Tetracyclic oxazepine compounds and their uses

Abstract

Provided herein are tetracyclic oxazepinyl compounds useful for the treatment of cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to International Patent Application No. PCT / CN2022 / 074435, filed January 27, 2022, and International Patent Application No. PCT / CN2021 / 076369, filed February 9, 2021, each of which is incorporated herein by reference in its entirety for all purposes.

[0002] FIELD OF THE INVENTION Provided herein are tetracyclic compounds useful for treating cancers that contain KRas mutations, compositions of such compounds, and methods of treating cancers that contain KRas mutations. [Background technology]

[0003] background Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch in central growth signaling pathways. In response to extracellular signals, Ras undergoes GDP-bound (Ras) exchange, catalyzed by guanine nucleotide exchange factors (GEFs), particularly the SOS1 protein. GDP ) state to GTP-bound (Ras GTP ) state. Active Ras GTP Ras mediates its diverse growth-stimulatory functions through direct interaction with effectors, including Raf, PI3K, and the Ral guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity can be further accelerated by interaction with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

[0004] Mutant Ras has reduced GTPase activity, which maintains Ras in an activated state, thereby promoting Ras-dependent signaling and cancer cell survival or proliferation. Mutations in Ras that affect its ability to interact with GAPs or convert GTP back to GDP result in sustained activation of the protein, resulting in sustained signals that promote continued growth and division. Because these signals lead to cell growth and division, overactive RAS signaling can ultimately lead to cancer. Mutations in any one of the three major RAS isoforms (HRas, NRas, or KRas) are common events in human tumorigenesis. Of the three Ras isoforms (K, N, and H), KRas is the most frequently mutated.

[0005] The most common KRas mutations are found at residues G12 and G13 in the P-loop and at 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. Therefore, Ras is widely considered to be an exceptionally important oncological target.

[0006] Therefore, there is an urgent need for therapies for G12D mutant KRas-mediated cancers. Summary of the Invention

[0007] overview Solutions to the above problems and other problems in the art are provided herein.

[0008] In a first aspect, a compound of formula (I) as described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0009] In another aspect, provided herein is a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih), as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0010] In another aspect, provided herein is a compound of Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIg), or (IIh), as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0011] In another aspect, provided herein is a compound of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIg), or (IIIh), as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0012] In another aspect, provided herein are compounds shown in Table 1, or pharmaceutically acceptable salts thereof.

[0013] In another aspect, provided herein are compounds shown in Table 2, or pharmaceutically acceptable salts thereof.

[0014] In another aspect, provided herein is a pharmaceutical composition comprising a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, as described herein.

[0015] In another aspect, provided herein is a method of treating a cancer harboring a KRas mutation, comprising administering to a patient having such a cancer a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, as described herein.

[0016] In another aspect, provided herein is a method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0017] In another aspect, provided herein is a method for inhibiting proliferation of a cell population, comprising contacting the cell population with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0018] 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 a pharmaceutical composition described herein.

[0019] In another aspect, provided herein is a method for preparing a labeled KRas G12D mutant protein, comprising reacting a KRas G12D mutant protein with a labeled compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to obtain the labeled KRas G12D mutant protein.

[0020] In another aspect, provided herein are processes for synthesizing the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0021] definition In certain embodiments, the present disclosure provides tetracyclic oxazepine compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, which are inhibitors or modulators of mutant KRas, and pharmaceutical compositions thereof. In certain cases, such compounds and compositions are inhibitors or modulators of mutant G12D KRas provided herein. The compounds and compositions described herein are useful for treating diseases and disorders mediated by mutant KRas.

[0022] It will be understood that while the disclosure herein provides enumerated embodiments, they are not intended to limit the compounds and methods described herein to those embodiments. On the contrary, the disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the disclosure as defined by the claims.

[0023] Unless otherwise specified, 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 IUPAC systematic nomenclature unless otherwise indicated.

[0024] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0025] 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.

[0026] The term "alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon radical. In one example, an alkyl group has 1 to 18 carbon atoms (C1~18 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 1~3 Examples of alkyl groups are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(C H3)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(CH3 )CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, and 1-octyl.

[0027] The term "oxo" means =O.

[0028] The term "alkoxy" refers to --O-alkyl.

[0029] The term "cyano" or "nitrile" refers to -C≡N or -CN.

[0030] The term "haloalkoxy" refers to an --O-haloalkyl.

[0031] The terms "hydroxy" and "hydroxyl" refer to --OH.

[0032] The term "alkylidene" refers to a straight- or branched-chain monovalent hydrocarbon radical having the formula =CR'R'', where R' and R' can be the same or different. In one example, an alkylidene 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).

[0033] The term "alkenyl" means a straight- or branched-chain monovalent hydrocarbon having at least one carbon-carbon double bond, including groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one example, an alkenyl group is an alkyl group 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 2~3Examples 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.

[0034] The term "alkynyl" means a linear or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one example, an alkynyl radical is an alkynyl 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.

[0035] The term "alkylene" means a saturated, branched, or straight-chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. In one example, a divalent alkylene group has 1 to 18 carbon atoms (C 1~18 In another example, the divalent alkylene group is C 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~5 , C 1~4 , or C 1~3Examples of alkylene groups include methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), (1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 2,2-propyl (-C(CH3)2-), 1,2-propyl (-CH(CH3)CH2-), 1,3-propyl (-CH2CH2CH2-), 1,1-dimethyleth-1,2-yl (-C(CH3)2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0036] The term "cycloalkyl" means a saturated hydrocarbon ring group. Cycloalkyl includes monocyclic, bicyclic, tricyclic, spiro, and bridged saturated ring systems. In one example, a cycloalkyl group contains 3 to 12 carbon atoms (C 3~12 In other examples, cycloalkyl is C 3~4 , C 3~5 , C 3~7 , C 3~8 , C 3~10 , or C 5~10 In another example, the cycloalkyl group as a single ring is C 3~4 , C 3~8 , C 3~6 , or C 5~6 In another example, the cycloalkyl group for the bicycle is 7-C 12 In another example, the cycloalkyl group as a spiro system is C 5~12Examples 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.

[0037] The terms "heterocyclic group," "heterocyclic," "heterocycle," "heterocyclyl," or "heterocyclo" are used interchangeably and refer to any mono-, bi-, tricyclic, spiro-, or bridged, saturated, partially saturated, or unsaturated non-aromatic ring system having 3 to 20 ring atoms, in which the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the ring system is a heteroatom, the system is heterocyclic, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl contains 3 to 10 ring atoms ("members"), including mono-, bi-, tricyclic, spiro-, and bridged ring systems in which the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclyl contains 4 to 10, or 5 to 10 ring atoms. In one example, a heterocyclyl contains 1 to 4 heteroatoms. In one example, a heterocyclyl includes 1 to 3 heteroatoms. In another example, a heterocyclyl includes 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 includes 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 includes a 3-membered monocyclic ring. In another example, a heterocyclyl includes a 4-membered monocyclic ring. In another example, a heterocyclyl includes a 5- to 6-membered monocyclic ring. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, a heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR]). + Cl - , [NR4] + OH -Exemplary heterocycles 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, hexahydrothio ... Dropyrimidinyl, 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 Benzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl , pyrimidinonyl, pyrimidindionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl.

[0038] In certain embodiments, the heterocyclyl or heteroaryl group is bonded at a carbon atom of the heterocyclyl or heteroaryl group. For example, carbon-bonded heterocyclyl groups include those bonded at the 2-, 3-, 4-, 5-, or 6-positions of the pyridine ring, the 3-, 4-, 5-, or 6-positions of the pyridazine ring, the 2-, 4-, 5-, or 6-positions of the pyrimidine ring, the 2-, 3-, 5-, or 6-positions of the pyrazine ring, the 2-, 3-, 4-, or 5-positions of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, the 2-, 4-, or 5-positions of the oxazole, imidazole, or thiazole ring, the 3-, 4-, or 5-positions of the isoxazole, pyrazole, or isothiazole ring, the 2-, or 3-positions of the aziridine ring, the 2-, 3-, or 4-positions of the azetidine ring, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-positions of the quinoline ring, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-positions of the isoquinoline ring.

[0039] In certain embodiments, the heterocyclyl or heteroaryl group is N-linked. For example, nitrogen-linked heterocyclyl or heteroaryl groups include attachment 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.

[0040] "Fused" refers to any ring structure described herein that shares one or more atoms (eg, carbon atoms or nitrogen atoms) with an existing ring structure in the compounds described herein.

[0041] The term "acyl" refers to a carbonyl containing a substituent represented by -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).

[0042] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Examples of haloalkyl include trifluoromethyl, difluoromethyl, and fluoromethyl. Substituted haloalkyl refers to a haloalkyl having a moiety other than a halogen.

[0043] As used herein, a wavy line "" crossing a bond in a chemical structure TIFF2024506029000001.tif3170" indicates the point of attachment of an atom in a chemical structure where a wavy bond connects it to the rest of the molecule, or to the rest of a fragment of a molecule.

[0044] In certain embodiments, a divalent group is described generically without a specific bond structure. Unless otherwise specified, the generic description is understood to be meant to include both bond structures. For example, the group R 1 -R 2 -R 3 In the formula, the group R 2 When is depicted as -CHC(O)-, unless otherwise specified, this group is represented by R 1 -CH2C(O)-R 3 and R 1 -C(O)CH2-R 3 It is understood that both are combinable.

[0045] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other side reactions when properly administered to an animal, such as a human.

[0046] The compounds described herein may be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free base and which are biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and the organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0047] The term "pharmaceutically acceptable base addition salts" includes salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines, including basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0048] In some embodiments, the salt is hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate), , or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate) (1S)-(+)-10-camphor-sulfonate), camsylate (camphor 10-sulfonate, e.g., (1S)-(+)-10-camphor-sulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0049] A "sterile" preparation is aseptic or free of all viable microorganisms and their spores.

[0050] The term "stereoisomers" means 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.

[0051] The term "chiral" refers to molecules that possess the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0052] The term "diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activity. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0053] The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0054] The term "atropisomers" refers to two conformers resulting from hindered rotation about a single bond where the steric strain barrier to rotation can be high enough to allow isolation of each conformer.

