Azatetracyclic oxazepine compounds and uses thereof

Abstract

Compounds for the therapeutic and / or prophylactic treatment of cancers involving the KrasG12D mutation are provided. The present invention provides a compound represented by the following formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof: TIFF2026000916000490.tif36170 In the formula, X is O or NR 6 m and n are 1 or 2, and R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or two R 5 together form a bridge between two carbon atoms of ring A, which bridge contains 1 to 3 carbons and optionally 1 heteroatom selected from O and N.

Description

[Technical Field]

[0001] background

[0001] 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 is converted to a GDP-bound state (Ras) catalyzed by guanine nucleotide exchange factors (GEFs), particularly the SOS1 protein. GDP ) to the GTP-bound state (Ras GTP ) is converted into activated Ras GTP Ras mediates diverse growth-stimulatory functions through direct interaction with effectors such as Raf, PI3K, and Ral guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity is further accelerated by interaction with GTPase-activating proteins (GAPs), such as the neurofibromin 1 tumor suppressor.

[0002] Mutant Ras has reduced GTPase activity and remains activated for a prolonged period, promoting Ras-dependent signaling and cancer cell survival or proliferation. Mutations in Ras that affect its ability to interact with GAP or convert GTP back to GDP result in prolonged activation of the protein, resulting in extended signals that tell cancer cells to continue growing and dividing. Because these signals lead to cell growth and division, excessive RAS signaling can ultimately lead to cancer. Mutations in any of the three major isoforms of the RAS (HRas, NRas, or KRas) gene are common events in human tumorigenesis. Of the three Ras isoforms (K, N, and H), KRas is the most frequently mutated.

[0003]

[0003] The most common KRas mutations are found in residues G12 and G13 in the P loop and residue Q61. G12D is a frequent mutation in the KRas gene (glycine 12 to aspartic acid). 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 a critical oncology target.

[0004]

[0004] Therefore, there is an urgent need for treatments for G12D mutant KRas-mediated cancers. Summary of the Invention

[0005]

[0005] This specification provides solutions to the above problems and other problems in the art.

[0006] In a first aspect provided herein, there is provided a compound of formula (I) as described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0007]

[0007] In a second aspect provided herein, there is provided a compound of formula (IId) as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0008] In another aspect, provided herein are compounds set forth in Table 1 or pharmaceutically acceptable salts thereof.

[0009]

[0009] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0010]

[0010] In another aspect, provided herein is a method for treating a cancer containing a KRas mutation, the method comprising administering to a patient having such a cancer a compound described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0011]

[0011] In another aspect, provided herein is a method for regulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0012]

[0012] In another aspect, provided herein is a method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0013]

[0013] In another aspect, provided herein is a method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or administering to a subject in need thereof a pharmaceutical composition described herein.

[0014] In another aspect, provided herein is a method for preparing a labeled KRas G12D mutant protein, the method comprising reacting a KRas G12D mutant protein with a labeled compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, as described herein, to obtain the labeled KRas G12D mutant protein. [Brief explanation of the drawings]

[0015] [Figure 1]

[0014] Figure 1 shows the pharmacokinetic profiles of compounds 6, 7, 81, 194 and comparative compounds. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition

[0015] Disclosed herein are 6-azatetracyclic oxazepine compounds described herein or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which, in certain embodiments, are inhibitors or modulators of mutant KRas. In certain instances, such compounds and compositions are inhibitors or modulators of mutant G12D KRas as provided herein. The compounds and compositions described herein inhibit KRas. G12D The present invention is useful for treating diseases and disorders mediated by mutant KRas containing mutations.

[0017]

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

[0018]

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly 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 the IUPAC systematic nomenclature unless otherwise specified.

[0019]

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

[0020]

[0019] The terms "halogen" and "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.

[0021] The term "alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon radical. In some instances, an alkyl radical has 1 to 18 carbon atoms (C 1-18 In another example, the alkyl radical is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 or C 1-3Examples 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, -CHCHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, -CH(CH)). 3)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 (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH 3)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.

[0022] The term "oxo" refers to =O.

[0023] The term "alkoxy" refers to --O-alkyl.

[0024] The term "cyano" or "nitrile" refers to --C.ident.N or --CN.

[0025] The term "haloalkoxy" refers to --O-haloalkyl.

[0026] The terms "hydroxy" and "hydroxyl" refer to --OH.

[0027] 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 certain instances, an alkylidene radical is an alkylene radical having 1 to 6 carbon atoms (C 1-6 In another example, the alkylidene radical is C 1-3 , C 1-2 or C1. Exemplary alkylidenes include, but are not limited to, methylidene (=CH2), ethylidene (=CHCH3), and propylidene (=CH-CH2-CH3).

[0028] The term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbon radical having at least one carbon-carbon double bond, and includes radicals having both "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In certain instances, an alkenyl radical is an alkyl radical having 2 to 18 carbon atoms (C 2-18 In other examples, the alkenyl radical 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.

[0029] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In certain instances, an alkynyl radical is an alkyl group having 2 to 18 carbon atoms (C 2-18 In other examples, the alkynyl radical is C 2-12 , C 2-10 , C 2-8 , C 2-6 or C 2-3 Examples 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.

[0030] 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 certain instances, 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 (-CH2CH2CH2-), and the like.

[0031] 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 (C3-C 12In other examples, cycloalkyl is C 3-4 , C 3-5 , C 3-7 , C 3-8 , C 3-10 or C 5-10 In other examples, the monocyclic cycloalkyl group is C 3-4 , C 3-8 , C 3-6 or C 5-6 In another example, the bicyclic cycloalkyl group is C7-C 12 In another example, the cycloalkyl group of the 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.

[0032] The terms "heterocyclic group," "heterocyclic," "heterocycle," "heterocyclyl," or "heterocyclo" are used interchangeably and refer to a monocyclic, bicyclic, tricyclic, spiro, or bridged, saturated, partially saturated, or unsaturated non-aromatic ring system having 3 to 20 ring atoms, where 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 of the ring atoms in the ring system is a heteroatom, the system is heterocyclic, regardless of the point of attachment to the rest of the molecule. In one example, a heterocyclyl contains 3 to 10 ring atoms ("members") and includes monocyclic, bicyclic, tricyclic, spiro, and bridged ring systems where 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 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 a 3- to 7-membered monocyclic ring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl contains a 4- to 6-membered monocyclic ring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl contains a 3-membered monocyclic ring. In another example, a heterocyclyl contains a 4-membered monocyclic ring. In another example, a heterocyclyl contains a 5- to 6-membered monocyclic ring. In some embodiments, a heterocycloalkyl contains at least one nitrogen. In one example, a heterocyclyl group contains 0 to 3 double bonds. The nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO), and the nitrogen heteroatom may be optionally quaternized (e.g., [NR]). + Cl - , [NR4] + OH -Exemplary heterocyclyls include 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, and hexahydrothiopyranyl. oxahydropyrimidinyl, 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, tetrahydro[2H]indazolyl Hydrobenzimidazolyl, 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, dithio Ranipyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazedionyl, 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.

[0033] In certain embodiments, the heterocyclyl group or heteroaryl group is bonded through the carbon atom of the heterocyclyl group or heteroaryl group. For example, the carbon-bonded heterocyclyl group includes the bonding position at the 2, 3, 4, 5 or 6 position of the pyridine ring, the 3, 4, 5 or 6 position of the pyridazine ring, the 2, 4, 5 or 6 position of the pyrimidine ring, the 2, 3, 5 or 6 position of the pyrazine ring, the 2, 3, 4 or 5 position of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, the 2, 4 or 5 position of the oxazole, imidazole or thiazole ring, the 3, 4 or 5 position of the isoxazole, pyrazole or isothiazole ring, the 2 or 3 position of the aziridine ring, the 2, 3 or 4 position of the azetidine ring, the 2, 3, 4, 5, 6, 7 or 8 position of the quinoline ring, or the 1, 3, 4, 5, 6, 7 or 8 position of the isoquinoline ring.

[0034] In certain embodiments, the heterocyclyl or heteroaryl group is N-linked. Exemplary nitrogen-linked heterocyclyl or heteroaryl groups include those bonded at the 1-position of 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, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline.

[0035]

[0034] "Fused" refers to a ring structure described herein that shares one or more atoms (e.g., carbon atoms or nitrogen atoms) with an existing ring structure in a compound described herein.

[0036] The term "acyl" refers to a carbonyl-containing substituent of the formula -C(=O)-R, where R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, where alkyl, cycloalkyl, aryl, and heterocyclyl are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).

[0037]

[0036] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms have been replaced by halogen. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl. Substituted haloalkyl refers to a haloalkyl having moieties other than halogen. Unsubstituted haloalkyl refers to a haloalkyl that is not substituted with moieties other than hydrogen or halogen, as described herein.

[0038] As used herein, a bond that crosses a bond in a chemical structure TIFF2026000916000001.tif5170A wavy bond indicates the point of attachment of the atom to which it is bonded in a chemical structure to the rest of the molecule or to the rest of a fragment of a molecule.

[0039] In certain embodiments, divalent groups are described generically without a specific bonding arrangement. Unless otherwise specified, the generic description is understood to mean both bonding arrangements are included. For example, the group R 1 -R 2 -R 3 In the formula, the group R 2 When is depicted as -CH2C(O)-, this group is represented by R 1 -CH2C(O)-R 3 Even so, R 1-C(O)CH2-R 3 It is understood that they can also be combined as

[0040]

[0039] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered as needed to an animal, such as a human.

[0041]

[0040] The compounds described herein may be in the form of a salt, such as a pharmaceutically acceptable salt. "Pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, e.g., 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, which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable.

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

[0043]

[0042] In some embodiments, the salt is hydrochloride, hydrobromide, trifluoroacetate, sulfate, 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), napadisilate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethanesulfonate), or the like. Tan-1-(sulfonic acid)-2-sulfonate), isethionate (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), camsylate (camphor-10-sulfonate, e.g., (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]

[0043] A "sterile" preparation is aseptic or free of all living microorganisms and their spores.

[0045]

[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, conformational isomers, etc.

[0046]

[0045] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0047] 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, spectral properties, and biological activity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

[0048]

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

[0049]

[0048] The term "atropisomers" refers to two conformational isomers resulting from hindrance of rotation about a single bond, where the steric strain barrier to rotation is high enough to allow isolation of each conformer.

[0050] 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 l meaning that the compound is levorotatory. Compounds prefixed with (+) 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.

[0051] The term "tautomer" or "tautomeric form" refers to structural isomers of 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.

[0052] Certain compounds described herein can exist in unsolvated and solvated forms, including hydrated forms. A "solvate" refers to an association or complex of one or more solvent molecules with a compound 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 or amorphous forms. Generally, all physical forms are contemplated herein. The term "hydrate" refers to a complex where the solvent molecule is water.

[0053] The compounds described herein and their pharmaceutically acceptable salts also encompass isotopically labeled compounds that are identical to those described herein except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. All isotopes of the particular atom or element designated herein and their uses are contemplated. 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, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. 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), can 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 in 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 below, substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0054] The compounds described herein and their pharmaceutically acceptable salts may contain one or more asymmetric carbon atoms. Thus, the compounds of the present invention may exist as diastereomers, enantiomers, or mixtures thereof. In the synthesis of the compounds of the present invention, racemates, diastereomers, or enantiomers may be used as starting materials or intermediates. Mixtures of specific diastereomeric compounds can be separated or enriched for one or more specific diastereomers by chromatography or crystallization methods. Similarly, enantiomeric mixtures can be separated or enriched for enantiomers 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 configurations are contemplated herein.

[0055] In the structures depicted herein, when no particular chiral atom is specified, all stereoisomers are contemplated and included. When stereochemistry is specified by a solid wedge or dotted line representing a particular configuration, that stereoisomer is so specified and defined. Unless otherwise specified, when a solid wedge or dashed line is used, relative stereochemistry is intended.

[0056] 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, horses), primates, mice, and rats. In certain embodiments, the mammal is a human. In embodiments involving administration of a compound to a patient, the patient is typically in need thereof.

[0057] The terms "inhibit" and "reduce," or variations of these terms, include a measurable decrease or complete inhibition to achieve a desired result. For example, there can be a decrease in activity of about, at most about, or at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or more, as compared to normal, or any range derivable therein.

[0058] The term "treatment" refers to a clinical intervention designed to alter the natural history 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 condition, and achieving remission or improved prognosis. For example, a patient is successfully "treated" when one or more symptoms associated with a cancer described herein are alleviated or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancerous cells, reducing symptoms resulting from the disease, improving the quality of life of those suffering from the disease, reducing the dose of other medications required to treat the disease, and / or prolonging patient survival.

[0059] The term "delaying progression" of a disease refers to delaying, preventing, stalling, slowing, stabilizing, and / or postponing the onset of a cancer as described herein. The length of this delay may vary depending on the cancer being treated and / or the patient's medical history. As will be apparent to one of skill in the art, a sufficient or significant delay may, in fact, encompass prevention of a patient from developing or recurring cancer.

[0060] "Mutant KRas-mediated disease" and the like refers to a disease as described herein (e.g., a cancer as described herein) having a symptom as described herein or in need of treatment that is related, resulting from, dependent on, or otherwise correlated, in whole or in part, to mutant KRas activity as described herein. In certain such embodiments, the mutant KRas is KRas G12D is.

[0061] An "effective amount" or "therapeutically effective amount" is at least the minimum amount required to produce a measurable improvement or prevention of a cancer described herein. The effective amount herein may vary depending on factors such as the patient's condition, age, sex, and weight, as well as the ability of the agent to elicit a desired response in the patient. An effective amount is also an amount in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. Beneficial or desired results include results such as elimination or reduction of risk, alleviation of severity, delay in onset of disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and pathological endophenotypes manifested during disease development), reduction of one or more symptoms attributable to the disease, improvement in the quality of life of a person suffering from the disease, reduction in the dosage of other medications required to treat the disease, enhancement of the effectiveness of another medication, such as by targeting, delay in disease progression, and / or prolonged survival. In some embodiments, an effective amount of a drug may be effective to reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow or stop) cancer cell invasion into peripheral organs; inhibit (i.e., slow or stop) tumor metastasis; inhibit (i.e., slow or stop) tumor growth; and / or alleviate one or more symptoms associated with the disorder. An effective amount can be administered in one or more administrations.

[0062] As used herein, the terms "co-administration," "concomitant administration," and grammatical equivalents include 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 in separate compositions, administration at different times in separate compositions (i.e., sequential administration), or administration in which both agents are present in a single composition.

[0063]

[0062] The term "package insert" is used to refer to instructions customarily included in the commercial packaging of a therapeutic product that contain information about the efficacy, usage, dosage, administration, contraindications and / or precautions for use of that therapeutic product.

[0064] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function of a target protein, whether by inhibiting the activity or expression of the 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. Preferred antagonists herein specifically interact with (e.g., bind to) the target, although compounds that inhibit the biological activity of the target protein by interacting with other members of a 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 tumor development, growth, or spread.

[0065]

[0064] As used herein, the term "agonist" refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. Preferred agonists herein specifically interact with (e.g., bind to) the target, although compounds that initiate or enhance the biological activity of a target polypeptide by interacting with other members of a signal transduction pathway of which the target polypeptide is a member are also specifically included in this definition.

[0066] "Cancer" and "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" contains 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, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous cell carcinoma of the lung. Other cancers include: skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cavity, pharynx (oral cavity), lip, tongue, mouth, salivary gland, esophagus, larynx, hepatocellular, gastric, stomach, digestive tract, small intestine, large intestine, pancreas, cervix, ovary, liver, bladder, hepatoma, breast, colon, rectum, colorectal, genitourinary tract, biliary tract, thyroid, nipple, liver, endometrium, uterine corpus, salivary gland, kidney (kidney or renal), prostate, testis, vulva, peritoneum, anus, penis, bone, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system, brain, head and neck, Hodgkin's disease, and related metastases. Other examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocytopenia, myelofibrosis (including primary myelofibrosis), and chronic myelogenous leukemia (CML).

[0067] A "chemotherapeutic agent" is an agent useful in the treatment of a given disorder, such as, for example, cancer or an inflammatory disorder. Examples of chemotherapeutic agents are well known in the art. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of a chemotherapeutic agent, and combinations of two or more thereof.

[0068]

[0067] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds described herein and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, e.g., 2H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 Isotopically labeled compounds (e.g., 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes can be useful for their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds described herein and pharmaceutically acceptable salts thereof, one or more carbon atoms are 13 C or 14 It is replaced by C-enriched carbon. 15 O. 13 N, 11 C and 18 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following the schemes described herein or procedures analogous to those disclosed in the Examples, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0069] It is specifically contemplated that limitations discussed with respect to one embodiment provided herein may apply to other embodiments provided herein. Furthermore, any compound described herein and its pharmaceutically acceptable salts or compositions described herein can be used in any method provided herein, and any method provided herein can be used to make or utilize any compound described herein and its pharmaceutically acceptable salts or compositions described herein.

[0070]

[0069] 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 determine the value.

[0071]

[0070] The compounds described herein may have the stereochemistry depicted below. TIFF2026000916000002.tif33170 All three stereochemical depictions above are understood to be equivalent as described herein.

[0072] compound Provided herein are compounds having the following formula: Compounds of Formula (I). TIFF2026000916000003.tif36170 In the above formula, X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; R 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted indanyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7Asubstituted phenyl, or R 7A is a substituted pyridinyl; Each R 7 are independently halogen, OH, NH2, N(Me)2, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Alkynyl, unsubstituted C 1-3 Alkoxy or unsubstituted C 1-3 is haloalkyl, Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo or C 1-3 is alkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; or R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle, R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R6A a substituted or unsubstituted 3- to 4-membered heterocycle, R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle, R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 It is haloalkyl.

[0073]

[0072] In certain embodiments, further provided herein are compounds of Formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; R 1 is R 7A Substituted phenyl or R 7A is a substituted pyridinyl; Each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 It is haloalkyl.

[0074] In another embodiment, further provided herein is a compound of formula (I-1): TIFF2026000916000004.tif36170 In the above formula, R 1 , R 3 , R 4 , R 5 , X, m, and n are as described herein.

[0075] In certain embodiments, each R 4 is hydrogen. In another embodiment, R 4 One of the is hydrogen, and R 4 In another embodiment, one R 4 is hydrogen and one R 4 is CF3.

[0076] In one embodiment, R 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted indanyl, or R 7 In some embodiments, R is a substituted or unsubstituted benzothiazolyl. 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted isoquinolinyl, or R 7 In another embodiment, R is a substituted or unsubstituted indazolyl. 1 is R 7 In another embodiment, R 1 is R 7 In another embodiment, R 1 is R 7A Substituted phenyl or R 7A In certain embodiments, R 1 is R 7 In certain such embodiments, R 1 is R 7 substituted isoquinolinyl, and each R 4 is hydrogen. In another embodiment, R 1 is R 7 Substituted naphthyl, R 7 Substituted isoquinolinyl, R 7 Substituted indazolyl, R 7 Substituted indanyl, R 7 Substituted benzothiazolyl, or R 7AIn such embodiments, each R 4 is hydrogen or one R 4 is hydrogen and one R 4 is methyl.

[0077] In certain embodiments, each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 In another embodiment, each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 In another embodiment, at least one R 7A is NH. In some such embodiments, at least one R 7A is NH2, then at least one other R 7A is unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 It is haloalkyl or halogen.

[0078] In certain embodiments, each R 7 are independently halogen, OH, NH2, N(Me)2, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Alkynyl, unsubstituted C 1-3 Alkoxy or unsubstituted C 1-3 In another embodiment, each R 7A are independently halogen, OH, NH2, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 In another embodiment, at least one R 7 is NH2. In another embodiment, at least one R 7 is OH.

[0079] In one embodiment, R 1 teeth, TIFF2026000916000005.tif21170 In the above formula, X 1 is N or CR 7C is.

[0080] In one such embodiment, X 1 is N or CF, and each R 7A are independently hydrogen, halogen, or unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 In some such embodiments, each R 7A are independently hydrogen, Cl, methyl, ethyl, or CF3, where not more than one R 7A is hydrogen. In certain embodiments, at least one R 7A is NH. In certain embodiments, each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 In certain embodiments, one R 7A is cyclopropyl. In some such embodiments, one R 7A is cyclopropyl and is para to the amino group. In another such embodiment, one R 7A is cyclopropyl and is meta to the amino group. 1 is N. In some embodiments, X 1 is CR 7C In some such embodiments, R 7C is hydrogen or halogen.

