Oxazepine compounds containing a 6-aza moiety and uses thereof

Abstract

Provided herein are oxazepinyl compounds containing a 6-aza moiety that are useful in the treatment of cancer.

Description

[Technical Field]

[0001] Technical Field Provided herein are acyclic compounds comprising a 6-aza moiety useful for treating cancers containing KRas mutations, compositions of such compounds, and methods of treating cancers containing KRas mutations. [Background technology]

[0002] background Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch in central growth signaling pathways. In response to extracellular signals, Ras undergoes GDP-bound (Ras) exchange, catalyzed by guanine nucleotide exchange factors (GEFs), particularly the SOS1 protein. GDP ) state to GTP-bound (Ras GTP ) state. Active Ras GTP Ras mediates its diverse growth-stimulatory functions through direct interactions with effectors, including Raf, PI3K, and the Ral guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity can be further accelerated by interaction with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

[0003] Mutant Ras has reduced GTPase activity, which sustains Ras activation, thereby promoting Ras-dependent signaling and cancer cell survival or proliferation. Ras mutations that affect its ability to interact with GAPs or convert GTP back to GDP result in the protein remaining active and, consequently, the signals that tell cells to continue growing and dividing. Because these signals lead to cell growth and division, overactive RAS signaling can ultimately lead to cancer. Mutations in any one of the three major RAS isoforms (HRas, NRas, or KRas) genes are common events in human tumorigenesis. Of the three Ras isoforms (K, N, and H), KRas is the most frequently mutated.

[0004] The most common KRas mutations are found at residues G12 and G13 in the P loop and residue Q61. Ras mutations in cancer are associated with poor prognosis. Inactivation of oncogenic Ras in mice results in tumor regression. Thus, Ras is widely considered to be an exceptionally important oncological target.

[0005] Therefore, there is an urgent need for therapies for mutant KRas-mediated cancers. Summary of the Invention

[0006] overview Solutions to the above problems and other problems in the art are provided herein.

[0007] In one aspect, provided herein are compounds of Formula (I), as described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0008] In another aspect, provided herein are compounds of Formula (Ia), as described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0009] In another aspect, provided herein are compounds of Formula (II), (IIa), (IIb), or (IIc), as described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0010] In another aspect, provided herein are compounds of Formula (III), (IIIa), (IIIb), or (IIIc), as described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0011] In another aspect, provided herein are compounds of Formula (IV), (IVa), (IVb), or (IVc), as described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0012] In another aspect, provided herein are compounds of Formula (V), (Va), (Vb), or (Vc), as described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0013] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0014] In another aspect, provided herein is a method of treating a cancer described herein by administering an effective amount of a compound described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description In certain embodiments, the present disclosure provides acyclic oxazepine compounds as described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and pharmaceutical compositions thereof, which are inhibitors or modulators of mutant KRas.In certain cases, these compounds and compositions are inhibitors or modulators of mutant KRas provided herein (i.e., pan-KRas inhibitors).The compounds and compositions described herein are useful for treating diseases and disorders mediated by mutant KRas.

[0016] It is understood that while the disclosure herein provides enumerated embodiments, they are not intended to limit the compounds and methods described herein to those embodiments. On the contrary, the disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the disclosure as defined by the claims.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art.All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0018] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0019] The terms "halogen" or "halo" are used interchangeably and refer to F, Cl, Br, or I. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl, polyhaloalkyl, and perhaloalkyl.

[0020] The term "alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon group. In one example, an alkyl group has 1 to 18 carbon atoms (C 1~18 In another example, the alkyl group is C 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~5 , C 1~4 , or C 1~3 Examples of alkyl groups include: methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCH), 2-propyl (i-Pr, i-propyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-C H2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 1-heptyl, and 1-octyl.

[0021] The term "oxo" refers to =O.

[0022] The term "alkoxy" refers to --O-alkyl.

[0023] The term "cyano" or "nitrile" refers to -C≡N or -CN.

[0024] The term "haloalkoxy" refers to an --O-haloalkyl.

[0025] The terms "hydroxy" and "hydroxyl" refer to --OH.

[0026] The term "alkylidene" refers to a straight- or branched-chain monovalent hydrocarbon radical having the formula =CR'R", where R' and R' can be the same or different. In one example, an alkylidene group is an alkylidene group having 1 to 6 carbons (C 1~6 In another example, the alkylidene group is C 1~3 , C 1~2 or C. Exemplary alkylidenes include, but are not limited to, methylidene (=CH), ethylidene (=CHCH), and propylidene (=CH-CH-CH).

[0027] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, an alkenyl group has 2 to 18 carbon atoms (C 2~18 In other examples, the alkenyl group is C 2-12 , C 2~10 , C 2~8 , C 2~6 , or C 2~3 Examples include, but are not limited to, ethenyl or vinyl (-CH=CH), prop-1-enyl (-CH=CHCH), prop-2-enyl (-CHCH=CH), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0028] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one example, an alkynyl group has 2 to 18 carbon atoms (C 2~18 In other examples, the alkynyl group is C 2~12 , C 2~10 , C 2~8 , C 2~6 , or C 2~3Examples include, but are not limited to, ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH), prop-2-ynyl (propargyl, -CHC≡CH), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0029] The term "alkylene" refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. In one example, a divalent alkylene group has 1 to 18 carbon atoms (C 1~18 In another example, the divalent alkylene group is C 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~5 , C 1~4 , or C 1~3 Examples of alkylene groups include methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), (1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 2,2-propyl (-C(CH3)2-), 1,2-propyl (-CH(CH3)CH2-), 1,3-propyl (-CH2CH2CH2-), 1,1-dimethyleth-1,2-yl (-C(CH3)2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0030] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyl includes monocyclic, bicyclic, tricyclic, spiro, and bridged saturated ring systems. In one example, a cycloalkyl group contains 3 to 12 carbon atoms (C 3~12 In other examples, cycloalkyl is C 3~4 , C 3~5 , C 3~7 , C 3~8 , C 3~10 , or C 5~10 In another example, the cycloalkyl group as a single ring is C 3~4 , C 3~8 , C 3~6 , or C 5~6In another example, the cycloalkyl group for the bicycle is C7 to C 12 In another example, the cycloalkyl group as a spiro system is C 5~12 Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary configurations of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Examples of spirocycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.

[0031] The terms "heterocyclic group," "heterocyclic," "heterocycle," "heterocyclyl," or "heterocyclo" are used interchangeably and refer to any monocyclic, bicyclic, tricyclic, spiro, or bridged, saturated, partially saturated, or unsaturated non-aromatic ring system having 3 to 20 ring atoms in which the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the ring system is a heteroatom, the system is heterocyclic, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl contains 3 to 10 ring atoms ("members"), including monocyclic, bicyclic, tricyclic, spiro, and bridged ring systems in which the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclyl contains 3 to 6, 5 to 9, 4 to 10, or 5 to 10 ring atoms. In one example, a heterocyclyl contains 1 to 4 heteroatoms. In one example, a heterocyclyl contains 1 to 3 heteroatoms. In another example, a heterocyclyl contains 3 to 7-membered monocyclic rings having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl contains 4 to 6-membered monocyclic rings having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl contains 3-membered monocyclic rings. In another example, a heterocyclyl contains 4-membered monocyclic rings. In another example, a heterocyclyl contains 5 to 6-membered monocyclic rings. In another example, a heterocyclyl contains 8-, 9-, or 10-membered rings. In such examples, the heterocyclyl group can be a 4,5-, 5,5-, 4,6-, 5,6-, or 6,6-fused ring system. In some embodiments, a heterocycloalkyl contains at least one nitrogen. In one example, a heterocyclyl group contains 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR]). + Cl - , [NR4] + OH -6 Examples of heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydro Pyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzyl benzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl , pyrimidinonyl, pyrimidindionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl.

[0032] "Aryl," as used herein, refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused or spiro rings (e.g., naphthyl or anthryl), which may or may not be aromatic. Particular aryl groups have from 6 to 14 annular (i.e., ring) carbon atoms ("C 6~14 Aryl groups are groups having a carbon atom or ring structure ("aryl"). Preferred aryl groups include those having 5 to 6 ring carbons. Aryl groups having two or more rings, in which at least one ring is non-aromatic, can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, aryl groups having two or more rings, in which at least one ring is non-aromatic, are attached to the parent structure at an aromatic ring position.

[0033] The term "heteroaryl" refers to any monocyclic or bicyclic aromatic ring system containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur; in six exemplary embodiments, at least one heteroatom is nitrogen. Any bicyclic group in which any of the above heteroaryl rings is fused to an aryl ring, and the aryl or heteroaryl ring is attached to the remainder of the molecule, is included. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple fused or spiro rings (e.g., indolizinyl, benzothienyl), which may or may not be aromatic. In one embodiment, heteroaryl includes 5- to 6-membered monocyclic aromatic groups in which one or more ring atoms is nitrogen, sulfur, or oxygen. Examples of 6 heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazole[1,2-a]pyrimidinyl and purinyl, and benzo-fused derivatives such as 6 benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl.

[0034] In certain embodiments, the heterocyclyl or heteroaryl group is bonded at a carbon atom of the heterocyclyl or heteroaryl group. Exemplary carbon-bonded heterocyclyl groups include those bonded at the 2-, 3-, 4-, 5-, or 6-positions of the pyridine ring, the 3-, 4-, 5-, or 6-positions of the pyridazine ring, the 2-, 4-, 5-, or 6-positions of the pyrimidine ring, the 2-, 3-, 5-, or 6-positions of the pyrazine ring, the 2-, 3-, 4-, or 5-positions of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, the 2-, 4-, or 5-positions of the oxazole, imidazole, or thiazole ring, the 3-, 4-, or 5-positions of the isoxazole, pyrazole, or isothiazole ring, the 2-, or 3-positions of the aziridine ring, the 2-, 3-, or 4-positions of the azetidine ring, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-positions of the quinoline ring, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-positions of the isoquinoline ring.

[0035] In certain embodiments, the heterocyclyl or heteroaryl group is N-linked. Exemplary nitrogen-linked heterocyclyl or heteroaryl groups include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole at the 1-position, isoindole or isoindoline at the 2-position, morpholine at the 4-position, and carbazole or β-carboline at the 9-position.

[0036] "Fused" refers to any ring structure described herein that shares one or more atoms (eg, carbon atoms or nitrogen atoms) with an existing ring structure in the compounds described herein.

[0037] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl. Substituted haloalkyl refers to a haloalkyl having moieties other than halogen.

[0038] As used herein, crossing a bond in a chemical structure TIFF2025535367000001.tif5170In a chemical structure, a wavy bond indicates the point of attachment of an atom to the rest of the molecule, or to the rest of a fragment of a molecule.

[0039] In certain embodiments, a divalent group is described generically without a specific bond structure. Unless otherwise specified, the generic description is understood to mean that both bond structures are included. For example, the group R 1 -R 2 -R 3 In the formula, the group R 2 When is depicted as -CHC(O)-, unless otherwise specified, this group is represented by R 1 -CH2C(O)-R 3 and R 1 -C(O)CH2-R 3 It is understood that both are combinable.

[0040] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other side reactions when properly administered to an animal, such as a human.

[0041] The compounds described herein may be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to a salt formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, which retain the biological effectiveness and properties of the free base and which is biologically or otherwise undesirable; the organic acid may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0042] The term "pharmaceutically acceptable base addition salts" includes those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines, including basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0043] In some embodiments, the salt is selected from the group consisting of hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonic acid), salt, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate) phthalenesulfonate), camsylate (camphor 10-sulfonate, e.g., 6(1S)-(+)-10-camphorsulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0044] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformers, etc.

[0045] The term "chiral" refers to molecules that possess the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0046] The term "diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.

[0047] The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0048] The term "atropisomers" refers to two conformers resulting from hindered rotation about a single bond where the steric strain barrier to rotation can be high enough to allow isolation of each conformer.

[0049] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0050] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0051] Certain compounds described herein can exist in non-solvated form and solvated form, including hydrated form. "Solvate" refers to the association or complex of one or more solvent molecules and the compounds described herein. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Certain compounds described herein can exist in multiple crystalline forms or amorphous forms. Generally, all physical forms are contemplated herein. The term "hydrate" refers to a complex where the solvent molecule is water.

[0052] The compounds described herein and their pharmaceutically acceptable salts also include the isotope-labeled compounds that are identical to those listed herein, except that one or more atoms are replaced by atoms with atomic mass or mass number different from the atomic mass or mass number that is usually found in nature.All isotopes of any specific atom or element designated and their use are contemplated herein.The exemplary isotopes that can be incorporated into the compounds described herein and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, for example: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds described herein or pharmaceutically acceptable salts thereof (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14C) isotopes are useful for their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H), may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferable in some circumstances. 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds described herein, or pharmaceutically acceptable salts thereof, can generally be prepared by following procedures similar to those disclosed in the Examples described herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0053] The compounds described herein and their pharmaceutically acceptable salts may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may use racemates, diastereomers, or enantiomers as starting materials or intermediates. A mixture of specific diastereomeric compounds may be separated or enriched into one or more specific diastereomers by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated or enantiomerically enriched using the same techniques, or other techniques known in the art. Each asymmetric carbon or nitrogen atom may be in the R or S configuration, and both of these configurations are contemplated herein.

[0054] In structures shown herein where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included. When stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, that stereoisomer is so designated and defined. Unless otherwise specified, when a solid wedge or dashed line is used, relative stereochemistry is intended.

[0055] A "subject," "individual," or "patient" is a vertebrate and is used interchangeably herein. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (e.g., cows), sport animals, pets (e.g., guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human. In embodiments involving administering a compound to a patient, the patient is typically in need of administration of the compound.

[0056] The terms "inhibiting" and "reducing," or any variation of these terms, include any measurable decrease or complete inhibition to achieve a desired result. For example, there can be a decrease in activity compared to normal of about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any variable of these ranges.

[0057] The term "treatment" refers to a clinical intervention designed to alter the natural course of the patient or cells being treated during the course of clinical pathology. Desirable effects of treatment include slowing the rate of disease progression, improving or mitigating the disease state, and achieving remission or improved prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with cancer as described herein are alleviated or eliminated, including, but not limited to, reduced proliferation (or destruction) of cancerous cells, reduced symptoms caused by the disease, improved quality of life for those suffering from the disease, reduced dosage of other medications required to treat the disease, and / or prolonged patient survival.

[0058] The term "delay in progression" of disease refers to postpone, prevent, delay, slow, stabilize, and / or postpone the onset of cancer as described herein. This delay can be of various lengths of time depending on the history of cancer and / or the patient being treated. As will be appreciated by those skilled in the art, a sufficient or significant delay can essentially encompass prevention, in that the patient does not develop or recur cancer.

[0059] "Mutant KRas-mediated disease" and the like refer to a disease described herein (e.g., a cancer described herein) having symptoms described herein or requiring treatment that are associated, resultant, functional, or otherwise correlated, in whole or in part, with mutant KRas activity described herein. In one embodiment, the mutant KRas is any G12 mutant of KRas.

[0060] The term "pan-KRas," as used herein, refers to an inhibitor described herein that inhibits the activity of a mutant KRas protein. In some embodiments, the mutant KRas protein contains a mutation corresponding to position 12 (G12).

[0061] "KRasG12X mutation" refers to a mutant KRas protein having a mutation corresponding to position Gly12. In some embodiments, the mutation corresponds to G12A, G12C, G12D, G12R, G12S, or G12V. In other embodiments, the mutation corresponds to G12C, G12D, G12R, or G12V.

[0062] An "effective amount" or "therapeutically effective amount" is at least the minimum amount required to achieve measurable improvement or prevention of cancer as described herein. The effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, and the ability of the agent to induce a desired response in the patient. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. Beneficial or desired results include results such as eliminating or reducing the risk, reducing the severity, delaying the onset of the disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the development of the disease), reducing one or more symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drug treatments required to treat the disease, enhancing the effectiveness of another drug treatment by targeting or otherwise, delaying disease progression, and / or prolonging survival. In some embodiments, an effective amount of a drug may be effective in reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., slowing or stopping) cancer cell invasion into peripheral organs, inhibiting (i.e., slowing or stopping) tumor metastasis, inhibiting (i.e., slowing or stopping) tumor growth, and / or alleviating one or more symptoms associated with the disorder. An effective amount may be administered in one or more administrations.

[0063] An "administration period" or "cycle" refers to a period that includes administration of one or more compounds described herein, or pharmaceutically acceptable salts thereof, or additional therapeutic agents (i.e., chemotherapeutic agents), as well as any period that does not include administration of one or more agents or compounds described herein. A "rest period" refers to a period during which at least one of the agents or compounds described herein is not administered. In one embodiment, a rest period refers to a period during which an agent or compound described herein is not administered. The rest periods provided herein may, in some cases, include administration of an additional agent in the absence of a compound described herein, or a pharmaceutically acceptable salt thereof, or vice versa. In such cases, administration of any agent during the rest period does not interfere with or impair the administration of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0064] A "dosing regimen" refers to a period of administration of a compound described herein, or a pharmaceutically acceptable salt thereof, that comprises one or more cycles, and each cycle may involve administration of a compound described herein, or a pharmaceutically acceptable salt thereof, at a different time or in a different amount.

[0065] "QD" refers to once-daily administration of a compound or a pharmaceutically acceptable salt thereof.

[0066] "BID" refers to administration of a compound or a pharmaceutically acceptable salt thereof twice daily.

[0067] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass the administration of two or more agents to an animal, including a human, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration of separate compositions, administration of separate compositions at different times (i.e., sequential administration), or administration of a composition in which both agents are present.

[0068] "1L therapy" refers to the first-line therapy administered to treatment-naive cancer patients. Similarly, 2L, 3L, etc. refer to subsequent treatments administered to patients.

[0069] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, uses, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic product.

[0070] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of a protein such as a mutant form of KRas. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of a target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are associated with the development, growth, or spread of tumors.

[0071] The term "agonist" as used herein refers to a compound that has the ability to initiate or enhance the biological function of target protein, whether by inhibiting the activity or expression of target protein.Therefore, the term "agonist" is defined in the context of the biological role of target polypeptide.Preferred agonists herein specifically interact with target (e.g., bind to target), while compounds that initiate or enhance the biological activity of target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0072] The terms "cancer," "cancerous," "neoplasm," and "tumor," and related terms, are used interchangeably herein to refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancers include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas) and lung cancers (such as small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cavity cancer, pharyngeal (mouth) cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, small intestine cancer, colon cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, liver cancer, uterine cancer, uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system, brain cancer, head and neck cancer, Hodgkin's disease, and related metastases. Other examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, myelofibroses such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0073] A "chemotherapeutic agent" is an agent useful for treating a given disorder, such as cancer or inflammatory disorder. Examples of chemotherapeutic agents are well known in the art. In addition, chemotherapeutic agents include any pharmaceutically acceptable salt, acid, or derivative of a chemotherapeutic agent, and combinations of two or more thereof.

[0074] It is specifically contemplated that any limitation described with respect to one embodiment provided herein may apply to any other embodiment provided herein. Furthermore, any compound described herein and its pharmaceutically acceptable salts, or composition described herein, may be used in any method provided herein, and any method provided herein may be used to produce or utilize any compound described herein and its pharmaceutically acceptable salts, or composition described herein.

[0075] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to measure the value.

[0076] compound Provided herein are compounds of formula (I), or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF2025535367000002.tif47170 (in the formula, Ring A is R 8 a substituted or unsubstituted 3- to 10-membered heterocycle, or R 8 a substituted or unsubstituted 5- to 10-membered heteroaryl; R 8 are independently halogen, CN, NH2, NHC 1~3 Alkyl, R 8A Substituted or unsubstituted C 1~6 Alkyl, or R 8A Substituted or unsubstituted C 1~6 is haloalkyl; R 8A is halogen, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 is haloalkyl; n is 1 or 2; R 1 is R 7 Substituted or unsubstituted indolyl, R 7 Substituted or unsubstituted benzofuranyl, R 7Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7A substituted or unsubstituted phenyl, or R 7A substituted or unsubstituted pyridinyl; Each R 7 are independently hydrogen, halogen, CN, CH2OH, -OH, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 2~5 Alkynyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; Each R 7a are independently hydrogen, halogen, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; R 2 OH, unsubstituted C 1~3 Alkoxy, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 is haloalkyl; R 3 is an R containing N, S, or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10 Substituted or unsubstituted C 1~3 Alkylidene, or R 10 Substituted or unsubstituted C 3~4 cycloalkyl, or R 10 a substituted or unsubstituted 3- or 4-membered heterocyclic ring; Or two R's 9 Let's get together and C 3~5 forming a cycloalkyl or 3- to 5-membered heterocyclic ring; R 10 is hydrogen or halogen; R 4 is hydrogen, halogen, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 is haloalkyl; R 5 and R 6 are each independently hydrogen or unsubstituted C 1~3 alkyl).

[0077] In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 5 and R 6 Each is hydrogen. In another embodiment, R 5 is CH3 and R 6 is hydrogen. In another embodiment, R 6 is hydrogen or unsubstituted C 1~3 In another embodiment, R 6 is CH3 and R 5 is hydrogen.

[0078] In one embodiment, the compound of formula (I) or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof has the formula (Ia): TIFF2025535367000003.tif47170, In the formula, R 1 , R 2 , R 3 , R 4 , R 8 , ring A and n are described herein.

[0079] In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 1 is R 7 Substituted or unsubstituted indolyl, R 7 Substituted or unsubstituted benzofuranyl, R 7Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7A substituted or unsubstituted phenyl, or R 7A It is a substituted or unsubstituted pyridinyl.

[0080] In another embodiment, R 1 is R 7 Substituted or unsubstituted indolyl, R 7 Substituted or unsubstituted benzofuranyl, R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 Substituted or unsubstituted benzothiazolyl, or R 7 In another embodiment, R 1 is R 7 Substituted or unsubstituted naphthyl, or R 7 It is a substituted or unsubstituted isoquinolinyl.