[0055] 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 have the ability to rotate the plane of plane-polarized light. When 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(s). The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0056] The term "tautomer" or "tautomeric form" means structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0057] Certain compounds described herein can exist in unsolvated and solvated forms, including hydrated forms. The term "solvate" refers to an association or complex of one or more solvent molecules and 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. In general, all physical forms are contemplated herein. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0058] The compounds described herein and their pharmaceutically acceptable salts also include isotopically labeled compounds that are identical to those listed herein, due to the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those usually found in nature.All isotopes of any particular atom or element designated and their use are contemplated herein.Exemplary isotopes that can be incorporated into the compounds described herein and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, for example: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 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, may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferable in some circumstances. 15 O. 13 N, 11 C, and 18 Positron emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds described herein, or pharmaceutically acceptable salts thereof, can generally be prepared by following procedures similar to those described in the Examples described herein below, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0059] As used herein, the term "amino-protecting group" refers to a derivative of a group commonly used to block or protect an amino group, while a reaction is carried out at another functional group in the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Specific amino-protecting groups are Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), and Cbz (carbobenzyloxy). Further examples of these groups can be found in T.W. Greene and P.G.M.Wuts, "Protecting Groups in Organic Synthesis, 3 rd ed., John Wiley & Sons, Inc., 1999. The term "protected amino" means an amino group substituted with one of the amino-protecting groups described above.

[0060] As used herein, the term "carboxy-protecting group" means a group that is stable to the conditions of subsequent reaction(s) elsewhere in the molecule and that can be removed at an appropriate point to yield an unprotected carboxy group without destroying the remainder of the molecule. Examples of carboxy-protecting groups include ester groups and heterocyclyl groups. An ester derivative of the carboxylic acid group may be used to block or protect the carboxylic acid group while the reaction is carried out at another functional group of the compound. Examples of such ester groups include substituted aryl alkyl, including substituted benzyl, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl or substituted alkyl esters, such as methyl, ethyl, t-butyl, allyl or t-amyl, triphenylmethyl (trityl), 4- Included are methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butylthioester, silyl esters such as trimethylsilyl, t-butyldimethylsilyl ester, phenacyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and similar moieties. Another example of a carboxy protecting group is a heterocyclyl group such as 1,3-oxazole. Further examples of these groups are found in T.W. Greene and P.G.M.Wuts, "Protecting Groups in Organic Synthesis, 3 rd ed., John Wiley & Sons, Inc., 1999. The term "protected carboxy" means a carboxy group substituted with one of the carboxy-protecting groups described above.

[0061] The compounds described herein and their pharmaceutically acceptable salts may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may use racemates, diastereomers, or enantiomers as starting materials or intermediates. A mixture of specific diastereomeric compounds may be separated or enriched into one or more specific diastereomers by chromatographic or crystallization techniques. Similarly, enantiomeric mixtures may be separated or enantiomerically enriched using the same techniques, or other techniques known in the art. Each asymmetric carbon or nitrogen atom may be in the R or S configuration, and both of these configurations are contemplated herein.

[0062] In structures shown herein where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, that stereoisomer is so specified and defined. Unless otherwise stated, when a solid wedge or dashed line is used, relative stereochemistry is intended.

[0063] 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 (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human. In embodiments involving administering a compound to a patient, the patient is typically in need of administration of the compound.

[0064] The terms "inhibit" and "reduce / diminish," or any variation of these terms, include any measurable reduction / decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in activity compared to normal of about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any variable of these ranges.

[0065] The term "treatment" refers to a clinical intervention designed to alter the natural course of the patient or cells being treated during the course of clinical disease. Desirable effects of treatment include reducing the rate of disease progression, ameliorating or alleviating the disease state, and achieving remission or improving prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with cancer as described herein are reduced or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancerous cells, alleviating symptoms caused by 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 extending the patient's survival.

[0066] The term "delaying progression" of a disease refers to putting off, preventing, delaying, slowing, stabilizing, and / or postponing the onset of cancer as described herein. This delay can be of varying lengths of time depending on the history of the cancer and / or the patient being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the patient does not develop or recur cancer.

[0067] "Mutant KRas-mediated disease" and the like refers to a disease described herein (e.g., a cancer described herein) having symptoms or requiring treatment as described herein that are associated, resultant, functional, or otherwise correlated, in whole or in part, with mutant KRas activity as described herein. In one such embodiment, the mutant KRas is KRas G12D is.

[0068] An "effective amount" or "therapeutically effective amount" is at least the minimum amount necessary to achieve a measurable improvement or prevention of a cancer as described herein. The effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, and the ability of the agent to elicit a desired response in the patient. An effective amount is also one in which any toxic or adverse 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 the disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifesting during the development of the disease), reduction in one or more symptoms attributable to the disease, improvement in the quality of life of those suffering from the disease, reduction in the dose of other drugs required to treat the disease, enhancing the effect of another drug, such as by targeting, delay in disease progression, and / or prolonged survival. In some embodiments, an effective amount of a drug may be effective in reducing the number of cancer cells, shrinking tumor size, inhibiting (i.e., slowing or stopping) cancer cell invasion into peripheral organs, inhibiting (i.e., slowing or stopping) tumor metastasis, inhibiting (i.e., slowing or stopping) tumor growth, and / or alleviating one or more symptoms associated with a disorder. An effective amount may be administered in one or more administrations.

[0069] An "administration period" or "cycle" refers to a period that includes administration of one or more compounds described herein or pharmaceutically acceptable salts thereof, or additional therapeutic agents (i.e., chemotherapeutic agents), as well as any period that does not include administration of one or more agents or compounds described herein. A "rest period" refers to a period during which at least one of the agents or compounds described herein is not administered. In one embodiment, a rest period refers to a period during which an agent or compound described herein is not administered. The rest periods provided herein can optionally include administration of an additional agent in the absence of a compound described herein or a pharmaceutically acceptable salt thereof, or vice versa. In such cases, administration of any agent during the rest period should not interfere with or impair the administration of a compound described herein or a pharmaceutically acceptable salt thereof.

[0070] A "dosing regimen" refers to a period of administration of a compound described herein, or a pharmaceutically acceptable salt thereof, that comprises one or more cycles, and each cycle may comprise administration of a compound described herein, or a pharmaceutically acceptable salt thereof, at a different time or in a different amount.

[0071] "QD" refers to once-daily administration of a compound or a pharmaceutically acceptable salt thereof.

[0072] "BID" refers to twice-daily administration of the compound or a pharmaceutically acceptable salt thereof.

[0073] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass the administration of two or more agents to an animal, including a human, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration of separate compositions, administration of separate compositions at different times (i.e., sequential administration), or administration of a composition in which both agents are present.

[0074] "1L therapy" refers to the first-line therapy administered to treatment-naive cancer patients. Similarly, 2L, 3L, etc. refer to subsequent treatments administered to patients.

[0075] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, uses, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic product.

[0076] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function of a target protein, such as a mutant form of KRas, whether by inhibiting the activity or expression of the protein. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of a target protein by interacting with other elements of a signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with tumor progression, growth, or spread.

[0077] 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. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance the biological activity of a target polypeptide by interacting with other elements of a signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0078] The terms "cancer," "cancerous," "neoplasm," and "tumor," and related terms, are used interchangeably herein to refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancers include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas) and lung cancers (such as small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cavity cancer, pharyngeal (mouth) cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, small intestine cancer, colon cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, liver cancer, uterine cancer, uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system, brain cancer, head and neck cancer, Hodgkin's disease, and related metastases. Other examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, myelofibroses such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0079] A "chemotherapeutic agent" is an agent useful in the treatment of a given disorder, such as cancer or an inflammatory disorder. Examples of chemotherapeutic agents are well known in the art. Additionally, chemotherapeutic agents include any pharmaceutically acceptable salt, acid, or derivative of the chemotherapeutic agent, as well as combinations of two or more thereof.

[0080] 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 may be incorporated into the compounds described herein and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 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. Additionally, heavier isotopes, such as deuterium (i.e., 2 H), may result in greater metabolic stability and may result in certain therapeutic advantages (e.g., longer in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds and pharmaceutically acceptable salts thereof described herein, one or more carbon atoms may be 13 C or 14 Replaced by C-rich carbon. 15 O. 13 N, 11 C, and 18Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those described in the schemes or examples herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0081] It is specifically contemplated that any limitation discussed with respect to one embodiment provided herein may apply to any other embodiment provided herein. Furthermore, any compound described herein and its pharmaceutically acceptable salts, or composition described herein, may be used in any method provided herein, and any method provided herein may be used to produce or utilize any compound described herein and its pharmaceutically acceptable salts, or composition described herein.

[0082] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to measure the value.

[0083] compound Provided herein are compounds of formula (I * ): TIFF2024506029000002.tif34170 (in the formula, X is O or NR 6 and n is 1, 2 or 3; m is 1, 2, or 3; p is 0, 1 or 2; q is 1 or 2; n and m together form a 6-, 7- or 8-membered ring A; Each R 0 are independently hydrogen or methyl; R 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7A substituted or unsubstituted phenyl, or R 7A substituted or unsubstituted pyridinyl, Each R 7 are independently hydrogen, halogen, -OH, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; Each R 7A are independently hydrogen, halogen, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; R 2 is hydrogen, L 1 -OL 2 -R 8 , R 8A Substituted or unsubstituted C 1~3 Alkyl, or R 8B a substituted or unsubstituted 4- to 10-membered heterocycle, where R 2 is hydrogen and R 1 R 7 substituted indazolyl, and when n and m are 1, p is not 0, and R 6 is not H, L 1 is a bond or R L1 Substituted or unsubstituted C 1~3 is alkylene, R L1 is a halogen or unsubstituted C 1~3 is alkyl, L 2 is a bond or unsubstituted C 1~3 is alkylene, R 8 is R 9 Substituted or unsubstituted C 1~3 R containing alkyl, N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle, Each R 9are independently selected from halogen, oxo, -OCF3, -OCHF2, -OCH2F, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10 Substituted or unsubstituted C 1~3 Alkylidene, or R 10 Substituted or unsubstituted C 3~4 Cycloalkyl, or R 10 a substituted or unsubstituted 3- or 4-membered heterocycle, or 2 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 forming a heterocyclic ring, R 10 is hydrogen, halogen, or unsubstituted C 1~3 is alkyl, Each R 8A are independently 9A Substituted or unsubstituted C 1~3 Alkyl, R 9A Substituted or unsubstituted C 1~3 Alkoxy, R 9A Substituted or unsubstituted C 3~4 Cycloalkyl, or R 9A a substituted or unsubstituted 4- to 6-membered heterocycle, Each R 9A are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, unsubstituted C 1~3 Alkylidene, R 9 Substituted or unsubstituted C 3~4 Cycloalkyl or R containing N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle, R 8B are independently selected from halogen, oxo, -NH2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3Alkoxy or unsubstituted C 1~3 is alkylidene, R 3 and R 4 are each independently hydrogen, -CN, halogen, or unsubstituted C 1~3 alkyl, or unsubstituted cyclopropyl; Each R 5 are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl, or 2 R's 5 taken 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 2 R's 5 taken together form a bridge between two carbon atoms of ring A, the bridge being O or NR 11 including one of R 11 is hydrogen, C(O)CH3, or unsubstituted C 1~3 is alkyl, R 6 is hydrogen or 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- or 4-membered heterocycle, R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O) R6B , unsubstituted C 1~3 alkyl or R 6B a substituted or unsubstituted 3- or 4-membered heterocycle, R 6B and R 6C are each independently 1~3 Alkyl or C 1~3haloalkyl) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0084] In one embodiment, X, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6A , R 6B , R 6C , R 7 , R 7A , R 8 , R 8A , R 8B , R 9 , R 9A , R 10 and R 11 is as described herein, q is 1, n and m are independently 1 or 2, and n and m together form a 6- or 7-membered ring A.