[0081]

[0080] In another embodiment provided herein, there is provided a compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; TIFF2026000916000006.tif21170where X 1 is N or CR 7C and R 7C is hydrogen or halogen; Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo or C 1-3 is alkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 It is haloalkyl.

[0082] In one such embodiment, X 1 is N and R 7A is hydrogen, halogen, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 In another such embodiment, at least one R 7A is unsubstituted C 1-3 Haloalkyl (e.g., CF3). X 1 is N, in some embodiments, R 1 is the formula (E1): Includes part TIFF2026000916000007.tif21170.

[0083] In another embodiment, provided herein are compounds of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; TIFF2026000916000008.tif21170 each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo or C 1-3 is alkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C1-3 It is haloalkyl.

[0084] In one embodiment, R 1 contains a moiety of formula E1, then each R 7A is independently hydrogen, Cl, methyl, or CF. In another such embodiment, each R 7A are independently hydrogen, methyl, or CF3.

[0085] In one embodiment, R 1 is part of formula (E), and X 1 If N, then R 1 teeth, TIFF2026000916000009.tif21170

[0086] In another embodiment, R 1 includes a portion of the following formula (E2). TIFF2026000916000010.tif26170 In the above formula, each R 7A are independently hydrogen, halogen, or unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 In some such embodiments, R 7A In another such embodiment, only one of R 7A is not hydrogen. In certain embodiments of moieties (E2) and (3), at least one R 7A is halogen. In certain embodiments of moieties (E2) and (E3), at least one R 7A is unsubstituted C1-3 haloalkyl (e.g., CF3, CHF2, CF2CF3, CHCF3 or CH2CF3).

[0087] In another embodiment, provided herein are compounds of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; R 1 is (E2) or (E3); TIFF2026000916000011.tif26170 each R 7A are independently hydrogen, halogen, or unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 It is haloalkyl.

[0088] In one embodiment, R 1 teeth, TIFF2026000916000012.tif155170

[0089] In another embodiment, provided herein are compounds of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; TIFF2026000916000013.tif160170L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 It is haloalkyl.

[0090] In one embodiment, R 1 teeth, The file is TIFF2026000916000014.tif162170.

[0091] In another embodiment, R 1 teeth, The file is TIFF2026000916000015.tif20170.

[0092] In another embodiment, provided herein are compounds of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; TIFF2026000916000016.tif21170L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C1-3 It is haloalkyl.

[0093] In another embodiment, R 1 teeth, TIFF2026000916000017.tif55170 or a stereoisomer thereof, wherein t is 0, 1, 2, or 3. In certain embodiments, t is 1 or 2. In other embodiments, t is 3. In certain embodiments of the compounds described herein, R 1 is not of formula F, F1, F2, F3, F4 or F5, but is a monocyclic ring.

[0094] In another embodiment, R 1 is a moiety of formula (F), (F1), (F2), or (F3), and t is 0, 1, 2, or 3. In some embodiments, t is 1 or 2. In other embodiments, t is 3.

[0095] In one embodiment, R 1 teeth, TIFF2026000916000018.tif33170 or a stereoisomer thereof, wherein R 7 is as described herein.

[0096] In another embodiment, R 1 teeth, TIFF2026000916000019.tif34170 or a stereoisomer thereof.

[0097] In another embodiment, R 1 teeth, TIFF2026000916000020.tif28170 or a stereoisomer thereof, wherein t is 0, 1, 2, or 3. In certain embodiments, t is 1 or 2. In certain embodiments, R 7 are halogens, NH2, OH, C 1-3 Alkyl or C 2-3 It is alkynyl.

[0098] In certain embodiments of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, R 2 R contains one or more heteroatoms selected from N or O. 9 In another embodiment of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, R 2 contains one or more nitrogen heteroatoms, R 9 In another embodiment, R 2 contains at least one nitrogen heteroatom, R 9 It is a substituted or unsubstituted 5- to 8-membered heterocycle.

[0099] In one embodiment, R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 In certain embodiments, each R 9 is independently halogen, CN, OH, OCF, OCHF, or OCHF. In another such embodiment, each R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, or R 10 Substituted or unsubstituted C 1-3In yet another embodiment, each R 9 is independently R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, or R 10 Substituted or unsubstituted C 1-3 In another embodiment, each R 9 are independently halogen, R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 It is a substituted or unsubstituted 3- or 4-membered heterocycle.

[0100] In another embodiment, two R 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 In some such embodiments, two R 9 together form an unsubstituted cyclopropyl moiety. In another embodiment, two R 9 together form an unsubstituted oxetanyl or azetidinyl.

[0101] In another embodiment, two R 9 taken together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons. In some such embodiments, the bridge contains 1 carbon atom. In other such embodiments, the bridge contains 2 carbon atoms.

[0102] In one embodiment, R 9 is a halogen or R 10 Substituted or unsubstituted C 1-3 It is an alkylidene.

[0103] In one embodiment, R2 teeth, TIFF2026000916000021.tif18170 or a stereoisomer thereof, wherein R 9 is a halogen or R 10 Substituted or unsubstituted C 1-3 is alkylidene, r is an integer from 0 to 12; j is 1, 2 or 3; k is 1 or 2.

[0104] In one embodiment, R 2 is the following formula: Part of TIFF2026000916000022.tif33170 or a stereoisomer thereof, wherein R 9 are independently halogen or R 10 a substituted or unsubstituted C1-3 alkylidene; Each R 10 are independently hydrogen or halogen; r is 1 or 2.

[0105] In one embodiment, R 2 is the following formula: It is a portion of TIFF2026000916000023.tif33170 or a stereoisomer thereof.

[0106] In one embodiment, R 2 is the following formula: TIFF2026000916000024.tif26170 or a stereoisomer thereof.

[0107] In one embodiment, R 2 is the following formula: TIFF2026000916000025.tif16170 or a stereoisomer thereof, 9and r are as described herein. In some such embodiments, r is 1 or 2. In some embodiments, each R 9 are independently halogen or R 10 Substituted or unsubstituted C 1-3 It is alkyl.

[0108] In one embodiment, R 2 is the following formula: TIFF2026000916000026.tif21170 or a stereoisomer thereof.

[0109] In another embodiment, R 2 teeth, TIFF2026000916000027.tif19170 or a stereoisomer thereof, wherein R 9 are independently halogen, oxo or unsubstituted C 1-3 is alkyl; r is 1 or 2.

[0110] In another embodiment, R 2 teeth, TIFF2026000916000028.tif17170 or a stereoisomer thereof.

[0111] In another embodiment, R 2 teeth, Contains a portion of TIFF2026000916000029.tif17170 or its stereoisomer.

[0112] In yet another embodiment, R 2 teeth, TIFF2026000916000030.tif21170 or a stereoisomer thereof.

[0113] In another embodiment, R 2 teeth, TIFF2026000916000031.tif17170 or a stereoisomer thereof, wherein X 2 is CR 9 or O. In one embodiment, X 2 is O. In some such embodiments, X 2 is O and r is 0.

[0114] In another embodiment, R 2 teeth, TIFF2026000916000032.tif23170 or a stereoisomer thereof, wherein X 3 is CR 9 , N.R. 9 Or O.

[0115] In one embodiment, R 2 is part of formula (D), where X 3 is CR 9 where R 9 is as described herein. In some such embodiments, X 3 is CH or CF. In another such embodiment, R 2 is a moiety of formula (D) or (D1), and X 3 is O. In some embodiments, R 2 is part of formula (D), and X 3 is O and R 9 is unsubstituted C 1-3 In another embodiment, R 2 is part of formula (D), and X 3 is NR 9 and R 9 is oxo or unsubstituted C 1-3 It is alkyl.

[0116] In one embodiment, R 2 teeth, TIFF2026000916000033.tif60170 or a stereoisomer thereof. In certain embodiments, r is 0 or 1.

[0117] In one embodiment, L 1 is methylene. In some embodiments, R 2 is as described herein, and L 1 is methylene. In another embodiment, L 1 is R L1 Substituted or unsubstituted C 2-3 In some such embodiments, L is alkylene. A is unsubstituted C 2-3 In another such embodiment, L is alkylene. 1 is R L1 substitution C 2-3 alkylene and two R L1 together to form unsubstituted C 3-4 In some such embodiments, L 1 ,formula: I have TIFF2026000916000034.tif10170.

[0118] In certain embodiments of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, R 3 is halogen. In another embodiment, R 3 is -CN.

[0119] In certain embodiments of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, each R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 In some such embodiments, each R 5 are independently unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 In some embodiments, p is 0 or 1.

[0120] In another embodiment, two R 5together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally one heteroatom selected from O and N. In some such embodiments, two R 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbon atoms. In some such embodiments, the bridge contains 1 or 2 carbon atoms. In other such embodiments, the bridge contains 1 carbon atom. In other such embodiments, the bridge contains 2 carbon atoms.

[0121] In some embodiments, two R 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 In one embodiment, the bridge comprises an O heteroatom. In another embodiment, the bridge comprises an NR 11 Contains R 11 is hydrogen or methyl.

[0122] In some embodiments, ring A is a 6-membered ring (i.e., m and n are both 1). In some embodiments, ring A is a 7-membered ring, m is 2, and n is 1. In other embodiments, ring A is a 7-membered ring, m is 1, and n is 2. In some embodiments, X is NR 6 and R 6 is as described herein.

[0123] In one embodiment, R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-3 In some embodiments, R 6 is R 6A Substituted or unsubstituted C 1-3 In some embodiments, R 6 is hydrogen. In certain embodiments, R 6 is methyl.

[0124] In some embodiments, R 6 is R6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 It is alkynyl.

[0125] In such an embodiment, R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B In another such embodiment, R 6A is halogen, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1-3 alkyl, or a four-membered heterocycle.

[0126] In certain embodiments, each R 6B independently C 1-3 Alkyl or C 1-3 In some such embodiments, R 6B independently C 1-3 It is alkyl.

[0127]

[0126] Further provided herein is a compound of the formula: TIFF2026000916000035.tif74170, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, L 1 , and p are as described herein.

[0128]

[0127] Further provided herein is a compound of the formula: TIFF2026000916000036.tif75170 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, and p are as described herein.

[0129]

[0128] Further provided herein is a compound of the formula: TIFF2026000916000037.tif36170, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 , R 3 , R 4 , R 5 , X, and p are as described herein.

[0130] In certain embodiments, the compound of Formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises the formula (IId-1): TIFF2026000916000038.tif44170 In the above formula, R 2 , R 3 , R 4 , R 5 , R 7A , X, X 1 and p is as described herein.

[0131] In certain embodiments, the compound of formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises formula (IId-2): TIFF2026000916000039.tif44170 In the above formula, R 2 , R 3 , R 4 , R 5 , R 7A, X, and p are as described herein.

[0132] In certain embodiments, the compound of Formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises Formula (IId-3): TIFF2026000916000040.tif44170In the above formula, R 2 , R 3 , R 4 , R 5 , R 7A , X, and p are as described herein.

[0133] In certain embodiments, the compound of Formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises Formula (IId-4): TIFF2026000916000041.tif44170In the above formula, R 2 , R 3 , R 4 , R 5 , R 7A , X, and p are as described herein.

[0134] In certain embodiments, the compound of Formula (IId) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof comprises Formula (IId-5): TIFF2026000916000042.tif41170 In the above formula, R 2 , R 3 , R 4 , R 5 , X, and p are as described herein.

[0135] In certain embodiments, X is NH or N(CH). In certain embodiments, R 1 is a moiety of formula (E), (E1), (E2), (E3), (F), (F1), (F2), (F3), (F4), or (F5) described herein. 2is a moiety of formula (A), (A-1), (A-2), (A-3), (A-4), (B), (C), (D) or (D1) described herein.

[0136] In certain embodiments of the compounds of Formula (IIa), (IIb), (IIc), or (IId) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 2 is the expression: TIFF2026000916000043.tif24170 or a stereoisomer thereof. In certain such embodiments, the compounds described herein, their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof comprise Formula (IId) as described herein. In other such embodiments, the compounds described herein, their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof comprise Formula (IId-1), (IId-2), (IId-3), (IId-4), or (IId-5) as described herein.

[0137] In certain such embodiments, in a compound of Formula (IIa), (IIb), (IIc), or (IId) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 2 is the expression: Includes part TIFF2026000916000044.tif24170.

[0138] In certain such embodiments, the compounds described herein, their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof comprise Formula (IId) as described herein. In other such embodiments, the compounds described herein, their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof comprise Formula (IId-1), (IId-2), (IId-3), (IId-4), or (IId-5) as described herein.

[0139] In another embodiment, the compounds of formula (I) described herein have the formula: TIFF2026000916000045.tif37170 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, and p are as described herein. In certain such embodiments, X is NR 6 where R 6 is water or R 6A Substituted or unsubstituted C 1-3 It is alkyl.

[0140]

[0139] Table 1: TIFF2026000916000046.tif215170TIFF2026000916000047.tif215170TIFF2026000916000048.tif223170TIFF2026000916000049.tif223170TIFF2026000916000050.tif230170TIFF2026000916000051.tif245170TIFF2026000916000052.tif235170TIFF2026000916000053.tif250170TIFF2026000916000054.tif250170TIFF2026000916000055.tif225170TIFF2026000916000056.tif229170TIFF2026000916000057.tif250170TIFF2026000916000058.tif225170TIFF2026000916000059.tif249170TIFF2026000916000060.tif241170TIFF2026000916000061.tif229170TIFF2026000916000062.tif232170TIFF2026000916000063.tif232170TIFF2026000916000064.tif215170TIFF2026000916000065.tif230170TIFF2026000916000066.tif243170TIFF2026000916000067.tif251170TIFF2026000916000068.tif235170TIFF2026000916000069.tif232170TIFF2026000916000070.tif233170TIFF2026000916000071.tif220170TIFF2026000916000072.tif227170TIFF2026000916000073.tif222170TIFF2026000916000074.tif235170TIFF2026000916000075.tif235170TIFF2026000916000076.tif242170TIFF2026000916000077.tif228170TIFF2026000916000078.tif246170TIFF2026000916000079.tif247170TIFF2026000916000080.tif245170TIFF2026000916000081.tif227170TIFF2026000916000082.tif232170TIFF2026000916000083.tif243170TIFF2026000916000084.tif252170TIFF2026000916000085.tif246170TIFF2026000916000086.tif238170TIFF2026000916000087.tif236170TIFF2026000916000088.tif233170TIFF2026000916000089.tif222170TIFF2026000916000090.tif232170TIFF2026000916000091.tif226170TIFF2026000916000092.tif221170TIFF2026000916000093.tif234170TIFF2026000916000094.tif225170TIFF2026000916000095.tif234170TIFF2026000916000096.tif226170TIFF2026000916000097.tif247170TIFF2026000916000098.tif247170TIFF2026000916000099.tif235170TIFF2026000916000100.tif233170TIFF2026000916000101.tif251170TIFF2026000916000102.tif246170TIFF2026000916000103.tif244170TIFF2026000916000104.tif248170TIFF2026000916000105.tif249170TIFF2026000916000106.tif248170TIFF2026000916000107.tif250170TIFF2026000916000108.tif249170TIFF2026000916000109.tif248170TIFF2026000916000110.tif246170TIFF2026000916000111.tif215170TIFF2026000916000112.tif211170TIFF2026000916000113.tif213170T IFF2026000916000114.tif211170TIFF2026000916000115.tif211170TIFF2026000 916000116.tif213170TIFF2026000916000117.tif211170TIFF2026000916000118. tif211170TIFF2026000916000119.tif211170TIFF2026000916000120.tif141170.

[0141]

[0140] In certain embodiments, provided herein is a compound selected from compounds 1-36, 38-45, 47-62, 64-108, 110-146, and 149-291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0142]

[0141] In certain embodiments, provided herein is a compound selected from compounds 1-36, 38-45, 47-62, 64-108, and 110-125 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0143]

[0142] In certain embodiments, provided herein is a compound selected from compounds 126-146 and 149-291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, provided herein is a compound selected from compounds 6, 15, 24, 26, 29, 31-32, 57-59, 61-62, 64-66, 75-76, 91, 96, 104, 106, 111, 113, 118-124, 126-146, 149-156, 158-175, 181, 183, 186, 190-192, 195, 200, 204, 224-225, 228-229, 232-239, 241, 244-250, 255, 258-259, and 263 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0145] In certain embodiments, provided herein is a compound selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 57-58, 60-62, 64-77, 90-97, 100-102, 104, 108, 111, 113, 115, 118-146, 149-175, 181-183, 186-187, 190, 195, 200, 204, 224-232, 234-239, 241, 244-250, 255, 258-259, and 263 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, provided herein is a compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 57-62, 64-72, 74, 76, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259, and 263 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0147] In certain embodiments, provided herein is a compound selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 42-45, 47-48, 52, 57-58, 60-78, 84-88, 90-97, 100-104, 106, 108, 111-113, 115, 118-146, 149-175, 177-178, 181-183, 185-187, 189-192, 194-195, 197-200, 203-232, 234-250, and 252-291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0148] In certain embodiments, provided herein is a compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 42-45, 47-48, 52, 57-62, 64-72, 74, 76, 84-88, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259, and 263 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0149]

[0148] In certain embodiments, provided herein is a compound selected from compounds 42-45, 47-48, and 52 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0150]

[0149] In certain embodiments, provided herein is a compound selected from compounds 112, 205-218, 242-243, 252-254, 261-262, and 264-291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0151] Compound synthesis The compounds described herein of this disclosure, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared by a variety of methods as 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 can be prepared as described in Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R.C. LaRock, Comprehensive Organic Transformations, 2 nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.), vols. 1-9, Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A.R. Katrittzky and C.W. Rees (Eds.), Pergamon, Oxford 1984, vols. 1-9; Comprehensive Heterocyclic Chemistry II, A.R. Katrittzky and C.W. Rees (Eds.), Pergamon, Oxford 1996, vols. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vols. 1-40, and are prepared by methods known to those skilled in the art. The following synthetic reaction schemes are merely illustrative of some of the ways in which the compounds described herein, or pharmaceutically acceptable salts thereof, may be synthesized; various modifications to these synthetic reaction schemes are possible and would be suggested to one of skill in the art in view of this disclosure.

[0152] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein, as well as 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 its successors.

[0153] 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., 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, of the formulas described herein, can be prepared by combinatorial split-and-mix methods or by multiple parallel synthesis, 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.

[0154] 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 recognize 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 shown and described 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 methods described can be further modified in light of this disclosure using conventional chemistry.

[0155] In preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, it may be necessary to protect remote functionalities (e.g., primary or secondary amines) of intermediates. The need for such protection will vary with the nature of the remote functional group and the conditions of the preparation method. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethylenoxycarbonyl (Fmoc). The need for such protection is readily determinable. 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.

[0156] In the processes for preparing the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, 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 require multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include 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 equipment; small-scale analytical; simulated moving bed (SMB), preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography.

[0157] Another type of separation method involves treatment of the mixture with a reagent selected to bind or otherwise render separable the desired product, unreacted starting materials, reaction by-products, etc. Such reagents include adsorbents or absorbents, e.g., 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 ether, a liquid / liquid ion extraction reagent (LIX), etc. The selection of an appropriate separation method depends on the properties of the substances involved, e.g., boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of the substances in acidic and basic media in multiphase extraction, etc.

[0158] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to 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 to 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 by use of a chiral HPLC column.

[0159] Single stereoisomers, e.g., enantiomers, substantially free of their own stereoisomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereomers with optically active resolving agents (Eliel, E. and Wilen, S. “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, CH, (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of 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 direct 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).

[0160] In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like, with asymmetric compounds bearing acidic functional groups, such as carboxylic acids or sulfonic acids. Separation of the diastereomeric salts can be induced by fractional recrystallization or ionic chromatography. In the case of separation of optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can result in the formation of diastereomeric salts.