[0081] In one embodiment, R 1 is R 7 Substituted or unsubstituted naphthyl, R 7 In another embodiment, R 1 is R 7A substituted or unsubstituted phenyl, or R 7A In another embodiment, R 1 teeth, TIFF2025535367000004.tif132170, where R 7 is defined herein.

[0082] In another embodiment, R 1 teeth, TIFF2025535367000005.tif121170

[0083] In another embodiment, R 1 teeth, TIFF2025535367000006.tif239170TIFF2025535367000007.tif152170.

[0084] In some embodiments, each R 7 are independently hydrogen, halogen, CN, CH2OH, -OH, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, or unsubstituted C 2~5 In one embodiment, each R 7 are independently hydrogen, halogen, -OH, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, or unsubstituted C 2~5 In another embodiment, each R 7 are independently hydrogen, halogen, -OH, NH2, methyl, ethyl, or unsubstituted C 2~3 In another embodiment, each R 7 is independently halogen or —OH. 7 are independently halogen, -OH, NH2, or unsubstituted C 2~3 It is alkynyl.

[0085] In one embodiment, R 1 is R 7A substituted or unsubstituted phenyl, or R 7A In one such embodiment, R 1 is R 7A In another such embodiment, R 1 is R 7A It is a substituted or unsubstituted pyridinyl.

[0086] In one embodiment, R 1 teeth, TIFF2025535367000008.tif69170(in the formula,1 is N, CH, CF, or CCl; R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 haloalkyl).

[0087] In one embodiment, R 1 is part of formula (A), and X 1 is N and R 7A are described herein. In another embodiment, R 1 is part of formula (B), and X 1 is N and R 7A are described herein. In another embodiment, R 1 is part of formula (A), and X 1 is CH, CF, or CCl, and R 7A is described herein.

[0088] In some embodiments, R 1 teeth, TIFF2025535367000009.tif28170, During the ceremony, X 1 is N, CH, CF, or CCl; R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 It is haloalkyl.

[0089] In one such embodiment, the moiety of formula (A) is R 1 but This is the part that is TIFF2025535367000010.tif28170, In the formula, R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 It is haloalkyl.

[0090] In one embodiment, R 1 teeth, The file is TIFF2025535367000011.tif54170.

[0091] In some embodiments, R 1 teeth, TIFF2025535367000012.tif34170, In the formula, R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 It is haloalkyl.

[0092] In some embodiments, R 1 teeth, TIFF2025535367000013.tif32170, In the formula, R 7A is hydrogen, F, or Cl. In one such embodiment, R 7A is F. In another such embodiment, R 7A is Cl. In one embodiment, R 7A is methyl. In one embodiment, R 7A is hydrogen.

[0093] Also further provided herein, in some embodiments, R 1 part is, TIFF2025535367000014.tif32170, In the formula, R 7A is hydrogen, F, or Cl. In one such embodiment, R 7A is F. In another such embodiment, R 7A is Cl. In one embodiment, R 7A is methyl. In one embodiment, R 7A is hydrogen.

[0094] In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 1 teeth, TIFF2025535367000015.tif171170.

[0095] In another embodiment of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, R 1 teeth, TIFF2025535367000016.tif189170.

[0096] In another embodiment of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, R 1 teeth, TIFF2025535367000017.tif126170.

[0097] In one embodiment, each R 7a are independently hydrogen, halogen, NH2, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 In another embodiment, each R 7a are independently hydrogen, F, Cl, NH2, methyl, or CF3.

[0098] In one embodiment of a compound described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 4 is the unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 In one such embodiment, R 4 is OCH3. In another embodiment, R 4 is Cl or F. In one such embodiment, R 4 is F. In another such embodiment, R 4 is Cl. In one embodiment, R 1 is a moiety of formula (A) described herein, and R 4 is Cl or F. In one such embodiment, R 1 is a moiety of formula (A) described herein, wherein X 1 is N or X1 is CH, CF, or CCl, and R 4 is F. In another such embodiment, R 1 is a moiety of formula (A) described herein, wherein X 1 is N or X 1 is CH, CF, or CCl, and R 4 is Cl. In such embodiments, R 7A is hydrogen, halogen, methyl, and / or CF3 as described herein.

[0099] In another embodiment, R 1 is a moiety of formula (C), (C1), (C2), or (C3) described herein; R 4 is Cl or F. In one such embodiment, R 4 is F. In another such embodiment, R 4 is Cl.

[0100] In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 3 is an R containing one or more N or O ring heteroatoms 9 In one such embodiment, R 3 is an R containing one or more N heteroatoms 9 A substituted or unsubstituted 4-10 membered heterocycle. In one such embodiment, the heterocycle contains 1 or 2 ring N heteroatoms.

[0101] In one embodiment, R 3 teeth, TIFF2025535367000018.tif23170, During the ceremony, Z is C(R 9 )2 or O; R 9 is hydrogen, halogen or R 10 Substituted or unsubstituted C 1~3 Is it alkylidene? Or two R's 9 Let's get together and C 3~5 Forms a cycloalkyl or 3- to 5-membered heterocycle r is an integer from 0 to 12; j is 1, 2, or 3; k is 1 or 2.

[0102] In one embodiment, Z is O and k is 2. In another embodiment, Z is O, k is 2 and j is 2. In another embodiment, Z is C(R 9 )2, where R 9 are described herein, k is 1 and j is 2. In one embodiment, R 3 teeth, TIFF2025535367000019.tif24170, During the ceremony, R 9 is halogen, -OCF3, -OCHF2, -OCH2F, R 10 Substituted or unsubstituted C 1~3 alkylidene or two R 9 Let's get together and 10 Substituted or unsubstituted C 3~5 Forming a cycloalkyl; r is an integer from 0 to 12; j is 1, 2, or 3; k is 1 or 2.

[0103] In one embodiment, R 3 is part of formula (D), and R 9 is a halogen, R 10 Substituted or unsubstituted C 1~3 alkylidene or two R 9 Let's get together and 10 Substituted or unsubstituted C 3~5 In one such embodiment, two R 9 is R 10 In one such embodiment, R 10is halogen (e.g., F). In another embodiment, R 3 is part of formula (D), k is 1, j is 2, and R 9 are described herein and r is 0, 1, 2, 3, or 4. In one embodiment, R 9 is a halogen or R 10 Substituted or unsubstituted C 1~3 alkylidene and r is 2 or 3. In one embodiment, R 3 teeth, TIFF2025535367000020.tif162170, Each R 9 are independently halogen or R 10 Substituted or unsubstituted C 1~3 is alkylidene; Each R 10 are independently hydrogen or halogen; r is 0, 1, or 2; s is 0, 1, or 2.

[0104] In one embodiment, R 3 is a moiety of (D1), (D2), or (D3), wherein: Each R 9 are independently halogen or R 10 Substituted or unsubstituted C 1~3 is alkylidene; Each R 10 are independently hydrogen or halogen; r is 1 or 2; s is 0, 1, or 2.

[0105] In another embodiment, R 3 is (D1), where r is 1. In another embodiment, R 3 is (D2), where r is 0 and each R 10 is independently hydrogen or F. In another embodiment, R 3 is (D3), where r is 0 and each R 9 is independently hydrogen or halogen.3 is (D4), where R 10 is a halogen and s is 0, 1, or 2.

[0106] In one embodiment, R 3 teeth, TIFF2025535367000021.tif202170.

[0107] In one embodiment, R 3 teeth TIFF2025535367000022.tif18170, In the formula, R 10 is halogen and s is 0, 1 or 2. In one such embodiment, R 10 is F and s is 1 or 2.

[0108] In one embodiment, R 3 teeth, TIFF2025535367000023.tif19170, In the formula, each R 9 are independently halogen, oxo, or unsubstituted C 1~3 is alkyl; r is 0, 1, or 2. In one such embodiment, R 9 is F and r is 1 or 2.

[0109] In one embodiment, R 3 teeth, TIFF2025535367000024.tif32170, In the formula, each R 9 are independently halogen, oxo, or unsubstituted C 1~3 is alkyl; r is 0, 1, or 2. In one embodiment, R 9 is halogen and r is 1. In another embodiment, r is 0. In one embodiment, the moiety of formula (F) is of the formula Contains compounds from TIFF2025535367000025.tif30170.

[0110] In a further embodiment, R 3 teeth, TIFF2025535367000026.tif24170, During the ceremony, Each R 9 are independently halogen, oxo, or unsubstituted C 1~3 Is it alkyl? or two R's 9 Let's get together and C 3~5 It forms a cycloalkyl or 3- to 5-membered heterocycle; r is 1 or 2.

[0111] In one embodiment, R 3 teeth, TIFF2025535367000027.tif23170, During the ceremony, Each R 9 are independently halogen, oxo, or unsubstituted C 1~3 Is it alkyl? or two R's 9 Let's get together and C 3~5 forming a cycloalkyl or 3- to 5-membered heterocyclic ring; r is 1 or 2. In one such embodiment, R 9 is halogen and r is 1 or 2. In one such embodiment, R 9 is a halogen and r is 1.

[0112] In one embodiment, R 3 teeth, The file is TIFF2025535367000028.tif118170.

[0113] In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 2 is -OH or unsubstituted C 1~3 In one such embodiment, R 2 is OH. In another embodiment, R 2 is the unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3In another embodiment, R 2 is the unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one such embodiment, R 2 is CHF, CHF, or CF. In another embodiment, R 2 is the unsubstituted C 1~3 In one such embodiment, R 2 is methyl.

[0114] In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, ring A is selected from the group consisting of R 8 a substituted or unsubstituted 3- to 10-membered heterocycle, or R 8 In one embodiment, ring A is a substituted or unsubstituted 5-10 membered heteroaryl. In one embodiment, ring A is a heterocyclic ring containing at least one nitrogen atom. 8 Substituted or unsubstituted 3- to 6-membered heterocycle or R containing at least one heterocyclic ring nitrogen atom 8 In one such embodiment, the heterocyclic ring or heteroaryl contains one or two ring nitrogen atoms. In another embodiment, ring A is an R that contains at least one heterocyclic ring nitrogen atom. 8 In another embodiment, ring A is a substituted or unsubstituted 5- or 6-membered heterocyclic ring. In another embodiment, ring A is a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing at least one heterocyclic ring nitrogen atom. 8 In one embodiment, ring A is R 8 Substituted or unsubstituted pyridinyl, R 8 Substituted or unsubstituted pyrimidinyl or R 8 It is a substituted or unsubstituted pyrazinyl.

[0115] In another embodiment, ring A has the formula: TIFF2025535367000029.tif54170 wherein X is CH or N and n is 1 or 2. In one such embodiment where ring A is a moiety of formula (H), X is N and n is 1.

[0116] In one embodiment where ring A is a moiety of formula (H) or (H1), R 8 are independently halogen, CN, NH2, or R 8A Substituted or unsubstituted C 1~6 In another embodiment, R 8 is independently halogen, CN, or NH. In another embodiment, R 8 are independently 8A Substituted or unsubstituted C 1~6 Alkyl, or R 8A Substituted or unsubstituted C 1~6 In another embodiment, R 8 is NH. In another embodiment, R 8 is NH2 and n is 1.

[0117] In another embodiment, ring A has the formula: This is the part of TIFF2025535367000030.tif54170, wherein X is CH or N. In one embodiment, X is CH. In one embodiment, X is N.

[0118] In some embodiments, ring A has the formula: This is the TIFF2025535367000031.tif79170 part.

[0119] In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, ring A is a group represented by the formula This is the TIFF2025535367000032.tif22170 part.

[0120] In one embodiment of a compound of Formula (I) or (Ia) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound has structural formula (II): TIFF2025535367000033.tif47170 (including stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof), wherein R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , n, r, and ring A are described herein.

[0121] In one embodiment of the compound of formula (II) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound of formula (II) has the following structure: TIFF2025535367000034.tif187170 (including stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof).

[0122] In one embodiment of a compound of Formula (II), (IIIa), (IIb), or (IIc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 9 are independently halogen or R 10 Substituted or unsubstituted C 1~3 alkylidene; each R 10 are independently hydrogen or halogen; and r is 1 or 2. In another such embodiment, two R 9 Together, C 3~5 In one such embodiment, two R 9 Together, R 10 In one such embodiment, R 10 is hydrogen or F. In one embodiment, the compound comprises the moiety: Includes TIFF2025535367000035.tif202170.

[0123] Further provided herein are compounds of formula (III), stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof: TIFF2025535367000036.tif58170, including stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , n, r, and ring A are described herein.

[0124] In one embodiment of the compound of formula (III) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound of formula (III) has the following structure: TIFF2025535367000037.tif187170, including stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof. In one embodiment of a compound of Formula (III), (IIIa), (IIIb), or (IIIc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the moiety is: Includes TIFF2025535367000038.tif30170.

[0125] Further provided herein is a compound of formula (IV), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF2025535367000039.tif47170, including stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , n, r, and ring A are described herein.

[0126] In one embodiment of the compound of formula (IV) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound of formula (IV) has the following structure: TIFF2025535367000040.tif183170, including stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof. In one embodiment of a compound of Formula (IV), (IVa), (IVb), or (IVc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the moiety is: Includes TIFF2025535367000041.tif54170.

[0127] Further provided herein are compounds of formula (V), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof: TIFF2025535367000042.tif52170, including stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , n, r, and ring A are described herein.

[0128] In one embodiment of the compound of formula (IV) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound of formula (IV) has the following structure: TIFF2025535367000043.tif183170, including stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof. In one embodiment of a compound of Formula (V), (Va), (Vb), or (Vc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the moiety is: Includes TIFF2025535367000044.tif118170.

[0129] In one embodiment of a compound of Formula (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb), or (Vc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, ring A is of the formula: Includes part TIFF2025535367000045.tif79170.

[0130] In one embodiment of a compound of Formula (II), (IIb), (IIc), (III), (IIIb), (IIIc), (IV), (IVb), (IVc), (V), (Vb), or (Vc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, X 1 is N, and each R 7a are independently hydrogen, halogen, NH2, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 In another such embodiment, when the compound is of formula (IIb) as described herein, X is haloalkyl. 1 is CH, CF, or CCl, and each R 7a is independently hydrogen, F, Cl, NH, methyl, or CF. In one embodiment of a compound of Formula (II), (IIb), or (IIc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound comprises the moiety: Includes TIFF2025535367000046.tif241170 and TIFF2025535367000047.tif66170.

[0131] In one embodiment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb), or (Vc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound is set forth in Table 1 below. [Table 1] TIFF2025535367000049.tif243170TIFF2025535367000050.tif247170TIFF2025535367000051.tif248170TIFF20255353670 00052.tif245170TIFF2025535367000053.tif254170TIFF2025535367000054.tif213170TIFF2025535367000055.tif114170

[0132] In one embodiment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb), or (Vc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound is set forth in Table 2 below. [Table 2]

[0133] In one embodiment of a compound of Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb), or (Vc) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound is set forth in Table 3 below. [Table 3] TIFF2025535367000058.tif207170TIFF2025535367000059.tif221170TIFF2025535367000060.tif255170TIFF20255353670 00061.tif217170TIFF2025535367000062.tif211170TIFF2025535367000063.tif220170TIFF2025535367000064.tif209170

[0134] Compound synthesis The compounds described herein of the present disclosure, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be made by a variety of methods illustrated in the exemplary synthetic reaction schemes shown and described below. The starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or are generally available from other sources, such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R.C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A.R. Katrittzky and C.W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A.R. Katrittzky and C.W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New They are prepared by methods known to those skilled in the art according to procedures described in references such as, for example, John Wiley & Sons, 1991, vol. 1-40. The synthetic reaction schemes provided herein are merely illustrative of some of the methods by which the compounds described herein or pharmaceutically acceptable salts thereof can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to those skilled in the art upon reading the disclosure contained herein.

[0135] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein and the necessary reagents and intermediates include those described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0136] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be prepared singly or as compound libraries containing at least two compounds, e.g., 65 to 1,000 compounds, or 10 to 100 compounds. Libraries of the compounds described herein of the formulae described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be prepared by combinatorial split and mix approaches or by multiple parallel syntheses, e.g., using either solution-phase or solid-phase chemistry. Thus, according to a further aspect, provided herein are compound libraries containing at least two compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0137] The examples provide exemplary methods for preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. While specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents can be substituted to provide a variety of derivatives and / or reaction conditions. Furthermore, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry.

[0138] In preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, protection of remote functionality (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection depends on the nature of the remote functionality and the conditions of the preparation method. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0139] In the processes for preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, it may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high-, medium-, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed (SMB) and preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography techniques.

[0140] Another class of separation methods involves treating the mixture with a selected reagent to bind or otherwise render separable the desired product, unreacted starting materials, reaction by-products, etc. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent may be an acid in the case of basic substances, a base in the case of acidic substances, a binding reagent such as an antibody, a binding protein, a selective chelating agent such as crown ethers, liquid-liquid ion extraction reagents (LIX), etc. The selection of an appropriate separation method depends on the properties of the materials involved, such as boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of the material in acidic and basic media in multiphase extraction, etc.

[0141] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Additionally, some of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, may be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated using chiral HPLC columns.

[0142] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer can be obtained by resolving a racemic mixture using methods such as the formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of the chiral compounds described herein or pharmaceutically acceptable salts thereof can be separated and isolated by any suitable method, including: (1) the formation of ionic diastereomeric salts with chiral compounds and separation by fractional recrystallization or other methods; (2) the formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers; and (3) the separation of substantially pure or enriched stereoisomers under chiral conditions. See "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

[0143] In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, and α-methyl-β-phenylethylamine (amphetamine), with asymmetric compounds containing acidic functional groups, such as carboxylic and sulfonic acids. The diastereomeric salts can be induced to separate by fractional recrystallization or ionic chromatography. To separate the optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can form diastereomeric salts.

[0144] Alternatively, method (2) involves reacting the substrate to be resolved with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting the asymmetric compound with an enantiomerically pure chiral derivatizing agent, such as a menthyl derivative, followed by separation and hydrolysis of the diastereomers to obtain the pure or enriched enantiomer. A method for determining optical purity involves preparing a chiral ester, such as a menthyl ester, e.g., (-)menthyl chloroformate, or Mosher's ester, α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. J. Org. Chem. (1982) 47:4165), in the presence of a base from the racemic mixture and then analyzing the mixture for the presence of the two atropisomers, either enantiomers or diastereomers. 1and analyzing the H NMR spectrum. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal-phase and reverse-phase chromatography following the method for separating atropisomeric naphthyl-isoquinolines (WO 96 / 15111). Method (3) allows the separation of racemic mixtures of two enantiomers by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0145] The chemical reactions described herein can be easily adapted to prepare other compounds described herein and their pharmaceutically acceptable salts. For example, the synthesis of compounds not exemplified herein and their pharmaceutically acceptable salts can be successfully carried out by modifications apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by routinely modifying the reaction conditions. Alternatively, it will be recognized that other reactions disclosed herein or known in the art have applicability for preparing other compounds described herein and their pharmaceutically acceptable salts.

[0146] Pharmaceutical preparations Also provided herein are pharmaceutical compositions comprising a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0147] The compounds described herein, or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, can be formulated into pharmaceutical compositions according to standard pharmaceutical practice.Therefore, the present invention further provides pharmaceutical compositions comprising the compounds described herein, or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients.

[0148] A typical formulation is prepared by mixing a compound described herein or a pharmaceutically acceptable salt thereof with an excipient. Suitable carriers, diluents, and excipients include, but are not limited to, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and other materials. The specific excipient used will depend on the means and purpose for which the compound described herein or a pharmaceutically acceptable salt thereof is to be administered. Solvents are generally selected based on solvents recognized as safe (GRAS) for mammalian administration. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide proper presentation of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0149] Formulations can be prepared using conventional dissolution and mixing procedures. For example, bulk drug substance (i.e., the compound described herein or its pharmaceutically acceptable salt, or its stabilized form (e.g., complex with cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, is typically formulated into a pharmaceutical dosage form to provide easily controllable drug dosage and enable patient compliance with a prescribed regimen.

[0150] Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, and metal cylinders. The container may also include a tamper-evident assembly to prevent inadvertent access to the contents of the package. In addition, the container has disposed thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0151] Pharmaceutical formulations of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be prepared for various routes and types of administration. For example, a compound having the desired purity, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be mixed with one or more pharmaceutically acceptable excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), optionally in the form of a lyophilized formulation, a pulverized powder, or an aqueous solution. Formulations can be made by mixing the compound at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage and concentration used. The pH of the formulation will depend primarily on the specific application and the concentration of the compound, but may range from about 3 to about 8. For example, a formulation in acetate buffer at pH 5 may be a preferred embodiment.

[0152] Pharmaceutical compositions may generally be stored as solid compositions, lyophilized formulations or aqueous solutions.

[0153] The pharmaceutical compositions described herein can be formulated, prescribed and administered in a manner that is compatible with full medical practicality, that is, in amount, concentration, schedule, course, vehicle and administration route.The factors that should be considered in this context include the specific disorder that is treated, the specific mammal that is treated, the clinical condition of individual patients, the cause of the disorder, the delivery site of the drug, administration method, administration schedule and other factors known to medical practitioners.The effective amount of the compound that is administered, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, is governed by such considerations and is the minimum amount that is necessary to improve or treat hyperproliferative disorder.

[0154] As a general proposition, the initial pharmaceutically effective amount of the parenterally administered compound, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, per dose will be in the range of about 0.01 to 100 mg / kg, i.e., about 0.1 to 20 mg / kg of patient body weight per day, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, the pharmaceutical compositions described herein comprise an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount of about: 1 mg to 10 mg; 10 mg to 25 mg; 20 mg to 50 mg; 50 mg to 75 mg; 70 mg to 100 mg; 100 mg to 150 mg; 100 mg to 200 mg; 100 mg to 500 mg; 200 mg to 500 mg; 250 mg to 500 mg; 500 mg to 1000 mg; or 750 mg to 1000 mg.