[0085] In one embodiment, q is 1.

[0086] Provided herein are compounds of formula (I): TIFF2024506029000003.tif34170 (in the formula, X is O or NR 6 and n is 1, 2 or 3; m is 1, 2, or 3; p is 0, 1 or 2; n and m together form a 6-, 7- or 8-membered ring A; Each R 0 are independently hydrogen or methyl; 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 benzothiazolyl, R 7A substituted or unsubstituted phenyl, or R7A substituted or unsubstituted pyridinyl, Each R 7 are independently hydrogen, halogen, -OH, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; Each R 7A are independently hydrogen, halogen, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; R 2 is hydrogen, L 1 -OL 2 -R 8 , R 8A Substituted or unsubstituted C 1~3 Alkyl, or R 8B a substituted or unsubstituted 4- to 10-membered heterocycle, where R 2 is hydrogen and R 1 R 7 substituted indazolyl, and when n and m are 1, p is not 0, and R 6 is not H, L 1 is a bond or R L1 Substituted or unsubstituted C 1~3 is alkylene, R L1 is a halogen or unsubstituted C 1~3 is alkyl, L 2 is a bond or unsubstituted C 1~3 is alkylene, R 8 is R 9 Substituted or unsubstituted C 1~3 R containing alkyl, N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle, Each R 9 are independently selected from halogen, oxo, -OCF3, -OCHF2, -OCH2F, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10Substituted 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 2 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 forming a heterocyclic ring, R 10 is hydrogen, halogen, or unsubstituted C 1~3 is alkyl, Each R 8A are independently 9A Substituted or unsubstituted C 1~3 Alkyl, R 9A Substituted or unsubstituted C 1~3 Alkoxy, R 9A Substituted or unsubstituted C 3~4 Cycloalkyl, or R 9A a substituted or unsubstituted 4- to 6-membered heterocycle, Each R 9A are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, unsubstituted C 1~3 Alkylidene, R 9 Substituted or unsubstituted C 3~4 Cycloalkyl or R containing N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle, R 8B are independently selected from halogen, oxo, -NH2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 is alkylidene, R 3 and R 4 are each independently hydrogen, -CN, halogen, or unsubstituted C 1~3alkyl, or unsubstituted cyclopropyl; Each R 5 are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl, or 2 R's 5 taken 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 2 R's 5 taken together form a bridge between two carbon atoms of ring A, the bridge being O or NR 11 including one of R 11 is hydrogen, C(O)CH3, or unsubstituted C 1~3 is alkyl, R 6 is hydrogen or 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- or 4-membered heterocycle, R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C , C(O) R6B , unsubstituted C 1~3 alkyl or R 6B a substituted or unsubstituted 3- or 4-membered heterocycle, R 6B and R 6C are each independently 1~3 Alkyl or C 1~3 haloalkyl) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0087] In one embodiment, X, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6A , R 6B , R 6C , R 7 , R 7A , R 8 , R 8A , R 8B , R 9 , R 9A , R 10 and R 11 is as described herein, n and m are independently 1 or 2, and n and m together form a 6- or 7-membered ring A.

[0088] In one embodiment, each R 0 is hydrogen, so that the compound of formula (I) has the formula: TIFF2024506029000004.tif34170 (where X, m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6A , R 6B , R 6C , R 7 , R 7A , R 8 , R 8A , R 8B , R 9 , R 9A , R 10 , and R 11 is as described herein for formula (I). It has.

[0089] In one embodiment, one R 0 is hydrogen and one R 0 is methyl, so that the compound of formula (I) has the formula: TIFF2024506029000005.tif34170 (where X, m, n, p, R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 6A , R 6B , R 6C , R 7 , R 7A , R 8 , R 8A , R 8B , R 9 , R 9A , R 10 , and R 11 is as described herein for formula (I). It has.

[0090] In one embodiment of the compounds described herein of formula (V) or a pharmaceutically acceptable salt thereof, the compound of formula (V) has the formula: TIFF2024506029000006.tif34170 (where X, m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6A , R 6B , R 6C , R 7 , R 7A , R 8 , R 8A , R 8B , R 9 , R 9A , R 10 , and R 11 are as described herein) It has.

[0091] In one embodiment, R 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7A substituted or unsubstituted phenyl, or R 7A In another embodiment, R is a substituted or unsubstituted pyridinyl. 1 is R 7 Substituted or unsubstituted naphthyl, R7 Substituted or unsubstituted indazolyl, R 7A substituted or unsubstituted phenyl, or R 7A In yet another embodiment, R is a substituted or unsubstituted pyridinyl. 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, or R 7 In yet another embodiment, R is a substituted or unsubstituted benzothiazolyl. 1 is R 7 Substituted or unsubstituted naphthyl or R 7 In another embodiment, R 1 is R 7A substituted or unsubstituted phenyl, or R 7A In another embodiment, R is a substituted or unsubstituted pyridinyl. 1 is R 7 substituted or unsubstituted phenyl, R 7 Substituted or unsubstituted indazolyl, or R 7 It is substituted or unsubstituted pyridinyl.

[0092] In one such embodiment, R 1 is R 7 In another such embodiment, R 1 is R 7 In another such embodiment, R 1 is R 7 It is substituted or unsubstituted pyridinyl.

[0093] In one embodiment, R 1 is the formula (A): TIFF2024506029000007.tif22170(in the formula, 1 is CH, N or CF, and R 7A are as described herein) or a stereoisomer thereof. In one such embodiment, X 1 is N or CF. In one such embodiment, R 7Ais hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 It is haloalkyl.

[0094] In one such embodiment, X 1 is N or CF, and each R 7A are independently hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one such embodiment, R 7A are independently hydrogen, Cl, methyl, ethyl, or CF3, and no more than one R 7A is hydrogen. In one embodiment, one R 7A is cyclopropyl.

[0095] In one such embodiment, the moiety of formula (A1) has the formula: I have TIFF2024506029000008.tif22170.

[0096] In one such embodiment, each R 7A is independently hydrogen, Cl, methyl, or CF. In another such embodiment, each R 7A are independently hydrogen, methyl, or CF3.

[0097] In one such embodiment, R 1 teeth, The file is TIFF2024506029000009.tif21170.

[0098] In another such embodiment, R 1 teeth, The file is TIFF2024506029000010.tif20170.

[0099] In one embodiment, R 1 teeth, The file is TIFF2024506029000011.tif20170.

[0100] In another embodiment, the moiety of formula (A) has the formula: TIFF2024506029000012.tif25170 (in the formula, each R 7A are independently hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) In one such embodiment, each R 7A are independently hydrogen, F, methyl, ethyl, or CF. In such embodiments, no more than one R 7A is hydrogen. In another such embodiment, R 7A is not hydrogen.

[0101] In one such embodiment, R 1 teeth, The file is TIFF2024506029000013.tif24170.

[0102] In one such embodiment, R 1 teeth, TIFF2024506029000014.tif27170 (in the formula, each R 7 are independently halogen, NH2, N(Me)2, or unsubstituted C 1~3 alkyl) is.

[0103] In one embodiment, R 1 teeth, The file is TIFF2024506029000015.tif27170.

[0104] In another embodiment, R 1 teeth, The file is TIFF2024506029000016.tif58170.

[0105] In another embodiment, R 1 teeth, The file is TIFF2024506029000017.tif24170.

[0106] In another embodiment, R 1 teeth, The file is TIFF2024506029000018.tif24170.

[0107] In one embodiment, R 7 are independently hydrogen, halogen, -OH, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 In another embodiment, R 7 are independently halogen, NH2, or unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 7 is not -OH.

[0108] In one embodiment, R 1 is R 7 are independently hydrogen, halogen, or unsubstituted C 1~3 In one such embodiment, R 7 are independently hydrogen or unsubstituted C 1~3 In another such embodiment, R 7 are independently halogen (e.g., F) or unsubstituted C 1~3 It is alkyl (eg, methyl).

[0109] In one embodiment, R 1 is a part of formula (B), where R 7 are independently hydrogen, halogen, -OH, NH2, N(Me)2, or unsubstituted C 1~3 In one embodiment, R 1 is a part of formula (C), where R 7 are independently hydrogen, halogen, NH2, N(Me)2, or unsubstituted C 1~3 In one such embodiment, R 7 are independently halogen or NH2.

[0110] In one embodiment, R 2 L1 -OL 2 -R 8 , R 8A Substituted or unsubstituted C 1~3 Alkyl, or R 8B In one embodiment, R is a substituted or unsubstituted 4-10 membered heterocycle. 2 is hydrogen or L 1 -OL 2 -R 8 In another embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 Alkyl, or R 8B In another embodiment, R 2 is R 8B In yet another embodiment, R is a substituted or unsubstituted 4- to 6-membered heterocycle. 2 L 1 -OL 2 -R 8 and R 8A Substituted or unsubstituted C 1~3 alkyl or R containing one nitrogen heteroatom 8B It is a substituted or unsubstituted 4- to 6-membered heterocyclic ring.

[0111] In one embodiment, R 2 is hydrogen, 1 is R 7 substituted indazolyl, and when n and m are 1, p is not 0, and R 6 is not hydrogen.

[0112] In one embodiment, the compound of formula I has the formula: TIFF2024506029000019.tif35170 (in the formula, R 1 , R 3 , R 4 , R 5 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (Ia1) has the formula: I have TIFF2024506029000020.tif34170.

[0113] In another embodiment, the compound of formula (I) has the formula: TIFF2024506029000021.tif78170 (in the formula, R 1 , R 3 , R 4 , R 5 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one embodiment, the compounds of Formula (Ib1) and Formula (Ic1) each have the formula: I have TIFF2024506029000022.tif37170.

[0114] In one embodiment, R 2 L 1 -OL 2 -R 8 In one embodiment, L 1 and L 2 One of L is a bond. 1 is a bond. In another embodiment, L 2 is a bond. In one embodiment, L 1 is unsubstituted C 1~3 alkylene, and L 2 is a bond. In another embodiment, L 1 and L 2 are each independently 1~3 It is alkylene.