[0161] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a pair of diastereomers (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 reagent, such as a menthyl derivative, followed by separation of the diastereomers and hydrolysis to produce the pure or enriched enantiomer. A method for determining optical purity involves making a chiral ester of the racemic mixture, such as a menthyl ester (e.g., (-)menthyl chloroformate in the presence of a base), or the Mosher ester, a-methoxy-a-(trifluoromethyl)phenylacetate (Jacob III. J. Org. Chem. (1982) 47:4165), and determining the presence of two atropisomeric 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 according to the method for separation of atropisomeric naphthyl-isoquinolines (WO 96 / 15111). According to method (3), a racemic mixture of two enantiomers can be separated 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.

[0162] 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 obvious 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, other reactions disclosed herein or known in the art are recognized as having applicability for preparing other compounds described herein and their pharmaceutically acceptable salts.

[0163] Pharmaceutical preparations

[0162] 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 additives.

[0164] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice. Accordingly, there is further provided herein a pharmaceutical composition comprising a compound described herein, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients.

[0165] A typical formulation is prepared by mixing a compound described herein or a pharmaceutically acceptable salt thereof with an additive. Suitable carriers, diluents, and additives 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 additives used will vary depending on the means and purpose for which the compound described herein or a pharmaceutically acceptable salt thereof is being administered. The solvent is selected based on Generally Regarded as Safe (GRAS) solvents and is administered to a mammal. 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), etc., and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavorings, flavoring agents, and other known additives to present the drug (i.e., a compound described herein or a pharmaceutical composition thereof) in an aesthetically pleasing manner or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0166]

[0165] These formulations can be prepared using conventional dissolution and mixing techniques. For example, the bulk drug substance (i.e., a compound described herein or a pharmaceutically acceptable salt thereof) or a stabilized form thereof (e.g., a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned additives. The compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts are typically formulated into pharmaceutical dosage forms to provide an easily controllable dose of the drug and to enable patient compliance with the prescribed regimen.

[0167] Pharmaceutical compositions (or formulations) for application can be packaged in a variety of ways depending on the method used for administering 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, metal cylinders, etc. The container may include a tamper-evident assembly to prevent inadvertent access to the contents of the package. In addition, the container may be provided with a label describing the contents of the container. The label may also include appropriate warnings.

[0168] 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, the compounds or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts having the desired purity can be mixed with one or more pharmaceutically acceptable additives (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.) in the form of a lyophilized formulation, a milled powder, or an aqueous solution. Formulation is carried out by mixing with a physiologically acceptable carrier (i.e., a carrier that is nontoxic to recipients at the dosages and concentrations used) at ambient temperature, at an appropriate pH, and at the desired purity. The pH of the formulation depends primarily on the particular application and the concentration of the compound, but can range from about 3 to about 8. For example, formulation in acetate buffer at pH 5 is a suitable embodiment.

[0169]

[0168] Pharmaceutical compositions can generally be stored as a solid composition, a lyophilized formulation, or an aqueous solution.

[0170] The pharmaceutical compositions described herein are to be formulated, dosed, and administered in a manner consistent with good medical practice, i.e., amount, concentration, schedule, course, vehicle, and route of administration. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the schedule of administration, and other factors known to the medical practitioner. The effective amount of the compound or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt to be administered will depend on such considerations and is the minimum amount necessary to ameliorate or treat the hyperproliferative disorder.

[0171] As a general proposition, the initial pharmaceutically effective single dose of a compound of the invention or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof administered parenterally will range from about 0.01 to 100 mg / kg, i.e., from about 0.1 to 20 mg / kg of patient body weight per day, with a typical initial range of about 0.3 to about 15 mg / kg / day of the compound used. 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 approximately: 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.

[0172] Acceptable pharmaceutically acceptable additives are non-toxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium 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, The active ingredient may also be encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in microcapsules prepared by coacervation or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively. Such techniques are described in Remington's Pharmaceutical Sciences 16 th edition, Osol, A. Ed. (1980).

[0173]

[0172] Sustained-release formulations of the compounds described herein or their pharmaceutically acceptable salts can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds described herein or their pharmaceutically acceptable salts, which matrices are in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOTO (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0174] The formulations include those suitable for the routes of administration detailed herein. The 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. The formulations are usually prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0175] Formulations suitable for oral administration of the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts 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 in a suitable machine the active ingredient in a free-flowing form (such as a powder or granules), optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets are optionally coated or scored, and optionally formulated so as to provide slow or controlled release of the active ingredient from the tablet. Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups, or elixirs may be prepared for oral use. Formulations of the compounds described herein or their pharmaceutically acceptable salts intended for oral use can be prepared according to any method for preparing pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. Such excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating 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 adsorption 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.

[0176] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations of the present invention may be applied as a topical ointment or cream containing, for example, 0.075 to 20 wt% of the active ingredient. When formulated as an ointment, the active ingredient may be employed with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may 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, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient into the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues. The oil phase of the emulsions provided herein may be constituted from known ingredients in a known manner. This phase may simply comprise an emulsifier, but desirably comprises a mixture of at least one emulsifier with a fat or oil, or a mixture of both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. Preferably, both an oil and a fat are included. Taken together, the emulsifier, with or without a stabilizer, constitutes 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. Emulsifiers and emulsion stabilizers suitable for use in the formulations described herein include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0177] Aqueous suspensions containing the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts may contain the active agent 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 natural phospholipids (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., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as 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.

[0178] Pharmaceutical compositions of the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally administrable diluents or solvents, such as solutions in 1,3-butanediol, or may be prepared as lyophilized powders. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and physiological saline. Additionally, sterile, fixed oils are commonly used as solvents or suspending media. Therefore, any non-irritating, fixed oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids, such as oleic acid, can also be used in the preparation of injectable preparations.

[0179] The amount of active ingredient which can be combined with carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active agent, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight (w / w)) of the total composition. Pharmaceutical compositions of the present invention can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution for intravenous infusion may contain from about 3 to 500 μg of active ingredient per milliliter of solution to permit infusion of a suitable volume at a rate of about 30 mL / hour.

[0180]

[0179] 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 suspension solutions which may contain suspending agents and thickening agents.

[0181] Formulations suitable for topical administration to the eye also include eye drops in which 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%.

[0182]

[0181] 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.

[0183] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0184] Formulations suitable for pulmonary or intranasal administration have, for example, particle sizes in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in increments of 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nasal passages or by inhalation through the oral cavity to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents, such as conventional compounds used in the treatment or prevention of the disorders described below.

[0185]

[0184] 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, carriers as may be appropriate.

[0186] The formulations may be presented 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 a sterile liquid carrier for injection, e.g., water, immediately prior to use. 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 unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0187] In certain embodiments, the compounds of the present invention or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts are formulated as prodrugs. 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 compounds of the present invention or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. As defined herein, prodrugs include derivatives containing one or more moieties that modulate or improve one or more physical, physiological, or pharmaceutical properties, such as, but not limited to, solubility, permeability, uptake, biodistribution, metabolic stability, onset of action, or some other drug-like property, and are converted to a biologically active or more biologically active substance, as provided herein. In certain embodiments, the prodrugs herein have no biological activity until the compounds of the present invention or their pharmaceutically acceptable salts are released.

[0188] Method of administration 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 (subcutaneous, intramuscular, intravenous (IV), intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intraperitoneal, pulmonary, and intranasal. In certain embodiments, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are administered orally or intravenously. For local immunosuppressive treatment, the compounds of the invention can be administered intralesionally, including perfusing or otherwise contacting the graft with an inhibitor prior to transplantation. It will be understood that the preferred route may vary, for example, depending on the condition of the recipient. When administered orally, the compounds of the invention or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts may be formulated with a pharmaceutically acceptable carrier or excipient as a pill, capsule, tablet, etc. When administered parenterally, the compounds of the invention or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts may be formulated in a unit dose injectable form with a pharmaceutically acceptable parenteral vehicle, as described in more detail below.

[0189]

[0188] Thus, in certain aspects, provided herein are pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In certain embodiments, a compound described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is administered to a subject as an oral or parenterally administrable pharmaceutical composition. The compounds described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof can be formulated for topical or parenteral use, in which case the compound of the invention or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is dissolved or suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion.

[0190] Oral administration can facilitate patient compliance in taking the compounds of the present invention (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 tablets, uncoated tablets, chewable tablets) and capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, 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 sustained release.

[0191] Doses for treating human patients can range from about 10 mg to about 1000 mg of the compounds described herein. Typical doses can be from about 100 mg to about 300 mg of the compounds described herein. 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, administration refers to dosing frequency and does not refer to, for example, the number of individual units that a patient described herein must take in a single administration. Thus, in some embodiments, a patient may take two or more dosage units (e.g., two or more pills / tablets / capsules) QD. Additionally, toxicity factors can affect the dosage and administration regimen. When administered orally, pills, tablets, capsules, or tablets can be taken orally daily or less frequently for a specified period of time. The regimen can be repeated for multiple cycles of treatment.

[0192] Treatment methods and uses The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as Ras inhibitors. In certain embodiments, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as KRas inhibitors. In other embodiments, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as NRas inhibitors. In other embodiments, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as HRas inhibitors. In certain embodiments, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as G12D Ras inhibitors and as G12D KRas inhibitors.

[0193] Provided herein are methods of inhibiting Ras activity (e.g., KRas activity) in a cell (e.g., an ex vivo cell) by contacting the cell with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the activity is mutant G12D KRas activity.

[0194] Also provided herein are methods of treating cancers containing a KRas mutation, the methods comprising administering to a patient with such cancer an effective amount of a compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as described herein. In certain embodiments, the KRas mutation is a KRas G12D It is a mutation.

[0195] In certain embodiments, the method includes analyzing a sample from a patient (e.g., as described herein) for KRas prior to administration of a compound described herein or a pharmaceutically acceptable salt thereof. G12D In one such embodiment, the patient sample further comprises testing for the presence or absence of a KRas mutation. G12DAfter determining positive for a mutation (e.g., for its presence), a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, or pharmaceutical composition thereof, is administered to the patient.

[0196] The methods of treating cancer described herein include acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, 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 myelogenous leukemia (CML), chronic myeloproliferative disorder (CMD), and rheumatoid arthritis (HRD). Reproductive disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor Cancer, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell neck cancer (occult primary), midline lining carcinoma, oral cavity cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, 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, oropharyngeal cancer, For the treatment of cancers such as 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, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers.

[0197] In some embodiments, the cancer is a blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In some embodiments, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In some embodiments, the cancer is pancreatic cancer, lung cancer, or colon cancer. Lung cancer may be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In some embodiments, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma.

[0198] The methods provided herein may include administering a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to a subject in need of treatment with KRas. G12D This may also include testing a sample from the patient for the presence or absence of a mutation. G12D After demonstrating the presence of the mutation, the compound, its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, or pharmaceutical composition is administered to the patient. G12D Unless containing the mutation, the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts are not administered.

[0199] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the cancer is tissue-agnostic (KRas G12D In some such embodiments, the pancreatic, lung, or colorectal cancer is a KRas G12D Including mutations.

[0200] Further provided herein are KRas G12D In one such embodiment, provided herein is a method for treating lung cancer in a patient having the lung cancer, the method comprising administering to the patient a therapeutically effective amount of a KRas mutation. G12DA method (M1) for treating lung cancer in a patient having the lung cancer comprising a mutation, the method 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 same). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is adenocarcinoma, NSCLC, squamous cell lung cancer (SCLC), or large cell lung cancer. In some embodiments, the lung cancer is adenocarcinoma, NSCLC, or SCLC. 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 II lung cancer. In some embodiments, the lung cancer is stage III or IV lung cancer. The methods provided herein include administering a compound as 1L therapy.

[0201] Further provided herein are KRas G12D In one such embodiment, provided herein is a method for treating pancreatic cancer in a patient having pancreatic cancer comprising a KRas mutation. G12D A method (M2) for treating pancreatic cancer in a patient having pancreatic cancer comprising a mutation, the method 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 at stage 0, I, or II. In another embodiment, the pancreatic cancer is at stage III or stage IV.

[0202] Further provided herein are KRas G12D In one such embodiment, provided herein is a method for treating colon cancer in a patient having a colon cancer comprising a KRas mutation. G12DA method of treating colon cancer in a patient having a colon cancer comprising a mutation (M3), the method 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 stage I or II. In another embodiment, the colon cancer is stage III or stage IV.

[0203] In certain embodiments of methods M1, M2, and M3 described herein, the method comprises: (a) KRas in samples from patients suspected of diagnosed cancer G12D Determining the presence or absence of mutations; (b) administering to said patient an effective amount of a compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, as described herein; Further includes:

[0204] Further provided herein are KRas G12D In one embodiment of such a method, the method comprises: (a) KRas in samples from patients suspected of diagnosed cancer G12D Determining the presence or absence of mutations; (b) administering to said patient an effective amount of a compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, as described herein; Includes.

[0205] In certain embodiments of such methods, the patient has been diagnosed with a cancer described herein. In other embodiments of such methods, the sample is a tumor sample taken from the subject. In certain such embodiments, the sample is taken before administration of any therapy. In other such embodiments, the sample is taken before administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and after administration of another chemotherapeutic agent. In other embodiments of such methods, a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered as described herein (e.g., orally or IV).

[0206] Also provided herein are compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, for use as therapeutically active substances. In certain such embodiments, the compounds of the invention, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are selected from the group consisting of Kras G12D It may be for the therapeutic treatment of cancers that contain the mutation.

[0207] Further provided herein is a method for the treatment of Kras G12D In one embodiment, the compounds of the present invention, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are compounds for the therapeutic and / or prophylactic treatment of cancers containing mutations in KRas. G12D In the preparation of a medicament for the therapeutic treatment of cancers containing the mutation. Further 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.

[0208] Also provided herein are methods for inhibiting tumor metastasis, the methods comprising administering to a patient having a tumor a therapeutically effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, the inhibition is achieved by inhibiting KRas G12D In another embodiment, 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 a stabilization of tumor size (e.g., no further growth). In another embodiment, inhibiting tumor metastasis in a patient described herein results in the amelioration of cancer and / or its symptoms.

[0209]

[0208] Also provided herein are methods of inhibiting proliferation of a cell population, the methods 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 in a human patient. In another embodiment, the cell population is in a human patient. G12D Including mutations.

[0210] Also provided herein are methods of inhibiting KRas in a patient in need thereof, 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 certain embodiments, the KRas inhibited is KRas G12D In another embodiment, inhibiting KRas results in a reduction in tumor size. In another embodiment, inhibiting KRas leads to the amelioration of cancer and / or its symptoms.

[0211] Further provided herein are methods for modulating the activity of a KRas mutant protein, the methods comprising reacting the mutant protein with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, the mutant protein is a KRas G12D In one embodiment, the activity of KRas is decreased after contact with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, downregulating the activity of a KRas mutant protein treats a cancer described herein in a patient described herein. In another embodiment, downregulating the activity of a KRas mutant protein reduces tumor size. In another embodiment, downregulating the activity of a KRas mutant protein ameliorates a cancer described herein and / or its symptoms.

[0212] In some embodiments, the methods provided herein involve inhibiting KRas in a cell. G12D and inhibiting Kras activity in the cell by contacting the cell with an amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, sufficient to inhibit Kras activity. G12D In some embodiments, the methods provided herein involve inhibiting Kras activity in a tissue. G12D and inhibiting the activity of Kras in the tissue by contacting the tissue with an amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, sufficient to inhibit the activity of Kras in the tissue. G12D In some embodiments, the methods provided herein include inhibiting Kras activity in a patient. G12D and inhibiting Kras in the patient by contacting the patient with an amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, sufficient to inhibit the activity of Kras. G12D This includes inhibiting the activity of a compound.

[0213] Further provided herein are labeled KRas G12D A method for preparing a mutant protein, the method comprising: G12D The mutant protein is reacted with a labeled compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to produce labeled KRas. G12D In some embodiments, the label is an imaging agent. In some embodiments, the labeled KRas G12D can be used to detect the presence or absence of G12D mutant KRas in patient samples, thereby detecting the presence or absence of cancer mediated by mutant KRas.

[0214] Also provided herein are methods for inhibiting Ras-mediated cell signaling. In certain embodiments, the methods include contacting cells with an effective amount of one or more compounds disclosed herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof. Inhibition of Ras-mediated signaling can be assessed and demonstrated by various methods known in the art. Non-limiting examples include demonstrating (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 levels of downstream signaling molecules in the Ras pathway, such as a decrease in pMEK levels, and / or (e) a decrease in binding of the Ras complex to downstream signaling molecules, including, but not limited to, Raf. Kits and commercially available assays are available for determining one or more of the above.

[0215] KRas mutations, including the G12D mutation, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to administering the disclosed compounds described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (e.g., in the form of a pharmaceutical composition), to a patient in need of treatment for a hematological malignancy. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the disclosed compounds can be used for the treatment of diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In another embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are useful in the treatment of lymphoma, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0216]

[0215] If the tumor or cancer G12D Determining whether or not a mutation is present 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 properties of a putative KRas mutant protein. The sequence of wild-type human KRas (e.g., Accession No. NP203524) is known in the art.

[0217] 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-specific 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 the G12d KRas mutation by real-time PCR. Real-time PCR uses a fluorescent probe specific for the KRas G12D mutation. If the mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRas G12D mutation is identified using direct sequencing of specific regions within the KRas gene (e.g., exon 2 and / or exon 3). This technique identifies all possible mutations within the sequenced region.

[0218]

[0217] If the tumor or cancer G12D Various samples can be used in the method for determining whether a sample contains a mutation. 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.

[0219]

[0218] 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 (e.g., IV administration). In some embodiments, the cancer is characterized by KRas G12D In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In some embodiments, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, 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.

[0220] 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 of the combined pharmaceutical formulation or administration regimen preferably has complementary activity to the compounds described herein, or their pharmaceutically acceptable salts, so as not to adversely affect each other. Combination therapy can produce "synergistic effects" and be proven to be "synergistic," i.e., the effect achieved when the active ingredients are used together exceeds the sum of the effects resulting from using the compounds separately.

[0221]

[0220] Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses. Combination administration includes co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in either order, preferably with a period during which both (or all) active agents simultaneously exert their biological activity.

[0222]

[0221] 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 therapeutic method. The amounts of the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and other pharmaceutically active agents, and the relative timing of administration, will be selected to achieve the desired combined therapeutic effect.

[0223]

[0222] 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 (such as irinotecan, or such as etoposide, or such as doxorubicin), a taxane (such as an anti-microtubule agent including paclitaxel and docetaxel), an antimetabolite (such as 5-FU, or such as gemcitabine), an alkylating agent (such as cisplatin, or such as cyclophosphamide), or a taxane.

[0224] 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 GFR inhibitor is a dual or pan-HER inhibitor. In other embodiments, the additional therapeutic agent is a phosphatidylinositol-3-kinase (PI3K) inhibitor such as GDC-0077, GDC-0941, MLN1117, BYL719 (alpelisib), or BKM120 (buparlisib). DC-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).

[0225] In yet 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 (figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (lovatumumab).

[0226] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, pacritinib, ruxolitinib, or TG101348.

[0227] In some other embodiments, the additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0228] In some other embodiments, the additional therapeutic agent is an antibody-drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vedotin, RG7986, RG7882, RG6109, or RO7172369.

[0229] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist. In some embodiments, the MDM2 antagonist is idasanutlin.

[0230] In some other embodiments, the additional therapeutic agent is an agonist antibody against CD40. In some embodiments, the agonist antibody against CD40 is cericrelumab (RG7876).

[0231] In some other embodiments, the additional therapeutic agent is a bispecific antibody. In some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0232] In some other embodiments, the additional therapeutic agent is a targeted immune cytokine. In some embodiments, the targeted immune cytokine is RG7813 or RG7461.

[0233] 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.

[0234] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine. In some embodiments, the personalized cancer vaccine is RG6180.

[0235] In some other embodiments, the additional therapeutic agent is an inhibitor of a BET (bromodomain and extraterminal family) protein (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0236] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0237] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545, diredestrant).

[0238] In some other embodiments, the additional therapeutic agent is a MET kinase inhibitor such as crizotinib, tivantinib, AMG337, cabozantinib, or foretinib, hi other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody against MET, such as onartuzumab.