[0155] Acceptable pharmaceutically acceptable excipients are nontoxic to recipients at the dosages and concentrations employed and include buffers, e.g., phosphate, citric acid, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, e.g., methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol; low molecular weight (less than about 10 residues) polypeptides; proteins, e.g., serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, e.g., polyvinylpyrrolidone; amino acids, e.g., glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates (e.g., glucose, mannosaccharides, mannose, thiamin monosaccharides ... The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0156] The sustained-release preparation of the compound described herein or its pharmaceutically acceptable salt can be prepared.Suitable examples of sustained-release preparations include the semipermeable matrix of solid hydrophobic polymer that contains the compound described herein or its pharmaceutically acceptable salt, and this matrix is ​​in the form of a shaped article such as film or microcapsule.Examples of sustained-release matrix include polyester, hydrogel (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (US Pat. No. 3,773,919), L-glutamic acid and gamma-L-glutamic acid copolymer, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymer such as LUPRON DEPOT (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0157] Formulations include those suitable for the administration routes detailed herein. Formulations may conveniently be presented in unit dosage form and may be prepared by any method. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0158] Formulations of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of such compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent, in a suitable machine. Molded tablets can be made by molding a mixture of moistened powdered active ingredient and an inert liquid diluent in a suitable machine. Tablets can optionally be coated or grooved, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups, or elixirs can be prepared for oral use.The compound described herein or its pharmaceutically acceptable salt preparation intended for oral use can be prepared according to any method for preparing pharmaceutical compositions, and such compositions can contain one or more agents, including sweeteners, flavorings, colorings, and preservatives, to provide a palatable preparation.Tablets containing active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable.These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0159] For treatment of the eye or other external tissues, e.g., the mouth and skin, the formulations are preferably applied as topical ointments or creams containing the active ingredient(s) in an amount of 0.075-20% w / w. When formulated in an ointment, the active ingredient can be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can contain a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations can optionally contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues. The oily phase of the emulsions of the compositions provided herein can be composed of known ingredients in a known manner. The phase may simply comprise an emulsifier, but preferably comprises a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Taken together, one or more emulsifiers, with or without one or more stabilizers, constitute the so-called emulsifying wax, which, together with the oil and fat, forms the oily dispersed phase of the cream formulation, the so-called emulsifying ointment base. Suitable emulsion and emulsion stabilizers for use in the formulations described herein include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0160] Aqueous suspensions containing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0161] Pharmaceutical compositions of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be prepared as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic monoglycerides or diglycerides, may be used. Furthermore, fatty acids, such as oleic acid, may also be used in the preparation of injectables.

[0162] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain about 1 to 1,000 mg of active ingredient combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution to result in infusion of a suitable volume at a rate of about 30 mL / hour.

[0163] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0164] Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w / w, e.g., about 0.5 to 10% w / w, e.g., about 1.5% w / w.

[0165] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0166] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0167] Formulations suitable for pulmonary or nasal administration have particle sizes in the range of, for example, 0.1 to 500 microns (in micron increments, such as 0.5, 1, 30 microns, 35 microns, etc., including particle sizes in the range of 0.1 to 500 microns), which are administered by rapid inhalation through the nostrils to reach the alveolar sacs, or by inhalation through the mouth. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds previously used to treat or prevent the disorders described below.

[0168] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, such carriers as are deemed appropriate.

[0169] The formulations may be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, immediately prior to use for injection. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0170] In one embodiment, a compound, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, is formulated as a prodrug. As used herein, the term prodrug refers to a derivative of a compound that can be hydrolyzed, oxidized, or cleaved under biological conditions to provide the compound, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt. As defined herein, prodrugs include derivatives that contain one or more moieties that modulate or improve one or more physical, physiological, or pharmaceutical properties, such as, but not limited to, solubilization, permeability, uptake, biodistribution, metabolic stability, onset of action, or any other drug-like properties, and are converted into the biologically active or more biologically active substance provided herein. In one embodiment, the prodrugs herein do not have biological activity until the release of the compound or its pharmaceutically acceptable salt.

[0171] Administration method The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be administered by any route appropriate to the condition being treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intraperitoneal, intrapulmonary, and intranasal. For localized immunosuppressive treatment, the compounds can be administered intralesionally, including by perfusing or otherwise contacting the graft with an inhibitor prior to transplantation. It will be understood that the preferred route may vary with the condition of the recipient, e.g., 6. When the compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are administered orally, they can be formulated as pills, capsules, tablets, etc., with a pharmaceutically acceptable carrier or excipient. When the compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered parenterally, it may be formulated in a unit dosage injectable form, as detailed below, with a pharmaceutically acceptable parenteral vehicle.

[0172] Therefore, in one aspect, provided herein is a pharmaceutical composition comprising the compound described herein or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.In one embodiment, the compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, is administered as a pharmaceutical composition that can be administered orally or parenterally to a subject.The compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, can be formulated for topical or parenteral use, and the compound, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, is dissolved or otherwise suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion.

[0173] Oral administration can promote patient compliance when taking a compound (e.g., formulated as a pharmaceutical composition), thereby increasing compliance and efficacy. Oral pharmaceutical compositions comprising the compounds described herein include, but are not limited to, tablets (e.g., coated, uncoated, chewing) and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric-coated capsules, and sustained-release capsules). Tablets can be prepared by direct compression, wet granulation, or dry granulation. Oral pharmaceutical compositions comprising the compounds described herein can be formulated for delayed release or extended release.

[0174] Doses for treating human patients can range from about 10 mg to about 1000 mg of the compounds described herein. Typical dosages can be from about 100 mg to about 300 mg of compound. Doses can be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion, of the particular compound. As used herein, "dosing" refers to the frequency of administration and not the number of individual units a patient must take for administration, e.g., as described herein. Thus, in some embodiments, a patient may take two or more dosage units (e.g., two or more pills / tablets / capsules) QD. In addition, toxicity factors can affect the dosage and administration regimen. When administered orally, pills, capsules, or tablets may be taken orally daily or at more spaced intervals for a specified time period. This regimen can be repeated for a predetermined number of treatment cycles.

[0175] Treatment Methods and Uses The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as Ras inhibitors. In one aspect, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as KRas inhibitors. In another embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as pan-KRas inhibitors (i.e., compounds that inhibit the activity of mutant KRas proteins). In one such embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as pan-KRas inhibitors containing a mutation at position 12 (e.g., a G12X mutation, where X is a mutation of a naturally occurring Gly residue to a different amino acid). In one embodiment, the compounds of Table 1 and Table 2 described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are useful as pan-KRas inhibitors.

[0176] Provided herein is a method for inhibiting KRas activity in cells, such as ex vivo cells, by contacting a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the activity is mutant KRas activity (e.g., mutant pan-KRas activity).

[0177] As used herein, active inhibition of two or more KRas mutations is referred to as pan-KRas inhibition. In such cases, the compounds described herein or their pharmaceutically acceptable salts inhibit the activity of two or more mutant KRas proteins. In certain cases, such compounds or their pharmaceutically acceptable salts selectively inhibit two or more mutant KRas proteins compared to wild-type (WT) KRas protein activity. In one such embodiment, the pan-KRas inhibitor described herein and used in the methods provided herein inhibits at least one mutant KRas protein at least 5-fold, 8-fold, 10-fold, 12-fold, 15-fold, 20-fold, 24-fold, 27-fold, 50-fold, 100-fold, 500-fold, 700-fold, 1000-fold, 1300-fold, 1700-fold, 2000-fold, 5000-fold, or more than WT KRas protein activity. In one embodiment, such KRas mutations are in the SWII domain. In one embodiment, such a KRas mutation corresponds to a change in the native amino acid at a position corresponding to G12, G13, Q61, or A146. In such embodiments, such compounds are useful in methods described herein where such cancer or disease is mediated by a KRasG12X mutation (e.g., where X is C, D, R, or V). In some embodiments, the mutation corresponds to G12A, G12C, G12D, G12R, G12S, G12V, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V, or A146T.

[0178] Also provided herein is a method for treating a cancer containing a KRas mutation, comprising administering to a patient with such a cancer an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In one embodiment, the mutation is a known KRas mutation described herein (e.g., a KRasG12X mutation) and demonstrates pan-KRas inhibition.

[0179] In one embodiment, the method further comprises testing a sample from the patient (e.g., as described herein) for the absence or presence of a KRas mutation (e.g., a KRasG12X mutation) prior to administration of a compound described herein or a pharmaceutically acceptable salt thereof. In one such embodiment, a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered to the patient after the patient sample has been determined to be positive for a KRas mutation (e.g., a KRas mutation is present). In one embodiment, the method further comprises testing a sample from the patient (e.g., as described herein) for the absence or presence of a KRas mutation prior to administration of a compound described herein, or a pharmaceutically acceptable salt thereof, and a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered to the patient after the patient sample has been determined to be positive for such a KRas mutation (e.g., a KRas mutation is present).

[0180] The methods of treating cancer described herein include, but are not limited to, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and leukemia-associated cancers (e.g., leukemia-associated leukemia). ML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, uterine cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic cancer Transendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasia, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasia, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, oropharynx For the treatment of cancers such as carcinoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, abnormal cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

[0181] In some embodiments, the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. The lung cancer can be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is lung adenocarcinoma.

[0182] The methods provided herein can also include testing a sample from a patient prior to administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the absence or presence of a KRas mutation corresponding to position 12 of KRas (e.g., Gly12). In one embodiment, the compound, a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered to the patient after the patient sample indicates the presence of a KRas mutation corresponding to position 12 of KRas (e.g., Gly12). In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is not administered unless the patient sample contains a KRas mutation corresponding to position 12 of KRas (e.g., Gly12).

[0183] The methods provided herein can further include testing a sample from a patient for the absence or presence of a KRas mutation prior to administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the compound, its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, or pharmaceutical composition is administered to the patient after the patient sample indicates the presence of a KRas mutation, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are not administered unless the patient sample contains a KRas mutation, and the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, have pan-KRas inhibition.

[0184] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the pancreatic cancer, lung cancer, or colorectal cancer contains a KRasG12X mutation. In yet another embodiment, the cancer is tissue-independent but contains a KRasG12X mutation.

[0185] In another embodiment, pancreatic cancer, lung cancer, or colorectal cancer contains a KRas mutation.In such an embodiment, the cancer is tissue-independent but contains a KRas mutation.In such an embodiment, the cancer can be treated as described herein with a compound having pan-KRas inhibition, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.In some embodiments, the KRas mutation is a mutation of a residue other than Gly12.

[0186] Also provided herein is a method for treating a lung cancer containing a KRasG12X mutation in a patient having such a lung cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same). In one embodiment, the lung cancer is non-small cell lung carcinoma (NSCLC). The NSCLC can be, for example, an adenocarcinoma, a squamous cell lung carcinoma, or a large cell lung carcinoma. In another embodiment, the lung cancer is small cell lung carcinoma. In yet another embodiment, the lung cancer is an adenocarcinoma, a carcinoid tumor, or an anaplastic carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. The methods provided herein include administering the compound as a first line of therapy. In one embodiment, the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, have pan-KRas inhibition.

[0187] Also provided herein is a method for treating a lung cancer containing a KRas mutation (e.g., corresponding to a position other than Gly12) in a patient having such a lung cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same), wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, inhibits pan-KRas in the patient. In one embodiment, the lung cancer is non-small cell lung carcinoma (NSCLC). NSCLC can be, for example, adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenocarcinoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or IV lung cancer. The methods provided herein include administering the compounds as a 1L treatment.

[0188] Also provided herein is a method for treating a pancreatic cancer comprising a KRasG12X mutation in a patient with such pancreatic cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the patient has previously been treated with radiation and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is stage 0, I, or II. In another embodiment, the pancreatic cancer is stage III or stage IV. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0189] Also provided herein is a method for treating a pancreatic cancer containing a KRas mutation (e.g., corresponding to a position other than Gly12) in a patient with such pancreatic cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the patient has previously been treated with radiation and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is in stage 0, I, or II. In another embodiment, the pancreatic cancer is in stage III or stage IV.

[0190] Also provided herein is a method for treating colon cancer containing the KRasG12X mutation in a patient with such colon cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the colon cancer is in stage I or II. In another embodiment, the colon cancer is in stage III or stage IV. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0191] Also provided herein is a method for treating colon cancer containing a KRas mutation (e.g., corresponding to a position other than Gly12) in a patient with such colon cancer, comprising administering to the patient an effective amount of a compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, has pan-KRas inhibition.In one embodiment, the colon cancer is in stage I or II.In another embodiment, the colon cancer is in stage III or stage IV.

[0192] Further provided herein is a method for treating tissue-independent cancers containing the KRasG12X mutation. In one embodiment of such a method, method (Ag2) comprises:

[0193] Determining the absence or presence of a KRasG12X mutation in a sample taken from a patient diagnosed with suspected cancer;

[0194] and administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0195] Further provided herein are methods for treating tissue-independent cancers containing KRas mutations (e.g., corresponding to positions other than Gly12). In one embodiment of such a method, method (Ag3) comprises:

[0196] Determining the absence or presence of a KRas mutation in a sample taken from a patient diagnosed with suspected cancer;

[0197] and administering to a patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0198] In one embodiment of the methods of Ag1, Ag2, and Ag3, the patient is diagnosed with a cancer described herein. In another embodiment of the methods of Ag1, Ag2, and Ag3, the sample is a tumor sample collected from the subject. In one such embodiment, the sample is collected before the administration of any treatment. In another such embodiment, the sample is collected before the administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and after the administration of another chemotherapeutic agent. In another embodiment of the methods of Ag1, Ag2, and Ag3, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered (e.g., orally) as provided herein.

[0199] Also provided herein are compounds, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, for use as therapeutic active substances.In another such embodiment, the compounds, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be used for the therapeutic treatment of cancers that contain KRasG12X mutation.In one embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, have pan-KRas inhibition.

[0200] In yet other such embodiments, the compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, may be for the therapeutic treatment of cancers containing KRas mutations (e.g., corresponding to positions other than Gly12), and the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, have pan-KRas inhibition.

[0201] Also provided herein are compounds, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, for therapeutic and / or prophylactic treatment of cancers that contain KRasG12X mutation. In one embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, have pan-KRas inhibition.

[0202] Still further provided herein are compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, for the therapeutic and / or prophylactic treatment of cancers containing a KRas mutation (e.g., corresponding to position Gly12), wherein the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, have pan-KRas inhibition.

[0203] In one embodiment, a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is used in the preparation of a medicament for the therapeutic treatment of a cancer involving KRasG12X. In one embodiment, a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0204] In one embodiment, a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is used in the preparation of a medicament for the therapeutic treatment of a cancer containing a KRas mutation (e.g., corresponding to a position other than Gly12), and the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0205] Also provided herein is the use of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0206] Also provided herein is a method for inhibiting tumor metastasis, comprising administering a therapeutically effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to a patient with a tumor. In one embodiment, the inhibition is inhibition of tumors containing KRasG12X mutation. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0207] In one embodiment, the inhibition is of tumors containing a KRas mutation (e.g., corresponding to a position other than Gly12), and the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, have pan-KRas inhibition.

[0208] In some embodiments of the methods described herein, inhibiting tumor metastasis in a patient described herein results in a reduction in tumor size. In another embodiment, inhibiting tumor metastasis in a patient described herein results in stabilization of tumor size (e.g., no further growth). In another embodiment, inhibiting tumor metastasis in a patient described herein results in remission of cancer and / or its symptoms.

[0209] Also provided herein is a method for inhibiting the proliferation of a cell population, comprising contacting the cell population with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the cell population is present in a human patient. In another embodiment, the cell population contains a KRasG12X mutation. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0210] In another embodiment, the cell population contains a KRas mutation (e.g., corresponding to a position other than Gly12), and a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0211] Also provided herein is a method for inhibiting KRas in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the inhibited KRas is KRasG12X. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0212] In one embodiment, the KRas being inhibited is a mutant KRas protein (e.g., corresponding to a position other than Gly12), and the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, have pan-KRas inhibition. In another embodiment, inhibiting KRas reduces tumor size. In another embodiment, inhibiting KRas results in the amelioration of cancer and / or its symptoms.

[0213] Also provided herein is a method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the mutant protein comprises a KRasG12X mutation. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0214] In one embodiment, the mutant protein comprises a KRas mutation, and the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the activity of KRas is reduced after contact with the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, active downregulation of the KRas mutant protein treats the cancer described herein in the patient described herein. In another embodiment, active downregulation of the KRas mutant protein results in a reduction in tumor size. In another embodiment, active downregulation of the KRas mutant protein results in the alleviation of the cancer described herein and / or its symptoms.

[0215] In some embodiments, the methods provided herein include inhibiting KRasG12X activity in a cell by contacting the cell with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit KRasG12X activity in the cell. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0216] In some embodiments, the methods provided herein include inhibiting KRasG12X activity in a tissue by contacting the tissue with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of KRasG12X in the tissue. In some embodiments, the methods provided herein include inhibiting KRasG12X activity in a patient by contacting the patient with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of KRasG12X in the patient. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition.

[0217] In some embodiments, the methods provided herein include inhibiting mutant KRasG12X activity in a cell by contacting the cell with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of mutant KRasG12X in the cell. In some embodiments, the methods provided herein include inhibiting mutant KRasG12X activity in a tissue by contacting the tissue with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of mutant KRasG12X in the tissue. In some embodiments, the methods provided herein include inhibiting mutant KRasG12X activity in a patient by contacting the patient with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of mutant KRasG12X in the patient. In such embodiments, the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are understood to have pan-KRas inhibition.

[0218] Further provided herein is a method for preparing labeled KRasG12X mutant protein, comprising reacting KRasG12X mutant protein with the labeled compound described herein, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, to obtain labeled KRasG12X mutant protein.In one embodiment, the label is an imaging agent.In one embodiment, labeled KRasG12X can be used to detect the absence or presence of KRasG12X mutant protein in patient samples, thereby detecting the presence or absence of cancer mediated by mutant KRas.

[0219] Also provided herein is a method for preparing a labeled mutant KRasG12X protein, comprising reacting a mutant KRasG12X protein with a labeled compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition, to obtain a labeled KRasG12X mutant protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled mutant KRasG12X protein can be used to detect the absence or presence of mutant KRasG12X protein in a patient sample, thereby detecting the presence or absence of cancer mediated by mutant KRas.

[0220] Also provided herein is a method for inhibiting Ras-mediated cell signaling. In one embodiment, the method comprises contacting cells with an effective amount of one or more compounds disclosed herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. Inhibition of Ras-mediated signaling can be assessed and demonstrated by various methods known in the art. Non-limiting examples include: (a) a decrease in Ras GTPase activity; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in GTP Koff or a decrease in GDP Koff; (d) a decrease in the level of signaling molecules downstream of the Ras pathway, such as a decrease in pMEK; and / or (e) a decrease in the binding of the Ras complex to downstream signaling molecules, including, but not limited to, Raf. Kits and commercially available assays can be used to determine one or more of the above.

[0221] KRas mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration of the disclosed compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof (e.g., in the form of a pharmaceutical composition) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the compounds disclosed herein can be used to treat diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are useful for treating all subtypes of lymphoma, such as Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0222] Determining whether a tumor or cancer contains a KRas mutation as described herein can be done by evaluating the nucleotide sequence encoding the KRas protein, by evaluating the amino acid sequence of the KRas protein, or by evaluating the characteristics of a putative KRas mutant protein. The sequence of wild-type human KRas (e.g., Accession No. NP203524) is known in the art.

[0223] Methods for detecting mutations in KRas nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for KRas mutations described herein by real-time PCR. In real-time PCR, a fluorescent probe specific to the KRas mutation is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRas mutations are identified using direct sequencing of specific regions of the KRas gene (e.g., exon 2 and / or exon 3). This method identifies all possible mutations within the sequenced region.

[0224] The methods for determining whether a tumor or cancer contains a KRas mutation described herein may use a variety of samples. In some embodiments, the sample is collected from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0225] Also provided herein is the use of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection. In some embodiments, the cancer comprises a KRasG12X mutation. In some embodiments, the cancer comprises a KRas mutation (e.g., a mutation other than Gly12) in which the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments is the use of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0226] Further provided herein are compounds described herein, or pharmaceutically acceptable salts thereof, for use in methods for treating cancer. In one embodiment, the cancer comprises a KRasG12X mutation. In one embodiment, the cancer comprises a KRas mutation (e.g., a mutation other than Gly12) in which the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In one such embodiment, the cancer is a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one such embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one such embodiment, the cancer is colorectal cancer. In one such embodiment, the cancer is pancreatic cancer. In one such embodiment, the cancer is lung adenocarcinoma.

[0227] Combination therapy The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be used alone or in combination with other therapeutic agents to treat the diseases or disorders described herein.The second compound in the pharmaceutical formulation or administration regimen preferably has complementary activity to the compounds described herein or their pharmaceutically acceptable salts, so that they do not adversely affect each other.Combination therapy can provide "synergistic effects" and can demonstrate "synergistic" effects, i.e., the effects achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately.

[0228] The combination therapy can be administered as a simultaneous regimen or a sequential regimen. When administered sequentially, the combination may be administered in two or more doses. The combination administration includes co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably with a period during which both (or all) active agents simultaneously exert their biological activity.

[0229] The combination therapy herein includes the administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and the use of at least one other treatment method. The amounts and relative timing of administration of the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and the other pharmaceutically active agent(s) will be selected to achieve the desired combined therapeutic effect.

[0230] In various embodiments of the method, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (e.g., irinotecan, or e.g., etoposide, or e.g., doxorubicin), a taxane (e.g., anti-microtubule inhibitors including paclitaxel and docetaxel), an antimetabolite (e.g., 5-FU, or e.g., gemcitabine), or an alkylating agent (e.g., cisplatin, or e.g., cyclophosphamide), or a taxane.