[0115] R 2 L 1 -OL 2 -R 8 In one embodiment, L 1 is a bond and L 2 is unsubstituted C 1~3 In one such embodiment, L 2 is methylene. In one such embodiment, R 8 is R 9 substitution C 1~3 In another such embodiment, R 8R containing N, S or O 9 It is a substituted or unsubstituted 4- to 10-membered heterocyclic ring.

[0116] In one embodiment, the compound of formula (I) has the formula: TIFF2024506029000023.tif35170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 , X, n, m and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (II1) has the formula: I have TIFF2024506029000024.tif34170.

[0117] In one such embodiment, the compound of formula (II) has the formula: TIFF2024506029000025.tif78170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0118] In one such embodiment, the compound of formula (II1) has the formula: TIFF2024506029000026.tif78170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0119] In one such embodiment, the compound of formula (II1) has the formula: TIFF2024506029000027.tif78170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0120] R 2 L 1 -OL 2 -R 8 In one embodiment, R 8 R containing N, S or O 9 In another such embodiment, R 8 is a 4-10 membered heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing one N heteroatom. 8 is a 5- or 6-membered monocyclic heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 5- or 6-membered monocyclic heterocycle containing one O heteroatom. In another such embodiment, R 8 is a 6-, 7-, 8-, or 9-membered fused bicyclic heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 7- or 8-membered fused bicyclic heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 7- or 8-membered fused bicyclic heterocycle containing one N heteroatom and one O heteroatom. In one embodiment, R 8 is pyrrolidinyl or tetrahydrofuranyl.

[0121] In such embodiments, each R 9 are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, or R 10Substituted or unsubstituted C 1~3 In another such embodiment, each R 9 are independently halogen, oxo, or R 10 Substituted or unsubstituted C 1~3 In one embodiment, each R 9 are independently unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one embodiment, each R 9 is R 10 Substituted or unsubstituted C 3~4 Cycloalkyl, or R 10 In one embodiment, two R 9 Together, R 10 Substituted or unsubstituted C 3~5 In one such embodiment, two R 9 Together, R 10 In one such embodiment, two R 9 But together, R 10 is halogen (e.g., F or Cl); 10 Form a substituted cyclopropyl. Two R 9 Together, R 10 In one embodiment of forming a substituted cyclopropyl, the cyclopropyl is R 8 In one embodiment, two R 9 Together, R 10 Form a substituted cyclopropyl, cyclopropyl is R 8 In another such embodiment, two R 9 together form an unsubstituted C containing one or more oxygen atoms 3~5 Forming a heterocycle. In one such embodiment, the heterocycle is 1,3-dioxolanyl.

[0122] In one embodiment, R 10 is hydrogen or halogen. In one embodiment, R 10 is hydrogen. In another embodiment, R 10is halogen. In one such embodiment, R 10 is F.

[0123] In one embodiment, R 2 L 1 -OL 2 -R 8 and R 8 teeth, TIFF2024506029000028.tif18170 (in the formula, R 9 is halogen, -OCF3, -OCHF2, -OCH2F, R 10 Substituted or unsubstituted 1~3 alkylidene or two R 9 Together, R 10 Substituted or unsubstituted C 3~5 forming a cycloalkyl, r is an integer from 0 to 12, j is 1, 2, or 3; k is 1 or 2) or a stereoisomer thereof.

[0124] In one embodiment, R 2 L 1 -OL 2 -R 8 and R 8 teeth, TIFF2024506029000029.tif18170 (in the formula, 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) or a stereoisomer thereof.

[0125] In one such embodiment, r is 0, 1, 2, 3, or 4. In another such embodiment, r is 0, 1, 2, or 3. In one embodiment, R 8 teeth, TIFF2024506029000030.tif64170 (in the formula, R 9 , R 10 and r is as described herein and s is 1 or 2. or a stereoisomer thereof. In one such embodiment, r is 0, 1, 2, 3, or 4. In another such embodiment, r is 0, 1, 2, or 3. In one embodiment, R 8 has formula D1, D2 or D3, and R 9 , R 10 and r is as described herein.

[0126] In one such embodiment, R 9 are independently a halogen or R 10 Substituted or unsubstituted C 1~3 alkylidene, and each R 10 are independently hydrogen or halogen, and r is 1 or 2.

[0127] In one embodiment, R 8 teeth, TIFF2024506029000031.tif23170 or a stereoisomer thereof, and r is 0.

[0128] In another embodiment, R 8 teeth, TIFF2024506029000032.tif34170 or a stereoisomer thereof, wherein r is 0, and each R 10 is independently hydrogen or F. In one such embodiment, r is 0 and each R 10 In another such embodiment, r is 0 and each R 10 is F. In another such embodiment, r is 0 and one R 10 is hydrogen and one R 10 is F. In another such embodiment, each R 10 are independently hydrogen or F, r is 1 or 2, and R 9 is F.

[0129] In another embodiment, R 8 teeth, TIFF2024506029000033.tif29170 (where r is 0, and each R 9 are independently hydrogen or halogen. or a stereoisomer thereof. In one such embodiment, each R 9 is F and r is 0. In one such embodiment, each R 9 is F and r is 1.

[0130] R 2 L 1 -OL 2 -R 8 In another embodiment, R 8 teeth, TIFF2024506029000034.tif15170 or a stereoisomer thereof. In one such embodiment, r is 1 and R 9 is halogen, oxo, or unsubstituted C alkylidene. In one such embodiment, two R 9 Together, R 10 Substituted or unsubstituted C 3~5 Forms a cycloalkyl.

[0131] In one embodiment, R 8 teeth, TIFF2024506029000035.tif19170 (in the formula, 10 is a halogen and s is 1 or 2) or a stereoisomer thereof. In one such embodiment, R 8 teeth, TIFF2024506029000036.tif25170 or a stereoisomer thereof.

[0132] R 2 L 1 -OL 2 -R 8 In another embodiment, R 8 teeth, TIFF2024506029000037.tif14170 (in the formula, R 9 is hydrogen or unsubstituted C 1~3 is alkyl, W is O, SO2, or NR 12 and R 12 is hydrogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) or a stereoisomer thereof.

[0133] In one such embodiment, W is O and R 9 In another such embodiment, W is NR 12 where R 12 is unsubstituted C 1~3 haloalkyl, and R 9 is hydrogen. In another such embodiment, W is SO and R 9 is hydrogen.

[0134] In one embodiment of the compounds described herein or pharmaceutically acceptable salts thereof, R 8 is azetidinyl, oxetanyl, or thietanedioxide.

[0135] In further embodiments provided herein, R 8 is the expression: TIFF2024506029000038.tif19170 (in the formula, R 9 are independently halogen, oxo, or unsubstituted C 1~3 is alkyl, r is 1 or 2) or a stereoisomer thereof.

[0136] In one such embodiment, R 8 is a moiety having the formula (G), where R 9 and r is as described herein. In one such embodiment, R 9 is oxo and r is 1. In another such embodiment, R 9is F and r is 1 or 2.

[0137] In another embodiment, R 8 is the expression: TIFF2024506029000039.tif16170 (in the formula, R 9 and r is as described herein). or a stereoisomer thereof.

[0138] In another embodiment, R 8 is the expression: TIFF2024506029000040.tif23170 (in the formula, R 9 and r is as described herein). or a stereoisomer thereof.

[0139] In another embodiment, R 8 is the expression: TIFF2024506029000041.tif17170 (in the formula, R 10 is a halogen and s is 1 or 2) or a stereoisomer thereof.

[0140] In yet another embodiment, R 8 is R 9 Substituted or unsubstituted C 1~3 In one such embodiment, R 8 is the expression: TIFF2024506029000042.tif13170 (in the formula, each R 9 are independently unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 alkoxy) or a stereoisomer thereof.

[0141] In another embodiment, R 8 is the expression: The part with TIFF2024506029000043.tif13170.

[0142] In one embodiment, R 8 teeth, TIFF2024506029000044.tif23170 or a stereoisomer thereof.

[0143] In one embodiment, R 8 teeth, TIFF2024506029000045.tif22170 or a stereoisomer thereof.

[0144] In one embodiment, R 8 teeth, TIFF2024506029000046.tif19170 or a stereoisomer thereof.

[0145] In one embodiment, R 8 teeth, The file is TIFF2024506029000047.tif17170.

[0146] In another embodiment, R 8 teeth, TIFF2024506029000048.tif27170 or a stereoisomer thereof.

[0147] In another embodiment, R 8 teeth, The file is TIFF2024506029000049.tif27170.

[0148] In another embodiment, R 8 teeth, TIFF2024506029000050.tif27170 or a stereoisomer thereof.

[0149] In another embodiment, R 8 teeth, The file is TIFF2024506029000051.tif26170.

[0150] In yet another embodiment, R 8 teeth, TIFF2024506029000052.tif23170 or a stereoisomer thereof.

[0151] In yet another embodiment, R 8 teeth, TIFF2024506029000053.tif28170 or a stereoisomer thereof.

[0152] In yet another embodiment, R 8 teeth, The file is TIFF2024506029000054.tif15170.

[0153] In yet another embodiment, R 8 teeth, The file is TIFF2024506029000055.tif13170.

[0154] In yet another embodiment, R 2 teeth, TIFF2024506029000056.tif80170 (in the formula, R 9 , R 10 , r, j, and k are as described herein. or a stereoisomer thereof. In one embodiment, R 9 is a halogen or R 10 Substituted or unsubstituted C 1~3 In another such embodiment, R 9 is halogen, oxo, R 10 Substituted or unsubstituted C 1~3 alkylidene, and r is independently 0, 1, or 2.

[0155] In one embodiment, R 2 teeth, TIFF2024506029000057.tif19170 or a stereoisomer thereof.

[0156] In another embodiment, R 2 teeth, TIFF2024506029000058.tif58170 or a stereoisomer thereof.

[0157] In another embodiment, R 2 teeth, TIFF2024506029000059.tif27170 or a stereoisomer thereof.

[0158] In yet another embodiment, R 2 teeth, TIFF2024506029000060.tif23170 or a stereoisomer thereof.

[0159] In yet another embodiment, R 2 teeth, TIFF2024506029000061.tif27170 or a stereoisomer thereof.

[0160] In yet another embodiment, R 2 teeth, The file is TIFF2024506029000062.tif15170.

[0161] In yet another embodiment, R 2 teeth, The file is TIFF2024506029000063.tif13170.

[0162] In another embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 Alkyl, or R 8B In one embodiment, each R 8A are independently 9A Substituted or unsubstituted C 1~3 Alkyl, or R 9A Substituted or unsubstituted C 1~3 In one embodiment, each R 8A are independently 9A substituted or unsubstituted alkoxy, or R 9AIn another embodiment, each R 8A are independent, R 9A Substituted or unsubstituted C 3~4 Cycloalkyl, or R 9A In one embodiment, R is a substituted or unsubstituted 4- to 6-membered heterocycle. 9A is R containing N 9 In another embodiment, R 9 are independently halogen, unsubstituted C 1~3 Alkyl, or R 10 Substituted or unsubstituted C 1~3 It is an alkylidene.