[0239] In a further embodiment, the additional therapeutic agent is an SRC family non-receptor tyrosine kinase inhibitor. For example, in some embodiments, the additional therapeutic agent is an inhibitor of a subfamily of SRC family non-receptor tyrosine kinases. Exemplary inhibitors in this regard include dasatinib. Other examples in this regard include ponatinib, saracatinib, and bosutinib.

[0240] 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.

[0241] 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.

[0242] In other embodiments, the protein kinase inhibitor is taselisib, ipatasertib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, atezolizumab, bevacizumab, bosutinib, cetuximab, crizotinib, dasatinib, or entrectinib. The additional therapeutic agent is selected from the group consisting of rulotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, and vemurafenib. In still other 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.

[0243] 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.

[0244] Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex® (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as many other chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metuledopa, and uredopa; ethylenimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphamide, and trimethylolmelamine; chloramphenicol, ... Nitrogen mustards such as mubucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; aclacinomycin, actinoma Isin, autramycin, 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, pepromycin antibiotics such as mycobacterium thiamin, thiamin thiamin, puromycin, chelamycin, 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; analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;Pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calucelone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziconazole; elfomithine; 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;Triazicon;2,2',2''-Trichlorotriethylamine;Urethane;Vindesine;Dacarbazine;Mannomustine;Mitobronitol;Mitolactol;Pipobroman;Gacytosine;Arabinoside ("Ara-C");Cyclophosphamide;Thiotepa;Taxanes, e.g., paclitaxel (Taxol™, Bristol-Myers Squibb) Squibb Oncology, Princeton, NJ) and docetaxel (Taxotere™, 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 also include antihormonal agents that limit or inhibit the action of hormones on tumors, such as tamoxifen (Nolvadex; TM), raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifen, keoxifen, LY Antiestrogens such as 117018, onapristone, and toremifene (Fareston); antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; 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 RFS 2000; and difluoromethylornithine (DMFO). Optionally, the compounds described herein or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof may be used in combination with other steroids such as Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD , Avicin, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alfalazine, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxin, Antitumor drug, Antitumor herbal medicine, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific antitumor agents, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, raltotecan, mafosfamide, mitozolomide, na It can be used in combination with commonly prescribed anticancer drugs such as foxidine, 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.

[0245] The exact method for administering a compound of the invention and an additional therapeutic agent will be apparent to one of skill in the art. In some exemplary embodiments, a compound of the invention and an additional therapeutic agent are co-administered. In other embodiments, a compound of the invention and an additional therapeutic agent are administered separately.

[0246] In some embodiments, a compound of the present invention and an additional therapeutic agent are administered simultaneously or separately with a second agent. This combined administration includes simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any additional therapeutic agent can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound described herein and any additional therapeutic agent can be administered simultaneously, where both agents are present in separate formulations. In another alternative, a compound of the present invention can be administered immediately followed by any additional therapeutic agent described herein, or vice versa. In some embodiments of separate administration protocols, a compound described herein and any additional therapeutic agent are administered minutes, hours, or days apart.

[0247] manufactured goods Also provided herein are articles of manufacture, or "kits," containing materials useful for treating cancer as provided herein. In some embodiments, the kits comprise a container containing a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. The kit may further comprise a label or package insert affixed to 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, or a formulation thereof, that is effective for treating a medical condition, and may have a sterile access port (e.g., the container may be an intravenous solution bag or vial having a stopper pierceable by a hypodermic needle). At least one active agent in the compositions of the invention 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. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0248] In another embodiment, the kit is suitable for delivery of a solid oral form (e.g., a tablet or capsule) of a compound described herein or a pharmaceutically acceptable salt thereof. Such a kit can include a plurality of unit dosages. An example of such a kit is a "blister pack." Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.

[0249] Implementation

[0248] The following are exemplary embodiments of the present invention.

[0250] Embodiment 0. A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; R 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted indanyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7A substituted phenyl, or R 7A is a substituted pyridinyl; Each R 7 are independently halogen, OH, NH2, N(Me)2, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Alkynyl, unsubstituted C 1-3 Alkoxy or unsubstituted C 1-3 is haloalkyl, Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo or C 1-3 is alkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle, R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle, R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 haloalkyl, A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0251] Embodiment 1. A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; R 1 is the formula (E), where X 1 is N or CR 7C and R 7C is hydrogen or halogen; Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo or C 1-3 is alkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 haloalkyl, A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0252]

[0251] Embodiment 2. X 1 is CR 7C and R 7C is hydrogen or halogen, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0253]

[0252] Embodiment 3. X 1 is N, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0254] Embodiment 4. A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; R 1 is a moiety of formula (E2) or (E3), Each R7A are independently hydrogen, halogen, or unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3haloalkyl, A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0255]

[0254] Embodiment 5. R 7A is hydrogen, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0256]

[0255] Embodiment 6. R 7A The compound of embodiment 4, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is not hydrogen.

[0257] Embodiment 7. At least one R 7A is halogen, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0258]

[0257] Embodiment 8. At least one R 7A Unsubstituted C 1-3 The compound of embodiment 4, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

[0259] Embodiment 9. A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; TIFF2026000916000121.tif160170L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 haloalkyl, A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0260] Embodiment 10. A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; R 1 is R 7A Substituted phenyl or R 7A is a substituted pyridinyl; Each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 haloalkyl, A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0261] Embodiment 11. A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; TIFF2026000916000122.tif185170L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 haloalkyl, A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0262] Embodiment 12. A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; R 1 is formula (E1); Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C1-3 Alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B is CN, oxo or C 1-3 is alkyl; L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6Care each independently C 1-3 Alkyl or C 1-3 haloalkyl, A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0263] Embodiment 13. A compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: X is O or NR 6 and; m is 1 or 2; n is 1 or 2; where n and m together form a 6- or 7-membered ring A; p is 0, 1 or 2; TIFF2026000916000123.tif22170L 1 is R L1 Substituted or unsubstituted C 1-4 is alkylene; R L1 is halogen or unsubstituted C 1-3 alkyl or two R L1 together to form unsubstituted C 3-4 forming a cycloalkyl; R 2 R contains one or more heteroatoms selected from N, S or O. 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or 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 The Two R's 9 Together, R 10 Substituted or unsubstituted C 3-5 Cycloalkyl or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 form a heterocyclic ring; or The Two R's 9 together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, the bridge containing 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen or C 1-3 is an unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 alkyl or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 is haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 haloalkyl; or The Two R's 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons and optionally 1 heteroatom selected from O and N; or The Two R's 5 together form a bridge between two carbon atoms of ring A, which bridge is O or NR 11 including one of the following; R 11 is hydrogen, C(O)CH3 or unsubstituted C 13 is alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle; R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle; R 6B and R 6C are each independently C 1-3 Alkyl or C 1-3 haloalkyl, A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0264]

[0263] Embodiment 14. R 4 14. The compound of any one of embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0265]

[0264] Embodiment 15. One R 4 is hydrogen and one R 4 14. The compound of any one of embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is methyl.

[0266]

[0265] Embodiment 16. R 4 is hydrogen and one R 4 14. The compound of any one of embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein

[0267]

[0266] Embodiment 17. Each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3The compound of any one of embodiments 1 to 3, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, which is haloalkyl.

[0268]

[0267] Embodiment 18. At least one R 7A or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 3, 10, 12, and 14 to 17, wherein is NH2.

[0269]

[0268] Embodiment 19. L 1 19. The compound of any one of embodiments 1 to 18, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is methylene.

[0270]

[0269] Embodiment 20. L 1 R L1 Substituted or unsubstituted C 2-3 19. The compound of any one of embodiments 1 to 18, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is alkylene.

[0271] Embodiment 21. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is a moiety of formula (A) or a stereoisomer thereof, wherein: R 9 is a halogen or R 10 Substituted or unsubstituted C 1-3 is alkylidene, r is an integer from 0 to 12; j is 1, 2 or 3; k is 1 or 2; The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0272] Embodiment 22. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is a moiety of formula (B) or a stereoisomer thereof, wherein: R 9 are independently halogen or unsubstituted C 1-3 is alkyl; r is 1 or 2; The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0273] Embodiment 23. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 but, TIFF2026000916000124.tif21170 or a stereoisomer thereof, The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0274] Embodiment 24. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 but, TIFF2026000916000125.tif34170 or a stereoisomer thereof, wherein R 9 are independently halogen or R 10 a substituted or unsubstituted C1-3 alkylidene; Each R 10 are independently hydrogen or halogen; r is 1 or 2; The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0275] Embodiment 25. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 but, TIFF2026000916000126.tif26170 or a stereoisomer thereof, The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0276] Embodiment 26. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is a moiety of formula (C) or a stereoisomer thereof, where X 2 is CR 9 or O, The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0277] Embodiment 27. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is a moiety of formula (D) or (D1) or a stereoisomer thereof, and X 3 is CR 9 , N.R. 9 or O, The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0278] Embodiment 28. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 but, TIFF2026000916000127.tif29170 or a stereoisomer thereof, The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0279] Embodiment 29. A compound according to any one of embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 but, TIFF2026000916000128.tif15170, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0280]

[0279] Embodiment 30. R 3 30. The compound of any one of embodiments 1 to 29, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is halogen.

[0281] Embodiment 31. A compound according to any one of embodiments 1 to 30, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein two R 5 together form a bridge between two carbon atoms of ring A, and this bridge contains 1 to 3 carbons; The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0282] Embodiment 32. The compound of Embodiment 31, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the bridge contains two carbon atoms.

[0283] Embodiment 33. The compound of embodiment 31, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the bridge contains one carbon atom.

[0284] Embodiment 34. X is NR 6 34. The compound of any one of embodiments 1 to 33, wherein:

[0285]

[0284] Embodiment 35. R6 is hydrogen or R 6A Substituted or unsubstituted C 1-3 35. The compound of embodiment 34, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0286]

[0285] Embodiment 36. R 6 R 6A Substituted or unsubstituted C 1-3 35. The compound of embodiment 34, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0287]

[0286] Embodiment 37. R 6A But halogen, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1-3 37. The compound of any one of embodiments 34 to 36, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: R is alkyl or a 4-membered heterocycle.

[0288]

[0287] Embodiment 38. R 6 is hydrogen, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0289]

[0288] Embodiment 39. R 2 Embodiment 39. The compound of any one of embodiments 1 to 38, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein is azetidinyl, oxetanyl, or thietanedioxide.

[0290]

[0289] Embodiment 40. A compound according to any one of embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) comprises formula (IIa), (IIb), (IIc) or (IId), or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0291]

[0290] Embodiment 41. A compound according to any one of embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) comprises formula (IIIa) or (IIIb), or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0292]

[0291] Embodiment 42. A compound selected from compounds 1 to 36, 38 to 45, 47 to 62, 64 to 108, 110 to 146, and 149 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0293]

[0292] Embodiment 43. A compound selected from compounds 1 to 36, 38 to 45, 47 to 62, 64 to 108, and 110 to 125 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0294]

[0293] Embodiment 44. A compound selected from compounds 126-146 and 149-291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0295]

[0294] Embodiment 45. A compound selected from compounds 6, 15, 24, 26, 29, 31-32, 57-59, 61-62, 64-66, 75-76, 91, 96, 104, 106, 111, 113, 118-124, 126-146, 149-156, 158-175, 181, 183, 186, 190-192, 195, 200, 204, 224-225, 228-229, 232-239, 241, 244-250, 255, 258-259, and 263 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0296]

[0295] Embodiment 46. A compound selected from compounds 6, 12 to 18, 23 to 24, 26, 29, 31 to 36, 57 to 58, 60 to 62, 64 to 77, 90 to 97, 100 to 102, 104, 108, 111, 113, 115, 118 to 146, 149 to 175, 181 to 183, 186 to 187, 190, 195, 200, 204, 224 to 232, 234 to 239, 241, 244 to 250, 255, 258 to 259, and 263 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0297]

[0296] Embodiment 47. A compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 57-62, 64-72, 74, 76, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259, and 263 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0298]

[0297] Embodiment 48. A compound selected from compounds 6, 12 to 18, 23 to 24, 26, 29, 31 to 36, 42 to 45, 47 to 48, 52, 57 to 58, 60 to 78, 84 to 88, 90 to 97, 100 to 104, 106, 108, 111 to 113, 115, 118 to 146, 149 to 175, 177 to 178, 181 to 183, 185 to 187, 189 to 192, 194 to 195, 197 to 200, 203 to 232, 234 to 250, and 252 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0299]

[0298] Embodiment 49. A compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 42-45, 47-48, 52, 57-62, 64-72, 74, 76, 84-88, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259, and 263 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0300] Embodiment 50. A compound selected from compounds 42-45, 47-48, and 52 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0301]

[0300] Embodiment 51. A compound selected from compounds 112, 205-218, 242-243, 252-254, 261-262, and 264-291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0302]

[0301] Embodiment 52. A pharmaceutical composition comprising a compound described in any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives.

[0303]

[0302] Embodiment 53. A method for treating cancer, comprising administering an effective amount of a compound described in any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 52.

[0304]

[0303] Embodiment 54. The method described in embodiment 53, characterized in that the cancer contains a KRas mutation.

[0305]

[0304] Embodiment 55. The KRas mutation is KRas G12DThe method of embodiment 54, which corresponds to a mutation.

[0306]

[0305] Embodiment 56. Before administration, KRas G12D 56. The method of any one of embodiments 53 to 55, further comprising testing a sample from the patient for the presence or absence of the mutation.

[0307]

[0306] Embodiment 57. The patient sample is KRas G12D 57. The method of embodiment 56, wherein after demonstrating the presence of the mutation, the compound, a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered to the patient.

[0308]

[0307] Embodiment 58. A method described in any one of embodiments 53 to 57, wherein the cancer is tissue-independent.

[0309]

[0308] Embodiment 59. A method described in any one of embodiments 53 to 57, wherein the cancer is pancreatic cancer, lung cancer or colorectal cancer.

[0310]

[0309] Embodiment 60. The method described in embodiment 59, wherein the lung cancer is lung adenocarcinoma, NSCLC or SCLC.

[0311]

[0310] Embodiment 61. The method described in embodiment 59, wherein the cancer is pancreatic cancer.

[0312]

[0311] Embodiment 62. The method described in embodiment 59, wherein the cancer is colorectal cancer.

[0313]

[0312] Embodiment 63. The method of any one of embodiments 53 to 62, further comprising at least one additional therapeutic agent.

[0314]

[0313] Embodiment 64. The method of embodiment 63, 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.

[0315]

[0314] Embodiment 65. A compound according to any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

[0316]

[0315] Embodiment 66. Kras G12D 52. Use of a compound according to any one of embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of cancers containing mutations.

[0317] Embodiment 67. Use of a compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutical salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0318]

[0317] Embodiment 68. Kras G12D 52. Use of a compound according to any one of embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer comprising a mutation.

[0319]

[0318] Embodiment 69. Kras G12D 52. The compound according to any one of embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutical salt thereof, for the therapeutic and / or prophylactic treatment of cancers that contain mutations.

[0320]

[0319] Embodiment 70. A method for regulating the activity of a Kras mutant protein, comprising reacting the mutant protein with a compound described in any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0321]

[0320] Embodiment 71. A method for inhibiting proliferation of a cell population, comprising contacting the cell population with a compound described in any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0322]

[0321] Embodiment 72. The method described in embodiment 71, wherein inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0323]

[0322] Embodiment 73. A method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound described in any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0324]

[0323] Embodiment 74. A compound described in any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof for use in modulating the activity of a KRas mutant protein.

[0325]

[0324] Embodiment 75. A compound according to any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof for use in inhibiting proliferation of a cell population.

[0326]

[0325] Embodiment 76. A compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof for use according to embodiment 75, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0327] Embodiment 77. A compound according to any one of embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis.

[0328]

[0327] Embodiment 78. Use of a compound described in any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating the activity of a KRas mutant protein.

[0329]

[0328] Embodiment 79. Use of a compound described in any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting proliferation of a cell population.

[0330]

[0329] Embodiment 80. The use described in embodiment 79, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0331] Embodiment 81. Use of a compound according to any one of embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis. [Example]

[0332] Example

[0331] The following examples are offered by way of illustration and not by way of limitation.

[0333]

[0332] Intermediate Intermediate 1: 4-amino-2,6-dichloro-5-fluoronicotinic acid TIFF2026000916000129.tif24170

[0334] Step 1: 2,6-dichloro-3-fluoropyridin-4-amine

[0335] A solution of 2,6-dichloropyridin-4-amine (9.01 g, 55.3 mmol) and SelectFlour (23.6 g, 66.6 mmol) in DMF (90 mL) / acetonitrile (90 mL) was stirred at 80 °C under nitrogen for 30 min. The mixture was concentrated in vacuo. The crude product was purified by reverse-phase chromatography (gradient: 0-40% acetonitrile in water (0.1% formic acid)) to give the title compound (4.62 g, 46.2% yield) as a light brown solid. LC-MS: (ESI, m / z): [M+H] + =181. 1 H NMR(300MHz,DMSO-d6,ppm)δ6.99(s,2H),6.70(d,J=5.4Hz,1H).

[0334]

[0336] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-3-fluoro-4-pyridyl)carbamate

[0337] Under nitrogen, to a solution of 2,6-dichloro-3-fluoropyridin-4-amine (4.82 g, 26.6 mmol) in THF (100 mL) was added NaHMDS (53.1 mL, 2 M in THF) at 0 °C. The resulting solution was stirred at 0 °C for 30 min. Then, a solution of BocO (29.0 g, 133 mmol) in THF (450 mL) was added at 0 °C and stirred at room temperature overnight. The reaction was quenched with aqueous NH Cl. Most of the THF was removed in vacuo, and the resulting solution was extracted with EtOAc. The combined organic layers were concentrated in vacuo to give the title compound (9.11 g, crude) as a white solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =381. 1 H NMR(300MHz,DMSO-d6,ppm)δ6.13(s,1H),1.42(s,9H),1.38(d,J=2.4Hz,9H).

[0335]

[0338] Step 3: tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

[0339] Under nitrogen, to a solution of tert-butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-3-fluoro-4-pyridyl)carbamate (9.11 g, 23.9 mmol) in THF (180 mL) was added LDA (41.9 mL, 1 M in THF) at -78 °C. The resulting solution was stirred at -78 °C for 0.5 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (300 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–10%) to afford the title compound (4.18 g, 45.9% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =381. 1 H NMR(300MHz,DMSO-d6,ppm)δ10.07(s,1H),1.54(s,9H),1.45(s,9H).

[0336]

[0340] Step 4: 4-amino-2,6-dichloro-5-fluoronicotinic acid

[0341] A solution of tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (4.18 g, 11.0 mmol) in TFA (15 mL) / DCM (15 mL) was stirred at 40° C. for 3 h. The solvent was concentrated in vacuo to give the title compound (2.86 g, crude) as a brown solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =225.

[0337]

[0342] Intermediate 2: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one TIFF2026000916000130.tif23170

[0343] Step 1: 5,7-dichloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one

[0344] To a solution of 4-amino-2,6-dichloro-5-fluoronicotinic acid (2.01 g, 8.92 mmol, Intermediate 1) in MeCN (60 mL) and pyridine (20 mL) was added ethoxycarbonyl isothiocyanate (4.20 mL, 35.6 mmol). The resulting solution was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by reverse-phase chromatography (gradient: 0-40% acetonitrile in water (0.1% formic acid)) to afford 1.58 g (46.6% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =264. 1 H NMR(400MHz,DMSO-d6,ppm)δ13.30(s,1H),12.86(s,1H).

[0338]

[0345] Step 2: 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0346] Under nitrogen, to a solution of 5,7-dichloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (1.58 g, 5.93 mmol) in DMF (20 mL) was added ChONa (320 mg, 5.93 mmol) at 0 °C. The resulting solution was stirred at room temperature for 10 minutes. Then, CHI (842 mg, 5.93 mmol) was slowly added at room temperature. The mixture was stirred overnight at room temperature. The reaction solution was slowly added to cold water with stirring. The solid was collected by filtration and dried in an oven to give the title compound (2.07 g, crude) as a yellow solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =280. 1 H NMR(300MHz,DMSO-d6,ppm)δ13.35(br,1H),2.61(s,3H).