[0231] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as erlotinib, or afatinib. In some embodiments, the additional therapeutic agent is gefitinib, osimertinib, or dacomitinib. In some embodiments, the additional therapeutic agent is a monoclonal antibody, such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments, the EGFR inhibitor is a dual or pan-HER inhibitor. In other embodiments, the additional therapeutic agent is a phosphatidylinositol-3-kinase (PI3K) inhibitor, e.g., GDC-0077, GDC-0941, MLN1117, BYL719 (Alpelisib), or BKM120 (Buparlisib). GDC-0941 refers to 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, or a salt thereof (e.g., the bismesylate salt).

[0232] In still other embodiments, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments, the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (linsitinib), BMS-754807, or in other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody specific for IGF1R, such as AMG-479 (ganitumab), CP-751,871 (fizitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (lovatumumab).

[0233] In some embodiments, the additional therapeutic agent is an SH2-containing protein tyrosine phosphatase-2 (SHP2) inhibitor. In one embodiment, the SHP2 inhibitor is RMC4550, GDC-1971, JAB-3068, JAB-3312, or TNO155, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0234] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor, hi some embodiments, the additional therapeutic agent is CYT387, GLPG0634, Baricitinib, Lestaurtinib, Momeltinib, Pacritinib, Ruxolitinib, or TG101348.

[0235] In some other embodiments, the additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0236] In some other embodiments, the additional therapeutic agent is an antibody-drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vetotin, RG7986, RG7882, RG6109, or RO7172369.

[0237] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist, hi some embodiments, the MDM2 antagonist is idasanutulin.

[0238] In some other embodiments, the additional therapeutic agent is an agonistic antibody against CD40, hi some embodiments, the agonistic antibody against CD40 is cericlerumab (RG7876).

[0239] In some other embodiments, the additional therapeutic agent is a bispecific antibody, hi some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0240] In some other embodiments, the additional therapeutic agent is a targeted immunocytokine, hi some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0241] In some other embodiments, the additional therapeutic agent is an antibody that targets colony-stimulating factor 1 receptor (CSF-1R). In some embodiments, the CSF-1R antibody is emactuzumab.

[0242] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine, hi some embodiments, the personalized cancer vaccine is RG6180.

[0243] In some other embodiments, the additional therapeutic agent is an inhibitor of BET (bromodomain and extraterminal family) proteins (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0244] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT, hi some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0245] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545).

[0246] In some other embodiments, the additional therapeutic agent is a MET kinase inhibitor such as crizotinib, tivantinib, AMG337, cabozantinib, or foretinib. In other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody against MET, such as onartuzumab.

[0247] In further embodiments, the additional therapeutic agent is an SRC family non-tyrosine kinase inhibitor.For example, in some embodiments, the additional therapeutic agent is an inhibitor of the subfamily of SRC family non-receptor tyrosine kinase.In this respect, exemplary inhibitors include Dasatinib.Other examples in this regard include Ponatinib, Saracatinib and Bosutinib.

[0248] In still other embodiments, the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, COTELLIC® (cobimetinib), PD0325901, or RO5126766. In other embodiments, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0249] In still other embodiments, the additional therapeutic agent is an extracellular signal-regulated kinase (ERK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.

[0250] In other embodiments, the protein kinase inhibitor is Taselisib, Ipataselitib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, Afatinib, Axitinib, Atezolizumab, Bevacizumab, Bostutinib, Cetuximab, Crizotinib, Dasatinib, Erlotinib, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Ibrutinib, Nilotinib, Panitumumab, Pazopanib, Pegaptanib, Ranibizumab, Ruxolitinib, Sorafenib, Sunitinib, SU6656, Trastuzumab, Tofacitinib, Vandetanib, or Vemurafenib. In still further embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some further embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include Taxol and Docetaxel.

[0251] In addition to the additional therapeutic agents described above, other chemotherapeutic agents are currently known in the art and can be used in combination with the compounds described herein, and their pharmaceutically acceptable salts. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0252] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules, e.g., Gleevec® (Imatinib Mesylate), Velcade® (Bortezomib), Casodex (Bicalutamide), Iressa® (Gefitinib), and Adriamycin, as well as a host of other chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine. Tilmelamine; chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; aclacinomycin, actinomycin , anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin Antibiotics such as isin, potfilomycin, puromycin, keramicin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridinene, doxifluridine, enocitabine, and floxiridine; androgens such as calucelone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotein, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate ;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Lonidamine;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Fenamet;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazine;Polysaccharide K;Razoxane;Sizofiran;Spirogermanium;Tenuazonic acid;Triaziquone;2,2',2"-Trichlorotriethylamine;Urethane;Vindesine;Dacarbazine;Mannomustine;Mitobronitol;Mitolactol;Pipobroman;Gacytosine;Arabinoside ("Ara-C");Cyclophosphamide;Thiotepa;Taxanes (e.g., Paclitaxel (TAXOL; 商標 , Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE 商標, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Suitable chemotherapeutic cell modulating agents include, for example, tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; cisplatin and carboplatin. Also included are antihormonal agents that act to regulate or inhibit hormone action in tumors, such as platinum analogs of; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda™; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS2000; and antiestrogens, including difluoromethylornithine (DMFO). If desired, the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be administered in combination with other pharmaceutical agents, including Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, anti-CD22 immunotoxin, Antineoplastic,Antitumor herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapeutic drug), Calyculin, Non-cell cycle specific anti-cancer drugs, Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Im It may be used in combination with commonly prescribed anticancer drugs such as iquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, proteasome inhibitors, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126, or Zosuquidar.

[0253] The exact method for administering the compound and additional therapeutic agent will be apparent to one of ordinary skill in the art. In some exemplary embodiments, the compound and additional therapeutic agent are administered simultaneously. In other embodiments, the compound and additional therapeutic agent are administered separately.

[0254] In some embodiments, the compound and the additional therapeutic agent are administered simultaneously with the second agent or separately. This combined administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound described herein and any of the additional therapeutic agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound described herein and any of the additional therapeutic agents can be administered simultaneously, in which case both agents are in separate formulations. In another alternative, the compound can be administered immediately followed by any of the additional therapeutic agents described herein, or vice versa. In some embodiments of the separate administration protocol, the compound described herein and any of the additional therapeutic agents are administered within minutes, hours, or days.

[0255] manufactured goods Also provided herein are articles of manufacture or "kits" containing materials useful for treating cancer as provided herein. In one embodiment, the kit includes a container containing a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. The kit may further include a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container may hold a compound described herein or a pharmaceutically acceptable salt thereof effective for treating a condition, or a formulation thereof, and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound described herein or a pharmaceutically acceptable salt thereof. Alternatively, or additionally, the article of manufacture may further comprise a second container containing a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution, and may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0256] In another embodiment, the kit is suitable for delivering the solid oral form (for example, tablet or capsule) of the compound described herein or its pharmaceutically acceptable salt.Such a kit can contain several unit doses.An example of such a kit is a "blister pack".Blister packs are known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.

[0257] Embodiment Provided below are exemplary embodiments of the invention described herein.

[0258] Embodiment 1: A compound having formula (I) as described herein, or an atropisomer, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. (Wherein, ring A is R 8 a substituted or unsubstituted 3- to 10-membered heterocycle, or R 8 a substituted or unsubstituted 5- to 10-membered heteroaryl; R 8 are independently halogen, CN, NH2, NHC 1~3 Alkyl, R 8A Substituted or unsubstituted C 1~6 Alkyl, or R 8A Substituted or unsubstituted C 1~6 is haloalkyl; R 8A is halogen, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 is haloalkyl; n is 1 or 2 R 1 is R 7 Substituted or unsubstituted indolyl, R 7 Substituted or unsubstituted benzofuranyl, R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7A substituted or unsubstituted phenyl, or R 7A substituted or unsubstituted pyridinyl; Each R 7 are independently hydrogen, halogen, CN, CH2OH, -OH, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 2~5 Alkynyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; Each R 7a are independently hydrogen, halogen, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; R 2 OH, unsubstituted C 1~3 Alkoxy, unsubstituted C1~3 Alkyl, or unsubstituted C 1~3 is haloalkyl; R 3 is an R containing N, S, or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10 Substituted or unsubstituted C 1~3 Alkylidene, or R 10 Substituted or unsubstituted C 3~4 cycloalkyl, or R 10 a substituted or unsubstituted 3- or 4-membered heterocycle; or two R 9 Let's get together and C 3~5 Forming a cycloalkyl or 3- to 5-membered heterocyclic ring; R 10 is hydrogen or halogen; R 4 is hydrogen, halogen, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 is haloalkyl; R 5 and R 6 are each independently hydrogen or unsubstituted C 1~3 alkyl).

[0259] Embodiment 2: R 1 But R 7 Substituted or unsubstituted indolyl, R 7 Substituted or unsubstituted benzofuranyl, R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 Substituted or unsubstituted benzothiazolyl, or R 7 2. The compound of claim 1, which is a substituted or unsubstituted isoquinolinyl.

[0260] Embodiment 3: R 1 But R 7 Substituted or unsubstituted naphthyl or R 7 3. The compound of claim 1 or 2, which is a substituted or unsubstituted isoquinolinyl.

[0261] Embodiment 4: R 1 is a moiety of formula (C), (C1), (C2), or (C3) described herein.

[0262] Embodiment 5: R 1 but, The compound of any one of embodiments 1 to 4, wherein the compound is TIFF2025535367000065.tif121170.

[0263] Embodiment 6: R 1 but, TIFF2025535367000066.tif239170TIFF2025535367000067.tif152170. The compound of any one of embodiments 1 to 5,

[0264] Embodiment 7: R 1 But R 7A substituted or unsubstituted phenyl, or R 7A The compound of embodiment 1, which is a substituted or unsubstituted pyridinyl.

[0265] Embodiment 8: R 1 is a moiety of formula (A) or (B) described herein, wherein X 1 is N, CH, CF, or CCl; R 7A But hydrogen, halogen, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 The compound of embodiment 1 or 7, wherein the compound is haloalkyl.

[0266] Embodiment 9:R 1 is the formula (A) moiety described herein, wherein X 1is N, CH, CF, or CCl; R 7A But hydrogen, halogen, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 The compound of any one of embodiments 1 or 7-8, wherein the compound is haloalkyl.

[0267] Embodiment 10: X 1 is N.

[0268] Embodiment 11:R 1 but TIFF2025535367000068.tif28170, R 7A But hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 The compound of any one of embodiments 1 or 9-10, wherein the compound is haloalkyl.

[0269] Embodiment 12:R 1 but, The compound of any one of embodiments 1 or 9-11, wherein the compound is TIFF2025535367000069.tif54170.

[0270] Embodiment 13: X 1 is CH, CF, or CCl.

[0271] Embodiment 14:R 1 but TIFF2025535367000070.tif32170, R 7A The compound of embodiment 9 or 13, wherein is hydrogen, F, or Cl.

[0272] Embodiment 15:R 1 but TIFF2025535367000071.tif32170, R 7A The compound of embodiment 9 or 13, wherein is hydrogen, F, or Cl.

[0273] Embodiment 16:R 1but TIFF2025535367000072.tif34170, R 7A But hydrogen, halogen, unsubstituted C 1~3 Alkyl, or unsubstituted C 1~3 The compound of any one of embodiments 1 or 7-8, wherein the compound is haloalkyl.

[0274] Embodiment 17:R 1 but, The compound of any one of embodiments 1 or 7-16, wherein the compound is TIFF2025535367000073.tif171170.

[0275] Embodiment 18:R 1 but, The compound of any one of embodiments 1 or 7-17, wherein the compound is TIFF2025535367000074.tif189170.

[0276] Embodiment 19:R 1 but, The compound of any one of embodiments 1 or 7-18, wherein the compound is TIFF2025535367000075.tif126170.

[0277] Embodiment 20:R 4 The compound of any one of embodiments 1-19, wherein is Cl or F.

[0278] Embodiment 21:R 4 The compound of any one of embodiments 1-20, wherein is F.

[0279] Embodiment 22:R 4 The compound of any one of embodiments 1-21, wherein is Cl.

[0280] Embodiment 23:R 4 The compound of any one of embodiments 1-22, wherein is OCH3.

[0281] Embodiment 24:R 3is a moiety of formula (DO) described herein, wherein Z is C(R 9 )2 or O; R 9 is hydrogen, halogen or R 10 Substituted or unsubstituted C 1~3 alkylidene; or two R 9 Together they form C 3~5 The compound of any one of embodiments 1 to 23, wherein r is an integer from 0 to 12; j is 1, 2, or 3; and k is 1 or 2.

[0282] Embodiment 25:R 3 is a moiety of formula (D) described herein, wherein R 9 However, halogens, -OCF3, -OCHF2, -OCH2F, R 10 Substituted or unsubstituted C 1~3 alkylidene or two R 9 Together, R 10 Substituted or unsubstituted C 3~5 25. The compound of any one of embodiments 1-24, wherein: cycloalkyl; r is an integer from 0 to 12; j is 1, 2, or 3; and k is 1 or 2.

[0283] Embodiment 26:R 3 is a moiety of formula (D1), (D2), (D3), or (D4) described herein, and each R 9 are independently halogen or R 10 Substituted or unsubstituted C 1~3 alkylidene; each R 10 The compound of any one of embodiments 1-25, wherein is independently hydrogen or halogen; r is 0, 1, or 2; and s is 0, 1, or 2.

[0284] Embodiment 27:R 3 is a moiety of formula (D1), (D2), or (D3) described herein, wherein each R 9 are independently halogen or R 10 Substituted or unsubstituted C1~3 alkylidene; each R 10 The compound of any one of embodiments 1-26, wherein is independently hydrogen or halogen; r is 0, 1, or 2; and s is 0, 1, or 2.

[0285] Embodiment 28:R 3 but, The compound of any one of embodiments 1 to 27, wherein the compound is TIFF2025535367000076.tif202170.

[0286] Embodiment 29:R 3 The compound of any one of embodiments 1 to 27, wherein: is a moiety of formula (D1), wherein r is 1.

[0287] Embodiment 30:R 3 is a portion of formula (D2), where r is 0 and each R 10 The compound of any one of embodiments 1-27, wherein is independently hydrogen or F.

[0288] Embodiment 31:R 3 is a portion of formula (D3), where r is 0 and each R 9 The compound of any one of embodiments 1-27, wherein is independently hydrogen or halogen.

[0289] Embodiment 32:R 3 is the moiety of formula (D4), wherein each R 10 The compound of any one of embodiments 1-26, wherein is halogen and s is 0, 1, or 2.

[0290] Embodiment 33:R 3 is the moiety of formula (D5), wherein each R 10 The compound of any one of embodiments 1-25, wherein is halogen and s is 0, 1, or 2.

[0291] Embodiment 34:R 3 is the moiety of formula (E), wherein each R 9are independently halogen, oxo, or unsubstituted C 1~3 The compound of any one of embodiments 1-25, wherein r is alkyl; and r is 0, 1, or 2.

[0292] Embodiment 35:R 3 is the moiety of formula (F), wherein each R 9 are independently halogen, oxo, or unsubstituted C 1~3 The compound of any one of embodiments 1-25, wherein r is alkyl; and r is 0, 1, or 2.

[0293] Embodiment 36:R 3 is a moiety of formula (G) described herein, wherein each R 9 are independently halogen, oxo, or unsubstituted C 1~3 alkyl; or two R 9 Together they form C 3~5 The compound of any one of embodiments 1 to 23, wherein r is 1 or 2, and r is 2 or 3.

[0294] Embodiment 37:R 3 but, The compound of any one of embodiments 1 to 23, wherein the compound is TIFF2025535367000077.tif30170.

[0295] Embodiment 38:R 3 but, The compound of any one of embodiments 1 to 23, wherein the compound is TIFF2025535367000078.tif118170.

[0296] Embodiment 39:R 2 The compound of any one of embodiments 1-38, wherein is methyl.

[0297] Embodiment 40:R 2 The compound of any one of embodiments 1-38, wherein is CHF2, CH2F, or CF3.

[0298] Embodiment 41: Ring A is R 8 a substituted or unsubstituted 3- to 10-membered heterocycle, or R 8 The compound of any one of embodiments 1 to 40, which is a substituted or unsubstituted 5-10 membered heteroaryl.

[0299] Embodiment 42: Ring A is R 8 a substituted or unsubstituted 3- to 6-membered heterocycle, or R 8 The compound of any one of embodiments 1 to 41, which is a substituted or unsubstituted 5-6 membered heteroaryl.

[0300] Embodiment 43: Ring A is an R 1 heterocyclic ring containing at least one nitrogen atom 8 Substituted or unsubstituted 3- to 6-membered heterocycle or R containing at least one heterocyclic ring nitrogen atom 8 The compound of any one of embodiments 1 to 42, which is a substituted or unsubstituted 5-6 membered heteroaryl.

[0301] Embodiment 44: Ring A is an R 1 heterocyclic ring containing at least one nitrogen atom 8 The compound of any one of embodiments 1-43, which is a substituted or unsubstituted 5- or 6-membered heterocycle.

[0302] Embodiment 45: Ring A is an R 1 heterocyclic ring containing at least one nitrogen atom 8 The compound of any one of embodiments 1-44, which is a substituted or unsubstituted 6-membered heteroaryl.

[0303] Embodiment 46: Ring A is R 8 Substituted or unsubstituted pyridinyl, R 8 Substituted or unsubstituted pyrimidinyl or R 8 The compound of any one of embodiments 1-45, which is a substituted or unsubstituted pyrazinyl.

[0304] Embodiment 47: The compound of any one of claims 1-46, wherein Ring A is a moiety of Formula (H) or (H1), as described herein, where X is CH or N, and n is 1 or 2.

[0305] Embodiment 48: Ring A is of the formula: 48. The compound of any one of claims 1 to 47, which is a portion of TIFF2025535367000079.tif54170, wherein X is CH or N.

[0306] Embodiment 49:R 5 and R 6 The compound of any one of embodiments 1-48, wherein each is hydrogen.

[0307] Embodiment 50: Each R 5 is CH3 and R 6 The compound of any one of embodiments 1-49, wherein is hydrogen.

[0308] Embodiment 51. A compound of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0309] Embodiment 52. A compound of Table 2, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0310] Embodiment 53. A compound of Table 3, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0311] Embodiment 54. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0312] Embodiment 55. A method of treating cancer, comprising administering an effective amount of a compound of any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 54.

[0313] Embodiment 56. A method of treating cancer, comprising administering an effective amount of a compound of any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0314] Embodiment 57. The method of embodiment 56, wherein the cancer comprises a KRas mutation.

[0315] Embodiment 58. The KRas mutation is KRas G12D Mutation or KRas G12V 58. The method of embodiment 57, corresponding to a mutation.

[0316] Embodiment 59. The method of embodiment 57, further comprising testing a sample from the patient prior to administration for the absence or presence of a KRas mutation.

[0317] Embodiment 60. The method of embodiment 59, wherein the compound, a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered to the patient after a patient sample indicates the presence of a KRas mutation.

[0318] Embodiment 61. The method of any one of embodiments 56 to 60, wherein the cancer is tissue-independent.

[0319] Embodiment 62. The method of any one of embodiments 56 to 60, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0320] Embodiment 63. The method of embodiment 62, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

[0321] Embodiment 64. The method of embodiment 62, wherein the cancer is pancreatic cancer.

[0322] Embodiment 65. The method of embodiment 62, wherein the cancer is colorectal cancer.

[0323] Embodiment 66. The method of any one of embodiments 56 to 65, further comprising administering at least one additional therapeutic agent.

[0324] Embodiment 67. The method of embodiment 66, wherein the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an antimetabolite, or an alkylating agent.

[0325] Embodiment 68. A compound according to any one of embodiments 1 to 68, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0326] Embodiment 69. Use of a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of cancers harboring KRas mutations.

[0327] Embodiment 70. Use of a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer harboring a KRas mutation.

[0328] Embodiment 71. Use of a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutical salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0329] Embodiment 72. A compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutical salt thereof, for the therapeutic and / or prophylactic treatment of cancers containing KRas mutations.

[0330] Embodiment 73. A method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound of any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0331] Embodiment 74. A method for inhibiting proliferation of a cell population, comprising contacting the cell population with a compound of any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0332] Embodiment 75. The method of embodiment 74, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0333] Embodiment 76. A method for preparing a labeled KRas mutant protein, comprising reacting a KRas mutant protein with a labeled compound of any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to obtain a labeled KRas mutant protein.

[0334] Embodiment 77. A method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 55.