[0163] In one embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 alkyl, and R 8A is R 9A Substituted or unsubstituted C 1~3 Alkoxy, R 9A Substituted or unsubstituted C 3~4 Cycloalkyl, or R 9A It is a substituted or unsubstituted 4- to 6-membered heterocyclic ring.

[0164] In one embodiment, R 9A are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 In another such embodiment, R 9A are independently halogen, oxo, or unsubstituted C 1~3 In yet another embodiment, R 9A R containing N, S or O 9 It is a substituted or unsubstituted 4- to 10-membered heterocyclic ring.

[0165] In one embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 alkyl, and R 8A is R 9ASubstituted or unsubstituted C 1~3 It is alkyl.

[0166] In one embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 alkyl, and R 8A is R 9A Substituted or unsubstituted C 1~3 In one such embodiment, R 9A are independently 9 Substituted or unsubstituted C 3~4 Cycloalkyl or R containing one N-heterocycle 9 In another such embodiment, R 9A independently, R containing one N-heterocycle; 9 In such embodiments, R is a substituted or unsubstituted 5- or 6-membered monocyclic heterocycle or a 7- or 8-membered fused bicyclic heterocycle containing one N-heterocycle. 9 are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, or R 10 Substituted or unsubstituted C 1~3 alkylidene, and R 10 is as described herein.

[0167] In another embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 alkyl, and R 8A is R 9A Substituted or unsubstituted C 3~4 In one embodiment, each R 8B are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 It is an alkylidene.

[0168] In one embodiment, R 2 is R 8B In one such embodiment, R8B is halogen, oxo, or unsubstituted C 1~3 In one embodiment, R 2 is an R containing one N heteroatom 8B It is a substituted or unsubstituted 4-, 5- or 7-membered heterocycle.

[0169] In one such embodiment, R 2 teeth, The file is TIFF2024506029000064.tif22170.

[0170] In one such embodiment, R 2 teeth, The file is TIFF2024506029000065.tif18170.

[0171] In one embodiment, R 3 and R 4 are each independently hydrogen, -CN, halogen, or unsubstituted C 1~3 alkyl, or unsubstituted cyclopropyl. In one embodiment, R 3 and R 4 are each independently hydrogen, halogen, or unsubstituted C 1~3 In one embodiment, R 3 and R 4 are each independently hydrogen or halogen. 3 and R 4 In another embodiment, R 3 and R 4 One of R is hydrogen and the other is halogen. 3 is halogen. In one such embodiment, R 3 is F or Cl. In another embodiment, R 4 is hydrogen. In another embodiment, R 4 is halogen. In one such embodiment, R 4 is F or Cl.

[0172] In one embodiment, each R 5 are independently selected from halogen, oxo, and unsubstituted C1~3 Alkyl or unsubstituted C 1~3 In one embodiment, p is 1 and R 5 is halogen, oxo, or unsubstituted C 1~3 In another embodiment, R 5 are independently oxo or unsubstituted C 1~3 In one such embodiment, n and m are taken together to form a 6- or 7-membered ring, where p is 1. In another such embodiment, n and m are taken together to form a 7-membered ring, where p is 0. In one embodiment, n and m are taken together to form a 6-membered ring, where p is 0 or 1. In yet another embodiment, n and m are taken together to form a 7-membered ring, where p is 0 or 1. In one such embodiment, n and m are taken together to form a 7-membered ring, where p is 0 or 1.

[0173] In one embodiment, p is 0.

[0174] In one embodiment, two R 5 together form a bridge between two carbon atoms of ring A, the bridge containing 1 to 3 carbons. In one embodiment, two R 5 together form a bridge between two carbon atoms of ring A, the bridge comprising one or two carbons. In one embodiment, the bridge comprises one carbon. In another embodiment, the bridge comprises two carbons. In one such embodiment, the compound of formula (I) has the formula: TIFF2024506029000066.tif75170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one such embodiment, p is 0.

[0175] In another such embodiment, the compound of formula (I) has the formula: TIFF2024506029000067.tif74170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one such embodiment, p is 0.

[0176] In another such embodiment, the compound of formula (I) has the formula: TIFF2024506029000068.tif74170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one such embodiment, p is 0.

[0177] In such embodiments, R 1 is as described herein. In another such embodiment, R 1 is a moiety of formula (A1), (A2), or (B). In another embodiment, R 2 is a moiety of formula (H), (J), (K), (L), (M), (N), (O), or (P). In such embodiments, X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S).

[0178] In another such embodiment, the compound of formula (II) has the formula: TIFF2024506029000069.tif70170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one such embodiment, p is 0.

[0179] In another such embodiment, the compound of formula (II1) has the formula: TIFF2024506029000070.tif70170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one such embodiment, p is 0.

[0180] In another such embodiment, the compound of formula (II1) has the formula: TIFF2024506029000071.tif70170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 , X, and p are as described herein. or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. In one such embodiment, p is 0.

[0181] In one such embodiment, R 1 is as described herein. In another such embodiment, R 1 is a moiety of formula (A1), (A2), (B) or (C). In another such embodiment, R 8 is a moiety of formula (D1), (D2), (D3), (D4), (D5), (E), (G), or (G1). In one embodiment, R8 is a moiety of formula (F). In such an embodiment, X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S).

[0182] In yet another embodiment, two R 5 taken together form a bridge between two carbon atoms of ring A, the bridge being O or NR 11 In one embodiment, the bridge comprises O. In another such embodiment, the bridge comprises NR 11 Contains R 11 is hydrogen, C(O)CH3, or methyl.

[0183] In one embodiment of a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, X is NR 6 In one embodiment, R 6 is hydrogen. In one embodiment, R 6 is R 6A Substituted or unsubstituted C 1~6 In one embodiment, R 6 is hydrogen or R 6A Substituted or unsubstituted C 1~6 Alkyl, R 6A Substituted or unsubstituted C 1~6 alkenyl, or R 6A Substituted or unsubstituted C 1~6 In one embodiment, R is alkynyl. 6 is hydrogen or R 6A Substituted or unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Alkenyl or unsubstituted C 1~6 In another embodiment, R 6 is hydrogen or R 6A Substituted or unsubstituted C 1~6 In yet another embodiment, R 6 is hydrogen or unsubstituted C 1~6 It is alkyl.

[0184] In one such embodiment, R 6 R 6A Substituted or unsubstituted C 1~6 If it is Rukill, R 6A is halogen, CN, OR 6B , S(O)2R 6C , unsubstituted C1~3 alkyl or R 6B In another such embodiment, R 6 R 6A Substituted or unsubstituted C 1~6 If it is alkyl, R 6A is halogen, CN, OR 6B , unsubstituted C 1~3 alkyl or R 6B In another such embodiment, R 6 R 6A Substituted or unsubstituted C 1~6 If it is alkyl, R 6A are halogens, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1~3 alkyl, or a four-membered heterocycle.

[0185] In another such embodiment, R 6 R 6A Substituted or unsubstituted C 1~6 If it is alkyl, R 6A is F, Cl, CN, CH, OH, OCH, OCF, SCH, SOCH, or a combination thereof. 6 R 6A Substituted or unsubstituted C 1~6 If it is alkyl, R 6A is halogen or oxetanyl. In another embodiment, R 6 is the unsubstituted C 1~6 It is alkyl (eg, methyl).

[0186] In another embodiment, R 6 is R 6A In one such embodiment, R 6 is azetidinyl or oxetanyl. In one embodiment, R 6 is unsubstituted oxetanyl.

[0187] In another embodiment, R 6 is R 6A Substituted or unsubstituted C1~3 In another embodiment, R 6 is R 6A Substituted or unsubstituted C 1~3 In another embodiment, R is alkenyl. 6 is R 6A Substituted or unsubstituted C 1~3 In one embodiment, R is alkynyl. 6 is hydrogen. In another embodiment, R 6 is methyl.

[0188] In one embodiment of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, R 6 is hydrogen, methyl, or a group of the formula: The file is TIFF2024506029000072.tif32170.

[0189] In one such embodiment, R 6A are F, Cl, CN, CH3, OH, OCH3, OCF3, SCH3, SO2CH3.

[0190] In another embodiment, R 6 teeth, TIFF2024506029000073.tif10170 (in the formula, R 6A are CH2F, CN, OH, OCH3, OCF3, SCH3, SO2CH3) is.

[0191] In another embodiment, R 6 teeth, TIFF2024506029000074.tif10170 (in the formula, R 6A are independently F, CH3, or OCH3. is.

[0192] In another embodiment, R 6 teeth, TIFF2024506029000075.tif15170 (in the formula, R 6A is hydrogen, CH3 or F) is.

[0193] In yet another embodiment, R 6 is hydrogen, methyl, or a group of the formula: The file is TIFF2024506029000076.tif34170.

[0194] In one embodiment, R 6B and R 6C are each independently 1~3 It is alkyl.

[0195] In one embodiment, the compound of formula (I) has the formula: TIFF2024506029000077.tif35170 (in the formula, R 1 is a moiety of formula (A1), (A2), or (B), and R 8 is a moiety of formula (D1), (D2), (D3), (E), (G) or (G1), and X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 In yet another embodiment, m and n are each 1. In yet another embodiment, m is 2 and n is 1. In yet another embodiment, m is 1 and n is 2. In yet another embodiment, two R 5 together form one to two carbon bridges as described herein.

[0196] In one embodiment, the compound of formula (I) has the formula: TIFF2024506029000078.tif34170 (in the formula, R 1 is a moiety of formula (A1), (A2), or (B), and R 8is a moiety of formula (D1), (D2), (D3), (E), (G) or (G1), and X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 In yet another embodiment, m and n are each 1. In yet another embodiment, m is 2 and n is 1. In yet another embodiment, m is 1 and n is 2. In yet another embodiment, two R 5 are taken together to form a 1-2 carbon bridge as described herein. In one embodiment, the compound of formula (II1) is a compound of formula (II1) as described herein. * )

[0197] In one embodiment, the compound has the formula: TIFF2024506029000079.tif78170 (in the formula, R 1 is a moiety of formula (A1), (A2), or (B), and R 8 is a moiety of formula (D1), (D2), (D3), (D4), (D5), (E), (G) or (G1), and X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 In yet another embodiment, two R 5 together form one to two carbon bridges as described herein.

[0198] In one embodiment, the compound has the formula: TIFF2024506029000080.tif78170 (in the formula, R 1 is a moiety of formula (A1), (A2), or (B), and R 8 is a moiety of formula (D1), (D2), (D3), (D4), (D5), (E), (G) or (G1), and X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 It is alkyl.

