected from the group consisting of: ,,,,,,, or.

[0491]

[203] The compound of any one of paragraphs

[101] to

[188] , or a pharmaceutically acceptable salt thereof, wherein W is -R14C(=O)R15, wherein R14 is 3 to 10 members Cycloalkyl and R15 is selected from optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl.

[0492]

[204] The compound of paragraph

[203] , or a pharmaceutically acceptable salt thereof, wherein W is selected from the group consisting of the following or stereoisomers thereof: ,,,,,,,,,,,,,, ,,,,,,,,or.

[0493]

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

[0494]

[206] A pharmaceutical composition comprising the compound according to any one of paragraphs [1] to

[205] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0495]

[207] A method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of any one of paragraphs [1] to

[205] , or a pharmaceutically acceptable salt, or a pharmaceutical composition as in paragraph

[206] .

[0496]

[208] The method of paragraph

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

[0497]

[209] The method of paragraph

[208] , wherein the Ras mutation is at position 12, 13 or 61. In some embodiments, the Ras mutation is at position 12.

[0498]

[210] The method of paragraph

[209] , wherein the Ras mutation is at a position selected from the group consisting of G12C, G12D, G12V, G12R, G13C, G13D, and Q61K, or a combination thereof.

[0499]

[211] The method of paragraph

[210] , wherein the Ras mutation is at a position selected from the group consisting of G12D, G12V, and G12R, or a combination thereof.

[0500]

[212] The method of paragraph

[211] , wherein the Ras mutation is at a position selected from the group consisting of: G12D and G12V, or a combination thereof.

[0501]

[213] The method of any of paragraphs

[207] to

[212] , wherein the cancer is pancreatic cancer.

[0502]

[214] The method of any of paragraphs

[207] to

[212] , wherein the cancer is lung cancer.

[0503]

[215] The method of any one of paragraphs

[207] to

[212] , wherein the cancer is colorectal cancer.

[0504]

[216] A method of treating a Ras protein-associated disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of any one of paragraphs [1] to

[205] or its pharmaceutical above acceptable salts, or the pharmaceutical composition of paragraph

[206] .

[0505]

[217] A method of inhibiting a Ras protein in a cell, the method comprising subjecting the cell to an effective amount of the compound of any one of paragraphs [1] to

[205] or a pharmaceutically acceptable salt, or the pharmaceutical composition as in paragraph

[206] .

[0506]

[218] The method of paragraph

[217] , wherein more than one Ras protein is inhibited in the cell.

[0507]

[219] The method of

[217] or

[218] , wherein the cell line is a cancer cell.

[0508]

[220] The method of paragraph

[219] , wherein the cancer cell is a pancreatic cancer cell.

[0509]

[221] The method of paragraph

[219] , wherein the cancer cell is a lung cancer cell.

[0510]

[222] The method of paragraph

[219] , wherein the cancer cell is a colorectal cancer cell.

[0511]

[223] The method of any of paragraphs

[207] to

[222] , wherein the Ras protein is KRAS.

[0512]

[224] The method or use of any one of paragraphs

[207] to

[223] , wherein the method further comprises administering an additional anti-cancer therapy.

[0513]

[225] The method of paragraph

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

[0514]

[226] The method of paragraph

[224] or

[225] , wherein the additional anticancer therapy is a SHP2 inhibitor.

[0515]

[227] The method of paragraph

[224] or

[225] , wherein the additional anticancer therapy comprises a SHP2 inhibitor and a PD-L1 inhibitor.

[0516]

[228] The method of paragraph

[224] or

[225] , wherein the additional therapy comprises a second Ras inhibitor and a PD-L1 inhibitor.

[0517]

[229] The method of paragraph

[225] or

[228] , wherein the second Ras inhibitor is a KRASG12C inhibitor.

[0518]

[230] The method of paragraph

[228] or

[229] , wherein the second Ras inhibitor is a KRASG12C(ON) inhibitor.

[0519]

[231] The method of paragraph

[228] or

[229] , wherein the second Ras inhibitor is a KRASG12C(OFF) inhibitor. example

[0520] The disclosure is further illustrated by the following examples and synthetic examples, which should not be construed to limit the scope or spirit of the 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 thereby limit the scope of the disclosure. It should also be understood that resort can also be made to various other embodiments, modifications and equivalents thereof, which will occur to those skilled in the art without departing from the spirit of the disclosure or the scope of the appended claims. chemical synthesis

[0521] The following examples and definitions used elsewhere herein are as follows: B 2 pin 2 Bis(pinacol)diboron BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene CH 2 Cl 2 , DCM Methylene chloride, dichloromethane CH 3 CN, MeCN Acetonitrile CuI Copper(I) iodide DIPEA, DIEA Diisopropylethylamine DMF N,N-Dimethylformamide EA ethyl acetate EDCl N-ethyl-N'-carbodiimide hydrochloride EtOAc ethyl acetate h Hour h 2 o water HCl hydrochloric acid HOB Hydroxybenzotriazole K 3 PO 4 Potassium phosphate (tribasic) MeOH Methanol Na 2 SO 4 sodium sulfate NMM N-Methylmorpholine NMP N-Methylpyrrolidone Pd(dppf)Cl 2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PE petroleum ether rt room temperature TFA Trifluoroacetate instrument