[0335] Embodiment 78. A method for synthesizing a compound of formula (I) described herein. [Example]

[0336] The following examples describe the preparation and biological evaluation of compounds within the scope of the present invention. These examples, and the preparations that follow, are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be construed as limiting the scope of the invention, but should be understood as merely illustrative and representative thereof. Example 1: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol TIFF2025535367000080.tif40170Synthetic pathway TIFF2025535367000081.tif128170

[0337] Step 1: tert-Butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-chloro-3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate TIFF2025535367000082.tif40170

[0338] To a solution of (3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol (315.3 mg, 1.93 mmol) in toluene (10 mL) was added sodium tert-butoxide (428.6 mg, 4.46 mmol) at 0 ° C. and stirred for 30 minutes at 0 ° C. Then, tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-(7-chloro-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-2-pyridyl]carbamate (950.0 mg, 1.49 mmol) was added at 25 ° C. and stirred for 1.5 hours at 25 ° C. After completion, the reaction was quenched with saturated ammonium chloride solution, concentrated in vacuo, diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (93:7) to afford tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-chloro-3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-eptaen13-yl]ethyl]-2-pyridyl]carbamate (680.3 mg, 0.73 mmol, 49.4% yield) as a white solid. LC-MS: (ESI, m / Z): 722.3 [M+H] +

[0339] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-7-[3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate TIFF2025535367000083.tif48170

[0340] tert-Butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-chloro-3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbohydrate was prepared under nitrogen in 1,4-dioxane (5 mL) and water (1 mL). A solution of bamate (630.0 mg, 0.68 mmol), tetrakis(triphenylphosphine)palladium(0) (157.3 mg, 0.14 mmol), cesium carbonate (669.3 mg, 2.04 mmol), and triisopropyl-[2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl]silane (403.8 mg, 0.82 mmol) was stirred at 100° C. for 1 hour. Upon completion, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-7-[3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (500.6 mg, 0.35 mmol, 50.9% yield) as a yellow solid. LC-MS: (ESI, m / Z): 1054.5 [M+H] +

[0341] Step 3: tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-7-[8-ethynyl-3-(methoxymethoxy)-1-naphthyl]-6-fluoro-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate TIFF2025535367000084.tif47170

[0342] A solution of tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-7-[3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (480.0 mg, 0.33 mmol) and cesium fluoride (350.0 mg, 2.33 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (93:7) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-7-[8-ethynyl-3-(methoxymethoxy)-1-naphthyl]-6-fluoro-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (310.5 mg, 0.25 mmol, 75.8% yield) as a yellow solid. LC-MS: (ESI, m / Z): 898.4 [M+H]+

[0343] Step 4: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol TIFF2025535367000085.tif47170

[0344] A solution of tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-7-[8-ethynyl-3-(methoxymethoxy)-1-naphthyl]-6-fluoro-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (300.0 mg, 0.33 mmol) in hydrogen chloride, 1,4-dioxane solution (3 mL, 12.00 mmol, 4.0 M in 1,4-dioxane) and acetonitrile (3 mL) was stirred at 25 °C for 5 hours. Upon completion, the reaction mixture was concentrated in vacuo, adjusted to pH > 7 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (8:1) to give the product. The product was further purified by Prep-HPLC using the following conditions: Column: XBridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 43% B to 58% B in 10 min, 58% B; wavelength: 254 / 220 nm; RT1 (min): 7, 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol (14.6 mg, 0.02 mmol, 6.6% yield). LC-MS: (ESI, m / Z): 654.3 [M+H] +

[0345] Example 1: 1H NMR(300MHz,DMSO-d6,ppm)δ 10.14(s,1H),7.98(d,J=4.5Hz,1H),7.88(d,J=7.2Hz,1H),7.65(d,J=7.8Hz,1H),7. 53-7.34(m,2H),7.32(s,1H),7.10(s,1H),6.79-6.60(m,1H),6.49-6.23(m,1H),5.93 -5.65(m,2H),4.55-4.17(m,4H),3.88-3.71(m,1H),3.70-3.61(m,1H),3.62-3.43(m ,1H),3.28-3.06(m,3H),2.79-2.54(m,2H),2.47-2.23(m,3H),1.61(d,J=6.0Hz,3H). LC-MS:(ESI,m / Z):654.3[M+H] + . Example 2: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol Synthetic Route TIFF2025535367000086.tif158170

[0346] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol TIFF2025535367000087.tif30170

[0347] A solution of 7-fluoronaphthalene-1,3-diol (5.00 g, 28.1 mmol), (bromoethynyl)triisopropylsilane (11.00 g, 42.10 mmol), potassium acetate (5.51 g, 56.13 mmol), and dichloro(p-cymene)ruthenium(II) dimer (1.73 g, 2.81 mmol) in 1,4-dioxane (80 mL) was stirred at 110 °C for 2 hours. After completion, the solution was concentrated in vacuo, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (8.7 g, crude) as a yellow solid. The crude product was used directly in the next step without purification. LC-MS: (ESI, m / Z): 359.2 [M+H] +

[0348] Step 2: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol TIFF2025535367000088.tif31170

[0349] Under nitrogen, a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (7.70 g, crude), bromo(methoxy)methane (4.03 g, 32.22 mmol), and N,N-diisopropylethylamine (8.33 g, 64.43 mmol) in dichloromethane (100 mL) was stirred at 0 °C for 1.5 h. After completion, the reaction solution was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (3:97) to give 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (6.60 g, 15.66 mmol, 72.9% yield) as a yellow solid. LC-MS: (ESI, m / Z): 403.2 [M+H] +

[0350] Step 3: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate TIFF2025535367000089.tif31170

[0351] A solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (5.00 g, 12.42 mmol) in tetrahydrofuran (50 mL) was added to sodium hydride (546.6 mg, 13.66 mmol, 60% dispersion in mineral oil) at 0° C. and stirred at 25° C. for 15 minutes. N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (5.85 g, 14.91 mmol) was then added and stirred at 25° C. for 1 hour. Upon completion, the reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (10:1) to give 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (5.10 g, 9.54 mmol, 76.8% yield) as a yellow oil. LC-MS: (ESI, m / Z): 535.1 [M+H] +

[0352] Step 4: ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane TIFF2025535367000090.tif35170

[0353] A solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (700.0 mg, 1.31 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (499.0 mg, 1.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (97.0 mg, 0.13 mmol), and potassium acetate (385.0 mg, 3.93 mmol) in toluene (15 mL) was stirred at 110° C. for 12 hours. Upon completion, the reaction solution was concentrated in vacuo, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to give ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (320.0 mg, 0.62 mmol, 47.6% yield) as a yellow solid. LC-MS: (ESI, m / Z): 513.3 [M+H] +

[0354] Step 5: tert-butyl (3-((R)-1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000091.tif49170

[0355] A solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (256.9 mg, 0.50 mmol), tert-butyl(3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro- A solution of 10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (300.0 mg, 0.49 mmol), methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (30.4 mg, 0.04 mmol), and tribasic potassium phosphate (266.0 mg, 1.25 mmol) was stirred at 80°C for 1.5 hours. Upon completion, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:9) to give tert-butyl (3-((R)-1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (190.0 mg, 0.20 mmol, 42.6% yield) as a yellow oil. LC-MS: (ESI, m / Z): 1068.5 [M+H] +

[0356] Step 6: tert-butyl (3-((R)-1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000092.tif48170

[0357] To a solution of tert-butyl (3-((R)-1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (190.0 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was added cesium fluoride (189.1 mg, 1.24 mmol) at 25° C. and stirred at 25° C. for 2 hours. Upon completion, the reaction was diluted with water, extracted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (3:2) to give the title compound (144.9 mg, 0.26 mmol, 89.3% yield) as a yellow solid. LC-MS: (ESI, m / Z): 912.4 [M+H] +

[0358] Step 7: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0359] A solution of tert-butyl (3-((R)-1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (190.0 mg, 0.21 mmol) in hydrochloric acid / 1,4-dioxane (3 mL, 12.00 mmol, 4.0 M in 1,4-dioxane) was stirred at 25° C. for 0.5 hours. Upon completion, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate, adjusted to pH >7 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was further purified by Prep-HPLC using the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 μm, Mobile Phase A: Water (0.1% FA), Mobile Phase B: Acetonitrile; Flow Rate: 60 mL / min; Gradient: 9% B to 22% B, 22% B in 8 min; Wavelength: 254 / 220 nm; RT1 (min): 8. The title compound (26.4 mg, 0.04 mmol, 17.8% yield) was obtained. LC-MS: (ESI, m / Z): 668.6 [M+H] +

[0360] Example 2: 1 H NMR (300 MHz, Methanol-d 4,ppm)δ 8.05-7.96(m,1H),7.91-7.78(m,2H),7.40-7.29(m,2H),7.22(d,J=2.5Hz,1H),6.85(d dd,J=7.4,5.2,2.1Hz,1H),6.66-6.53(m,1H),5.57(d,J=51.9Hz,1H),4.72(s,2H),4.61 -4.30(m,2H),4.11-3.83(m,4H),3.82-3.63(m,1H),3.62-3.51(m,1H),3.52-3.38(m,1H ),2.82-2.54(m,2H),2.53-2.26(m,3H),2.27-2.07(m,1H),1.72(dd,J=7.0,2.3Hz,3H). LC-MS:(ESI,m / Z):668.6[M+H] + Example 3: 3-((R)-1-(5-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000093.tif90170

[0361] Step 1: 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000094.tif46170

[0362] tert-Butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carba in dioxane / water (5 / 1) (2 mL) under nitrogen. A solution of methyl amine (150.0 mg, 0.24 mmol), [5-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (191.8 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (24.1 mg, 0.02 mmol), and cesium carbonate (136.1 mg, 0.4 mmol) was stirred at 100 °C for 2 hours. Upon completion, the filtrate was concentrated under reduced pressure. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give the title compound (60.0 mg, 0.1 mmol, 32% yield) as a yellow solid. LC-MS: (ESI, m / Z): 897.4 [M+H] +

[0363] Step 2: 3-((R)-1-(5-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0364] A solution of 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (60.0 mg, 0.07 mmol) in trifluoroacetic acid / trifluoromethanesulfonic acid (10 / 1) (0.5 mL) was stirred at 25° C. for 1 hour. After completion, the reaction mixture was adjusted to pH=7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:30) to give a crude solid. The crude product was purified by Prep-HPLC under the following conditions: (Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 29% to 54% B, 54% B in 9 min; Wavelength: 254 / 220) to give the title compound (8.6 mg, 0.01 mmol, 19.6% yield). LC-MS: (ESI, m / Z): 657.3 [M+H] +

[0365] Example 3: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 7.96(dd,J=4.9,1.7Hz,1H),7.62(dd,J=7.6,1.8Hz,1H),6.66(dd,J=7.5,4.9Hz,1H),6.59(d,J=2.3Hz,1H),6.41 -6.24(m,2H),5.86(s,2H),5.70(s,2H),5.28(d,J=54.3Hz,1H),4.41(dd,J=12.7,6.3Hz,1H),4.28(dd,J=12.7,6 .4Hz,1H),4.12(s,2H),3.71(dd,J=15.9,6.4Hz,1H),3.52-3.36(m,1H),3.20-3.02(m,2H),3.00(s,1H),2.91-2. 76(m,1H),2.35(d,J=2.3Hz,3H),2.25-2.11(m,1H),2.10-1.93(m,2H),1.92-1.70(m,3H),1.55(d,J=6.8Hz,3H). Example 4: 3-((R)-1-(5-(3-amino-8-ethynylnaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000095.tif147170

[0366] Step 1: (3-Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid TIFF2025535367000096.tif31170

[0367] A solution of triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (700.0 mg, 1.42 mmol) in hydrochloric acid / 1,4-dioxane (4.86 mL, 19.44 mmol, 4.0 M in 1,4-dioxane) was stirred at 25° C. for 1 h. After completion, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9:1) to afford the title compound (575.3 mg, 1.40 mmol, 99.3% yield) as a white solid. LC-MS: (ESI, m / Z): 369.2 [M+H] +

[0368] Step 2: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol TIFF2025535367000097.tif48170

[0369] A mixture of (3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (420.1 mg, 1.14 mmol), tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-chloro-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrahydro-2-methyl-4-( ...]boronic acid (420.1 mg, 1.14 mmol), tert-butyl N-tert-butoxycarbonyl-N A solution of lazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (630.0 mg, 0.88 mmol), [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (63.9 mg, 0.09 mmol), and tribasic potassium phosphate (558.6 mg, 2.63 mmol) was stirred at 80 °C for 1 hour. Upon completion, the reaction was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (7:3) to afford the title compound (300.0 mg, 0.24 mmol, 27.9% yield) as a white solid. LC-MS: (ESI, m / Z): 806.4 [M+H] +

[0370] Step 3: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl trifluoromethanesulfonate TIFF2025535367000098.tif48170

[0371] A solution of 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (255.0 mg, 0.33 mmol), N-phenylbis(trifluoromethanesulfonimide) (147.3 mg, 0.42 mmol), and N,N-diisopropylethylamine (122.7 mg, 0.96 mmol) in dichloromethane (5 mL) was stirred at 25° C. for 2.5 hours. After completion, the reaction was concentrated in vacuo. The residue was purified by flash chromatography on a reverse-phase column eluted with water / acetonitrile (1:49) to give the title compound (165.0 mg, 0.18 mmol, 52.8% yield) as an orange oil. LC-MS: (ESI, m / Z): 938.3 [M+H] +

[0372] Step 4: [4-[13-[(1R)-1-[2-[bis(tert-butoxycarbonyl)amino]-3-pyridyl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-5-(2-triisopropylsilylethynyl)-2-naphthyl]trifluoromethanesulfonate TIFF2025535367000099.tif49170

[0373] A solution of triethylamine (42.1 mg, 0.42 mmol), 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl trifluoromethanesulfonate (130.0 mg, 0.14 mmol), 4-dimethylaminopyridine (16.9 mg, 0.14 mmol), and di-tert-butyl dicarbonate (151.2 mg, 0.69 mmol) in tetrahydrofuran (3 mL) was stirred at 70° C. for 1 hour. Upon completion, the reaction was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / ethyl acetate (8:1) to give the title compound (140.0 mg, 0.10 mmol, 72.8% yield) as a white solid. LC-MS: (ESI, m / Z): 1138.4 [M+H] +

[0374] Step 5: tert-butyl (tert-butoxycarbonyl)(3-((R)-1-(5-(3-((tert-butoxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000100.tif50170

[0375] Under nitrogen, tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.01 mmol), cesium carbonate (98.6 mg, 0.30 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.7 mg, 0.02 mmol), [4-[13-[(1R)-1-[2-[bis(tert-butoxycarbonyl)amino]-3-pyridyl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1, A solution of [2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-5-(2-triisopropylsilylethynyl)-2-naphthyl]trifluoromethanesulfonate (140.0 mg, 0.10 mmol) and tert-butyl carbamate (11.8 mg, 0.10 mmol) was stirred at 100 °C for 2 hours. After completion, the reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (70.2 mg, 0.06 mmol, 55.9% yield) as a yellow oil. LC-MS: (ESI, m / Z): 1105.6 [M+H] +

[0376] Step 6: tert-butyl (tert-butoxycarbonyl)(3-((R)-1-(5-(3-((tert-butoxycarbonyl)amino)-8-ethynylnaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000101.tif49170

[0377] A solution of tert-butyl (tert-butoxycarbonyl)(3-((R)-1-(5-(3-((tert-butoxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (70.0 mg, 0.06 mmol) and cesium fluoride (0.06 g, 0.39 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (49:1) to give the title compound (55.2 mg, 0.05 mmol, 94.6% yield). LC-MS: (ESI, m / Z): 949.4 [M+H] +

[0378] Step 7: 3-((R)-1-(5-(3-amino-8-ethynylnaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000102.tif47170

[0379] A solution of tert-butyl (tert-butoxycarbonyl)(3-((R)-1-(5-(3-((tert-butoxycarbonyl)amino)-8-ethynylnaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (50.0 mg, 0.05 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL) was stirred at 25° C. for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo, diluted with dichloromethane, adjusted to pH >7 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic layers combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (8:1) to give the product. The product was further purified by Prep-HPLC using the following conditions: Column: XBridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 34% B to 48% B, 48% B in 8 min; Wavelength: 254 / 220 nm; RT1 (min): 8 to give the title compound (5.3 mg, 0.01 mmol, 14.9% yield). LC-MS: (ESI, m / Z): 649.3 [M+H] +

[0380] Example 4: 1 H NMR (300 MHz, Methanol-d 4,ppm)δ 7.96(d,J=5.1Hz,1H),7.76(d,J=7.4,1.5Hz,1H),7.71-7.62(m,1H),7.38(dd,J=7.1,3.6,1.4Hz,1H ),7.34-7.24(m,1H),7.14(d,J=2.4Hz,1H),7.07(t,J=2.6Hz,1H),6.84-6.74(m,1H),6.67-6.52(m,1 H),5.31(d,J=53.5Hz,1H),4.53-4.37(m,2H),4.38-4.20(m,2H),3.85-3.66(m,1H),3.64-3.39(m,1H) ),3.29-3.12(m,3H),3.10-2.94(m,2H),2.51-2.08(m,3H),2.07-1.80(m,3H),1.67(d,J=6.9Hz,3H). LC-MS:(ESI,m / Z):649.3[M+H] + Example 5: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000103.tif95170

[0381] Step 1: tert-butyl (3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000104.tif45170

[0382] tert-Butyl N-tert-butoxycarbonyl-N-(3-(rac-(1R)-1-(7-chloro-6-fluoro-3-((rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl)methoxy)-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl)-2-pi in 1,4-dioxane (2.0 mL) and water (0.2 mL) under nitrogen. A solution of 2-fluoro-N,N-bis(4-methoxybenzyl)carbamate (130.0 mg, 0.18 mmol) and 2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (121.0 mg, 0.22 mmol) was added to cesium carbonate (118.0 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium (21.0 mg, 0.02 mmol) and stirred at 100 °C for 3 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (9:1) to give the title compound (158.0 mg, 0.15 mmol, 78.3% yield) as a white solid. LC-MS: (ESI, m / Z): 1115.5 [M+H] +

[0383] Step 2: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000105.tif45170

[0384] A solution of tert-butyl (3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (158.0 mg, 0.15 mmol) in trifluoroacetic acid (1.5 mL) and trifluoromethanesulfonic acid (0.15 mL) was stirred at 25° C. for 15 minutes. After completion, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and adjusted to pH=7 with saturated sodium bicarbonate solution. The mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions: Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 34% B to 59% B, 59% B in 9 min; Wavelength: 254 / 220 nm; RT1 (min): 8.6. The title compound (26.0 mg, 0.04 mmol, 27.2% yield) was obtained as a white solid. LC-MS: (ESI, m / Z): 675.2 [M+H] +

[0385] Example 5: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 7.96(dd,J=4.9,1.7Hz,1H),7.62(dd,J=7.5,1.8Hz,1H),6.67(dd,J=7.5,4.9Hz,1H),6.54(d,J=8.7Hz, 1H),6.34(q,J=6.7Hz,1H),6.01(s,2H),5.71(s,2H),5.29(d,J=54.5Hz,1H),4.42(dd,J=12.9,6.3Hz,1 H),4.28(dd,J=12.6,6.3Hz,1H),4.13(s,2H),3.72(dd,J=16.0,6.4Hz,1H),3.46-3.35(m,1H),3.23-2. 93(m,3H),2.93-2.78(m,1H),2.31(s,3H),2.22-1.96(m,3H),1.96-1.72(m,3H),1.55(d,J=6.8Hz,3H). LC-MS:(ESI,m / Z):675.2[M+H] + Example 6: 6-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine Synthetic Route TIFF2025535367000106.tif98170

[0386] Step 1: 6-(allylthio)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2025535367000107.tif31170

[0387] Under nitrogen, a mixture of 6-bromo-N,N-bis(4-methoxyphenyl)methyl-4-methyl-5-(trifluoromethyl)pyridin-2-amine (5.0 g, 10.09 mmol) and potassium carbonate (2.8 g, 20.21 mmol) in N,N-dimethylformamide (48 mL) was stirred at 25 °C for 5 minutes. Allyl mercaptan (4.03 mL, 50.58 mmol) was then added and stirred at 25 °C for 2 days. Upon completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (10:1) to afford the title compound (4.89 g, 10.01 mmol, 99.2% yield) as a yellow solid. LC-MS: (ESI, m / Z): 489.2 [M+H] +

[0388] Step 2: 6-(allylsulfonyl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2025535367000108.tif25170

[0389] A solution of 6-(allylthio)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (4.92 g, 10.07 mmol) and 3-chloroperoxybenzoic acid (5.16 g, 29.90 mmol) in dichloromethane (40 mL) was stirred at 25° C. for 4 hours. 3-Chloroperoxybenzoic acid (1.72 g, 9.97 mmol) was then added and stirred at 25° C. for 1 hour. After completion, the solvent was added to saturated sodium sulfite solution and stirred for 5 minutes. The solution was then diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to give the title compound (1.12 g, 2.15 mmol, 21.4% yield) as a white solid. LC-MS: (ESI, m / Z): 520.9 [M+H] +

[0390] Step 3: 6-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2025535367000109.tif46170

[0391] Under nitrogen, tert-butyl N-tert-butoxycarbonyl-N-(3-(rac-(1R)-1-(7-chloro-6-fluoro-3-((rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl)methoxy)-10-oxa-2,4,8,13-tetrazatricyclo(7.4.1.05,14)tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl)-2-pyridyl)carbamate (300.0 mg) in 1,4-dioxane (6 mL), A mixture of 0.42 mmol), 6-(allylsulfonyl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (330.0 mg, 0.64 mmol), palladium(II) acetate (10.0 mg, 0.04 mmol), cesium carbonate (270.0 mg, 0.82 mmol), and methyl(bis(2-methyl-2-propanyl))phosphonium tetrafluoroborate (22.0 mg, 0.09 mmol) was added and stirred at 110° C. for 12 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (93:7) to give the title compound (163.0 mg, 0.18 mmol, 43.5% yield) as a yellow solid. LC-MS: (ESI, m / Z): 898.3 [M+H] +

[0392] Step 4: 6-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2025535367000110.tif45170

[0393] A solution of 6-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (163.0 mg, 0.18 mmol) in trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (0.5 mL) was stirred at 25° C. for 0.5 hours. After completion, the mixture was concentrated under vacuum. The residue was diluted with dichloromethane and adjusted to pH=7 with saturated sodium bicarbonate solution. The mixture was washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 17% B to 42% B, 42% B in 9 min; Wavelength: 254 / 220 nm; RT1 (min): 8.9; to give the title compound (24.1 mg, 0.037 mmol, 20.2% yield). LC-MS: (ESI, m / Z): 658.2 [M+H] +

[0394] Example 6: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 7.96(dd,J=4.9,1.7Hz,1H),7.62(dd,J=7.6,1.8Hz,1H),6.77(s,2H),6.66(dd,J=7.5,4.9Hz,1H),6.47(s,1 H),6.33(q,J=6.8Hz,1H),5.70(s,2H),5.29(d,J=54.3Hz,1H),4.41(dd,J=12.8,6.4Hz,1H),4.28(dd,J=12. 8,6.3Hz,1H),4.13(s,2H),3.71(dd,J=15.9,6.4Hz,1H),3.47-3.36(m,1H),3.22-2.93(m,3H),2.92-2.76(m ,1H),2.35(d,J=2.2Hz,3H),2.28-2.11(m,1H),2.12-1.93(m,2H),1.93-1.68(m,3H),1.56(d,J=6.8Hz,3H). LC-MS:(ESI,m / Z):658.2[M+H] + Example 7: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol Synthetic Route TIFF2025535367000111.tif42170