[0199] In one embodiment, the compound has the formula: TIFF2024506029000081.tif78170 (in the formula, R 1 is a moiety of formula (A1), (A2), or (B), and R 8 is a moiety of formula (D1), (D2), (D3), (D4), (D5), (E), (G) or (G1), and X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 It is alkyl.

[0200] In one embodiment, the compound has the formula: TIFF2024506029000082.tif78170 (in the formula, R 1 is a moiety of formula (A1), (A2), or (B), and R 8 is a moiety of formula (D1), (D2), (D3), (D4), (D5), (E), (G) or (G1), and X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 It is alkyl.

[0201] In one embodiment, the compound has the formula: TIFF2024506029000083.tif114170 (in the formula, R 1 is a moiety of formula (A1), (A2), (B), or (C), and R 2 is a moiety of formula (H), (J), (K), (L), (M), or (N), and X is NR 6 and R 6 is a moiety of formula (Q), (R), or (S) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 It is alkyl.

[0202] In one embodiment, the compound has the formula: TIFF2024506029000084.tif114170 (in the formula, R 1 is a moiety of formula (A1), (A2), (B), or (C), and R 2is a moiety of formula (H), (J), (K), (L), (M), or (N), and X is NR 6 and R 6 is a moiety of formula (Q), (R), or (S) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 It is alkyl.

[0203] Formula (Id), (Ie), (Ig), (Ih), (Id1), (Ie1), (Ig1), (Ih1), (Id1 * ), (Ie1 * ), (Ig1 * ) and (Ih1 * In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is a moiety of formula (A1), where each R 7A is independently hydrogen, halogen, methyl, or CF3, as described herein. In one embodiment of the compounds of Formula (Id), (Ie), (Ig), and (Ih), or pharmaceutically acceptable salts thereof, R 1 is each R 7 is a moiety of formula (B) where R is halogen or methyl as described herein. 2 is a moiety of formula (L), (M) or (N). In another such embodiment, R 2 is a moiety of formula (H1), (J), (K) or (O). In another such embodiment, R 2 is a moiety of formula (P). In such embodiments, X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S). In one embodiment, the compounds of formula (Id), (Ie), (Ig), (Ih), (Id1), (Ie1), (Ig1), (Ih1), (Id1 * ), (Ie1 * ), (Ig1* ), and (Ih1 * or a pharmaceutically acceptable salt thereof, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, R 1 is of formula (A1), (A2), (B), or (C), and R 8 is a moiety of formula (D), (D1), (D2), (D3), (E) or (G), and X is NR 6 , and R 6 is a moiety of formula (Q), (R), or (S). In another embodiment, p is 0. In another embodiment, p is 1 and R 5 is oxo or unsubstituted C 1~3 In yet another embodiment, R 4 is C 1~6 It is alkyl.

[0204] Formula (Id), (Ie), (Ig), (Ih), (Id1), (Ie1), (Ig1), (Ih1), (Id1 * ), (Ie1 * ), (Ig1 * ) and (Ih1 * In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is a moiety of formula (A1), where each R 7A is independently hydrogen, halogen, methyl, or CF3, as described herein. In one embodiment of the compounds of Formula (IId), (IIe), (IIg), and (IIh) or pharmaceutically acceptable salts thereof, R 1 is each R 7 is a moiety of formula (B) where R is halogen or methyl as described herein. 8 is a moiety of formula (D1), (D2), (D3), (D4), (D5), (E), (G), or (G1). 8 is a moiety of formula (F). In such embodiments, X is NR 6 and R 6 is hydrogen, methyl, or a moiety of formula (Q), (R), or (S).

[0205] In one embodiment, R of the compounds described herein 8 is a moiety of formula (D), (D6), (G), or (E) described herein.

[0206] In one embodiment, R of the compounds described herein 8 is a moiety of formula D1, D2, or D3 described herein.

[0207] In another embodiment, R of the compounds described herein 8 is a moiety of formula D6 described herein.

[0208] In one embodiment, R of the compounds described herein 8 teeth: The file is TIFF2024506029000085.tif19170.

[0209] Further provided herein is a compound of the formula: TIFF2024506029000086.tif253170TIFF2024506029000087.tif203170 (in the formula, R 3 , R 4 , R 5 , R 7A , X and P are as defined herein; R 8 teeth, TIFF2024506029000088.tif70170) or a stereoisomer thereof.

[0210] In one embodiment, a compound of Formula (I) described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is at least 5, 10, 25, 50, 100, 250, 500, 700, 1000, 1300, 1500, 2000, or 3000 times more selective for KRas G12D mutant protein over wild-type (WT) KRas protein.

[0211] In one embodiment, the compound of Formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is a compound of Table 1.

[0212] [Table 1] TIFF2024506029000090.tif184170TIFF2024506029000091.tif169170TIFF202 4506029000092.tif181170TIFF2024506029000093.tif176170TIFF20245060290 00094.tif213170TIFF2024506029000095.tif214170TIFF2024506029000096.t if176170TIFF2024506029000097.tif194170TIFF2024506029000098.tif174170 TIFF2024506029000099.tif178170TIFF2024506029000100.tif184170TIFF202 4506029000101.tif196170TIFF2024506029000102.tif163170TIFF20245060290 00103.tif186170TIFF2024506029000104.tif212170TIFF2024506029000105.t if188170TIFF2024506029000106.tif176170TIFF2024506029000107.tif221170

[0213] In one embodiment, the compound of Formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is a compound of Table 2.

[0214] [Table 2] TIFF2024506029000109.tif191170TIFF2024506029000110.tif126170TIFF2024506029000111.tif214170

[0215] In one embodiment, the compound of Formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is a compound of Table 3.

[0216] [Table 3] TIFF2024506029000113.tif186170TIFF2024506029000114.tif181170TIFF2024506029000115.tif193170TIFF20245060290 00116.tif199170TIFF2024506029000117.tif183170TIFF2024506029000118.tif179170TIFF2024506029000119.tif212170

[0217] Compound synthesis The compounds described herein of the present disclosure, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be made by a variety of methods illustrated in the exemplary synthetic reaction schemes shown and described below. The starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or are generally available from other sources such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R.C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A.R. Katrittzky and C.W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A.R. Katrittzky and C.W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New The compounds may be prepared by methods known to those skilled in the art according to procedures described in references such as, for example, John Wiley & Sons, 1991, vol. 1-40. The following synthetic reactions are merely illustrative of some of the methods by which the compounds described herein or pharmaceutically acceptable salts thereof may be synthesized, and various modifications to these synthetic reaction schemes may be made, which will be suggested to those skilled in the art with reference to the disclosure contained herein.

[0218] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein and the necessary reagents and intermediates include those described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0219] The compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared singly or as compound libraries comprising at least two, e.g., 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of the formulas described herein of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared by combinatorial split and mix approaches or by multiple parallel syntheses using, e.g., either solution-phase or solid-phase chemistry. Thus, according to a further aspect, provided herein are compound libraries comprising at least two compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0220] The examples provide illustrative methods for preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. While specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents can be substituted to provide a variety of derivatives and / or reaction conditions. Furthermore, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry.

[0221] In preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, protection of remote functionalities (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection will vary depending on 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 determined. For a general description of protecting groups and their uses, see T.W. Greene, "Protective Groups in Organic Synthesis," John Wiley & Sons, New York (1991).

[0222] 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 involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high-, medium-, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed (SMB) and preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography techniques.

[0223] Another class of separation methods involves treating the mixture with a selected reagent to bind or otherwise render separable the desired product, unreacted starting materials, reaction by-products, etc. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent may be an acid in the case of basic substances, a base in the case of acidic substances, a binding reagent such as an antibody, a binding protein, a selective chelating agent such as crown ethers, liquid-liquid ion extraction reagents (LIX), etc. The selection of an appropriate separation method depends on the properties of the materials involved, such as boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of the material in acidic and basic media in multiphase extraction, etc.

[0224] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods such as, for example, chromatography and / or fractional crystallization. Enantiomers can 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 Moscher'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 using chiral HPLC columns.

[0225] A single stereoisomer, e.g., an enantiomer, can be obtained substantially free of its stereoisomer by resolving a racemic mixture using methods such as the formation of diastereomers with an optically active resolving agent (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds described herein or pharmaceutically acceptable salts thereof can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional recrystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers; and (3) separation of substantially pure or enriched stereoisomers under chiral conditions. Reference: Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

[0226] In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, and α-methyl-β-phenylethylamine (amphetamine), with asymmetric compounds containing acidic functional groups, such as carboxylic and sulfonic acids. The diastereomeric salts can be induced to separate by fractional recrystallization or ionic chromatography. To separate the optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can form diastereomeric salts.

[0227] Alternatively, method (2) involves reacting the substrate to be resolved with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc. (1994) p. 322). Diastereomeric compounds can be formed by reacting the asymmetric compound with an enantiomerically pure chiral derivatizing agent, such as a menthyl derivative, followed by separation and hydrolysis of the diastereomers to obtain the pure or enriched enantiomer. A method for determining optical purity involves making a chiral ester, such as a menthyl ester (e.g., (-)-menthyl chloroformate) of the racemic mixture in the presence of a base or Mosher's ester, α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. J. Org. Chem. (1982) 47:4165), and testing for the presence of two atropisomeric enantiomers or diastereomers. 1This involves analyzing the H NMR spectrum. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal-phase and reverse-phase chromatography following the method for separating atropisomeric naphthyl-isoquinolines (WO 96 / 15111). Method (3) allows the separation of racemic mixtures of two enantiomers by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0228] The chemical reactions described herein can be readily 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 with modifications apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds described herein and their pharmaceutically acceptable salts.

[0229] Pharmaceutical preparations Also provided herein are pharmaceutical compositions comprising a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0230] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. Accordingly, further provided herein are pharmaceutical compositions comprising a compound described herein, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients.

[0231] A typical formulation is prepared by mixing a compound described herein or a pharmaceutically acceptable salt thereof with an excipient. Suitable carriers, diluents, and excipients include, but are not limited to, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and other materials. The specific excipients used depend on the means and purpose for which the compound described herein or a pharmaceutically acceptable salt thereof is being administered. Solvents are generally selected based on solvents recognized as safe (GRAS) for mammalian administration. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide proper presentation of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0232] Formulations can be prepared using conventional dissolution and mixing procedures. For example, a 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 additives described above. The compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are typically formulated into pharmaceutical dosage forms to provide easily controllable drug dosage and enable patient compliance with a prescribed regimen.