[0339]

[0347] Intermediate 3: tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2026000916000131.tif58170

[0348] Step 1: tert-butyl (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0349] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (50.0 g, 236 mmol) in DMF (800 mL) was added K2CO3 (65.1 g, 472 mmol) and BnBr (60.1 g, 353.53 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water (500 mL × 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–10%) to give the title compound (69 g, 96.9% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =303.

[0340]

[0350] Step 2: 3-(Tert-butyl) 2-methyl(1R,2S,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3-dicarboxylate and 3-(tert-butyl) 2-methyl(1R,2R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3-dicarboxylate TIFF2026000916000132.tif37170

[0351] Under N2, to a solution of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (23.0 g, 76.06 mmol) and TMEDA (17.7 g, 152.59 mmol) in diethyl ether (500 mL) was added dropwise s-BuLi (117 mL, 1.3 M in hexanes) at -78 °C, and the mixture was stirred at -78 °C for 1.5 h. Then, a solution of methyl carbonochloridate (17.9 g, 189 mmol) in Et2O (40 mL) was added dropwise at -78 °C. The reaction was gradually warmed to room temperature and stirred for an additional 16 h. The reaction was quenched with saturated NaHCO3 (aq), diluted with water, and extracted with ethyl acetate. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-10%) to give the racemic mixture (a mixture of cis isomers) as a yellow oil. The mixture was separated by chiral SFC (column: Lux® 5 μm cellulose-2, 5 × 25 cm, 5 μm, mobile phase A: CO₂, mobile phase B: MeOH (0.1% 2M NH₃-MeOH); flow rate: 180 mL / min; gradient: 18% B at 220 nm; RT1: 5.07; RT2: 5.57) to give 5.9 g of the earlier peak and 5.6 g of the later peak as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =361.

[0341]

[0352] Step 3: tert-butyl (1R,2S,5S)-8-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0353] Under nitrogen, to a solution of 3-(tert-butyl) 2-methyl (1R,2S,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3-dicarboxylate (20.0 g, 55.5 mmol, earlier peak from previous run) in THF (300 mL) was added LiAlH (4.20 g, 111 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 30 min and quenched with NaSO.10H O. The solid was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–20%) to afford the title compound (14.3 g, 77.5% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =333.

[0342]

[0354] Step 4: (6S,9R,9aS)-10-benzylhexahydro-1H,3H-6,9-epiminoxazolo[3,4-a]azepin-3-one

[0355] Under nitrogen, to a solution of tert-butyl 8-benzyl-4-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.1 g, 15.34 mmol) in THF (100 mL) was added NaH (1.35 g, 33.75 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at room temperature for 3 h, quenched with NHCl (aq), and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–40%) to afford the title compound (3.5 g, 88.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =259.

[0343]

[0356] Step 5: (6S,9R,9aS)-Hexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one

[0357] A mixture of (6S,9R,9aS)-10-benzylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one (10.0 g, 38.7 mmol) and Pd / C (3.0 g, 10% dry) in methyl alcohol (200 mL) was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was filtered off. The filtrate was concentrated under reduced pressure to give 6 g of crude product, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =169.

[0344]

[0358] Step 6: tert-butyl (6S,9R,9aS)-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-10-carboxylate

[0359] A solution of (6S,9R,9aS)-hexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one (6.00 g, 35.7 mmol), (Boc)2O (12.6 g, 57.8 mmol), and DIPEA (10.0 g, 77.5 mmol) in dichloromethane (100 mL) was stirred at room temperature for 2 h. The reaction mixture was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-40%) to afford 7.50 g (78.4% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =269.

[0345]

[0360] Step 7: tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0361] A solution of tert-butyl (6S,9R,9aS)-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-10-carboxylate (7.50 g, 28.0 mmol) and NaOH (16.8 g, 420 mmol) in ethanol (200 mL) and water (70 mL) was stirred at 80 °C for 16 h. Most of the EtOH was removed under reduced pressure. The remaining solution was adjusted to pH = 8 with aqueous HCl (1 M) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with DCM / MeOH (5 / 1) to give the title compound (5 g, 73.8% yield) as an off-white solid. LC-MS: (ESI, m / z): [M+H] + =243. 1 H NMR(400MHz,DMSO-d6,ppm)δ4.72-4.57(m,1H),4.02-3.90(m,2H),3.25-3.15(m,2H),2.82 -2.68(m,2H),2.64-2.53(m,1H),1.85-1.61(m,3H),1.61-1.47(m,step:1H),1.41(s,9H).

[0346]

[0362] Intermediate 4: tert-butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2026000916000133.tif60170

[0363] Step 1: tert-Butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0364] Under nitrogen, to a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.00 g, 23.5 mmol) in N,N-dimethylformamide (50 mL) was added K2CO3 (6.51 g, 47.1 mmol) and (bromomethyl)benzene (6.01 g, 35.1 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-30% EtOAc / petroleum ether) to afford the title compound 7 g (98.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =303.

[0347]

[0365] Step 2: (1S,6S,9R,9aS)-10-benzyl-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one TIFF2026000916000134.tif35170

[0366] Under nitrogen, to a solution of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (7.0 g, 23.1 mmol) and TMEDA (5.38 g, 46.3 mmol) in diethyl ether (70 mL) was added dropwise s-BuLi (35.6 mL, 46.3 mmol, 1.3 M in hexane) at −78° C. The resulting solution was stirred at −78° C. for 1.5 hours. Then, acetaldehyde (2.55 g, 57.8 mmol) was added at −78° C. The reaction was gradually warmed to room temperature and stirred overnight. The mixture was quenched with NH4Cl (aq) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0 to 50% EtOAc in petroleum ether) to give 5.1 g of a mixture of four diastereoisomers. The mixture was purified by preparative SFC (column: CHIRALPAK IH, 3 x 25 cm, 5 μm; mobile phase A: CO, mobile phase B: IPA (0.5% 2M NH 3-MeOH; flow rate: 70 mL / min; gradient: isocratic 35% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 6.31; RT2 (min): 8.33; sample solvent: MeOH (preparative); injection volume: 1.9 mL; run number: 50. Compound a (1.39 g, 22% yield) (first peak) and compound d (1.47 g, 23.3% yield) (third peak) were separated, and a mixture of compounds b and c (second peak) was obtained. The mixture of compounds b and c was separated by preparative SFC (column: CHIRALPAK IH, 3 x 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH4)). 3- MeOH; flow rate: 200 mL / min; gradient: isocratic 50% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 5.73; RT2 (min): 8.44; sample solvent: MeOH (preparative); injection volume: 10 mL; run number: 6) to give compound b (0.500 g, 7.9% yield) (early peak) and compound c (0.430 g, 6.8% yield) (late peak) as yellow solids. LC-MS: (ESI, m / z): [M+H] + =273.

[0348]

[0367] Step 3: (1S,6S,9R,9aS)-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one

[0368] A solution of (1S,6S,9R,9aS)-10-benzyl-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one (1.00 g, 3.67 mmol) (compound a from the previous step) and Pd / C (500 mg, 10%) in methyl alcohol (15 mL) was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The catalyst was filtered off. The filtrate was concentrated in vacuo to give 658 mg (crude) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =183.

[0349]

[0369] Step 4: tert-butyl (1S,6S,9R,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-10-carboxylate

[0370] A solution of (1S,6S,9R,9aS)-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one (658 mg, 3.61 mmol), (Boc)2O (1.18 g, 5.41 mmol), and DIPEA (1.4 g, 10.8 mmol) in dichloromethane (10 mL) was stirred at room temperature for 30 min. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-100% EtOAc / petroleum ether) to afford the title compound (920 mg, 90.2% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =283.

[0350]

[0371] Step 5: tert-butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0372] A solution of tert-butyl (1S,6S,9R,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-10-carboxylate (900 mg, 3.19 mmol) and NaOH (1.28 g, 32.0 mmol) in ethanol (12 mL) and water (4 mL) was stirred at 80 °C for 1 h. The reaction solution was cooled to room temperature, diluted with water, and extracted with DCM. The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo to give 815 mg (crude) as an oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =257. 1H NMR(300MHz,DMSO-d6)δ4.54(s,1H),3.94(d,J=5.1Hz,1H),3.82(s,1H),2.73(d,J=11.3Hz,1H),2.60(d,J=11. 5Hz,1H),2.41(d,J=8.1Hz,1H),2.15(s,1H),179-1.67(m,3H),1.56(s,1H),1.40(s,9H),1.04(d,J=6.3Hz,3H).

[0351]

[0373] Intermediate 5: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2026000916000135.tif76170

[0374] Step 1: Ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate and ethyl (R)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2026000916000136.tif35170

[0375] 20.0 g of ethyl 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (20.0 g, 94.6 mmol) was separated by SFC (column: AD 2.12 x 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: EtOH:ACN = 1:1; flow rate: 200 mL / min; gradient: 50% B; 220 nm; RT1: 2.44; RT2: 3.58; injection volume: 10 mL; run number: 15). Ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (8.21 g, faster peak) was obtained as a yellow oil. (R)-2,5-Dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.92 g, later peak) was obtained as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =212. 1H NMR(400MHz,Chloroform-d)δ4.22(q,J=7.2Hz,2H),4.14-4.05(m,1H),3.54(d,J=18.6Hz,1H),3 .02-2.91(m,2H),2.87-2.72(m,1H),2.60-2.38(m,2H),2.23-2.11(m,1H),1.28(t,J=7.1Hz,3H).

[0352]

[0376] Step 2: Ethyl (7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate

[0377] Under nitrogen, to a solution of ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.22 g, 5.68 mmol) in tetrahydrofuran (100 mL) was added NaBH4 (70.3 mg, 1.85 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction was quenched with water and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-6% MeOH / DCM) to give the title compound (0.631 g, 62% yield) as a light yellow oil. LC-MS: (ESI, m / z): [M+H] + =214.

[0353]

[0378] Step 3: Ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate and ethyl (2S,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2026000916000137.tif29170

[0379] Under nitrogen, DAST (923 mg, 5.74 mmol, dissolved in 20 mL of DCM) was added to a solution of ethyl (7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (809 mg, 3.80 mmol) at −15° C. The mixture was stirred for 3 hours at room temperature. The mixture was quenched with EtOH. The solvent was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient: 0% to 100% EtOAc / petroleum) to give 425 mg (52% yield) of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate as a colorless oil and 219 mg (26.9% yield) of ethyl (2S,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate as a white solid. LC-MS: (ESI, m / z): [M+H] + =216.

[0354]

[0380] Ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (early peak). 1 H NMR(400MHz,Chloroform-d)δ5.32(d,J=19.2Hz,1H),4.26-4.11(m,3H),3.25-3.12(m ,1H),2.85-2.59(m,3H),2.48-2.39(m,1H),2.37-2.07(m,2H),1.30(t,J=7.1Hz,3H).

[0355]

[0381] Ethyl (2S,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (later peak). 1 H NMR(400MHz,Chloroform-d)δ5.47-5.32(m,1H),4.29-4.24(m,2H),4.08-3.96(m,1H),3.46-3.35(m,1 H),2.98-2.78(m,2H),2.53-2.42(m,2H),2.20-2.12(m,1H),1.91-1.76(m,1H),1.31(t,J=7.1Hz,3H).

[0356]

[0382] Step 4: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol

[0383] To a solution of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (310 mg, 1.44 mmol) in tetrahydrofuran (7 mL) under nitrogen was added LiAlH (3.1 mL, 1 M in THF) at 0 °C. The mixture was stirred at 70 °C for 0.5 h. The mixture was quenched with NaSO.10H O and filtered. The solvent was removed by N blowing to give 124 mg (crude) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =160.

[0357]

[0384] Intermediate 6: (3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2026000916000138.tif29170

[0385] Step 1. 1-(tert-butyl) 2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate

[0386] Under nitrogen, LiHMDS (10 mL, 10 mmol) was added to a solution of 1-tert-butyl 2-methyl(2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.0 g, 7.54 mmol) in tetrahydrofuran (30 mL) at -78 °C and stirred at -78 °C for 0.5 h. Then, 1-chloro-2-iodoethane (2.87 g, 15.1 mmol) was added and stirred at room temperature for 1 h. The reaction was quenched with NH4Cl (aq) and extracted with EtOAc. The combined organic layers were dried over NaSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-60%) to afford 900 mg (36.4% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =328

[0358]

[0387] Step 2. Methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate

[0388] Under nitrogen, TFA (1 mL) was added to a solution of 1-(tert-butyl) 2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (470 mg, 1.43 mmol) in dichloromethane (5 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo to give 300 mg (crude) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =228

[0359]

[0389] Step 3. Methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate

[0390] Under nitrogen, a solution of methyl 2-(2-chloroethyl)-4,4-difluoro-pyrrolidine-2-carboxylate (300 mg, 1.32 mmol) in acetonitrile (5 mL) was added with EtN (1 mL) at room temperature and stirred at 85 °C for 12 h. The solvent was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with DCM / MeOH (0-6%) to afford 150 mg (59.5% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =192

[0360]

[0391] Step 4. (3,3-Difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol

[0392] Under nitrogen, to a solution of methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate (150 mg, 0.780 mmol) in tetrahydrofuran (3 mL) was added LiAlH (2.4 mL, 2.4 mmol, 1 M in THF) at 0 °C. The solution was stirred at 0 °C for 0.5 h. LC-MS: (ESI, m / z): [M+H] +=164.Refining

[0361]

[0393] Intermediate 6A: (3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2026000916000139.tif29170

[0394] Step 1. 1-(tert-butyl) 2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate

[0395] Under nitrogen, LiHMDS (10 mL, 10 mmol) was added to a solution of 1-tert-butyl 2-methyl(2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.0 g, 7.54 mmol) in tetrahydrofuran (30 mL) at -78 °C, and the mixture was stirred at -78 °C for 0.5 h. 1-Chloro-2-iodoethane (2.87 g, 15.1 mmol) was then added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with NH4Cl (aq) and then extracted with EtOAc. The combined organic layers were dried over NaSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-60%) to afford 900 mg (36.4% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =328

[0362]

[0396] Step 2. Methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate

[0397] Under nitrogen, TFA (1 mL) was added to a solution of 1-(tert-butyl) 2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (470 mg, 1.43 mmol) in dichloromethane (5 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo to give 300 mg (crude) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =228

[0363]

[0398] Step 3. Methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate

[0399] Under nitrogen, EtN (1 mL) was added to a solution of methyl 2-(2-chloroethyl)-4,4-difluoro-pyrrolidine-2-carboxylate (300 mg, 1.32 mmol) in acetonitrile (5 mL) at room temperature, and the mixture was stirred at 85 °C for 12 h. The solvent was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with DCM / MeOH (0-6%) to afford 150 mg (59.5% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =192

[0364]

[0400] Step 4. (3,3-Difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol

[0401] Under nitrogen, LiAlH4 (2.4 mL, 2.4 mmol, 1 M in THF) was added to a solution of methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate (150 mg, 0.780 mmol) in tetrahydrofuran (3 mL) at 0 °C. The solution was stirred at 0 °C for 0.5 h. The solvent was removed by nitrogen blowing to give 110 mg of the crude title compound as a yellow oil, which was used in the next reaction without further purification. LC-MS: (ESI, m / z): [M+H] + =164.Refining

[0365]

[0402] Intermediate 7: tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000140.tif38170

[0403] Step 1: tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0404] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (289 mg, 1.19 mmol, Intermediate 3) in THF (20 mL) was added NaH (191 mg, 4.78 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at room temperature for 0.5 h. Then, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (803 mg, 1.43 mmol, Intermediate 2) was added at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with aqueous NaHCO, diluted with water, and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (1.05 g, crude) as a white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =486.

[0366]

[0405] Step 2: tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0406] To a solution of tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 2.15 mmol) in DCM (10 mL) was added DIPEA (4.16 g, 32.3 mmol) and BOPCl (2.20 g, 8.61 mmol). The resulting solution was stirred at room temperature for 2 h, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–40%) to afford the title compound (381 mg, 37.8% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M+H] + =469

[0367]

[0407] Intermediate 8: tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000141.tif33170

[0408] To a solution of tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (381 mg, 0.816 mmol, Intermediate 7) in EtOAc (5 mL) was added mCPBA (423 mg, 2.45 mmol) at 0 °C. The solution was stirred at room temperature for 1 h, diluted with saturated NaHCO3 solution (20 mL), and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–60%) to afford 372 mg (91.3% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =500. 1 H NMR(300MHz,DMSO-d6,ppm)δ4.99(d,J=13.5Hz,1H),4.77(dd,J=13.5,1.9Hz,1H),4.59(dd,J=13.5,7.4Hz,1H),4.38(d,J=8 .3Hz,2H),4.20(d,J=7.1Hz,1H),3.42(s,3H),3.22(d,J=13.6Hz,1H),1.93(d,J=6.7Hz,1H),1.86-1.64(m,3H),1.45(s,9H).

[0368]

[0409] Intermediate 9: tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000142.tif33170

[0410] Under nitrogen, to a mixture of tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (201 mg, 0.401 mmol, Intermediate 8) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (128 mg, 0.802 mmol, Intermediate 5) in toluene (2 mL) was added t-BuONa (77.1 mg, 0.802 mmol) at 0 °C. The solution was stirred at room temperature for 1 h, diluted with water (20 mL), and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography eluting with CHOH / DCM (0-10%) to afford the title compound (151 mg, 64.8% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M+H] + =579. 1 H NMR(300MHz,DMSO-d6,ppm)δ5.29(d,J=54.2Hz,1H),4.89(d,J=13.4Hz,1H),4.72-4.62(m,1H),4.48(dd,J=13.3,7.3Hz,1H),4.40-4.25 (m,2H),4.19-3.95(m,3H),3.15-2.97(m,4H),2.89-2.76(m,1H),2.17-2.11(m,1H),2.07-2.02(m,1H),1.94-1.62(m,8H),1.45(s,9H).

[0369]

[0411] Intermediate 10: tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000143.tif38170

[0412] Step 1: tert-butyl (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0413] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (769 mg, 3.00 mmol, Intermediate 4) in THF (10 mL) was added NaH (480 mg, 12.0 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at room temperature for 0.5 h. Then, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.01 g, 3.60 mmol, Intermediate 2) was added at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction was quenched with aqueous NH4Cl, diluted with water, and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (1.61 g, crude) as a white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =500.

[0370]

[0414] Step 2: tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0415] To a solution of tert-butyl (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.61 g, 3.21 mmol) in DCM (15 mL) was added DIPEA (6.22 g, 48.2 mmol) and BOPCl (3.28 g, 12.9 mmol). The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–55%) to afford the title compound (1.21 g, 77.9% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M+H] + =482.

[0371]

[0416] Intermediate 11: tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000144.tif33170

[0417] To a solution of tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (1.21 g, 2.5 mmol, Intermediate 10) in EtOAc (20 mL) was added mCPBA (1.30 g, 7.52 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, diluted with NaHCO3, and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–60%) to afford the title compound (931 mg, 72.4% yield) as a white solid. LC-MS: (ESI, m / z): [M+H]+ =514. 1 H NMR(300MHz,DMSO-d6,ppm)δ5.32-5.16(m,1H),4.74(t,J=7.7Hz,1H),4.35(d,J=5.2Hz,1H),4.30-4. 10(m,2H),3.42(s,3H),3.20(d,J=13.4Hz,1H),1.93-1.70(m,4H),1.53(d,J=6.3Hz,3H),1.47(s,9H).

[0372]

[0418] Intermediate 12: tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000145.tif33170

[0419] Under nitrogen, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (37.5 mg, 0.240 mmol, Intermediate 5) and tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (60.6 mg, 0.120 mmol, Intermediate 11) in toluene (1.5 mL) was added t-BuONa (22.6 mg, 0.240 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, quenched with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with CHOH / DCM (0-10%) to give the title compound (40.6 mg, 58.1% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M+H] + =593.