[0395] Step 1: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0396] A solution of 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (91.0 mg, 0.13 mmol) and hydrochloric acid (0.5 mL, 2.00 mmol, 4 mol / L solution in 1,4-dioxane) in acetonitrile (1 mL) was stirred at 25° C. for 0.5 hours. After completion, the reaction mixture was concentrated in vacuo. The crude product was purified by Prep-HPLC using the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 8% B to 24% B, 24% B in 8 min; Wavelength: 254 / 220 nm; RT (min): 7.5 to give the title compound (13.0 mg, 0.02 mmol, 19.7% yield). LC-MS: (ESI, m / Z): 650.2 [M+H] +

[0397] Example 7: 1 H NMR (300 MHz, Methanol-d 4, ppm)δ 8.26(s,1H),7.99-7.88(m,1H),7.77(d,J=2.3Hz,1H),7.69(d,J=8.0Hz,2H),7.56-6.81(m,2H),6.75(t,J=6.4Hz,1H),6.44(d,J =7.1Hz,1H),5.42(d,J=52.9Hz,1H),4.52-4.05(m,4H),3.80-3.38(m,5H),3.22(s,1H),2.59-1.89(m,7H),1.57(d,J=6.7Hz,3H). Example 8: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine Synthetic Route TIFF2025535367000112.tif120170

[0398] Step 1: (R)-7-chloro-8-fluoro-5-(2-((1-(3-((4-methoxybenzyl)amino)pyrazin-2-yl)ethyl)amino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one TIFF2025535367000113.tif56170

[0399] Sodium hydride (2.9 g, 72.5 mmol, 60% in mineral oil) was added to a solution of 2-[[(1R)-1-[3-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]ethyl]amino]ethanol (6.5 g, 21.4 mmol) in tetrahydrofuran (50.0 mL) under a nitrogen atmosphere at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was then added to a solution of 5,7-dichloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (5.0 g, 17.8 mmol) in tetrahydrofuran (50.0 mL) and stirred at room temperature for 1 h. Upon completion, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was used in the next step without purification. LC-MS: (ESI, m / Z): 546.2 [M+H] +

[0400] Step 2: (R)-3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000114.tif39170

[0401] A mixture of 7-chloro-8-fluoro-5-[2-[[(1R)-1-[3-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]ethyl]amino]ethoxy]-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (9.8 g, crude), bis(2-oxo-3-oxazolidinyl)phosphine chloride (6.8 g, 26.9 mmol), and N,N-diisopropylethylamine (9.4 mL, 53.8 mmol) in chloroform (80 mL) was stirred at 70° C. for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4:1) to give the title compound (7.0 g, 13.3 mmol, 74% yield) as a pale yellow solid. LC-MS: (ESI, m / Z): 528.0 [M+H] +

[0402] Step 3: (R)-3-(1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000115.tif47170

[0403] A mixture of (R)-3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (350.0 mg, 0.66 mmol), [5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (474.0 mg, 0.99 mmol), tetrakis(triphenylphosphine)palladium (77 mg, 0.07 mmol), and cesium carbonate (652 mg, 1.99 mmol) in 1,4-dioxane (5.0 mL) and water (0.2 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (98:2) to give the title compound (480.0 mg, 0.52 mmol, 79% yield) as a pale yellow solid. LC-MS: (ESI, m / Z): 925.5 [M+H] +

[0404] Step 4: (R)-3-(1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000116.tif47170

[0405] 3-Chloroperoxybenzoic acid (176.0 mg, 0.86 mmol, 85% purity) was added to a solution of 3-[(1R)-1-[7-[5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-6-fluoro-3-methylsulfanyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (200.0 mg, 0.22 mmol) in dichloromethane (10.0 mL) and stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with saturated aqueous sodium sulfite and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97:3) to give the title compound (180.0 mg, 0.19 mmol, 87% yield) as a pale yellow solid. LC-MS: (ESI, m / Z): 957.4 [M+H] +

[0406] Step 5: 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000117.tif47170

[0407] Sodium tert-butoxide (72 mg, 0.75 mmol) was added to a solution of [(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol (85 mg, 0.56 mmol) in toluene (3.0 mL) under a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for 0.5 hours. The mixture was then added to a solution of 3-[(1R)-1-[7-[5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (180.0 mg, 0.19 mmol) in toluene (3.0 mL) and stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97:3) to give the title compound (130.0 mg, 0.13 mmol, 67% yield) as a pale yellow solid. LC-MS: (ESI, m / Z): 1028.4 [M+H] +

[0408] Step 6: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine TIFF2025535367000118.tif47170

[0409] A mixture of 3-[(1R)-1-[7-[5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-3-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6-fluoro-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (125.0 mg, 0.12 mmol) in trifluoroacetic acid (5.0 mL) and trifluoromethanesulfonic acid (0.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, basified with saturated aqueous sodium bicarbonate to pH 8, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by Prep-HPLC using the following conditions: (Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 35% B to 55% B in 11 min; Wavelength: 254 nm; RT1 (min): 10.8; to give the title compound (23.8 mg, 0.04 mmol, 29% yield).

[0410] Example 8: 1 H NMR (300 MHz, DMSO-d 6, ppm)δ 7.95(d,J=2.7Hz,1H),7.78(d,J=2.7Hz,1H),6.55(d,J=8.6Hz,1H),6.44-6.2 4(m,3H),6.00(s,2H),4.65-4.26(m,4H),3.88(dd,J=15.7,6.4Hz,1H),3.79-3 .60(m,1H),3.50-3.36(m,1H),3.03-2.86(m,1H),2.78-2.56(m,1H),2.48-2. 39(m,1H),2.37(s,3H),2.32(s,3H),2.28-2.05(m,1H),1.57(d,J=6.8Hz,3H). LC-MS: (ESI, m / Z): 668.2 [M+H] + Example 9: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine Synthetic Route TIFF2025535367000119.tif84170

[0411] Step 1: 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000120.tif41170

[0412] Sodium tert-butoxide (350.0 mg, 3.6 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (435.0 mg, 2.7 mmol) in toluene (15.0 mL) under a nitrogen atmosphere at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours. The mixture was then added to a solution of 3-[(1R)-1-(7-chloro-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (510.0 mg, 0.9 mmol) in toluene (15.0 mL) and stirred at room temperature for 1 hour. After completion, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97:3) to give the title compound (195.0 mg, 0.3 mmol, 34% yield) as a pale yellow solid. LC-MS: (ESI, m / Z): 639.2 [M+H] +

[0413] Step 2: 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000121.tif47170

[0414] 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazine-2-a in 1,4-dioxane (6.0 mL) and water (0.6 mL). A mixture of [5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (218.0 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol), and cesium carbonate (300.0 mg, 0.9 mmol) was stirred at 100° C. for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (49:1) to afford the title compound (300.0 mg, 0.3 mmol, 95% yield) as a pale yellow solid. LC-MS: (ESI, m / Z): 1036.6 [M+H] +

[0415] Step 3: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine TIFF2025535367000122.tif46170

[0416] A mixture of 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (300.0 mg, 0.3 mmol) in trifluoroacetic acid (6.0 mL) and trifluoromethanesulfonic acid (0.6 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, basified with saturated aqueous sodium bicarbonate solution, the pH adjusted to 8, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by Prep-HPLC under the following conditions (Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 29% B to 56% B, 56% B in 9.5 min; Wavelength: 254 / 220 nm; RT1 (min): 8.33) to give the title compound (31.8 mg, 0.047 mmol, 16% yield).

[0417] Example 9: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 7.94(d,J=2.7Hz,1H),7.78(d,J=2.7Hz,1H),6.55(d,J=8.7Hz,1H),6.37(d,J=6.8Hz,3H),6.00(s, 2H),5.27(d,J=56.1,Hz,1H),4.64-4.45(m,1H),4.39(dd,J=12.8,6.4Hz,1H),4.21-3.99(m,2H),3 .89(dd,J=15.9,6.5Hz,1H),3.78-3.55(m,1H),3.17-3.02(m,2H),3.05-2.92(m,1H),2.92-2.69(m ,1H),2.44-2.26(m,3H),2.21-2.08(m,1H),2.00(s,2H),1.89-1.67(m,3H),1.56(d,J=6.8Hz,3H). LC-MS:(ESI,m / Z):676.2[M+H] + Example 10: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine Synthetic Route TIFF2025535367000123.tif85170

[0418] Step 1: 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000124.tif49170

[0419] Sodium tert-butoxide (72.0 mg, 0.75 mmol) was added to a solution of ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (98.0 mg, 0.63 mmol) in toluene (3.0 mL) under a nitrogen atmosphere at 0°C, and the mixture was stirred at 0°C for 0.5 h. The mixture was then added to a solution of 3-[(1R)-1-[7-[5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (200.0 mg, 0.21 mmol) in toluene (3.0 mL) and stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97:3) to give the title compound (130.0 mg, 0.13 mmol, 60% yield) as a pale yellow solid. LC-MS: (ESI, m / Z): 1034.5 [M+H] +

[0420] Step 2: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine TIFF2025535367000125.tif48170

[0421] A mixture of 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (130.0 mg, 0.13 mmol), trifluoroacetic acid (4.0 mL), and trifluoromethanesulfonic acid (0.4 mL) was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with dichloromethane and basified with saturated aqueous sodium bicarbonate to adjust the pH to 10. The combined organic layer was then extracted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: (Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 29% B to 49% B in 10 min; Wavelength: 254 nm; RT1 (min): 10.2) to give the title compound (38.0 mg, 0.06 mmol, 45% yield, 99.1% purity).

[0422] Example 10: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 7.94(d,J=2.7Hz,1H),7.78(d,J=2.7Hz,1H),6.55(d,J=8.6Hz,1H),6.46-6.24(m,3H),6 .00(s,2H),4.69-4.13(m,4H),3.88(dd,J=15.9,6.4Hz,1H),3.77-3.58(m,1H),3.58-3. 47(m,1H),3.48-3.38(m,3H),3.13(t,J=10.3Hz,1H),3.03-2.74(m,3H),2.32(dd,J=4.4 ,2.1Hz,3H),2.17-1.96(m,1H),1.87-1.68(m,1H),1.69-1.49(m,4H),1.43-1.19(m,1H). LC-MS:(ESI,m / Z):674.2[M+H] + Example 11: 4-(10-((R)-1-(3-aminopyrazin-2-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol Synthetic Route TIFF2025535367000126.tif73170

[0423] Step 1: 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine TIFF2025535367000127.tif41170

[0424] A solution of 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (644.7 mg, 0.4 mmol) in 2,2,2-trifluoroacetic acid (5.0 mL) and trifluoromethanesulfonic acid (0.5 mL) was stirred at 25° C. for 10 minutes. After completion, the solvent was concentrated in vacuo. The reaction mixture was diluted with dichloromethane and adjusted to pH=8 with saturated aqueous sodium carbonate. The solution was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give the title compound (277.1 mg, 0.5 mmol, 52.6% yield) as a yellow solid. LC-MS: (ESI, m / Z): 519.2 M+H] +

[0425] Step 2: 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine TIFF2025535367000128.tif48170

[0426] 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine (277.1 mg, 0.5 mmol) in tetrahydrofuran (3.0 mL) and water (0.6 mL) under nitrogen. A solution of (3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (880.8 mg, 2.1 mmol), [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (155.4 mg, 0.2 mmol), and tribasic potassium phosphate (452.8 mg, 2.1 mmol) was added at 25 °C. The resulting solution was stirred at 60 °C for 1 h. Upon completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to afford the title compound (365.1 mg, 0.3 mmol, 71.9% yield) as a yellow solid. LC-MS: (ESI, m / Z): 851.4 [M+H] +

[0427] Step 3: 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine TIFF2025535367000129.tif48170

[0428] A solution of 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine (365.1 mg, 0.3 mmol) and cesium fluoride (184.5 mg, 1.2 mmol) in N,N-dimethylformamide (4.0 mL) was stirred at 25° C. for 1 hour. After completion, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / ethyl acetate (1:1) to give the title compound (244.4 mg, 0.3 mmol, 82.5% yield) as a yellow solid. LC-MS: (ESI, m / Z): 695.3 [M+H] +

[0429] Step 4: 4-(10-((R)-1-(3-aminopyrazin-2-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol TIFF2025535367000130.tif47170

[0430] A solution of 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine (50.0 mg, 0.07 mmol) and hydrochloric acid in 1,4-dioxane (1 mL, 4.0 M in 1,4-dioxane) in acetonitrile (0.5 mL) was stirred at 25° C. for 30 minutes. After completion, the solvent was concentrated under vacuum. The residue was dissolved in dichloromethane and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give the product as a yellow solid. The product was purified by prep-HPLC using the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 30% B, 30% B in 9 min; Wavelength: 254 / 220 nm; RT1 (min): 9 to give the title compound (4.6 mg, 0.007 mmol, 9.8% yield). LC-MS: (ESI, m / Z): 651.2 [M+H] +

[0431] Example 11: 1H NMR(300MHz,Methanol-d4,ppm)δ 7.93(dd,J=2.8,1.4Hz,1H),7.85(d,J=2.7Hz,1H),7.80(d,J=8.2Hz,1H),7.55-7.4 6(m,1H),7.45-7.33(m,1H),7.30(d,J=2.6Hz,1H),7.14(dd,J=6.4,2.6Hz,1H),6.5 1(q,J=6.9Hz,1H),5.40(d,J=52.7Hz,1H),4.73-4.31(m,4H),4.17-3.84(m,2H),3. 70-3.42(m,3H),3.26-3.03(m,2H),2.58-1.88(m,6H),1.71(dd,J=6.9,2.5Hz,3H). LC-MS:(ESI,m / Z):651.3[M+H] + Example 12: 3-((1R)-1-(5-(3-amino-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000131.tif212170

[0432] Step 1: (R)-5-(2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one TIFF2025535367000132.tif56170

[0433] A solution of 2-[[(1R)-1-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-pyridyl]ethyl]amino]ethanol (3.31 g, 7.8 mmol) in tetrahydrofuran (20 mL) was added to sodium hydride (1.14 g, 28.5 mmol, 60% purity) and stirred at room temperature for 10 minutes. The reaction mixture was then added to a solution of 5,7-dichloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (2.00 g, 7.1 mmol) in tetrahydrofuran (20 mL) and stirred for 1 hour. Upon completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give the title compound (2.4 g, 3.6 mmol, 50.5% yield) as a white solid. LC-MS: (ESI, m / Z): 665.3 [M+H] +

[0434] Step 2: (R)-3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine TIFF2025535367000133.tif39170

[0435] A solution of (R)-5-(2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (3.6 g, 5.41 mmol) and N,N-diisopropylethylamine (4.7 mL, 27.0 mmol) in chloroform (40 mL) was added to bis(2-oxo-3-oxazolidinyl)phosphine chloride (2.1 g, 8.1 mmol) and stirred at 70° C. for 1 hour. Upon completion, the reaction was diluted with water, extracted with ethyl acetate, and concentrated over anhydrous sodium sulfate. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3:2) to give the title compound (1.37 g, 1.9 mmol, 36.2% yield) as a white solid. LC-MS: (ESI, m / Z): 647.5 [M+H] +

[0436] Step 3: 3-Bromo-2,6-difluoro-5-methylbenzoic acid TIFF2025535367000134.tif24170

[0437] Under nitrogen, a solution of 1-bromo-2,4-difluoro-5-methyl-benzene (10.0 g, 48.3 mmol) in tetrahydrofuran (100 mL) was slowly added to lithium diisopropylamide (31.5 mL, 63.0 mmol) (2 M in tetrahydrofuran) at −78° C. and stirred at −78° C. for 2 hours. Dry ice was then poured into the reaction solution, which was then stirred at room temperature for 1 hour. Upon completion, the reaction solution was quenched with saturated ammonium chloride solution and adjusted to pH=7 with 1N hydrochloric acid. The reaction mixture was then diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3-bromo-2,6-difluoro-5-methyl-benzoic acid (9.00 g, crude) as a pale yellow solid. The crude product was used directly in the next step. LC-MS: (ESI, m / Z): 251.3 [MH] +

[0438] Step 4: 3-Bromo-2,6-difluoro-5-methylaniline TIFF2025535367000135.tif24170

[0439] A solution of 3-bromo-2,6-difluoro-5-methyl-benzoic acid (5.80 g, 19.9 mmol), diphenylphosphonicazide (12.70 g, 39.8 mmol), and triethylamine (7.0 g, 59.7 mmol) in tert-butanol (50.0 mL) was stirred at 85° C. for 1.5 hours. The solution was then added to 2N hydrogen chloride (10 mL) and stirred for 1 hour. Upon completion, the reaction mixture was quenched with saturated aqueous sodium carbonate solution. The resulting solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (2.50 g, crude) as a yellow oil. The crude product was used directly in the next step. LC-MS: (ESI, m / Z): 222.4 [M+H] +

[0440] Step 5: 3-Bromo-2,6-difluoro-4-iodo-5-methylaniline TIFF2025535367000136.tif24170

[0441] A solution of 3-bromo-2,6-difluoro-5-methyl-aniline (1.0 g, 4.5 mmol) in acetic acid (10 mL) was added to N-iodosuccinimide (1.22 g, 5.4 mmol) and stirred at 25° C. for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure. The reaction was then quenched with saturated sodium bicarbonate solution. The reaction mixture was then diluted with water. The resulting solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:8) to give the title compound (1.10 g, 3.1 mmol) as a white solid. LC-MS: (ESI, m / Z): 348.2 [M+H] +

[0442] Step 6: 3-Bromo-2,6-difluoro-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline TIFF2025535367000137.tif24170

[0443] A solution of 3-bromo-2,6-difluoro-4-iodo-5-methyl-aniline (1.0 g, 2.87 mmol) and potassium tert-butoxide (1.29 g, 11.5 mmol) in N,N-dimethylformamide (10 mL) was added to p-methoxybenzyl chloride (1.3 g, 8.6 mmol) and stirred at 0 °C for 1.5 hours. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:9) to give the title compound (1.2 g, 2.0 mmol, 71% yield) as a white solid. LC-MS: (ESI, m / Z): 588.7 [M+H] +

[0444] Step 7: 3-Bromo-2,6-difluoro-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline TIFF2025535367000138.tif25170

[0445] Under nitrogen, a solution of 3-bromo-2,6-difluoro-4-iodo-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-aniline (100.0 mg, 0.2 mmol) and cuprous iodide (323.0 mg, 1.7 mmol) in N,N-dimethylformamide (1 mL) was stirred at -40 °C for 10 minutes. Then, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.2 mL, 1.7 mmol) was added at room temperature and stirred at 90 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:8) to give the title compound (80.0 mg, 0.15 mmol, 88.7% yield) as a white solid. LC-MS: (ESI, m / Z): 530.1 [M+H] +

[0446] Step 8: 3-((1R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine TIFF2025535367000139.tif46170

[0447] Isopropylmagnesium chloride and lithium chloride (1.3 M in tetrahydrofuran) (2.6 mL, 3.4 mmol) were added to a solution of 3-bromo-2,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-4-(trifluoromethyl)aniline (1.20 g, 2.3 mmol) in tetrahydrofuran (13 mL) at −78°C under a nitrogen atmosphere. After stirring at −78°C for 30 minutes, zinc chloride (1.9 M in 2-methyltetrahydrofuran) (3.4 mL, 6.79 mmol) was added to the mixture and stirred for 10 minutes. The mixture was then warmed to room temperature and stirred at room temperature for 30 minutes. The reaction solution was then added to a solution of 3-[(1R)-1-(7-chloro-6-fluoro-3-methylsulfanyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (1.40 g, 2.3 mmol) and tetrakis(triphenylphosphine)palladium (0.30 g, 0.2 mmol) in tetrahydrofuran (13 mL) under nitrogen and stirred at 80 °C for 5 hours. Upon completion, the reaction was quenched with saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:8) to give the title compound (600.0 mg, 0.5 mmol, 25% yield) as a white solid. LC-MS: (ESI, m / Z): 1062.5 [M+H] +

[0448] Step 9: 3-((1R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine TIFF2025535367000140.tif46170

[0449] Under nitrogen, a solution of 3-[(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-methylsulfanyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (100.0 mg, 0.1 mmol) and 3-chloroperoxybenzoic acid (48.7 mg, 0.3 mmol) in dichloromethane (1 mL) was stirred at 25 °C for 1.5 hours. Upon completion, the reaction was quenched with saturated sodium sulfite solution. The resulting solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:8) to give the title compound (70.0 mg, 0.06 mmol, 68% yield) as a white solid. LC-MS: (ESI, m / Z): 1093.9 [M+H] +

[0450] Step 10: 3-((1R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine TIFF2025535367000141.tif46170

[0451] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (43.6 mg, 0.3 mmol) in toluene (1 mL) was added to sodium tert-butoxide (43.8 mg, 0.5 mmol) and stirred at 0° C. for 10 minutes. The reaction mixture was then added to 3-[(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (100.0 mg, 0.1 mmol) and stirred at 25 °C for 1.5 hours. Upon completion, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to give the title compound (90.0 mg, 0.07 mmol, 83.9% yield) as a yellow solid. LC-MS: (ESI, m / Z): 1173.6 [M+H] +

[0452] Step 11: 3-((1R)-1-(5-(3-amino-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000142.tif46170

[0453] A solution of 3-((1R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (120.0 mg, 0.1 mmol) in trifluoroacetic acid (1.0 mL) and trifluoromethanesulfonic acid (0.1 mL) was stirred at 25° C. for 20 minutes. Upon completion, the filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane and adjusted to pH=7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give a crude solid. The crude material was purified by Prep-HPLC using the following conditions: Column: XBridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 38% B to 60% B, 60% B in 10 min; Wavelength: 220 / 254 nm; RT1 (min): 7.72 to give the title compound (59.0 mg, 0.08 mmol, 83.3% yield).