[0522] Mass spectral data collection was performed using a Shimadzu LCMS-2020, Agilent 1260LC-6120 / 6125MSD, Shimadzu LCMS-2010EV or Waters Acquity UPLC with QDa detector or SQ detector 2. Samples were injected in liquid phase onto C-18 reversed phase. Compounds were eluted from the column using an acetonitrile gradient and fed into the mass analyzer. Initial data analysis was performed with Agilent ChemStation, Shimadzu LabSolutions or Waters MassLynx. NMR data were collected with a Bruker AVANCE III HD 400MHz, Bruker Ascend 500MHz instrument or Varian 400MHz and raw data were analyzed using TopSpin or Mestrelab Mnova. Synthetic intermediate 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 Step 1

[0523] 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (65 g, 137 mmol, crude product) was prepared at 0° C. under N2 atmosphere To the mixture in DCM (120 mL) was slowly added 1M SnCl4 in DCM (137 mL, 137 mmol). The mixture was stirred for 30 min at 0 °C, 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 min, then diluted with EtOAc (300 mL), washed with brine (400 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 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] calcd for C29H32BrNO2SiNa 556.1; found 556.3. step 2

[0524] Under N Atmosphere, to 1-(5-bromo-1H-indol-3-yl)-3-((tertiary butyldiphenylsilyl)oxyl group)-2 at 0°C, To a mixture of 2-dimethylpropan-1-one (50 g, 93.6 mmol) in THF (100 mL) was added LiBH4 (6.1 g, 281 mmol). The mixture was heated to 60 °C and stirred for 20 h, then MeOH (10 mL) and EtOAc (100 mL) were added and the mixture was washed with brine (50 mL), dried over Na2SO4, 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.H2O (890 mg, 4.7 mmol) were added. At 10 °C, the mixture was stirred 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] calcd for C29H34BrNOSi 519.2; found 520.1; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.75 - 7.68 (m, 5H), 7.46 - 7.35 (m, 6H), 7.23 - 7.19 (m, 2H), 6.87 (d,J= 2.1 Hz, 1H), 3.40 (s, 2H), 2.72 (s, 2H), 1.14 (s, 9H), 0.89 (s, 6H). step 3

[0525] At room temperature, to 1-(5-bromo-1H-indol-3-yl)-3-((tertiary butyldiphenylsilyl)oxy)-2,2-dimethyl To a mixture of propan-1-one (1.5 g, 2.9 mmol) and I2 (731 mg, 2.9 mmol) in THF (15 mL) was added AgOTf (888 mg, 3.5 mmol). The mixture was stirred at room temperature for 2 h, 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, as a solid. 2-Dimethylpropyl)-2-iodo-1H-indole (900 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.68 (d,J= 1.3 Hz, 1H), 7.64 - 7.62 (m, 4H), 7.46 - 7.43 (m, 6H), 7.24 - 7.22 (d, 1H), 7.14 - 7.12 (dd, J= 8.6, 1.6 Hz, 1H), 3.48 (s, 2H), 2.63 (s, 2H), 1.08 (s, 9H), 0.88 (s, 6H) . step 4

[0526] To a stirred mixture of HCOOH (66.3 g, 1.44 mol) in TEA (728 g, 7.2 mol) was added portionwise (4S,5S)-2-chloro-2 at 0°C under Ar atmosphere. -Methyl-1-(4-methylbenzenesulfonyl)-4,5-diphenyl-1,3-diaza-2-rutheniumcyclopentane isopropyltoluene (3.9 g, 6.0 mmol) . The mixture was heated to 40°C and stirred for 15 minutes, then cooled to room temperature and l-(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, the mixture was extracted with EtOAc (4 x 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. step 5

[0527] To a stirred mixture of (1S)-1-(3-bromopyridin-2-yl)ethanol (100 g, 495 mmol) in DMF (1 L) was added NaH in portions at 0°C. 60% dispersion in oil (14.25 g, 594 mmol). The mixture was stirred at 0°C for 1 hour. At 0 °C, MeI (140.5 g, 990 mmol) was added dropwise 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 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 3-bromo-2-[(1S)-1-methoxyethyl]pyridine as an oil (90 g, 75% yield ). LCMS (ESI): m / z [M+H] calcd. for C8H10BrNO 215.0; found 215.9. step 6

[0528] Under Ar atmosphere, 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (90 g, 417 mmol) and Pd(dppf)Cl (30.5 g, 41.7 mmol) in toluene (900 mL) was added bis(pinacol)diboron (127 g, 500 mmol) and KOAc (81.8 g, 833 mmol) in portions. 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). LCMS (ESI): m / z [M+H] calcd for C14H22BNO3 263.2; found 264.1. step 7