[0373]

[0420] Intermediate 13: tert-butyl (5S,5aS,6S,9R)-2-chloro-12-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000146.tif40170

[0421] Under nitrogen, to a solution of tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (3.50 g, 6.81 mmol, Intermediate 11) and (3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol (1.30 g, 7.97 mmol, Intermediate 6) in toluene (35 mL) was added t-BuONa (1.30 g, 13.5 mmol) at 0 °C. The resulting solution was stirred at room temperature for 1 h, quenched with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient: 0-6% MeOH / DCM) to give 2.06 g (50.7% yield) of a mixture of two diastereoisomers as a white solid. The diastereoisomers were separated by chiral preparative HPLC (Column: CHIRALPAK IE-3, 4.6 x 50 mm, 3 μm; Mobile phase A: Hex (0.1% DEA): EtOH = 50:50; Flow rate: 1 mL / min; Gradient: 0% B to 0% B; Injection volume: 5 μL mL) to give 643 mg of the earlier peak and 676 mg of the later peak as a white solid. LC-MS: (ESI, m / z): [M+H] + =597.

[0374]

[0422] Faster peak (desired isomer): 1H NMR(300MHz,DMSO-d6,ppm):δ5.18(d,J=13.2Hz,1H),4.64(t,J=7.6Hz,1H),4.44-4. 29(m,3H),4.16(s,1H),3.99(d,J=9.0Hz,1H),3.54(dd,J=9.0,4.7Hz,1H),3.33-3.1 5(m,1H),3.15(d,J=4.4Hz,1H),3.13-2.98(m,2H),2.75-2.52(m,1H),2.50-2.38(m, 1H),2.41-2.25(m,1H),1.87(s,3H),1.73(s,1H),1.50(d,J=6.3Hz,3H),1.47(s,9H).

[0375]

[0423] Late peak: 1 H NMR (300MHz, DMSO-d6, ppm): 1 H NMR(300MHz,DMSO-d6,ppm):δ5.18(d,J=13.2Hz,1H),4.64(t,J=7.6Hz,1H),4.44-4. 29(m,3H),4.16(s,1H),3.99(d,J=9.0Hz,1H),3.54(dd,J=9.0,4.7Hz,1H),3.33-3.1 5(m,1H),3.15(d,J=4.4Hz,1H),3.13-2.98(m,2H),2.75-2.52(m,1H),2.50-2.38(m, 1H),2.41-2.25(m,1H),1.87(s,3H),1.73(s,1H),1.50(d,J=6.3Hz,3H),1.47(s,9H).

[0376]

[0424] Intermediate 14: tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000147.tif37170

[0425] Step 1: 4-amino-2,6-dichloro-5-fluoronicotinamide

[0426] A solution of 4-amino-2,6-dichloro-5-fluoronicotinic acid (2.86 g, 12.7 mmol), NH₄Cl (3.38 g, 63.8 mmol), HATU (7.25 g, 19.1 mmol), and DIPEA (16.5 g, 127 mmol) in DMA (28 mL) was stirred at room temperature for 0.5 h. The resulting solution was diluted with EtOAc (80 mL) and washed with water (60 mL x 4). The organic layer was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with CH₃OH / DCM (0-5%) to give the title compound (1.61 g, 56.5% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =224. 1 H NMR(400MHz,DMSO-d6,ppm)δ8.06(s,1H),7.81(s,1H),6.87(s,2H).

[0377]

[0427] Step 2: 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one

[0428] A solution of 4-amino-2,6-dichloro-5-fluoronicotinamide (1.51 g, 6.74 mmol) in triethoxymethane (30 mL) was stirred at 150° C. for 3 hours. The mixture was then concentrated in vacuo. The residue was triturated with EtOAc / petroleum ether (1:1, 10 mL). The solid was collected by filtration to give the title compound (1.04 g, crude) as a yellow solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =234. 1 H NMR(400MHz,DMSO-d6,ppm)δ13.02(brs,1H),8.41(s,1H).

[0378]

[0429] Step 3: tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0430] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (624 mg, 2.58 mmol, Intermediate 3) in DMF (6 mL) was added NaH (134 mg, 3.35 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at room temperature for 30 min. Then, 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (601 mg, 2.57 mmol) was added and stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, filtered, and quenched with aqueous NH4Cl. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (500 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with CHOH / DCM (0-10%) to give the title compound (452 ​​mg, 40% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =440. 1 H NMR(400MHz,d6,ppm)δ8.32(s,1H),4.25-4.05(m,3H),3.98(d,J=6.4Hz,1H),3.20-3.11(m,1H), 2.80(d,J=11.5Hz,1H),2.60(s,1H),2.03-1.92(m,1H),1.82-1.57(m,3H),1.37(t,J=9.6Hz,9H).

[0379]

[0431] Step 4: tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0432] A solution of tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (452 ​​mg, 1.03 mmol), BOP-Cl (1.05 g, 4.12 mmol), and DIPEA (1.99 g, 15.5 mmol) in DCM (10 mL) was stirred under nitrogen at room temperature for 2 h. The mixture was then concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-40%) to afford the title compound (315 mg, 72.6% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =422.

[0380]

[0433] Intermediate 15: tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate TIFF2026000916000148.tif41170

[0434] Step 1: tert-butyl (1R,2S,5S)-2-((S)-1-((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0435] Under nitrogen, to a solution of tert-butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (229 mg, 0.890 mmol, Intermediate 4) in DMF (6 mL) was added NaH (71.6 mg, 1.79 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at room temperature for 30 min. Then, 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (251 mg, 1.07 mmol, Intermediate 14) was added and stirred at 80 °C for 1 h. The reaction mixture was quenched with aqueous NH4Cl, diluted with EtOAc (20 mL), and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (476 mg, crude) as a white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =454.

[0381]

[0436] Step 2: tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate

[0437] To a solution of tert-butyl (1R,2R,5S)-2-((S)-1-((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (476 mg, 1.05 mmol) in DCM (20 mL) was added DIPEA (2.03 g, 15.71 mmol) and BOPCl (1.07 g, 4.19 mmol). The solution was stirred at room temperature for 2 h and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-50%) to afford the title compound (221 mg, 48.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =436.

[0382]

[0438] Intermediate 16: 6-Fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole TIFF2026000916000149.tif27170

[0439] Step 1: 7-bromo-6-fluoro-1-methyl-1H-indazole

[0440] Under nitrogen, a solution of 3-bromo-2,4-difluorobenzaldehyde (500 mg, 2.26 mmol), 1-methylhydrazine sulfate (1.63 g, 11.3 mmol), and K2CO3 (3.12 g, 22.6 mmol) in NMP (15 mL) was stirred at 200 °C under microwave irradiation for 2 h. The reaction was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–10%) to give 7-bromo-6-fluoro-1-methyl-indazole (333.2 mg, 64.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =229 / 231; 1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.80(dd,J=8.7,5.0Hz,1H),7.15(t,J=8.9Hz,1H),4.31(s,3H).

[0383]

[0441] Step 2: 6-fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0442] A solution of 7-bromo-6-fluoro-1-methyl-1H-indazole (150 mg, 0.660 mmol), Pin2B2 (836 mg, 3.29 mmol), Pd(dppf)Cl (48.2 mg, 0.0700 mmol), and KOAc (258 mg, 2.63 mmol) in DMF (5 mL) was stirred overnight at 80 °C under nitrogen. The resulting solution was purified by reverse-phase chromatography (gradient: 0 to 60% acetonitrile in water (0.05% NH4HCO3)) to afford the title compound (49.9 mg, 27.5% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =277. 1 H-NMR(300MHz,DMSO-d6,ppm):δ8.07(s,1H),7.88(dd,J=8.8,5.6Hz,1H),6.98(dd,J=9.5,8.8Hz,1H),4.05(s,3H),1.38(s,12H)

[0384]

[0443] Intermediate 17: 6-(allylsulfonyl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2026000916000150.tif42170

[0444] Step 1: 6-(allylthio)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0445] Under nitrogen, to a solution of allyl mercaptan (3.74 g, 50.5 mmol) and K2CO3 (2.79 g, 20.2 mmol) in DMF (20 mL) was added 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (5.01 g, 10.1 mmol). The solution was stirred at room temperature overnight and diluted with acetonitrile (20 mL). The solid was filtered off. The filtrate was concentrated under reduced pressure to give 5.05 g (crude) of the title compound as a dark red oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =489.

[0385]

[0446] Step 2: 6-(allylsulfonyl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2 amine

[0447] To a solution of 6-allylsulfanyl-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (5.05 g, 10.3 mmol) in DCM (150 mL) was added mCPBA (14.3 g, 82.7 mmol). The reaction mixture was stirred overnight at room temperature, quenched with saturated aqueous NaHCO3 (100 mL), and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (gradient: 0-65% ethyl acetate / petroleum ether) to afford 1.70 g (31.6% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =521. 1 H NMR(400MHz,DMSO-d6,ppm)δ7.16(d,J=8.6Hz,4H),7.01(s,1H),6.90(d,J=8.7Hz,4H),5.61(ddt,J=18.8,9.4,7. 1Hz,1H),5.30(s,1H),5.27(dd,J=6.0,1.7Hz,1H),4.76(s,4H),4.15(d,J=7.2Hz,2H),3.72(s,6H),2.38(s,3H).

[0386]

[0448] Intermediate 18: ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane TIFF2026000916000151.tif38170

[0449] Step 1: 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

[0450] Under nitrogen, to a solution of 7-fluoronaphthalen-1-ol (2.50 g, 15.4 mmol) and (bromoethynyl)triisopropylsilane (4.82 g, 18.4 mmol) in DCE (24 mL) was added dichloro(p-cymene)ruthenium(II) dimer (1.42 g, 2.31 mmol), KCO (2.13 g, 15.4 mmol), and NaOAc (253 mg, 3.09 mmol). The mixture was stirred at 40 °C overnight and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–15%) to afford 5.01 g (94.7% yield) of the title compound as a yellow oil. 1 H-NMR(300MHz,CDCl3,ppm)δ9.00(s,1H),7.68(dd,J=9.1,5.8Hz,1H),7.30-7.21(m,2H),7.18-7.06(m,1H),6.96-6.88(m,1H),1.13-1.06(m,21H).

[0387]

[0451] Step 2: 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[0452] Under nitrogen, to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (8.95 g, 26.1 mmol) and DIPEA (6.75 g, 52.3 mmol) in DCM (90 mL) was added trifluoromethanesulfonic anhydride (11.1 g, 39.2 mmol) dropwise over 15 min at -40 °C. The solution was stirred at -40 °C for 1 h and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-15%) to give 10.4 g (83.5% yield) as a yellow oil. 1 H-NMR (300MHz, CDCl3, ppm) δ7.90-7.81(m,2H),7.58(d,J=7.8Hz,1H),7.48(t,J=8.0Hz,1H),7.43-7.35(m,1H),1.33-1.15(m,21H).

[0388]

[0453] Step 3: ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0454] Under nitrogen, a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (3.01 g, 6.32 mmol), Pin2B2 (3.22 g, 12.7 mmol), Pd(dppf)Cl2 (486 mg, 0.630 mmol), and KOAc (1.24 g, 12.7 mmol) in 1,4-dioxane (12 mL) was stirred at 110 °C overnight. The resulting reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0–13%) to afford 1.61 g (55.9% yield) of the title compound as a yellow solid. 1 H-NMR (300MHz, CDCl3, ppm) δ7.87-7.71(m,3H),7.48-7.37(m,1H),7.32-7.18(m,1H),1.44(s,12H),1.26-1.07(m,21H).

[0389]

[0455] Intermediate 19: 2-fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline TIFF2026000916000152.tif27170

[0456] Step 1: 3-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline

[0457] Under nitrogen, a solution of 3-bromo-2-fluoro-5-methylaniline (10.3 g, 50.4 mmol) in THF (90 mL) was added with NaH (6.06 g, 151 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at room temperature for 20 min. Then, PMBCl (19.7 g, 125 mmol) was added at 0 °C and stirred at room temperature for 1.5 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-9% EtOAc / DCM) to afford the title compound (20.4 g, 90.9% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =443.

[0390]

[0458] Step 2: 2-fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0459] A solution of 3-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline (5.01 g, 11.2 mmol), Pin2B2 (5.72 g, 22.5 mmol), Pd(dppf)Cl2 (1.73 g, 2.25 mmol), and KOAc (3.31 g, 33.7 mmol) in 1,4-dioxane (55 mL) was stirred at 120 °C for 5 h under nitrogen. The resulting solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-20% EtOAc / petroleum ether) to afford 4.81 g (79.2% yield) of the title compound as a yellow syrup. LC-MS: (ESI, m / z): [M+H] + =492. 1 H NMR (300MHz, DMSO-d6, ppm): δ7.28(s,6H),7.24-7.10(m,4H),6.80(d,J=30.0Hz,4H),3.78(s,6H),2.12(s,3H),1.40(s,12H).

[0391]

[0460] Intermediate 20: (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid TIFF2026000916000153.tif47170

[0461] Step 1: 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methylaniline

[0462] Under nitrogen, to a solution of 5-bromo-2-fluoro-3-methylaniline (4.81 g, 23.5 mmol) in DMF (40 mL) was added NaH (2.82 g, 70.5 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at room temperature for 20 minutes. Then, PMBCl (7.42 g, 47.3 mmol) was added. After stirring at room temperature for 1 hour, it was quenched with aqueous NH4Cl. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was slurried with ethanol to give 6.50 g (crude) of the title compound as an off-white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =444

[0392]

[0463] Step 2: 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3-methylaniline

[0464] Under nitrogen, to a solution of 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methylaniline (5.70 g, 12.8 mmol) in acetic acid (50 mL) was added NIS (3.20 g, 14.2 mmol) at room temperature. The solution was stirred at room temperature for 20 minutes. The reaction was quenched with aqueous NaSO and diluted with EtOAc (150 mL). The phases were separated. The combined organic layers were washed with water (4 x 100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-30%) to afford 7.21 g (98.5% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] +=570.

[0393]

[0465] Step 3: 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)aniline

[0466] To a solution of 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3-methylaniline (7.08 g, 12.4 mmol) in DMF (80 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (15.2 mL, 119 mmol) and CuI (23.4 g, 123 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 75 °C for 6 h, diluted with HO (40 mL), and extracted with EtOAc (70 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-50%) to afford the title compound (3.47 g, 54.5% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =512.

[0394]

[0467] Step 4: (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid

[0468] Under nitrogen, to a solution of 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)aniline (2.40 g, 4.68 mmol) and triisopropyl borate (1.60 mL, 6.91 mmol) in THF (35 mL) was added n-BuLi (2.2 mL, 2.5 M in THF) at -78 °C. The resulting solution was stirred at -78 °C for 1 h. The reaction was quenched with aqueous NH4Cl, diluted with HO (20 mL), and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc (0.1% TEA) / petroleum ether (10% DCM) (0–30%) to afford 1.22 g (54.4% yield) of the title compound as a yellow syrup. LC-MS: (ESI, m / z): [M+H] + =477.

[0395]

[0469] Intermediate 21: 5-chloro-4-(trimethylstannyl)isoquinoline TIFF2026000916000154.tif18170

[0470] A solution of 4-bromo-5-chloroisoquinoline (450 mg, 1.86 mmol), Sn2Me6 (2.00 g, 6.10 mmol), and Pd(PPh3)4 (215 mg, 0.190 mmol) in toluene (5 mL) was stirred at 100 °C under nitrogen for 48 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by reverse-phase chromatography (gradient: 0–78% acetonitrile / water (0.1% FA)) to afford 341 mg (56.3% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =328. 1 H NMR(400MHz,Chloroform-d,ppm)δ9.22(s,1H),8.71(s,1H),7.95-7.88(m,1H),7.85-7.78(m,1H),7.58-7.50(m,1H),0.47(s,9H).

[0396]

[0471] Intermediate 22: 2-fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline TIFF2026000916000155.tif20170

[0472] Step 1: 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)aniline

[0473] Under nitrogen, a solution of 5-bromo-2-fluoroaniline (10.1 g, 53.2 mmol) in DMF (70 mL) was added with NaH (6.40 g, 160 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred at room temperature for 30 min. Then, PMBCl (18.2 g, 117 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with aqueous NHCl (20 mL), diluted with EtOAc (250 mL), and washed with water (200 mL x 4). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-17% EtOAc / petroleum ether) to give 24.1 g of the title compound as a yellow syrup. LC-MS: (ESI, m / z): [M+H] + =430.

[0397]

[0474] Step 2: 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline

[0475] A solution of 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)aniline (23.9 g, 55.5 mmol) and NIS (14.9 g, 66.5 mmol) in acetic acid (150 mL) was stirred under nitrogen at room temperature for 1.5 h. The reaction was quenched with aqueous NaSO (15 mL), diluted with EtOAc (300 mL), and washed with water (250 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-22% EtOAc / petroleum ether) to afford 16.7 g (54.0% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] +=556.

[0398]

[0476] Step 3: 5-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline

[0477] A solution of 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline (1.01 g, 1.82 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.46 g, 18.0 mmol), and CuI (3.42 g, 18.0 mmol) in DMF (10 mL) was stirred at 90 °C for 24 h under nitrogen. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (35 mL x 4). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a C18 column (solvent gradient: 0-85% ACN in water (0.05% NH4HCO3)) to afford the title compound (460 mg, 51.3% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =498.

[0399]

[0478] Step 4: 2-fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[0479] A solution of 5-bromo-2-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (321 mg, 0.640 mmol), Pin2B2 (327 mg, 1.29 mmol), Pd(dppf)Cl2 (99.1 mg, 0.131 mmol), and KOAc (189 mg, 1.93 mmol) in 1,4-dioxane (2 mL) was stirred at 110 °C for 1 h under nitrogen. The mixture was then concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-12% EtOAc / petroleum ether) to afford 160 mg (45.5% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =546.

[0400]

[0480] Intermediate 23: 2-Fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline TIFF2026000916000156.tif21170

[0481] A solution of 5-bromo-2-fluoro-3-methyl-aniline (101 mg, 0.493 mmol), Pin2B2 (253 mg, 0.996 mmol), KOAc (145 mg, 1.48 mmol), and Pd(dppf)Cl2 (38.4 mg, 0.0500 mmol) in 1,4-dioxane (3 mL) was stirred at 110 °C for 3 h under nitrogen. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-8%) to afford 184 mg of the title compound (crude, containing some Pin2B2) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =251.

[0401]

[0482] Intermediate 24: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol TIFF2026000916000157.tif23170

[0483] A solution of 4-bromonaphthalen-2-ol (400 mg, 1.79 mmol), Pin2B2 (911 mg, 3.59 mmol), Pd(dppf)Cl2 (275 mg, 0.360 mmol), and KOAc (527 mg, 5.38 mmol) in 1,4-dioxane (2 mL) was stirred at 110 °C for 2 h under nitrogen. The mixture was then concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-15% EtOAc / petroleum ether) to afford 335 mg (92% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =271. 1H NMR (300MHz, DMSO-d6, ppm): δ9.66(s,1H),8.49(d,J=8.3Hz,1H),7.70(d,J=9Hz,1H),7.5(d,J=3Hz,1H),7.42-7.24(m,3H),1.38(s,12H).

[0402]

[0484] Intermediate 25: 2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2026000916000158.tif51170

[0485] Step 1: N-(5-bromonaphthalen-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine

[0486] Under nitrogen, LiHMDS (451 mL, 1 M in THF) was added to a solution of 5-bromonaphthalen-1-amine (45.3 g, 204 mmol) in THF (500 mL) at −78° C. and stirred at 20° C. for 3 hours. The solution was then cooled to −78° C. TMSCl (48.7 g, 448 mmol) was added at −78° C. The mixture was allowed to warm to 20° C. and stirred at 20° C. for 3 hours. The mixture was then concentrated in vacuo. The residue was treated with hexane. The solid was filtered off. The filtrate was concentrated in vacuo to give 87.1 g (crude) of the title compound as a red oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H]+ = 443. 1 H-NMR (300MHz, CDCl3, ppm) δ8.21-8.16(m,1H),7.97-7.84(m,2H),7.63-7.55(m,1H),7.49-7.41(m,1H),7.22-7.17(m,1H),0.04(s,21H).

[0403]

[0487] Step 2: N-(5-fluoronaphthalen-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine

[0488] Under nitrogen, n-BuLi (148 mL, 2.5 M in n-hexane) was added to a solution of N-(5-bromonaphthalen-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (87.2 g, 238 mmol) in THF (800 mL) at −78° C. and stirred for 20 minutes at −78° C. Subsequently, N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (121 g, 382 mmol) was added at this temperature. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 1 hour. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient: 100% petroleum ether) to give 45.1 g (62.1%) of the title compound as a light red syrup. LC-MS: (ESI, m / z): [M+H] + =203.