[0233] Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, and metal cylinders. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, the container has disposed thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0234] Pharmaceutical formulations of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be prepared for various routes and types of administration. For example, a compound having the desired purity, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be mixed with one or more pharmaceutically acceptable excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), optionally in the form of a lyophilized formulation, a pulverized powder, or an aqueous solution. Formulation can be carried out by mixing the compound at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage and concentration used. The pH of the formulation will depend primarily on the specific application and the concentration of the compound, but can range from about 3 to about 8. For example, a formulation in acetate buffer at pH 5 may be a preferred embodiment.

[0235] Pharmaceutical compositions may generally be stored as solid compositions, lyophilized formulations or aqueous solutions.

[0236] The pharmaceutical compositions described herein can be formulated, prescribed, and administered in a manner consistent with full medical utility, i.e., in amounts, concentrations, schedules, courses, vehicles, and routes of administration. Factors to consider in this context 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 administration schedule, and other factors known to physicians. The effective amount of the administered compound, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, will be governed by such considerations and will be the minimum amount necessary to ameliorate or treat the hyperproliferative disorder.

[0237] As a general proposition, an initial pharmaceutically effective amount of a parenterally administered compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, would be in the range of about 0.01 to 100 mg / kg, i.e., about 0.1 to 20 mg / kg, of patient body weight per day, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, the pharmaceutical compositions described herein comprise an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount of about: 1 mg to 10 mg; 10 mg to 25 mg; 20 mg to 50 mg; 50 mg to 75 mg; 70 mg to 100 mg; 100 mg to 150 mg; 100 mg to 200 mg; 100 mg to 500 mg; 200 mg to 500 mg; 250 mg to 500 mg; 500 mg to 1000 mg; or 750 mg to 1000 mg.

[0238] Acceptable pharmaceutically acceptable excipients are nontoxic 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 (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens (such as methyl or propyl paraben); catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins (such as serum albumin). , gelatin, or immunoglobulins; hydrophilic polymers (such as polyvinylpyrrolidone); amino acids (such as glycine, glutamine, asparagine, histidine, arginine, or lysine); monosaccharides, disaccharides, and other sugar chains (including glucose, mannose, or dextrin); chelating agents (such as EDTA); sugars (such as sucrose, mannitol, trehalose, or sorbitol); salt-forming counterions (such as sodium); metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants (such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG)). The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0239] Sustained-release preparations of the compounds described herein or their pharmaceutically acceptable salts may also 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)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ-L-ethyl glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0240] Formulations include those suitable for the routes of administration detailed herein. Formulations may conveniently be presented in unit dosage form and may be prepared by any method. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0241] Formulations of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of such compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in free-flowing form as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of moistened powdered active ingredient and an inert liquid diluent. Tablets may optionally be coated or grooved, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups, or elixirs may be prepared for oral use. Formulations of the compounds described herein or their pharmaceutically acceptable salts intended for oral use may 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 additives suitable for tablet manufacture are acceptable. These additives may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating agents and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, for example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0242] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount of 0.075 to 20% w / w. When formulated in an ointment, the active ingredient can be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can contain a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations can optionally contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues. The oily phase of the emulsions of the compositions provided herein can be constituted from known ingredients in a known manner. The phase may simply comprise an emulsifier, but preferably comprises a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Taken together, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, and the wax together with the oil and fat constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. Suitable emulsifiers and emulsion stabilizers for use in the formulations described herein include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0243] Aqueous suspensions containing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, may contain the active material in admixture with additives suitable for the manufacture of aqueous suspensions, such as suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0244] Pharmaceutical compositions of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, may be in the form of sterile injectable preparations, such as sterile aqueous or oily injectable suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be prepared as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or as lyophilized powders. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids, such as oleic acid, may also be used in the preparation of injectables.

[0245] The amount of active ingredient that may 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 ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution to result in infusion of a suitable volume at a rate of about 30 mL / hour.

[0246] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0247] Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w / w, for example, about 0.5 to 10% w / w, for example, about 1.5% w / w.

[0248] 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.

[0249] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0250] Formulations suitable for pulmonary or nasal administration have, for example, particle sizes in the range of 0.1 to 500 microns (in micron increments, such as 0.5, 1, 30 microns, 35 microns, etc., including particle sizes in the range of 0.1 to 500 microns), which are administered by rapid inhalation through the nostrils to reach the alveolar sacs, or by inhalation through the mouth. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered together with other therapeutic agents, such as compounds previously used to treat or prevent the disorders described below.

[0251] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, such carriers as are deemed appropriate.

[0252] The formulations may be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, for injection 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 daily unit sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0253] In one embodiment, a compound or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt is formulated as a prodrug. As used herein, the term prodrug refers to a derivative of a compound that can be hydrolyzed, oxidized, or cleaved under biological conditions to provide the compound or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt. As defined herein, prodrugs include derivatives containing one or more moieties that modulate or improve one or more physical, physiological, or pharmaceutical properties, such as solubilization, permeability, uptake, biodistribution, metabolic stability, onset of action, or any other drug-like property, and are converted to a biologically active or more biologically active substance as provided herein. In one embodiment, the prodrugs herein have no biological activity until release of the compound or its pharmaceutically acceptable salt.

[0254] Administration method The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be administered by any route appropriate to the condition being treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous (IV), intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intraperitoneal, intrapulmonary, and intranasal. In one embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are administered orally or by IV. For localized immunosuppressive treatment, the compounds can be administered intralesionally, including by perfusing or otherwise contacting the graft with an inhibitor prior to transplantation. It will be understood that the preferred route may vary with, for example, the condition of the recipient. When the compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered orally, it may be formulated with a pharmaceutically acceptable carrier or excipient as a pill, capsule, tablet, etc. When the compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle in a unit dosage form for injection, as described in more detail below.

[0255] Thus, in one aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that can be administered orally or parenterally to a subject. The compound 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, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is dissolved or otherwise suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion.

[0256] Oral administration can facilitate patient compliance when taking a compound (e.g., formulated as a pharmaceutical composition), thereby increasing compliance and efficacy. Oral administration can facilitate patient compliance when taking a compound (e.g., formulated as a pharmaceutical composition), thereby increasing compliance and efficacy. Oral pharmaceutical compositions comprising the compounds described herein include, but are not limited to, tablets (e.g., coated, uncoated, chewable) and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric-coated capsules, and sustained-release capsules). Tablets can be prepared by direct compression, wet granulation, or dry granulation. Oral pharmaceutical compositions comprising the compounds described herein can be formulated for delayed release or extended release.

[0257] Doses for treating human patients can range from about 10 mg to about 1000 mg of a compound described herein. Typical dosages can be from about 100 mg to about 300 mg of compound. Doses can be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion, of a particular compound. As used herein, "dosing" refers to the frequency of administration and not the number of individual units a patient must take for administration, e.g., as described herein. Thus, in some embodiments, a patient may take two or more dosage units (e.g., two or more pills / tablets / capsules) QD. In addition, toxicity factors can affect the dose and administration regimen. When administered orally, pills, capsules, or tablets may be taken orally daily for a specified time period, or at more spaced intervals. This regimen can be repeated for a predetermined number of treatment cycles.

[0258] Treatment Methods and Uses The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as Ras inhibitors. In one aspect, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as KRas inhibitors. In another aspect, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as NRas inhibitors. In another aspect, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as HRas inhibitors. In one embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as G12D Ras inhibitors and G12D KRas inhibitors.

[0259] Provided herein are methods of inhibiting Ras activity (e.g., KRas activity) in a cell, such as 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.

[0260] Further provided herein is a method of treating a cancer containing a KRas mutation, comprising administering to a patient having such a cancer an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In one embodiment, the KRas mutation is KRas G12D It is a mutation.

[0261] In one embodiment, the method comprises: G12D In one such embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered to a patient sample to determine whether the patient sample is KRas or not.G12D It is administered to a patient after testing positive for (eg, the presence of) a mutation.

[0262] The methods of treating cancer described herein include, but are not limited to, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and leukemia-associated cancers (e.g., leukemia-associated leukemia). L), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, uterine cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic Neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasia, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasia, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, oropharynx For the treatment of cancers such as carcinoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, sarcoma of soft tissue, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, abnormal cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

[0263] In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. The lung cancer can be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is lung adenocarcinoma.

[0264] The methods provided herein also include methods for detecting KRas G12D This may include testing a sample from the patient for the absence or presence of a mutation prior to administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered to a patient sample prior to administration of the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition. G12D In one embodiment, a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered to a patient after the patient sample has demonstrated the presence of a KRas mutation. G12D It will not be administered unless it contains a mutation.

[0265] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the cancer is cross-tissue (KRas G12D including mutations).

[0266] KRas G12DFurther provided herein is a method for treating a lung cancer comprising a mutation in a patient having such a lung cancer, 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 the same). In one embodiment, the lung cancer is non-small cell lung carcinoma (NSCLC). The NSCLC can be, for example, an adenocarcinoma, a squamous cell lung carcinoma, or a large cell lung carcinoma. In another embodiment, the lung cancer is a small cell lung carcinoma. In yet another embodiment, the lung cancer is an adenocarcinoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. The methods provided herein include administering the compound as a first line of therapy.

[0267] KRas G12D Further provided herein is a method of treating a pancreatic cancer comprising a mutation in a patient having such pancreatic cancer, 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 stage 0, stage I, or stage II. In another embodiment, the pancreatic cancer is stage III or stage IV.

[0268] KRas G12D Further provided herein is a method of treating a mutation-containing colon cancer in a patient having such colon cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the colon cancer is stage I or stage II. In another embodiment, the colon cancer is stage III or stage IV.

[0269] KRas G12D Further provided herein is a method for treating a cross-sectional cancer comprising a mutation. In one embodiment of such a method, the method comprises: (a)(a) KRas in samples taken from patients diagnosed with suspected cancer. G12D determining the absence or presence of a mutation; (b)(b) administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0270] In one embodiment of such a method, the patient is diagnosed with a cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before administration of any therapy. In another such embodiment, 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 another embodiment of such a method, a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered as provided herein (e.g., orally or IV).

[0271] Also provided herein are compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, for use as therapeutically active substances. In one such embodiment, the compound, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, is a KRas G12D It may be for the therapeutic treatment of cancers that contain KRas mutations. G12D Further provided herein are compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, for the therapeutic and / or prophylactic treatment of cancers containing mutations. In one embodiment, the compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are KRas G12Dand for use 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.

[0272] Further provided herein is a method for inhibiting tumor metastasis, 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 one embodiment, the inhibition is via KRas G12D In another embodiment, the inhibition of tumor metastasis in a patient described herein results in a reduction in tumor size. In another embodiment, the inhibition of tumor metastasis in a patient described herein results in a stabilization of tumor size (e.g., no further growth). In another embodiment, the inhibition of tumor metastasis in a patient described herein results in the remission of cancer and / or its symptoms.