[0454] Example 12: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 7.96(d,J=4.9Hz,1H),7.68-7.58(m,1H),6.67(dd,J=7.5,4.9Hz,1H),6.34(d,J=7.0Hz,1H ),6.15(s,2H),5.68(s,2H),5.28(d,J=54.5Hz,1H),4.51-4.36(m,1H),4.29(dd,J=12.8,6. 3Hz,1H),4.12(s,2H),3.80-3.55(m,2H),3.17-3.00(m,2H),2.99(s,1H),2.89-2.68(m,1H) ),2.30(s,3H),2.23-2.08(m,1H),2.07-1.91(m,2H),1.91-1.70(m,3H),1.62-1.47(m,3H). LC-MS:(ESI,m / Z):693.3[M+H] + Example 13: 3-((1R)-1-(5-(3-amino-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine Synthetic Route TIFF2025535367000143.tif191170

[0455] Step 1: 2,6-Difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline TIFF2025535367000144.tif29170

[0456] Under nitrogen, a solution of 3-bromo-2,6-difluoro-5-methyl-aniline (3.0 g, 13.5 mmol), bis(pinacolato)diboron (5.1 g, 20.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.0 g, 1.3 mmol), and potassium acetate (3.9 g, 40.5 mmol) in N,N-dimethylformamide (30 mL) was heated at 80° C. for 12 h. After completion, the reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to give 2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 g, 11.1 mmol, 99% yield) as a yellow solid. LC-MS: (ESI, m / Z): 270.2 [M+H] +

[0457] Step 2: (R)-5-(2-((1-(3-(bis(4-methoxybenzyl)amino)pyrazin-2-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one TIFF2025535367000145.tif36170

[0458] Sodium hydride (828.0 mg, 20.7 mmol, 60% in mineral oil) was added to a solution of 2-[[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]amino]ethanol (3.30 g, 7.8 mmol) in tetrahydrofuran (15.0 mL) under a nitrogen atmosphere at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was then added to a solution of 5,7-dichloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (1.40 g, 5.0 mmol) in tetrahydrofuran (15 mL) and stirred at room temperature for 1 h. Upon completion, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was used in the next step without purification. LC-MS: (ESI, m / Z): 666.0 [M+H] +

[0459] Step 3: (R)-3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000146.tif39170

[0460] A solution of 7-chloro-8-fluoro-2-methylsulfanyl-5-[2-[[rac-(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]amino]ethoxy]-3H-pyrido[4,3-d]pyrimidin-4-one (2.88 g, crude), bis(2-oxo-3-oxazolidinyl)phosphine chloride (2.2 g, 8.65 mmol), and N,N-diisopropylethylamine (3.7 mL, 21.6 mmol) in chloroform (28 mL) was stirred at 70 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to give the title compound (1.58 g, 2.3 mmol, 55.1% yield) as a white solid. LC-MS: (ESI, m / Z): 648.3 [M+H] +

[0461] Step 4: (R)-3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000147.tif40170

[0462] A solution of 3-[(1R)-1-(7-chloro-6-fluoro-3-methylsulfanyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine (300.0 mg, 0.4 mmol) and 3-chloroperoxybenzoic acid (319.5 mg, 1.8 mmol) in dichloromethane (3 mL) was stirred at 25 °C for 1 hour. Upon completion, the reaction was quenched with saturated sodium sulfite solution. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to give the title compound (190.0 mg, 0.3 mmol, 60.4% yield) as a yellow solid. LC-MS: (ESI, m / Z): 680.3 [M+H] +

[0463] Step 5: 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000148.tif41170

[0464] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.33 g, 8.3 mmol) and sodium tert-butoxide (1.34 g, 13.8 mmol) in toluene (20 mL) was dissolved in 0.5 mL of toluene. oThe mixture was stirred at 25° C. for 20 minutes. The reaction mixture was then added to a solution of (R)-3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (1.89 g, 2.7 mmol) in toluene (20 mL) and stirred at 25° C. for 1.5 hours. Upon completion, the reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to afford the title compound (910.0 mg, 1.1 mmol, 43.1% yield) as a yellow solid. LC-MS: (ESI, m / Z): 759.3 [M+H] +

[0465] Step 6: 3-((R)-1-(5-(3-amino-2,4-difluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000149.tif41170

[0466] 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazine in 1,4-dioxane (10 mL) and water (1 mL) under nitrogen. A solution of 2-(4,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (387.0 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium (138.5 mg, 0.12 mmol), and potassium carbonate (331.2 mg, 2.4 mmol) was stirred at 100° C. for 1.5 hours. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to afford the title compound (330.0 mg, 0.4 mmol, 31.8% yield) as a yellow oil. LC-MS: (ESI, m / Z): 866.3 [M+H] +

[0467] Step 7: 3-((1R)-1-(5-(3-amino-2,4-difluoro-6-iodo-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine TIFF2025535367000150.tif46170

[0468] A solution of 3-((R)-1-(5-(3-amino-2,4-difluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (600.0 mg, 0.7 mmol) and N-iodosuccinimide (155.4 mg, 0.7 mmol) in acetic acid (3.0 mL) and N,N-dimethylformamide (3.0 mL) was stirred at 25° C. for 1.5 hours. Upon completion, the reaction was quenched with saturated sodium carbonate solution. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to give the title compound (500.0 mg, 0.5 mmol, 72.8% yield) as a yellow solid. LC-MS: (ESI, m / Z): 992.4 [M+H] +

[0469] Step 8: tert-butyl N-[3-[13-[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-2,6-difluoro-4-iodo-5-methyl-phenyl]-N-tert-butoxycarbonyl-carbamate TIFF2025535367000151.tif46170

[0470] Under nitrogen, a solution of 3-((1R)-1-(5-(3-amino-2,4-difluoro-6-iodo-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (500.0 mg, 0.5 mmol), 4-dimethylaminopyridine (215.6 mg, 1.7 mmol), and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol) in tetrahydrofuranic acid was stirred at 70° C. for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:8) to give the title compound (430.0 mg, 0.3 mmol, 71.6% yield) as a white solid. LC-MS: (ESI, m / Z): 866.3 [M+H] +

[0471] Step 9: tert-butyl N-[3-[13-[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-2,6-difluoro-5-methyl-4-(trifluoromethyl)phenyl]-N-tert-butoxycarbonyl-carbamate TIFF2025535367000152.tif45170

[0472] tert-Butyl N-[3-[13-[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14 A solution of ]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-2,6-difluoro-4-iodo-5-methyl-phenyl]-N-tert-butoxycarbonyl-carbamate (430.0 mg, 0.3 mmol) and copper (230.8 mg, 3.6 mmol) was added to bis[(2,2-difluoro-2-fluorosulfonyl-acetyl)oxy]copper (868.0 mg, 3.6 mmol) at -60 °C for 8 minutes. The reaction mixture was then stirred at 90 °C for 1.5 hours. Upon completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:8) to give the title compound (160.0 mg, 0.14 mmol, 39.1% yield) as a white solid. LC-MS: (ESI, m / Z): 1134.6 [M+H] +

[0473] Step 10: 3-((1R)-1-(5-(3-amino-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine TIFF2025535367000153.tif46170

[0474] A solution of tert-butyl N-[3-[13-[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-2,6-difluoro-5-methyl-4-(trifluoromethyl)phenyl]-N-tert-butoxycarbonyl-carbamate (160.0 mg, 0.1 mmol) in trifluoroacetic acid (1.0 mL) and trifluoromethanesulfonic acid (0.1 mL) was stirred at 25 °C for 30 minutes. Upon completion, the reaction mixture was diluted with dichloromethane and adjusted to pH=7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give the product. The product was further purified by Prep-HPLC under the following conditions (Column: XSelect CSH Fluoro Phenyl, 30×150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 4% B to 20% B in 10 min; Wavelength: 694 nm) to give the title compound (11.0 mg, 0.01 mmol, 10.5% yield). LC-MS: (ESI, m / Z): 694.0 [M+H] +

[0475] Example 13: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 7.94(t,J=2.3Hz,1H),7.78(t,J=2.6Hz,1H),6.37(s,3H),6.17(s,2H),5.28 (d,J=54.4Hz,1H),4.65-4.34(m,2H),4.22-4.02(m,2H),3.99-3.83(m,1H),3 .80-3.61(m,1H),3.17-2.97(m,2H),2.98-2.88(m,1H),2.86-2.75(m,1H),2. 31(s,3H),2.19-1.93(m,3H),1.89-1.68(m,3H),1.56(dd,J=6.9,2.1Hz,3H). LCMS(ESI,m / Z):694.0[M+H] + . Example 14: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine Synthetic Route TIFF2025535367000154.tif128170

[0476] Step 1: 4-Bromo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine TIFF2025535367000155.tif23170

[0477] A solution of 4-bromo-6-methyl-pyridin-2-amine (2.0 g, 10.6 mmol) and potassium tert-butoxide (4.80 g, 42.7 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0° C. for 30 minutes. 4-Methoxybenzyl chloride (5.02 g, 32.0 mmol) in N,N-dimethylformamide (20 mL) was then added and stirred at 0° C. for 1.5 hours. Upon completion, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:99) to afford the title compound (1.50 g, 3.5 mmol, 32.8% yield) as a white solid. LCMS (ESI, m / Z): 429.1 [M+H] + .

[0478] Step 2: 4-Bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine TIFF2025535367000156.tif29170

[0479] A solution of 4-bromo-N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-pyridin-2-amine (2.09 g, 4.8 mmol) and N-iodosuccinimide (1.10 g, 4.8 mmol) in acetic acid (20 mL) was stirred at 25° C. for 1.5 hours. After completion, the reaction was quenched with saturated aqueous sodium carbonate solution. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:98) to afford the title compound (1.50 g, 2.7 mmol, 55.4% yield) as a yellow oil. LCMS (ESI, m / Z): 554.1 [M+H] + .

[0480] Step 3: 4-Bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2025535367000157.tif29170

[0481] Under nitrogen, a solution of 4-bromo-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-pyridin-2-amine (1.50 g, 2.7 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.4 mL, 27.1 mmol), and cuprous iodide (5.16 g, 27.1 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90 °C for 1.5 hours. Upon completion, the reaction mixture was filtered and the filter was diluted with water. The resulting solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:19) to afford the title compound (1.14 g, 2.3 mmol, 84.9% yield) as a yellow solid. LCMS (ESI, m / Z): 497.2 [M+H] + .

[0482] Step 4: N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine TIFF2025535367000158.tif33170

[0483] Under nitrogen, a solution of 4-bromo-N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, 0.3 mmol), bis(pinacolato)diboron (115.3 mg, 0.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.4 mg, 0.03 mmol), and potassium acetate (0.04 mL, 0.6 mmol) in 1,4-dioxane (1.5 mL) was added at 100 °C for 1.5 h. After completion, the reaction mixture was used directly in the next step without further purification. LCMS (ESI, m / Z): 543.4 [M+H] + .

[0484] Step 5: tert-butyl (3-((R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000159.tif50170

[0485] N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, crude), tert-butyl(3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methacrylate)-2-(2-fluoro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methyl ... A solution of (C)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (170.9 mg, 0.3 mmol), [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate (40.2 mg, 0.06 mmol), and potassium phosphate (117.26 mg, 0.55 mmol) was stirred at 60 °C for 2 hours. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:8) to give the title compound (43.0 mg, 0.04 mmol, 15.6% yield). LCMS (ESI, m / Z): 998.5 [M+H] + .

[0486] Step 5: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2025535367000160.tif46170

[0487] A solution of tert-butyl (3-((R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (80.0 mg, 0.08 mmol) in trifluoroacetic acid (0.5 mL) and trifluoromethanesulfonic acid (0.05 mL) was stirred at 25° C. for 30 minutes. Upon completion, the filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane, and the reaction mixture was adjusted to pH=7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give a crude solid. The crude material was purified by Prep-HPLC under the following conditions (Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 28% B to 50% B in 7.5 min; Wavelength: 220 nm) to give the title compound (18.0 mg, 0.03 mmol, 34.1% yield) as a white solid.

[0488] Example 14: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 7.96(dd,J=4.9,1.7Hz,1H),7.62(d,J=7.4Hz,1H),6.83(s,2H),6.66(dd,J=7.5,4.9Hz,1H),6.33(q,J =6.7Hz,1H),6.20(s,1H),5.69(s,2H),5.28(d,J=54.4Hz,1H),4.42(dd,J=12.9,6.4Hz,1H),4.28(dd, J=12.6,6.3Hz,1H),4.12(s,2H),3.82-3.60(m,2H),3.17-3.02(m,2H),2.99(s,1H),2.90-2.70(m,1H) ,2.46(d,J=2.3Hz,3H),2.19-2.11(m,1H),2.09-1.95(m,2H),1.92-1.71(m,3H),1.55(d,J=6.8Hz,3H). LCMS(ESI,m / Z):658.3[M+H] + . Example 15: 3-((1R)-1-(5-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000161.tif104170

[0489] Step 1: 3-((R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000162.tif46170

[0490] tert-Butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (42) in 1,4-dioxane (3 mL) and water (0.60 mL) was added under nitrogen. A solution of 2-fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (431.0 mg, 0.88 mmol), potassium carbonate (242.4 mg, 1.75 mmol), and tetrakis(triphenylphosphine)palladium (67.5 mg, 0.06 mmol) was stirred at 100° C. for 2 hours. Upon completion, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to give 3-((R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (400.0 mg, 0.47 mmol, 80.8% yield) as a yellow solid. LC-MS: (ESI, m / Z): 847.4 [M+H] + .

[0491] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methyl-phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate TIFF2025535367000163.tif46170

[0492] A solution of 3-((R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (400.0 mg, 0.47 mmol), di-tert-butyl dicarbonate (515.3 mg, 2.36 mmol), and triethylamine (0.33 mL, 2.36 mmol) in dichloromethane (4 mL) was stirred at 25 °C for 1 hour. After completion, the reaction solution was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methyl-phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (250.0 mg, 0.22 mmol, 47.3% yield) as a yellow solid. LC-MS: (ESI, m / Z): 1047.5 [M+H] + .

[0493] Step 3: tert-Butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-6-iodo-5-methyl-phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate TIFF2025535367000164.tif46170

[0494] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methyl-phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (240.0 mg, 0.23 mmol) in acetic acid (2.5 mL), N-iodosuccinimide (61.8 mg, 0.28 mmol) was added and the mixture was stirred at 25 °C for 0.5 h. After completion, the reaction was quenched with saturated sodium thiosulfate solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-6-iodo-5-methyl-phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (140.0 mg, 0.10 mmol, 47.9% yield) as a yellow solid. LC-MS: (ESI, m / Z): 1173.4 [M+H] + .

[0495] Step 4: tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate TIFF2025535367000165.tif45170

[0496] tert-Butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-6-iodo-5-methyl-phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatoate in N,N-dimethylformamide (1 mL) under nitrogen. To a solution of ricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (140.0 mg, 0.12 mmol) and copper (75.8 mg, 1.19 mmol), bis[(2,2-difluoro-2-fluorosulfonyl-acetyl)oxy]copper (498.8 mg, 1.19 mmol) was added and stirred at -78 °C for 10 minutes. The mixture was then removed to 90 °C and stirred for 1 hour. Upon completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (110.0 mg, 0.097 mmol, 81.8% yield) as a yellow solid. LC-MS: (ESI, m / Z): 1115.5 [M+H] + .

[0497] Step 5: 3-((1R)-1-(5-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000166.tif45170

[0498] A solution of tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (110.0 mg, 0.10 mmol) in 2,2,2-trifluoroacetic acid (1 mL) was stirred for 5 hours at 50° C. After completion, the solvent was removed in vacuo. The resulting solution was diluted with dichloromethane and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to give the crude product. The product was further purified by Prep-HPLC under the following conditions: XSelect CSH Fluoro Phenyl, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 31% B to 56% B in 9 min; 254 / 220 nm; RT: 10.4 min to give 3-((1R)-1-(5-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (6.5 mg, 0.01 mmol, 9.2% yield). LC-MS: (ESI, m / Z): 675.2 [M+H] + .

[0499] Example 15: 1H NMR(300MHz,Methanol-d4)δ 8.14-7.89(m,1H),7.95-7.65(m,1H),6.87(d,J=8.8Hz,1H),6.80(dd,J=7.5,5.1Hz,1 H),6.62(q,J=6.9Hz,1H),5.33(d,J=53.2Hz,1H),4.55-4.42(m,1H),4.42-4.27(m,3H) ),3.78(dd,J=16.1,6.6Hz,1H),3.63-3.48(m,1H),3.33-3.13(m,3H),3.11-2.94(m,1 H),2.42(d,J=2.7Hz,3H),2.37-2.12(m,3H),2.13-1.82(m,3H),1.67(d,J=7.0Hz,3H). Example 16: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000167.tif79170

[0500] Step 1: 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000168.tif49170

[0501] Tetrakis(triphenylphosphine)palladium (86.8 mg, 0.08 mmol), cesium carbonate (367.0 mg, 1.13 mmol), [5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (319.2 mg, 0.67 mmol), and tert-butyl ether were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL) under nitrogen. A solution of (3-((R)-1-(5-chloro-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (240.0 mg, 0.34 mmol) was stirred at 100° C. for 2 hours. Upon completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to give 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (240.0 mg, 0.20 mmol, 60.8% yield) as a yellow solid. LC-MS: (ESI, m / Z): 913.4 [M+H] + .

[0502] Step 2: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000169.tif48170

[0503] A solution of 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (230.0 mg, 0.25 mmol) in trifluoromethanesulfonic acid (0.3 mL) and 2,2,2-trifluoroacetic acid (3 mL) was stirred at 25° C. for 1 hour. Upon completion, the solvent was removed under vacuum. The resulting solution was diluted with dichloromethane and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by Prep-HPLC under the following conditions: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH₄HCO₃), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 10% B to 40% B in 9 min; 254 / 220 nm; RT: 8.9 min. 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (81.2 mg, 0.11 mmol, 44.0% yield). LC-MS: (ESI, m / Z): 673.1 [M+H] + .

[0504] Example 16: 1H NMR(400MHz,DMSO-d6)δ 7.97(dd,J=4.9,1.7Hz,1H),7.62(dd,J=7.5,1.8Hz,1H),6.67(dd,J=7.5,4.9Hz,1H),6.54(d, J=8.7Hz,1H),6.33(q,J=6.8Hz,1H),6.02(s,2H),5.68(s,2H),4.42-4.38(m,2H),4.26-4.22( m,2H),3.72(dd,J=15.9,6.5Hz,1H),3.67-3.36(m,5H),3.14(t,J=10.4Hz,1H),3.05-2.78(m, 3H),2.32(s,3H),2.22-1.97(m,1H),1.86-1.70(m,1H),1.70-1.48(m,4H),1.43-1.20(m,1H). Example 17: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol Synthetic Route TIFF2025535367000170.tif95170

[0505] Step 1: ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol TIFF2025535367000171.tif19170

[0506] To a solution of (6S,8aS)-6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (1.6 g, 9.35 mmol) in tetrahydrofuran (16 mL) was added lithium aluminum hydride (2.1 g, 56.07 mmol) at 0 °C, and the mixture was stirred at 65 °C for 1 h. The reaction was quenched with sodium sulfate decahydrate. The solid was filtered off. After filtration, the filtrate was concentrated under reduced pressure to give ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (650 mg, 4.13 mmol, 44.2% yield) as a pink oil. LC-MS: (ESI, m / Z): 158.1 [M+H] +

[0507] Step 2: tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000172.tif49170

[0508] Under nitrogen, to a solution of ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (812.0 mg, 5.17 mmol) in toluene (11 mL) was added sodium tert-butoxide (497.0 mg, 5.17 mmol), and the mixture was stirred at 0° C. for 10 minutes. Then, tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-(7-chloro-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-2-pyridyl]carbamate (1.1 g, 1.72 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (24:1) to afford tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (690.0 mg, 1.12 mmol, 65.1% yield) as a yellow solid. LC-MS: (ESI, m / Z): 616.2 [M+H] +

[0509] Step 3: 3-((R)-1-(4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000173.tif49170

[0510] Under nitrogen, tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (500 mL) in water (1 mL) and 1,4-dioxane (5 mL). A solution of 100.0 mg, 0.81 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (415.0 mg, 0.84 mmol), tetrakis(triphenylphosphine)palladium (162.0 mg, 0.14 mmol), and cesium carbonate (684.0 mg, 2.1 mmol) was stirred at 100° C. for 1 hour. Upon completion, the resulting solution was quenched with water and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (19:1) to give 3-((R)-1-(4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (320 mg, 0.37 mmol, 45.6% yield) as a yellow solid. LC-MS: (ESI, m / Z): 848.4 [M+H] +

[0511] Step 4: 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000174.tif49170

[0512] A solution of 3-((R)-1-(4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (300.0 mg, 0.35 mmol) and cesium fluoride (304.0 mg, 2 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (47 / 3) to give 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (240.0 mg, 0.35 mmol, 92% yield) as a yellow solid. LC-MS: (ESI, m / Z): 692.3 [M+H] +

[0513] Step 5: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol TIFF2025535367000175.tif48170

[0514] To a solution of 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (220.0 mg, 0.25 mmol) in acetonitrile (1 mL) was added 4 M hydrochloric acid in dioxane (1 mL) and the mixture was stirred at room temperature for 30 minutes. After completion, the solvent was removed in vacuo. The resulting solution was adjusted to pH 7 with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by Prep-HPLC under the following conditions: Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 54% B, 54% B in 10 min; Wavelength: 254 / 220 nm; RT1 (min): 9.6, 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2- (((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol (15.3 mg, 0.023 mmol, 9.3% yield). LC-MS: (ESI, m / Z): 648.2 [M+H] +