[0404]

[0489] Step 3: 5-Fluoronaphthalen-1-amine

[0490] A solution of N-(5-fluoronaphthalen-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (45.1 g, 148 mmol) in MeOH (300 mL) was added to aqueous HCl (40 mL, 1 M) and stirred at room temperature for 10 minutes. The mixture was then concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (gradient: 0-65% acetonitrile in water (0.1% TFA)) to afford the title compound (23.4 g, 98.4% yield) as a brown solid. LC-MS: (ESI, m / z): [M+H] + =162. 1 H-NMR (300MHz, CDCl3, ppm) δ7.69-7.55(m,2H),7.47-7.26(m,2H),7.20-7.11(m,1H),6.88-6.83(m,1H),4.20(s,2H).

[0405]

[0491] Step 4: 2,4-Dibromo-5-fluoronaphthalen-1-amine

[0492] To a solution of 5-fluoronaphthalen-1-amine (10.0 g, 62.0 mmol) in HOAc (100 mL) was added a solution of bromine (21.4 g, 134 mmol) in HOAc (100 mL) at 0° C. Then, the mixture was stirred for 70 o The mixture was stirred at RT for 3 h. The mixture was cooled to room temperature. The solid was collected by filtration and washed with HOAc (300 mL). The solid was then suspended in aqueous NaOH (15%, 200 mL) and stirred for 20 min. The solid was collected by filtration, washed with water (200 mL), and dried under vacuum to give 20.1 g (crude) of the title compound as a black solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =318. 1 H-NMR (300MHz, CDCl3, ppm) δ7.85(s,1H),7.65-7.59(m,1H),7.51-7.39(m,1H),7.32-7.22(m,1H),4.67(brs,2H).

[0406]

[0493] Step 5: 5-bromo-6-fluoronaphtho[1,2-d][1,2,3]oxadiazole

[0494] To a solution of 2,4-dibromo-5-fluoronaphthalen-1-amine (18.0 g, 56.4 mmol) in propionic acid (45.0 mL, 603 mmol) and HOAc (360 mL) was added NaNO (5.84 g, 84.6 mmol) at 0 °C. The mixture was then stirred at 0 °C for 50 min, warmed to 20 °C, and stirred for 1.5 h. The solid was collected by filtration, washed with water (200 mL), and dried under vacuum to give 10.9 g (crude) of the title compound as a brown solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =269. 1 H-NMR (300MHz, CDCl3, ppm) δ7.59-7.50(m,1H),7.20(s,1H),7.14-6.99(m,2H).

[0407]

[0495] Step 6: 4-Bromo-5-fluoronaphthalen-2-ol

[0496] To a solution of 5-bromo-6-fluoronaphtho[1,2-d][1,2,3]oxadiazole (10.9 g, 40.8 mmol) in EtOH (150 mL) and THF (75 mL) was added NaBH4 (3.15 g, 82.9 mmol) at 0 °C. The mixture was then stirred at room temperature for 1.5 h and quenched with NaHSO4 (125 mL, 10% in water). Most of the EtOH was removed in vacuo. The remaining reaction mixture was extracted with EtOAc (3 × 150 mL). The combined organic phase was washed with water (150 mL), brine (150 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0–55% EtOAc / petroleum ether) to give 5.10 g (51.8% yield) of the title compound as a brown solid. LC-MS: (ESI, m / z): [M+H] + =241. 1 H-NMR (300MHz, CDCl3, ppm) δ7.56-7.43(m,2H),7.42-7.33(m,1H),7.22-7.02(m,2H).

[0408]

[0497] Step 7: 1-Bromo-8-fluoro-3-(methoxymethoxy)naphthalene

[0498] To a solution of 4-bromo-5-fluoronaphthalen-2-ol (4.11 g, 17.0 mmol) in DCM (42.0 mL) was added MOMBr (3.82 g, 30.6 mmol) and DIPEA (5.52 g, 42.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-15% EtOAc / petroleum ether) to afford the title compound (4.12 g, 84.4% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =299. 1H-NMR (300MHz, CDCl3, ppm) δ7.64-7.50(m,2H),7.45-7.34(m,2H),7.15-7.05(m,1H),5.29(s,2H),3.54(s,3H).

[0409]

[0499] Step 8: 2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0500] Under nitrogen, a solution of 1-bromo-8-fluoro-3-(methoxymethoxy)naphthalene (5.1 g, 17.9 mmol), Pin2B2 (11.4 g, 44.9 mmol), Pd(dppf)Cl2 (1.38 g, 1.80 mmol), and KOAc (5.28 g, 53.8 mmol) in 1,4-dioxane (100 mL) was stirred at 110 °C for 4 h. After cooling to room temperature, the resulting reaction mixture was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0 to 25% EtOAc / petroleum ether) to afford 7.60 g of the title compound (containing 45% Pin2B2) as a white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =333. 1 H-NMR (300MHz, CDCl3, ppm) δ7.54-7.49(m,1H),7.45-7.24(m,3H),7.07-6.99(m,1H),5.31(s,2H),3.52(s,3H),1.46(s,12H).

[0410]

[0501] Intermediate 26: Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane TIFF2026000916000159.tif41170

[0502] Step 1: 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[0503] To a solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.00 g, 2.60 mmol) and N-(4-chlorophenyl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.23 g, 3.13 mmol) in THF (10 mL) was added NaH (114.6 mg, 2.86 mmol, 60% in oil) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was diluted with water (30 mL) and extracted with EtOAc (150 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-15% EtOAc / petroleum ether) to give the title compound (1.41 g, 92.7% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =580. 1 H-NMR (300MHz, CDCl3, ppm) δ7.81-7.70(m,2H),7.51-7.39(m,2H),7.35-7.31(m,1H),5.31(s,2H),3.54(s,3H),1.27-1.13(m,21H).

[0411]

[0504] Step 2: Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane

[0505] A solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (1.12 g, 2.17 mmol), Pin2B2 (1.65 g, 6.50 mmol), Pd(dppf)Cl2 (166.7 mg, 0.22 mmol), and KOAc (745 mg, 7.59 mmol) in toluene (11 mL) was stirred at 110 °C overnight under nitrogen. The mixture was partitioned between EtOAc and water. The organic phase was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-10% EtOAc / petroleum ether) to afford 833 mg (77.7% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =558. 1 H-NMR(300MHz,CDCl3,ppm)δ7.76-7.66(m,2H),7.49(d,J=2.6Hz,1H),7.42 -7.32(m,2H),5.30(s,2H),3.52(s,3H),1.45(s,12H),1.23-1.15(m,21H).

[0412]

[0506] Intermediate 27: 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2026000916000160.tif32170

[0507] Step 1: 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate

[0508] Under nitrogen, to a solution of 8-ethyl-3-(methoxymethoxy)naphthalen-1-ol (1.00 g, 4.31 mmol) in DCM (15 mL) was added DIPEA (2.22 g, 17.2 mmol) and TfO (1.82 g, 6.45 mmol) at -40 °C. The resulting solution was stirred at -40 °C for 1 h and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-15% EtOAc / petroleum ether) to afford 1.41 g (89.3% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] = 365. 1H-NMR (300MHz, CDCl3, ppm) δ7.69-7.63(m,1H),7.50-7.39(m,2H),7.37-7. 25(m,2H),5.32(s,2H),3.55(s,3H),3.32-3.22(m,2H),1.35-1.28(m,3H).

[0413]

[0509] Step 2: 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0510] Under nitrogen, a solution of 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.41 g, 3.87 mmol), Pin2B2 (2.95 g, 11.6 mmol), Pd(dppf)Cl2 (298 mg, 0.390 mmol), and KOAc (949 mg, 9.67 mmol) in 1,4-dioxane (15 mL) was stirred at 110 °C overnight. The mixture was partitioned between EtOAc and water. The organic phase was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0–15% EtOAc / petroleum ether) to afford 872 mg (65.8% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+ = 343. 1 H-NMR(300MHz,CDCl3,ppm)δ7.65-7.58(m,1H),7.46-7.34(m,3H),7.30-7.25(m,1 H),5.31(s,2H),3.53(s,3H),3.26-3.16(m,2H),1.46(s,12H),1.42-1.34(m,3H).

[0414]

[0511] Intermediate 28: N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline TIFF2026000916000161.tif30170

[0512] Step 1: 3-bromo-N,N-bis(4-methoxybenzyl)-5-methylaniline

[0513] Under nitrogen, to a solution of 3-bromo-5-methyl-aniline (500 mg, 2.69 mmol) in DMF (5 mL) was added NaH (324 mg, 8.10 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred for 0.5 h. PMBCl (1.05 g, 6.69 mmol) was then added and stirred at room temperature for 12 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-10% ethyl acetate / petroleum ether) to give the title compound (441 mg, 87.8% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =426 / 428.

[0415]

[0514] Step 2: 3-bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline

[0515] To a solution of 3-bromo-N,N-bis[(4-methoxyphenyl)methyl]-5-methylaniline (2.00 g, 4.69 mmol) in DMF (20 mL), NIS (1.58 g, 7.03 mmol) and TsOH (96.0 mg, 0.560 mmol) were added portionwise at room temperature. The resulting solution was stirred at room temperature for 20 minutes and then quenched with aqueous NaSO. The solution was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0–18% ethyl acetate / petroleum ether) to afford the title compound (1.58 g, 50.6% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =552 / 554.

[0416]

[0516] Step 3: 3-bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline

[0517] Under nitrogen, a solution of 3-bromo-4-iodo-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-aniline (1.58 g, 2.86 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.82 mL, 14.3 mmol), and CuI (547 mg, 2.86 mmol) in DMF (15 mL) was stirred at 90 °C for 1 h. The reaction mixture was partitioned between EtOAc and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0–10% ethyl acetate / petroleum ether) to afford the title compound (695 mg, 43.2% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =494 / 496.

[0417]

[0518] Step 4: N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[0519] A solution of 3-bromo-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-4-(trifluoromethyl)aniline (100 mg, 0.2 mmol), Pin2B2 (153.6 mg, 0.600 mmol), PdCl2(dppf) (15.0 mg, 0.0200 mmol), and KOAc (59.3 mg, 0.610 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C under nitrogen for 3 h. The mixture was then concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-10% ethyl acetate / petroleum ether) to afford the title compound (33.0 mg, 22.7% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =542.

[0418]

[0520] Intermediate 29: 2,3-Difluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline TIFF2026000916000162.tif29170

[0521] Step 1: 5-bromo-2,3-difluoro-N,N-bis(4-methoxybenzyl)aniline

[0522] Under nitrogen, to a solution of 5-bromo-2,3-difluoroaniline (500 mg, 2.40 mmol) in DMF (10 mL) was added NaH (384 mg, 9.6 mmol, 60% in mineral oil) at 0 °C, and the mixture was stirred at room temperature for 1 h. Then, PMBCl (1.13 g, 7.21 mmol) was added and stirred at room temperature for 4 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-5% ethyl acetate / petroleum ether) to give the title compound (900 mg, 84.6% yield) as an oil. LC-MS: (ESI, m / z): [M+H] + =448.

[0419]

[0523] Step 2: 5-bromo-2,3-difluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline

[0524] A solution of 5-bromo-2,3-difluoro-N,N-bis[(4-methoxyphenyl)methyl]aniline (900 mg, 2.01 mmol) and NIS (676 mg, 3.02 mmol) in acetic acid (10 mL) was stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-5% ethyl acetate / petroleum ether) to afford the title compound (800 mg, 69.4% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =574.

[0420]

[0525] Step 3: 5-bromo-2,3-difluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline

[0526] Under nitrogen, to a solution of 5-bromo-2,3-difluoro-4-iodo-N,N-bis[(4-methoxyphenyl)methyl]aniline (900 mg, 1.57 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.50 g, 7.85 mmol) in DMA (9 mL) was added CuI (300 mg, 1.57 mmol) at room temperature. The reaction was stirred at 90 °C for 4 h. The resulting mixture was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-10% ethyl acetate / petroleum ether) to afford the title compound (600 mg, 74.1% yield) as an oily brown solid. LC-MS: (ESI, m / z): [M+H] + =516.

[0421]

[0527] Step 4: 2,3-difluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[0528] A solution of 5-bromo-2,3-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (500 mg, 0.970 mmol), Pin2B2 (739 mg, 2.91 mmol), PdCl2(dppf) (71.0 mg, 0.100 mmol), and KOAc (285 mg, 2.91 mmol) in 1,4-dioxane (5 mL) was stirred at 100 °C under nitrogen for 4 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0–10% ethyl acetate / petroleum ether) to afford the title compound (260 mg, 47.7% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =564.

[0422]

[0529] Intermediate 30: 3-fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline TIFF2026000916000163.tif30170

[0530] Step 1: 3-bromo-5-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline

[0531] To a solution of 3-bromo-5-fluoro-N,N-bis[(4-methoxyphenyl)methyl]aniline (600 mg, 1.39 mmol) and NIS (484 mg, 2.16 mmol) in DMF (5 mL) was added TsOH (29.0 mg, 0.170 mmol). The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with aqueous NaSO and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-25% ethyl acetate / petroleum ether) to afford 200 mg (25.5% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =556.

[0423]

[0532] Step 2: 3-bromo-5-fluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline

[0533] Under nitrogen, 2,2-difluoro-2-(fluorosulfonyl)acetate (0.16 mL, 1.19 mmol) was added to a solution of 3-bromo-5-fluoro-4-iodo-N,N-bis[(4-methoxyphenyl)methyl]aniline (100 mg, 0.180 mmol) and CuI (46.0 mg, 0.240 mmol) in DMF (1 mL) at room temperature. The resulting solution was stirred at 90 °C for 2 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-25% ethyl acetate / petroleum ether) to afford 125 mg (crude) of the title compound as a light yellow solid. LC-MS: (ESI, m / z): [M+H]+ =498.

[0424]

[0534] Step 3: 3-fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[0535] A solution of 3-bromo-5-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (129 mg, 0.260 mmol), PdCl2(dppf) (19.0 mg, 0.0300 mmol), KOAc (76.0 mg, 0.780 mmol), and Pin2B2 (198 mg, 0.780 mmol) in 1,4-dioxane (2 mL) was stirred overnight at 110 °C under nitrogen. The resulting solution was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (solvent gradient: 0–60% ACN in water (0.05% NH4HCO3)) to afford 50 mg (35.4% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + =546.

[0425]

[0536] Intermediate 31: 2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline TIFF2026000916000164.tif26170

[0537] Step 1: 3-Bromo-2,6-difluoro-5-methylbenzoic acid

[0538] Under nitrogen, to a stirred solution of 1-bromo-2,4-difluoro-5-methylbenzene (1.00 g, 4.83 mmol) in THF (25 mL) was added LDA (3.14 mL, 6.28 mmol, 2 mol / L in THF) at −85° C. The solution was stirred at −85° C. for 2 hours. The reaction mixture was then poured into a solution of dry ice (250 g) in THF (25 mL). The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with NH4Cl solution (100 mL). THF was removed under reduced pressure, and the remaining solution was acidified to pH = 1 with 1 mol / L HCl solution. The solid was collected by filtration and washed with HO to give the title compound (980 mg, 80.8% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ14.14(s,1H),7.90-7.77(m,1H),2.23(s,3H).

[0426]

[0539] Step 2: tert-butyl (3-bromo-2,6-difluoro-5-methylphenyl)carbamate

[0540] A solution of 3-bromo-2,6-difluoro-5-methyl-benzoic acid (2.00 g, 7.97 mmol), diphenyl azidophosphate (3.28 g, 11.9 mmol), and triethylamine (1.62 g, 16.0 mmol) in 2-methyl-2-propanol (50 mL) was stirred at 90 °C overnight and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient: 0-10% EtOAc / petroleum ether) to give the title compound (2.00 g, 77.9% yield) as a white solid. LC-MS-ESI, m / z: [M+H] + =320.

[0427]

[0541] Step 3: 3-Bromo-2,6-difluoro-5-methylaniline

[0542] A solution of tert-butyl N-(3-bromo-2,6-difluoro-5-methylphenyl)carbamate (2.00 g, 6.21 mmol) and HCl (30 mL, 4 mol / L in dioxane) in dichloromethane (30 mL) was stirred at room temperature for 5 hours. The mixture was then concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 (aq) and EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-20% EtOAc / petroleum ether) to afford the title compound (1 g, 77.9% yield) as a white solid. LC-MS: (ESI, m / z): [M+1 + MeCN] + =263.

[0428]

[0543] Step 4: 2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0544] To a stirred solution of 3-bromo-2,6-difluoro-5-methyl-aniline (300 mg, 1.35 mmol) in 1,2-dimethoxyethane (DME) (10 mL) under nitrogen, Pin2B2 (515 mg, 2.03 mmol), Pd(dppf)Cl2 (98.9 mg, 0.140 mmol), and KOAc (265 mg, 2.70 mmol) were added at room temperature. The resulting solution was stirred at 90 °C overnight. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient: 0-20% EtOAc / petroleum ether) to afford the title compound (310 mg, 85.3% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+1 + MeCN] + =311.

[0429]

[0545] Intermediate 32: ((3S)-3-Fluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2026000916000165.tif28170

[0546] Step 1: 1-(tert-butyl) 2-methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-1,2-dicarboxylate

[0547] Under nitrogen, a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (5.00 g, 20.2 mmol) and HMPA (10.9 g, 60.9 mmol) in tetrahydrofuran (70 mL) was added with a solution of LiHMDS in THF (60.7 mL, 60.7 mmol, 1 M) at -78 °C. The resulting solution was stirred at -78 °C for 1 h. Then, 1-bromo-2-chloroethane (8.36 mL, 100 mmol) was added. The resulting solution was stirred at room temperature for 1 h. The mixture was quenched with NH4Cl (aq) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0 to 100% EtOAc / petroleum ether) to afford 1.26 g (20.1% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + =310.

[0430]

[0548] Step 2: Methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-2-carboxylate

[0549] Under nitrogen, TFA (5 mL) was added to a solution of 1-(tert-butyl) 2-methyl 2-(2-chloroethyl)-4-difluoropyrrolidine-1,2-dicarboxylate (1.26 g, 3.87 mmol) in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo to give 2 g (crude) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =210.

[0431]

[0550] Step 3: Methyl (3S)-3-fluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate

[0551] A solution of methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-2-carboxylate (2.00 g, 3.82 mmol) and K2CO3 (1.60 g, 11.6 mmol) in acetonitrile (30 mL) was stirred at 85 °C for 1 h. The solid was filtered off. The filtrate was concentrated in vacuo to give 2.9 g (crude) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =174.

[0432]

[0552] Step 4: ((3S)-3-fluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol

[0553] Under nitrogen, a solution of LiAlH in THF (16.7 mL, 16.7 mmol, 1 M) was added to a solution of methyl (3S)-3-fluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate (2.90 g, 16.7 mmol) in tetrahydrofuran (20 mL) at 0 °C. The resulting solution was stirred at 0 °C for 30 min. The mixture was quenched with NaSO.10H0 and filtered. The solvent was removed by N (volatile) blowing to give 2 g (crude) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =146.

[0433]

[0554] Intermediate 33: ((7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol

[0555] Step 1: Ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate & Ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2026000916000166.tif36170

[0556] Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (19.9 g, separated by chiral SFC (Column: CHIRALPAK IH, 50 x 250 mm; Mobile Phase A: CO2, Mobile Phase B: EtOH; Flow Rate: 150 mL / min; Gradient: 26% B; 220 nm; RT1: 4.8; RT2: 6.43; Injection Volume: 1.8 mL; Runs: 122) gave ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.61 g, earlier peak) and ethyl (S)-2-Methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.29 g, later peak) was obtained. LC-MS: (ESI, m / z): [M+H] + =210. 1 H NMR (400 MHz, Chloroform-d) δ 5.12-5.00 (m, 2H), 4.32-4.28 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.73 (d, J = 15.7 Hz, 1H), 3.06 (d, J = 15.7 Hz, 1H), 2.85-2.72 (m, 1H), 2.66-2.57 (m, 1H), 2.53-2.41 (m, 2H), 2.19-2.08 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). The H NMR of the two isomers is identical.