[0529] Under Ar atmosphere, at room temperature to 5-bromo-3-[3-[(tertiary 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 To a stirred mixture of -dioxaborolan-2-yl)pyridine (100 g, 380 mmol) in 1,4-dioxane (1.4 L) was added K2CO3 (74.8 g, 541 mmol) in portions ), Pd(dppf)Cl2 (15.9 g, 21.7 mmol) and H2O (280 mL). The mixture was heated to 85 °C and stirred for 4 h, then cooled, H2O (5 L) was added and the mixture was extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 x 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 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2 as a solid. 2-Dimethylpropyl]-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indole (71 g, 45% yield). LCMS (ESI): m / z [M+H] calcd. for C37H43BrN2O2Si 654.2; found 655.1. Step 8

[0530] Under N2 atmosphere, to 5-bromo-3-[3-[(tertiary butyldiphenylsilyl) oxygen group]-2,2-dimethylpropyl]-2 at 0°C -[2-[(1S)-1-Methoxyethyl]pyridin-3-yl]-1H-indole (71 g, 108 mmol) was added in portions to a stirred mixture in DMF (0.8 L) Cs2CO3 (70.6 g, 217 mmol) and EtI (33.8 g, 217 mmol). The mixture was warmed to room temperature and stirred for 16 h, then H2O (4 L) was added and the mixture was 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. 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 as an oil -Dimethylpropyl]-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indole (66 g, 80% yield). LCMS (ESI): m / z [M+H] calcd. for C39H47BrN2O2Si 682.3; found 683.3. step 9

[0531] To a stirred mixture of TBAF (172.6 g, 660 mmol) in THF (660 mL) was added 5-bromo-3-[3-[(tert-butyl Diphenylsilyl)oxy]-2,2-dimethylpropyl]-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl] Indole (66 g, 97 mmol). The mixture was heated to 50 °C and stirred for 16 h, 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 obtain 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl]pyridine Both atropisomers of -3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (as a single atropisomer), both as solids (combined into 30 g, 62% yield). LCMS (ESI): m / z [M+H] calculated for C23H29BrN2O2 444.1; found 445.1. Intermediate 1. Via Fisher Indole Route (Fisher Indole Route ) for an alternative synthetic step 1 To a mixture of i-PrMgCl (2M in THF, 0.5 L) was added dropwise a solution of 2.5 Mn-BuLi in hexanes (333 mL, 833 mmol) at -10°C over 15 min under N2 atmosphere . The mixture was stirred at -10°C for 30 minutes, then 3-bromo-2-[(1S)-1-methoxyethyl in THF (0.5 L) was added dropwise over 30 minutes at -10°C ] Pyridine (180 g, 833 mmol). The resulting mixture was warmed to -5 °C and stirred for 1 h, then 3,3-dimethyloxane-2,6-dione in THF (1.2 L) was added dropwise over 30 min at -5 °C (118 g, 833 mmol). The mixture was warmed to 0 °C and stirred for 1.5 h, then quenched by adding pre-cooled 4M HCl in 1,4-dioxane (0.6 L) at 0 °C to adjust the pH to ~5. The mixture was diluted with ice water (3 L) and extracted with EtOAc (3 x 2.5 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 5-[2-[(1S)-1-methoxyl as a solid Ethyl]pyridin-3-yl]-2,2-dimethyl-5-oxopentanoic acid (87 g, 34% yield). LCMS (ESI): m / z [M+H] calcd for C15H21NO4 279.2; found 280.1. step 2

[0533] Under N atmosphere, at room temperature to 5-[2-[(1S)-1-methoxyethyl] pyridin-3-yl]-2,2-dimethyl-5-oxo To a mixture of valeric acid (78 g, 279 mmol) in EtOH (0.78 L) was added (4-bromophenyl)hydrazine hydrochloride (68.7 g, 307 mmol) in portions. The mixture was heated to 85 °C and stirred for 2 hours, cooled to room temperature, and then 4M HCl 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 h, 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, concentrated under reduced pressure and the residue was adjusted to about pH 5 with saturated NaHCO3, followed by extraction with EtOAc (3 x 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-dimethylpropionic 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] calcd for C21H23BrN2O3 430.1 and calcd for C23H27BrN2O3 458.1; found 431.1 and 459.1. step 3

[0534] Under N Atmosphere, 3-(5-bromo-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indole- 3-yl)-2,2-dimethylpropionic acid and (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-ind To a mixture of ethyl indol-3-yl)-2,2-dimethylpropanoate (198 g, 459 mmol) in DMF (1.8 L) was added Cs2CO3 (449 g, 1.38 mol) in portions. Then, EtI (215 g, 1.38 mmol) in DMF (200 mL) was 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 x 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 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyl as a solid Ethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylpropanoic acid ethyl ester (160 g, 57% yield). LCMS (ESI): m / z [M+H] calcd for C25H31BrN2O3 486.2; found 487.2. step 4

[0535] Under N ...

Claims

1. A compound with the following structure 1. Or a pharmaceutically acceptable salt of the compound or a hydrate of the salt.

2. A compound with the following structure:

3. A pharmaceutical composition comprising a compound with the following structure:

3. Or a pharmaceutically acceptable salt or hydrate of the compound or salt, and a pharmaceutically acceptable excipient.

4. A pharmaceutical composition comprising a compound with the following structure:

4. And medically acceptable excipients.

Images