[0515] Example 17: 1 H NMR(300MHz,Methanol-d4,ppm)δ 7.98-7.96(m,1H),7.81-7.78(m,2H),7.53-7.49(m,1H),7.40-7.38(m,1H),7.33 (d,J=2.6Hz,1H),7.29-7.15(m,1H),6.82-6.77(m,1H),6.64-6.57(m,1H),4.86- 4.65(m,2H),4.55-4.41(m,2H),4.02(s,1H),3.92-3.71(m,4H),3.67-3.60(m,4H) ),3.31-3.14(m,2H),2.44-2.35(m,1H),2.19-2.07(m,3H),1.70(d,J=7.0Hz,3H). Example 18: 3-((R)-1-(5-(5-ethynylisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000176.tif203170

[0516] Step 1: 5-chloro-4-(trimethylstannyl)isoquinoline TIFF2025535367000177.tif23170

[0517] Under nitrogen, a solution of 4-bromo-5-chloroisoquinoline (1.5 g, 6.19 mmol), hexamethyldistannane (6.1 g, 18.62 mmol), and tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol) in toluene (15 mL) was stirred at 100 °C for 48 h. After completion, the resulting solution was quenched with saturated potassium fluoride solution and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (acetonitrile / water with 0.1% NH4HCO3) to afford 5-chloro-4-(trimethylstannyl)isoquinoline (1.0 g, 3.06 mmol, 49.5% yield) as a colorless oil. LC-MS: (ESI, m / Z): 328.0 [M+H] +

[0518] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolyl)-6-fluoro-3-methylsulfanyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate TIFF2025535367000178.tif42170

[0519] Under nitrogen, tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-(7-chloro-6-fluoro-3-methylsulfanyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-2-pyridyl]carbamate (800.0 mg, 1.32 mmol), (5-chloro A solution of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (107.0 mg, 0.13 mmol) was stirred at 90 °C for 1 h. After completion, the resulting solution was quenched with saturated potassium fluoride solution and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97:3) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolyl)-6-fluoro-3-methylsulfanyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (653 mg, 0.89 mmol, 67.5% yield) as a yellow solid. LC-MS: (ESI, m / Z): 734.2 [M+H] +

[0520] Step 3: tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolyl)-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate TIFF2025535367000179.tif54170

[0521] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolyl)-6-fluoro-3-methylsulfanyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (633.0 mg, 0.86 mmol) in dichloromethane (7 mL), 3-chloroperoxybenzoic acid (374.0 mg, 2.17 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. After completion, the resulting solution was quenched with saturated sodium bisulfite solution and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97:3) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolyl)-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (493.0 mg, 0.64 mmol, 74.6% yield) as a yellow solid. LC-MS: (ESI, m / Z): 766.2 [M+H] +

[0522] Step 4: tert-butyl (3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000180.tif42170

[0523] Under nitrogen, sodium tert-butoxide (181.0 mg, 1.88 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (300.0 mg, 1.88 mmol) in toluene (5 mL), and the mixture was stirred for 10 minutes at 0° C. Then, tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolyl)-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (480.0 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Upon completion, the resulting solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (91:9) to afford tert-butyl (3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (170 mg, 0.23 mmol, 36.4% yield) as a yellow solid. LC-MS: (ESI, m / Z): 745.3 [M+H] +

[0524] Step 5: 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(5-((triisopropylsilyl)ethynyl)isoquinolin-4-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000181.tif44170

[0525] tert-Butyl(3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl) in acetonitrile (2 mL) under nitrogen. A solution of pyridin-2-yl)carbamate (150.0 mg, 0.18 mmol), ethynyltriisopropylsilane (367.0 mg, 2.01 mmol), bis(acetonitrile)dichloropalladium(II) (6.0 mg, 0.02 mmol), X-phos (58.0 mg, 0.12 mmol), and cesium carbonate (197.0 mg, 0.60 mmol) was added at 90 °C for 4 h. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (89:11) to give 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(5-((triisopropylsilyl)ethynyl)isoquinolin-4-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, 0.09 mmol, 49.1% yield) as a yellow solid. LC-MS: (ESI, m / Z): 791.4 [M+H] +

[0526] Step 6: 3-((R)-1-(5-(5-ethynylisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000182.tif41170

[0527] A solution of 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-(5-((triisopropylsilyl)ethynyl)isoquinolin-4-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (65.0 mg, 0.08 mmol) and cesium fluoride (39.0 mg, 0.26 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 1.5 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by Prep-HPLC under the following conditions: Column: XBridge Prep OBD C18 Column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 50% B to 80% B, 80% B in 7 min; Wavelength: 254 / 220 nm; RT₁ (min): 6.4. 3-((R)-1-(5-(5-ethynylisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (8.4 mg, 0.01 mmol, 15.7% yield) was obtained. LC-MS: (ESI, m / Z): 635.3 [M+H] +

[0528] Example 18: 1H NMR(300MHz,Methanol-d6,ppm)δ 9.41(s,1H),8.50(s,1H),8.28(dd,J=8.1,1.3Hz,1H),8.04-7.96(m,2H),7.78 -7.68(m,2H),6.82-6.76(m,1H),6.62(q,J=6.7Hz,1H),5.31(d,J=53.5Hz,1H) ,4.87-4.36(m,4H),3.49-3.37(m,1H),3.32-3.30(m,2H),3.25-3.17(m,3H),3 .03-2.98(m,1H),2.24-2.02(m,3H),2.00-1.95(m,3H),1.69(d,J=6.6Hz,3H). Example 19: 3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000183.tif43170

[0529] Step 1: 3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000184.tif41170

[0530] A solution of tert-butyl (3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (60.0 mg, 0.07 mmol) in 4 M hydrochloric acid in dioxane (1 mL) was stirred at room temperature for 0.5 h. After completion, the resulting solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 52% B in 8.5 min; Wavelength: 220 nm; RT₁ (min): 6.6; Run number: 2. Obtained 3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (13.9 mg, 0.02 mmol, 30.2% yield). LC-MS: (ESI, m / Z): 645.3 [M+H] +

[0531] Example 19: 1H NMR(300MHz,DMSO-d6,ppm)δ 9.53(s,1H),8.52(s,1H),8.30(d,J=8.3Hz,1H),7.99-7.92(m,2H),7.80-7.74(m,1H),7.65-7 .63(m,1H),6.66(dd,J=7.5,4.9Hz,1H),6.36(q,J=6.8Hz,1H),5.74(d,J=20.0Hz,2H),5.27(d, J=54.0Hz,1H),4.46-4.43(m,2H),4.12(d,J=1.7Hz,2H),3.75-3.71(m,1H),3.54-3.38(m,1H), 3.18-2.94(m,3H),2.84-2.82(m,1H),2.22-2.04(m,3H),1.85-1.78(m,3H),1.60-1.56(m,3H). Example 20: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine Synthetic Route TIFF2025535367000185.tif89170

[0532] Step 1: tert-butyl (3-((R)-1-(5-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate TIFF2025535367000186.tif41170

[0533] Under nitrogen, to a solution of [(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol (280.0 mg, 1.85 mmol) in toluene (4 mL) was added sodium tert-butoxide (180.0 mg, 1.87 mmol), and the resulting solution was stirred for 10 minutes at 0° C. Then, tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-(7-chloro-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetrazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-2-pyridyl]carbamate (400.0 mg, 0.63 mmol) was added and stirred at room temperature for 1 hour. Upon completion, the resulting solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97:3) to afford tert-butyl (3-((R)-1-(5-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (320 mg, 0.32 mmol, 52.6% yield) as a yellow solid. LC-MS: (ESI, m / Z): 610.2 [M+H] +

[0534] Step 2: 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000187.tif46170

[0535] Under nitrogen, tert-butyl (3-((R)-1-(5-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (300 mL) in 1,4-dioxane (3 mL) and water (0.6 mL) was dissolved in water. A solution of [5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (465.0 mg, 0.97 mmol), tetrakis(triphenylphosphine)palladium (105.0 mg, 0.0900 mmol), and cesium carbonate (420.0 mg, 1.29 mmol) was stirred at 100° C. for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (96:4) to give 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (399 mg, 0.36 mmol, 85.4% yield) as a yellow solid. LC-MS: (ESI, m / Z): 907.3 [M+H] +

[0536] Step 3: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine TIFF2025535367000188.tif46170

[0537] A solution of 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (380.0 mg, 0.34 mmol) in trifluoromethanesulfonic acid (0.4 mL) in 2,2,2-trifluoroacetic acid (4 mL) was stirred at room temperature for 10 minutes. After completion, the solvent was removed in vacuo. The resulting solution was diluted with dichloromethane and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC under the following conditions: Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 55% B, 55% B in 10 min; Wavelength: 254 / 220 nm; RT (min): 8.9. 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (55.4 mg, 0.08 mmol, 24% yield) was obtained. LC-MS: (ESI, m / Z): 667.4 [M+H] +

[0538] Example 20: 1H NMR(400MHz,DMSO-d6,ppm)δ 7.97(dd,J=4.9,1.7Hz,1H),7.63(dd,J=7.5,1.8Hz,1H),6.67(dd,J=7.5,4.9Hz,1H),6.54( d,J=8.6Hz,1H),6.33(q,J=6.8Hz,1H),6.02(s,2H),5.65(s,2H),4.46-4.29(m,4H),3.71(dd ,J=15.9,6.4Hz,1H),3.36-3.34(m,1H),3.01-2.95(m,1H),2.73-2.62(m,1H),2.60-2.53(m ,1H),2.48-2.45(m,1H),2.38(s,3H),2.32(s,3H),2.24-2.06(m,1H),1.56(d,J=6.8Hz,3H). Example 21a: 3-((R)-1-((R)-5-(3-amino-2-chloro-5-methyl-6-(trifluo...

Claims

1. A compound having formula (I) or an atropisomer, stereoisomer, tautomer or pharmaceutically acceptable salt thereof (In the formula, Ring A is R ８ a substituted or unsubstituted 3- to 10-membered heterocycle, or R ８ a substituted or unsubstituted 5-10 membered heteroaryl; R ８ are independently halogen, CN, NH ２ , N.H.C. １～３ Alkyl, R ８Ａ Substituted or unsubstituted C １～６ alkyl, or R ８Ａ Substituted or unsubstituted C １～６ haloalkyl; R ８Ａ is halogen, unsubstituted C １～３ Alkyl, or unsubstituted C １～３ haloalkyl; n is 1 or 2; R １ is R ７ Substituted or unsubstituted indolyl, R ７ substituted or unsubstituted benzofuranyl, R ７ substituted or unsubstituted naphthyl, R ７ substituted or unsubstituted indazolyl, R ７ substituted or unsubstituted indenyl, R ７ substituted or unsubstituted benzothiazolyl, R ７ substituted or unsubstituted isoquinolinyl, R ７Ａ substituted or unsubstituted phenyl, or R ７Ａ substituted or unsubstituted pyridinyl; Each R ７ are independently hydrogen, halogen, CN, CH ２ OH, -OH, NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl, unsubstituted C ２～５ Alkynyl, unsubstituted C １～３ haloalkyl, or unsubstituted cyclopropyl; Each R ７ａ are independently hydrogen, halogen, NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ haloalkyl, or unsubstituted cyclopropyl; R ２ is OH, unsubstituted C １～３ Alkoxy, unsubstituted C １～３ Alkyl, or unsubstituted C １～３ haloalkyl; R ３ is an R containing N, S, or O ９ a substituted or unsubstituted 4- to 10-membered heterocycle; R ９ are independently selected from halogen, oxo, unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ Alkoxy, R １０ Substituted or unsubstituted C １～３ alkylidene, or R １０ Substituted or unsubstituted C ３～４ cycloalkyl, or R １０ a substituted or unsubstituted 3- or 4-membered heterocycle; Or, two R ９ Let's join together and ３～５ forming a cycloalkyl or 3- to 5-membered heterocycle; R １０ is hydrogen or halogen; R ４ is hydrogen, halogen, unsubstituted C １～３ Alkyl, unsubstituted C １～３ Alkoxy, or unsubstituted C １～３ haloalkyl; R ５ and R ６ are each independently hydrogen or unsubstituted C １～３ alkyl).

2. R １ But, R ７ Substituted or unsubstituted indolyl, R ７ substituted or unsubstituted benzofuranyl, R ７ substituted or unsubstituted naphthyl, R ７ substituted or unsubstituted indazolyl, R ７ substituted or unsubstituted indenyl, R ７ substituted or unsubstituted benzothiazolyl, or R ７ The compound of claim 1 which is a substituted or unsubstituted isoquinolinyl.

3. R １ But, R ７ Substituted or unsubstituted naphthyl or R ７ 3. The compound of claim 1 or 2, which is a substituted or unsubstituted isoquinolinyl.

4. R １ but, The compound according to any one of claims 1 to 3,

5. R １ but, The compound according to any one of claims 1 to 4,

6. R １ but, The compound according to any one of claims 1 to 5,

7. R １ But, R ７Ａ substituted or unsubstituted phenyl, or R ７Ａ The compound of claim 1 which is a substituted or unsubstituted pyridinyl.

8. R １ but, (In the formula, X １ is N, CH, CF, or CCl; R ７Ａ is hydrogen, halogen, unsubstituted C １～３ Alkyl, or unsubstituted C １～３ haloalkyl) 8. The compound of claim 1 or 7, wherein:

9. R １ but, (In the formula, X １ is N, CH, CF, or CCl; R ７Ａ is hydrogen, halogen, unsubstituted C １～３ Alkyl, or unsubstituted C １～３ haloalkyl) 9. The compound of claim 1, 7 or 8, wherein:

10. X １ The compound of claim 9 wherein is N.

11. R １ but, (In the formula, R ７Ａ is hydrogen, halogen, unsubstituted C １～３ Alkyl or unsubstituted C １～３ haloalkyl) The compound according to any one of claims 1 or 9 to 10,

12. R １ but, 12. The compound of any one of claims 1 or 9 to 11, wherein

13. X １ 10. The compound of claim 9, wherein is CH, CF, or CCl.

14. R １ but, (In the formula, R ７Ａ is hydrogen, F, or Cl) 14. The compound of claim 9 or 13, wherein:

15. R １ but, (In the formula, R ７Ａ is hydrogen, F, or Cl) 14. The compound of claim 9 or 13, wherein:

16. R １ but, (In the formula, R ７Ａ is hydrogen, halogen, unsubstituted C １～３ Alkyl, or unsubstituted C １～３ haloalkyl) 9. The compound of claim 1, 7 or 8, wherein:

17. R １ but, 17. The compound of any one of claims 1 or 7 to 16, wherein

18. R １ but, 18. The compound of any one of claims 1 or 7 to 17, wherein

19. R １ but, 19. The compound of any one of claims 1 or 7 to 18, wherein

20. R ４ The compound of any one of claims 1 to 19, wherein is Cl or F.

21. R ４ The compound according to any one of claims 1 to 20, wherein is F.

22. R ４ The compound according to any one of claims 1 to 21, wherein is Cl.

23. R ４ But OCH ３ The compound according to any one of claims 1 to 22,

24. R ３ but, (In the formula, Z is C(R ９ ) ２ or O; R ９ is hydrogen, halogen or R １０ Substituted or unsubstituted C １～３ Is alkylidene; Or, two R ９ Let's join together and ３～５ Forms a cycloalkyl or 3- to 5-membered heterocycle r is an integer from 0 to 12; j is 1, 2, or 3; k is 1 or 2. The compound according to any one of claims 1 to 23, wherein

25. R ３ but, (In the formula, R ９ is a halogen, -OCF ３ , -OCHF ２ , -OCH ２ F, R １０ Substituted or unsubstituted C １～３ alkylidene, or two R ９ Let's join together and １０ Substituted or unsubstituted C ３～５ Forming a cycloalkyl; r is an integer from 0 to 12; j is 1, 2, or 3; k is 1 or 2. The compound according to any one of claims 1 to 24,

26. R ３ but, (In the formula, Each R ９ are independently halogen or R １０ Substituted or unsubstituted C １～３ is alkylidene; Each R １０ are independently hydrogen or halogen; r is 0, 1, or 2; s is 0, 1, or 2. The compound according to any one of claims 1 to 25,

27. R ３ is (D1), (D2), or (D3) (In the formula, each R ９ are independently halogen or R １０ Substituted or unsubstituted C １～３ is alkylidene; Each R １０ are independently hydrogen or halogen; r is 0, 1, or 2; s is 0, 1, or 2. The compound according to any one of claims 1 to 26,

28. R ３ but, The compound according to any one of claims 1 to 27,

29. R ３ The compound according to any one of claims 1 to 27, wherein is (D1) (wherein r is 1).

30. R ３ (D2) (wherein r is 0 and each R １０ are independently hydrogen or F.

31. R ３ (D3) (wherein r is 0 and each R ９ and are independently hydrogen or halogen.

32. R ３ (D4) (wherein R １０ is halogen and s is 0, 1, or 2.

33. R ３ but, (In the formula, R １０ is a halogen and s is 0, 1, or 2. The compound according to any one of claims 1 to 25,

34. R ３ but, (In the formula, each R ９ are independently halogen, oxo, or unsubstituted C １～３ is alkyl; r is 0, 1 or 2. The compound according to any one of claims 1 to 25,

35. R ３ but, (In the formula, R ９ are independently halogen, oxo, or unsubstituted C １～３ is alkyl; r is 0, 1 or 2. The compound according to any one of claims 1 to 25,

36. R ３ but, (In the formula, Each R ９ are independently halogen, oxo, or unsubstituted C １～３ Is alkyl; or two R's ９ Let's join together and ３～５ forming a cycloalkyl or 3- to 5-membered heterocycle; r is 1 or 2. The compound according to any one of claims 1 to 23, wherein

37. R ３ but, The compound according to any one of claims 1 to 23, wherein

38. R ３ but, The compound according to any one of claims 1 to 23, wherein

39. R ２ The compound of any one of claims 1 to 38, wherein is methyl.

40. R ２ But CHF ２ , C.H. ２ F or CF ３ The compound according to any one of claims 1 to 38, wherein

41. Ring A is R ８ a substituted or unsubstituted 3- to 10-membered heterocycle, or R ８ The compound of any one of claims 1 to 40, which is a substituted or unsubstituted 5- to 10-membered heteroaryl.

42. Ring A is R ８ a substituted or unsubstituted 3- to 6-membered heterocycle, or R ８ The compound of any one of claims 1 to 41, which is a substituted or unsubstituted 5- to 6-membered heteroaryl.

43. Ring A is an R group containing at least one heterocyclic ring nitrogen atom ８ a substituted or unsubstituted 3- to 6-membered heterocyclic ring or R containing at least one heterocyclic ring nitrogen atom; ８ The compound of any one of claims 1 to 42, which is a substituted or unsubstituted 5- to 6-membered heteroaryl.

44. Ring A is an R group containing at least one heterocyclic ring nitrogen atom ８ The compound of any one of claims 1 to 43, which is a substituted or unsubstituted 5- or 6-membered heterocycle.

45. Ring A is an R group containing at least one heterocyclic ring nitrogen atom ８ The compound of any one of claims 1 to 44, which is a substituted or unsubstituted 6-membered heteroaryl.

46. Ring A is R ８ substituted or unsubstituted pyridinyl, R ８ Substituted or unsubstituted pyrimidinyl or R ８ 46. ​​The compound of any one of claims 1 to 45, which is a substituted or unsubstituted pyrazinyl.

47. Ring A is of the formula wherein X is CH or N, and n is 1 or 2.

47. The compound of any one of claims 1 to 46, which is a moiety of

48. Ring A is of the formula wherein X is CH or N.

48. The compound of any one of claims 1 to 47, which is a moiety of

49. R ５ and R ６ The compound of any one of claims 1 to 48, wherein each is hydrogen.

50. R ５ is CH ３ and R ６ 50. The compound of any one of claims 1 to 49, wherein is hydrogen.

51. A compound of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

52. A compound of Table 2, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

53. A compound of Table 3, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

54. 54. A pharmaceutical composition comprising a compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

55. 54. A method of treating cancer, comprising administering an effective amount of a compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 54.

56. 54. A method of treating cancer, comprising administering an effective amount of a compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

57. 57. The method of claim 56, wherein the cancer comprises a KRas mutation.

58. The KRas mutation is KRas Ｇ１２Ｄ Mutation or KRas Ｇ１２Ｖ 58. The method of claim 57, corresponding to a mutation.

59. 58. The method of claim 57, further comprising testing a sample from the patient prior to administration for the absence or presence of a KRas mutation.

60. 60. The method of claim 59, wherein the compound, its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, or pharmaceutical composition is administered to the patient after the patient sample indicates the presence of a KRas mutation.

61. 61. The method of any one of claims 56 to 60, wherein the cancer is tissue-independent.

62. 61. The method of any one of claims 56 to 60, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

63. 63. The method of claim 62, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

64. 63. The method of claim 62, wherein the cancer is pancreatic cancer.

65. 63. The method of claim 62, wherein the cancer is colorectal cancer.

66. 66. The method of any one of claims 56 to 65, further comprising administering at least one additional therapeutic agent.

67. 67. The method of claim 66, wherein the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an antimetabolite, or an alkylating agent.

68. 54. A compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

69. 54. Use of a compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of cancers involving KRas mutations.

70. 54. Use of a compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer involving a KRas mutation.

71. 54. Use of a compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutical salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

72. 54. A compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutical salt thereof, for the therapeutic and / or prophylactic treatment of cancers involving KRas mutations.

73. 54. A method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

74. 54. A method for inhibiting proliferation of a cell population, comprising contacting said cell population with a compound of any one of claims 1-53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

75. 75. The method of claim 74, wherein said inhibition of proliferation is measured as a decrease in cell viability of said cell population.

76. A method for preparing a labeled KRas mutant protein, comprising reacting a KRas mutant protein with a labeled compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to obtain the labeled KRas mutant protein.

77. 54. A method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or to a subject in need thereof a pharmaceutical composition of claim 55.

78. Methods for synthesizing the compounds described herein.

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