[0434]

[0557] Step 2: Ethyl (7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate TIFF2026000916000167.tif38170

[0558] Under nitrogen, a solution of ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (200 mg, 0.960 mmol) and NaI (71.7 mg, 0.480 mmol) in THF (5 mL) was added with TMSCF (476 mg, 3.35 mmol) at room temperature. The resulting solution was stirred at 65 °C for 2.5 h. The solution was diluted with DCM, washed with sodium thiosulfate solution, and dried over NaSO. The organic layer was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0% to 35% ethyl acetate / petroleum ether) to give 95.0 mg (38.3% yield) of the fast peak (gradient: 35% to 90% ethyl acetate / petroleum ether) and 108 mg (43.6% yield) of the slow peak as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =260. Faster peak: 1 H NMR(300MHz,DMSO-d6,ppm)δ4.25-4.19(m,2H),3.80-3.70(m,1H),3.04(d,J=12.1,3.5Hz,1H) ,2.62-2.58(m,1H),2.51-2.12(m,5H),1.60(t,J=9.3Hz,2H),1.24(t,J=7.1Hz,3H).Slower peak: 1 H NMR(300MHz,DMSO-d6,ppm)δ4.24-4.08(m,2H),3.61(d,J=11.7,2.7Hz,1H),3.11(d,J=11 .6Hz,1H),2.72-2.54(m,1H),2.44-2.13(m,5H),1.79-1.58(m,2H),1.22(t,J=7.1Hz,3H).

[0435]

[0559] Step 2: ((7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol

[0560] Under nitrogen, to a solution of ethyl (7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate (95.0 mg, 0.370 mmol, earlier peak from previous step) in THF (2.5 mL) was added LiAlH4 (1.1 mL, 1 M in THF). The solution was stirred at 65 °C for 1 h. The reaction was cooled to room temperature, filtered, and quenched with Na2SO4·10H2O. After filtration, the filtrate was concentrated under reduced pressure to give 42.0 mg (56.4% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =204.

[0436]

[0561] Intermediate 34: (Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (mixture of trans isomers) TIFF2026000916000168.tif55170

[0562] Step 1: Diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (mixture of trans isomers)

[0563] To a solution of diethyl cis-1-benzylpyrrolidine-2,5-dicarboxylate (8.60 g, 28.2 mmol) in tetrahydrofuran (120 mL) was added LiHMDS (43.4 mL, 56.4 mmol) at -35 °C. After 1 h, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-15% ethyl acetate / petroleum ether) to afford 1.27 g (14% yield) of the title compound as a light yellow oil. The cis isomer was recovered (6.3 g). LC-MS: (ESI, m / z): [M+H] + =306.2. 1 H NMR(300MHz,DMSO-d6,ppm)δ7.32-7.20(m,5H),4.13-3.87(m,6H),3.75-3.60(m,3H),2.25-2.11(m,2H),1.91-1.75(m,2H),1.25-1.06(m,3H).

[0437]

[0564] Step 2: (1-benzylpyrrolidine-2,5-diyl)dimethanol (mixture of trans isomers)

[0565] Under nitrogen, to an ice-cold solution of diethyl trans-1-benzylpyrrolidine-2,5-dicarboxylate (2.30 g, 7.53 mmol) in tetrahydrofuran (30 mL) was added LiAlH4 (716 mg, 18.8 mmol) in several portions. The reaction was allowed to warm to room temperature. After 2 h, the mixture was quenched with Na2SO4·10H2O. The solid was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0–10% MeOH / DCM) to afford 1.65 g (99% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =222.1. 1 H NMR(400MHz,DMSO-d6,ppm)δ7.38-7.15(m,5H),4.34(s,2H),3.95-3.82(m,2H),3.46-3 .36(m,2H),3.28-3.20(m,2H),3.01-2.90(m,2H),1.90-1.75(m,2H),1.71-1.58(m,2H).

[0438]

[0566] Step 3: Pyrrolidine-2,5-diyldimethanol (mixture of trans isomers)

[0567] A solution of (1-benzylpyrrolidine-2,5-diyl)dimethanol (0.60 g, 2.7 mmol) and Pd / C (180 mg, 10% w / w) in methyl alcohol (10 mL) was stirred under hydrogen (1 atm) at room temperature for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to give 405 mg (crude) of the title compound as a light yellow oil. LC-MS: (ESI, m / z): [M+H] + = 132.1. The crude product was used without further purification.

[0439]

[0568] Step 4: 1-(2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-2-bromoethan-1-one (mixture of trans isomers)

[0569] To an ice-cold solution of pyrrolidine-2,5-diyldimethanol (355 mg, 2.71 mmol) and N-methylmorpholine (410 mg, 4.06 mmol) in tetrahydrofuran (10 mL) was added 2-bromoacetyl bromide (539 mg, 2.67 mmol). After 1 h, the reaction was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-10% MeOH / DCM) to afford 130 mg (19% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =252.1. 1 H NMR(400MHz,DMSO-d6,ppm)δ5.03(s,1H),4.71(s,1H),4.24(d,J=11.4Hz,1H),4. 09-3.99(m,1H),3.92-3.87(m,2H),3.69(s,2H),3.17(s,2H),2.04-1.72(m,4H).

[0440]

[0570] Step 5: 6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (mixture of trans isomers)

[0571] To an ice-cold suspension of NaH (65.0 mg, 1.63 mmol, 60% in mineral oil) in tetrahydrofuran (5 mL) was added a solution of 1-(2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-2-bromoethan-1-one (130 mg, 0.517 mmol) in THF (1 mL). After 1 h, the resulting solution was allowed to warm to room temperature for 3 h. The reaction was diluted with water and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-6% MeOH / DCM) to afford the title compound (37.0 mg, 42% yield). LC-MS: (ESI, m / z): [M+H] + =172.2. 1H NMR(400MHz,DMSO-d6,ppm)δ4.88-4.82(m,1H),4.14-3.97(m,3H),3.84(d,J=16Hz,1H),3.71-3.61(m ,1H),3.59-3.48(m,2H),3.23-3.15(m,1H),2.03-1.87(m,2H),1.82-1.66(m,1H),1.39-1.19(m,1H).

[0441]

[0572] Step 6: (Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (mixture of trans isomers)

[0573] Under nitrogen, to an ice-cooled suspension of LiAlH (27.3 mg, 0.720 mmol) in tetrahydrofuran (5 mL) was added a solution of 6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (60.0 mg, 0.350 mmol) in THF (0.5 mL). The resulting solution was warmed to 60 °C for 2 h. The reaction was cooled to room temperature, filtered, and quenched with NaSO 10H O. The solid was filtered, and the filtrate was concentrated to give the title compound as a light yellow oil (60 mg, crude). LC-MS: (ESI, m / z): [M+H] + = 158.1. The crude product was used in the next step without further purification.

[0442]

[0574] Intermediate 34A: ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol TIFF2026000916000169.tif62170

[0575] Step 1: Diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (mixture of trans isomers)

[0576] To a solution of diethyl cis-1-benzylpyrrolidine-2,5-dicarboxylate (8.60 g, 28.2 mmol) in tetrahydrofuran (120 mL) was added LiHMDS (43.4 mL, 56.4 mmol) at -35 °C. After 1 h, the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-15% ethyl acetate / petroleum ether) to afford 1.27 g (14% yield) of the title compound as a light yellow oil. The cis isomer was recovered (6.3 g). LC-MS: (ESI, m / z): [M+H] + =306.2. 1 H NMR(300MHz,DMSO-d6,ppm)δ7.32-7.20(m,5H),4.13-3.87(m,6H),3.75-3.60(m,3H),2.25-2.11(m,2H),1.91-1.75(m,2H),1.25-1.06(m,3H).

[0443]

[0577] Step 2: (1-benzylpyrrolidine-2,5-diyl)dimethanol (mixture of trans isomers)

[0578] Under nitrogen, to an ice-cold solution of diethyl trans-1-benzylpyrrolidine-2,5-dicarboxylate (2.30 g, 7.53 mmol) in tetrahydrofuran (30 mL) was added LiAlH4 (716 mg, 18.8 mmol) in several portions. The reaction was allowed to warm to room temperature. After 2 h, the mixture was quenched with Na2SO4·10H2O. The solid was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0–10% MeOH / DCM) to afford 1.65 g (99% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =222.1. 1H NMR(400MHz,DMSO-d6,ppm)δ7.38-7.15(m,5H),4.34(s,2H),3.95-3.82(m,2H),3.46-3 .36(m,2H),3.28-3.20(m,2H),3.01-2.90(m,2H),1.90-1.75(m,2H),1.71-1.58(m,2H).

[0444]

[0579] Step 3: Pyrrolidine-2,5-diyldimethanol (mixture of trans isomers)

[0580] A solution of (1-benzylpyrrolidine-2,5-diyl)dimethanol (0.60 g, 2.7 mmol) and Pd / C (180 mg, 10% w / w) in methanol (10 mL) was stirred under hydrogen (1 atm) at room temperature for 2 h. The catalyst was filtered off, and the filtrate was concentrated to give 405 mg (crude) of the title compound as a light yellow oil. LC-MS: (ESI, m / z): [M+H] + = 132.1. The crude product was used without further purification.

[0445]

[0581] Step 4: (6R,8aR)-6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one & (6S,8aS)-6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one TIFF2026000916000170.tif26170

[0582] To a solution of pyrrolidine-2,5-diyldimethanol (7.9 g, 60.305 mmol) in IPA (300.0 mL) was added potassium trimethylsilanolate (16.98 g, 132.671 mmol) at 0 °C. 2-Bromoacetyl bromide (13.27 g, 66.336 mmol) was then added. The solution was stirred at 0 °C for 1 min. The reaction was quenched with MeOH (20 mL). The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-10% MeOH / DCM) to afford 3.9 g of the title compound (a mixture of trans isomers) as a yellow oil. The enantiomers were separated by chiral SFC under the following conditions (column: CHIRAL ART Amylose-SA, 3 x 25 cm, 5 μm; mobile phase: CO (70%) and MeOH (0.1% 2M NH3-MeOH) (30%)) to give 1.98 g of the fast peak and 1.9 g of the slow peak (desired isomer) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =172.H-NMR-PH-GNE-VINT-073-0: 1 H NMR(300MHz,DMSO-d6)δ4.85(t,J=5.7Hz,1H),4.14-3.99(m,3H),3.84(d,J=16.5Hz,1H),3.67-3.56( m,1H),3.67-3.51(m,2H),3.23-3.16(m,1H),2.00-1.89(m,2H),1.80-1.69(m,1H),1.34-1.25(m,1H).

[0446]

[0583] Step 5: ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol

[0584] Under nitrogen, to an ice-cooled suspension of LiAlH (27.3 mg, 0.720 mmol) in tetrahydrofuran (5 mL) was added a solution of (6S,8aS)-6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (60.0 mg, 0.350 mmol) in THF (0.5 mL). The resulting solution was warmed to 60 °C for 2 h. The reaction was cooled to room temperature, filtered, and quenched with NaSO 10H O. The solid was filtered, and the filtrate was concentrated to give the title compound as a light yellow oil (60 mg, crude). LC-MS: (ESI, m / z): [M+H] + = 158.1. The crude product was used in the next step without further purification.

[0447]

[0585] Intermediate 35: ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol TIFF2026000916000171.tif15170

[0586] Under nitrogen, LiAlH (19.6 g, 515 mmol) was added to a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (60.0 g, 257 mmol) in tetrahydrofuran (1000 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour and then at 60 °C for 2 hours. The reaction mixture was cooled in an ice bath, and water (20 mL) was slowly added to quench the reaction, followed by 20% aqueous NaOH (20 mL) and 20 mL of water. The solid was filtered off, and the filtrate was concentrated in vacuo. The residue was redissolved in DCM, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0-15% MeOH in DCM (0.1% TEA)) to give 12.4 g (36% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =134. 1 H NMR (300 MHz, DMSO-d 6,ppm)δ5.25-4.97(m,1H),4.44(dd,J=6.0,5.0Hz,1H),3.50-3.22(m,3H),2.57-2. 50(m,1H),2.46-2.31(m,1H),2.30(s,3H),2.07-1.87(m,1H),1.87-1.60(m,1H).

[0448]

[0587] Intermediate 36: (R)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol and (S)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2026000916000172.tif23170

[0588] Under nitrogen, to a solution of ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (110 mg, 0.510 mmol, Intermediate 33, Step 1) in tetrahydrofuran (5 mL) was added LiAlH (1.1 mL, 1 M in THF) at 0 °C. The mixture was stirred at 70 °C for 0.5 h. The mixture was quenched with NaSO.10H O and filtered. The solvent was removed by blowing with nitrogen (this product has a low boiling point) to give the title compound (62.8 mg, crude), which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =154.

[0449]

[0589] Intermediate 37: 4'-((((2R,7aS)-7a-(hydroxymethyl)hexahydro-1H-pyrrolidin-2-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile TIFF2026000916000173.tif33170

[0590] Step 1: 4'-(hydroxymethyl)-[1,1'-biphenyl]-2-carbonitrile

[0591] A solution of 2-bromobenzonitrile (1.25 g, 6.87 mmol), Pd(PPh3)4 (793 mg, 0.690 mmol), 4-(hydroxymethyl)phenylboronic acid (1.15 g, 7.55 mmol), K2CO3 (1.90 g, 13.8 mmol), and water (5 mL) in 1,2-dimethoxyethane (50 mL) was stirred at 100 °C for 12 h under nitrogen. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient: 0 to 30% EtOAc / petroleum ether) to afford the title compound (1.26 g, 87.7% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ8.00-7.90(m,1H),7.85-7.75(m,1H),7.69-7.51(m,6H),5.75(s,1H),4.69(s,2H).

[0450]

[0592] Step 2: (2'-cyano-[1,1'-biphenyl]-4-yl)methyl methanesulfonate

[0593] Under nitrogen, to a solution of 2-[4-(hydroxymethyl)phenyl]benzonitrile (235 mg, 1.12 mmol)] and N,N-diisopropylethylamine (0.58 mL, 3.36 mmol) in dichloromethane (10 mL) was added methanesulfonic anhydride (254 mg, 1.46 mmol) at 0 °C. The resulting solution was stirred at room temperature for 2 h, diluted with CHCl, and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (320 mg, crude) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+Na] + =310.

[0451]

[0594] Step 3: 4'-((((2R,7aS)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-2-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile

[0595] Under nitrogen, a solution of (2R,8S)-8-(trityloxymethyl)-1,2,3,5,6,7-hexahydropyrrolidin-2-ol (448 mg, 1.12 mmol) in tetrahydrofuran (4 mL) was added with NaH (269 mg, 6.73 mmol, 60% in mineral oil) at 0 °C. The resul...

Claims

1. Compound of formula (I): or its tautomers or pharmaceutically acceptable salts, (In the above formula, X is O or NR ６ And; m is either 1 or 2; n is either 1 or 2; Here, n and m together form a ring A of six or seven members; p is 0, 1, or 2; R １ R ７Ａ Substituting phenyl or R ７Ａ It is a substituted pyridinyl; Each R ７Ａ These are halogen and unsubstituted C, independently. １－３ Alkyl or unsubstituted C １－３ It is a haloalkyl; L １ is R Ｌ１ substituted or unsubstituted C １－４ alkylene; R Ｌ１ is halogen or unsubstituted C １－３ Alkyl or two R Ｌ１ Together they become non-substituted C ３－４ It forms a cycloalkyl group; R ２ R contains one or more heteroatoms selected from N, S, or O. ９ It is a substituted or unsubstituted 4- to 10-membered heterocycle; Each R ９ These are independently halogen, CN, OH, and OCF ３ , OCHF ２ , OCH ２ F, R １０ Substituted or unsubstituted C １－３ Alkyl, R １０ Substituted or unsubstituted C １－３ Haloalkyl, unsubstituted C １－３ Alkoxy, R １０ Substituted or unsubstituted C １－３ Alkyridene, or R １０ Substituted or unsubstituted C ３－４ Cycloalkyl, or R １０ It is a substituted or unsubstituted three-membered or four-membered heterogly ring; or Two R's ９ They came together, R １０ Substituted or unsubstituted C ３－５ Cycloalkyl, or R containing one or more oxygen atoms １０ Substituted or unsubstituted C ３－５ To form a heterocycle; or Two R's ９ These together form a bridge between two carbon atoms of a cycloalkyl or heterocycle, and this bridge contains 1 to 3 carbon atoms; Each R １０ These are independently hydrogen, oxo, CN, halogen, or C １－３ It is an unsubstituted alkyl group; R ３ This includes hydrogen, -CN, halogens, and unsubstituted C. １－３ It is alkyl or unsubstituted cyclopropyl; Each R ４ These are independently hydrogen, methyl, or C １－３ It is a haloalkyl; Each R ５ These are independently halogen, oxo, and unsubstituted C １－３ Alkyl or unsubstituted C １－３ It is a haloalkyl; or Two R's ５ Together, they form a bridge between two carbon atoms of ring A, which comprises one to three carbon atoms and optionally one heteroatom selected from O and N; or Two R's ５ Together, they form a bridge between the two carbon atoms of ring A, and this bridge is O or NR １１ Including one of the following; R １１ This is hydrogen, C(O)CH ３ or unsubstituted C １３ It is alkyl; R ６ is hydrogen, R ６Ａ Substituted or unsubstituted C １－６ Alkyl, R ６Ａ Substituted or unsubstituted C １－６ Haloalkyl, R ６Ａ Substituted or unsubstituted C １－６ Alkenil; R ６Ａ Substituted or unsubstituted C １－６ Alkinyl, or R ６Ａ It is a substituted or unsubstituted 3-4 member complex ring; Each R ６Ａ is halogen, CN, OR ６Ｂ , SR ６Ｃ , S(O) ２ R ６Ｃ , C(O)R ６Ｂ , unsubstituted C １－３ Alkyl, unsubstituted C １－３ Haloalkyl, or R ６Ｂ It is a substituted or unsubstituted 3-4 member complex ring; R ６Ｂ and R ６Ｃ Each is independently C １－３ Alkyl or C １－３ It is a haloalkyl, A compound of formula (I), or its tautomers or pharmaceutically acceptable salts.

2. R １ but, (In the above formula, X １ (is N) The compound according to claim 1, or its tautomers or pharmaceutically acceptable salts.

3. X is NR ６ And R ６ The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

4. The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein both m and n are 1.

5. One R ４ It is hydrogen, and one R ４ The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

6. L １ The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein methylene is present.

7. R ２ but (In the above formula, Each R ９ is halogen, or R １０ Substituted or unsubstituted C １－３ It is alkyridene, r is an integer between 0 and 12; j is 1, 2, or 3; k is either 1 or 2. The compound according to claim 1, or its tautomers or pharmaceutically acceptable salts.

8. R ２ but The compound according to claim 1, or its tautomers or pharmaceutically acceptable salts.

9. R ２ but (In the above formula, R ９ is independently halogen or R １０ substituted or unsubstituted C １ - ３ alkylidene; Each R １０ These are independently hydrogen or halogen; (r is 1 or 2) The compound according to claim 1, or its tautomers or pharmaceutically acceptable salts.

10. R ２ but The compound according to claim 1, or its tautomers or pharmaceutically acceptable salts.

11. R ２ but (In the above equation, r is either 0 or 1) The compound according to claim 1, or its tautomers or pharmaceutically acceptable salts.

12. R ３ The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the halogen is...

13. Two R's ５ The compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the two carbon atoms together form a bridge between the two carbon atoms of ring A, and this bridge contains two carbon atoms.

14. The compound of formula (I) is: A compound of the compound described in claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

15. R １ is The compound according to claim 1, or its tautomers or pharmaceutically acceptable salts.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives.

18. A pharmaceutical agent for treating cancer, comprising an effective amount of a compound according to any one of claims 1 to 16, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

19. The cancer is characterized by containing a KRas mutation, and the KRas mutation is KRas Ｇ１２Ｄ A pharmaceutical product according to claim 18, which corresponds to a mutation.

20. The pharmaceutical product according to claim 18, wherein cancer is not tissue-dependent.

21. The pharmaceutical product according to claim 18, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

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