[0273] Further provided herein is a method for inhibiting proliferation of a cell population, comprising contacting the cell population with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the cell population is present in a human patient. In another embodiment, the cell population is a cell population that expresses KRas G12D Including mutations.

[0274] Further provided herein is a method 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 one embodiment, the KRas inhibited is KRas G12D In another embodiment, inhibiting KRas reduces tumor size. In another embodiment, inhibiting KRas results in the amelioration of cancer and / or its symptoms.

[0275] Further provided herein is a method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the mutant protein is a KRas G12D In one embodiment, the activity of KRas is reduced 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 results in a reduction in tumor size. In another embodiment, downregulating the activity of a KRas mutant protein results in the amelioration of a cancer described herein and / or its symptoms.

[0276] In some embodiments, the methods provided herein include detecting a cell expressing KRas in the cell. G12D and inhibiting the activity of KRas in the cells by contacting the cells with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of KRas. G12D In some embodiments, the methods provided herein include inhibiting the activity of KRas in the tissue. G12D and inhibiting KRas activity in the tissue by contacting the tissue with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of KRas. G12D In some embodiments, the methods provided herein include treating a patient described herein by inhibiting KRas activity in the patient. G12D and inhibiting KRas in the patient by contacting the patient with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of KRas. G12D This includes inhibiting the activity of a compound.

[0277] Labeled KRas G12D A method for preparing a mutant protein 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 Further provided herein is a method comprising obtaining the mutant protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled KRas G12D can be used to detect the presence or absence of G12D mutant KRas in a patient sample, and thereby the presence or absence of cancer mediated by mutant KRas.

[0278] Further provided herein are methods for inhibiting Ras-mediated cell signaling. In one embodiment, the method comprises contacting a cell with an effective amount of one or more compounds disclosed herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. Inhibition of Ras-mediated signaling can be assessed and demonstrated by various methods known in the art. Non-limiting examples include 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 amount of signaling molecules downstream of the Ras pathway, such as a decrease in the amount of pMEK, 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 measuring one or more of the above.

[0279] KRas mutations, including G12D mutations, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration (e.g., in the form of a pharmaceutical composition) of the disclosed compounds described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, 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 compounds disclosed herein 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 other embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are useful for treating lymphoma, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0280] The tumor or cancer is KRas G12D Determining whether a mutation is present can be performed 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 predicted KRas mutant protein. The sequence of wild-type human KRas (e.g., accession number NP203524) is known in the art.

[0281] Methods for detecting mutations in KRas nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for the G12D KRas mutation by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRas G12D mutation is used. 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 of the KRas gene (e.g., exon 2 and / or exon 3). The method identifies all possible mutations within the sequenced region.

[0282] The tumor or cancer is KRas G12D The methods for determining whether a sample contains a mutation can use a variety of samples. In some embodiments, the sample is taken 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.

[0283] 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 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 a KRas G12D In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, 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.

[0284] Further provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer. In one embodiment, the cancer is a KRas G12D In one such embodiment, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one such embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one such embodiment, the cancer is colorectal cancer. In one such embodiment, the cancer is pancreatic cancer. In one such embodiment, the cancer is lung adenocarcinoma.

[0285] 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 dosing regimen preferably has complementary activity to the compounds described herein, or their pharmaceutically acceptable salts, so that they do not adversely affect each other. Combination therapy can provide "synergistic effects," and can be proven to be "synergistic," i.e., an effect achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately.

[0286] The combination therapy can be administered as a simultaneous regimen or a sequential regimen. When administered sequentially, the combination is administered in two or more doses. The combination administration includes co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably with time for both (or all) active agents to simultaneously exert their biological activity.

[0287] Combination therapy herein includes the administration of a compound described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and the use of at least one other treatment method. The amounts and relative timing of administration of the compound described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and the other pharmaceutically active agent(s) will be selected to achieve the desired combined therapeutic effect.

[0288] 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 anti-microtubule inhibitors, including paclitaxel and docetaxel), an antimetabolite (such as 5-FU, or such as gemcitabine), or an alkylating agent (such as cisplatin, or such as cyclophosphamide), or a taxane.

[0289] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as erlotinib, or such as afatinib. In some aspects, 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, e.g., GDC-0077, GDC-0941, MLN1117, BYL719 (alpelisib), or BKM120 (buparlisib). GDC-0941 refers to 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, or a salt thereof (e.g., the bismesylate salt).

[0290] In still other embodiments, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments, the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (linsitinib), BMS-754807, or in other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody specific for IGF1R, such as AMG-479 (ganitumab), CP-751, 871 (fizitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (lovatumumab).

[0291] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor, hi some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, pacritinib, ruxolitinib, or TG101348.

[0292] In some other embodiments, the additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0293] In some other embodiments, the additional therapeutic agent is an antibody-drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vetotin, RG7986, RG7882, RG6109, or RO7172369.

[0294] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist, hi some embodiments, the MDM2 antagonist is idasanutulin.

[0295] In some other embodiments, the additional therapeutic agent is an agonistic antibody to CD40, hi some embodiments, the agonistic antibody to CD40 is cericrelumab (RG7876).

[0296] In some other embodiments, the additional therapeutic agent is a bispecific antibody, hi some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0297] In some other embodiments, the additional therapeutic agent is a targeted immunocytokine, hi some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0298] 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.

[0299] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine, hi some embodiments, the personalized cancer vaccine is RG6180.

[0300] In some other embodiments, the additional therapeutic agent is an inhibitor of BET (bromodomain and extraterminal family) proteins (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0301] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT, hi some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0302] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545, diredestrant).

[0303] In some other embodiments, the additional therapeutic agent is crizotinib, tivantinib, AMG337, cabozantinib, or foretinib. In other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody against methionine, such as onartuzumab.

[0304] In further embodiments, the additional therapeutic agent is an SRC family non-tyrosine kinase inhibitor. For example, in some embodiments, the additional therapeutic agent is an inhibitor of 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.

[0305] 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.

[0306] 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.

[0307] In other embodiments, the protein kinase inhibitor is taselisib, ipataselitib, 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 further embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some further embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include taxol and docetaxel.

[0308] 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 chemotherapy 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.

[0309] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as a host of other chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; chlorambucil, methylmelamine, and methylmelamine. Nitrogen mustards such as cyclosporine, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; aclacinomycin, actinomycin, anthramycin, azaserine, and bromide; Rheomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, keramycin Antibiotics such as cyclosporine, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur,Pyrimidine analogs such as cytarabine, dideoxyuridinene, doxifluridine, enocitabine, and floxiridine; androgens such as calucelone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotein, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; Lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide K; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes (e.g., paclitaxel (TAXOL™, Bristol-Myers 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 include, for example, tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); 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 anti-hormonal agents that act to regulate or inhibit hormone action in tumors, such as antiestrogens including difluoromethylornithine (DMFO). If desired, the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be administered in combination with other steroids, including Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxot®, and other steroids. ere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfalazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agent, tumorigenic herb, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific anticancer drugs, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, eclulind, ferruginol, forodesin, fosfestol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucansone, lurtotecan, mafosfamide,It can be used in combination with commonly prescribed anticancer drugs such as mitozolomide, nafoximide, 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 zosquidar.

[0310] The exact method for administering the compound and additional therapeutic agent will be apparent to one of ordinary skill in the art. In some exemplary embodiments, the compound and additional therapeutic agent are administered simultaneously. In other embodiments, the compound and additional therapeutic agent are administered separately.

[0311] In some embodiments, the compound and the additional therapeutic agent are administered simultaneously with the second agent or separately. This combined administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound described herein and any of the additional therapeutic agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound described herein and any of the additional therapeutic agents can be administered simultaneously, where both agents are present in separate formulations. In another alternative, the compound can be administered immediately after any of the additional therapeutic agents described herein, or in the reverse order. In some embodiments of the separate administration protocol, the compound described herein and any of the additional therapeutic agents are administered within minutes, hours, or days.

[0312] manufactured goods Also provided herein are articles of manufacture, or "kits," containing materials useful for treating cancer as provided herein. In one embodiment, the kit includes a container containing a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. The kit may further include a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container can be formed from a variety of materials, such as glass or plastic. The container can hold a compound described herein, or a pharmaceutically acceptable salt thereof, or a formulation thereof, effective for treating a condition, and can have a sterile access port (e.g., the container can be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound described herein, or a pharmaceutically acceptable salt thereof. Alternatively, or additionally, the article of manufacture may further comprise a second container containing a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution. The article of manufacture may further comprise other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0313] 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 contain multiple unit doses. 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. Embodiment

[0314] Some exemplary embodiments of the invention described herein are provided below.

[0315] Embodiment 1. Formula (I): TIFF2024506029000120.tif35170 (in the formula, X is O or NR 6 and n is 1, 2 or 3; m is 1, 2, or 3; p is 0, 1 or 2; n and m together form a 6-, 7- or 8-membered ring A; Each R 0 are independently hydrogen or methyl; 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 benzothiazolyl, R 7A substituted or unsubstituted phenyl, or R 7A substituted or unsubstituted pyridinyl, Each R 7 are independently hydrogen, halogen, -OH, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; Each R 7A are independently hydrogen, halogen, NH2, N(Me)2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; R 2 is hydrogen, L 1 -OL 2 -R 8 , R 8A Substituted or unsubstituted C 1~3 Alkyl, or R 8B a substituted or unsubstituted 4- to 10-membered heterocycle, where R 2 is hydrogen and R 1 R 7 substituted indazolyl, and when n and m are 1, p is not 0, and R 6 is not H, L 1 is a bond or R L1 Substituted or unsubstituted C 1~3 is alkylene, R L1 is a halogen or unsubstituted C1~3 is alkyl, L 2 is a bond or unsubstituted C 1~3 is alkylene, R 8 R containing N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle, Each R 9 are independently selected from halogen, oxo, -OCF3, -OCHF2, -OCH2F, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10 Substituted or unsubstituted C 1~3 Alkylidene, or R 10 Substituted or unsubstituted C 3~4 Cycloalkyl, or R 10 a substituted or unsubstituted 3- or 4-membered heterocycle, or 2 R's 9 Together, R 10 Substituted or unsubstituted C 3~5 Cycloalkyl or R containing one or more oxygen atoms 10 forming a substituted or unsubstituted C3-5 heterocycle, R 10 is hydrogen, halogen, or C 1~3 is an unsubstituted alkyl; Each R 8A are independently 9A Substituted or unsubstituted C 1~3 Alkyl, R 9A Substituted or unsubstituted C 1~3 Alkoxy, R 9A Substituted or unsubstituted C 3~4 Cycloalkyl, or R 9A a substituted or unsubstituted 4- to 6-membered heterocycle, Each R 9A are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, unsubstituted C 1~3 Alkylidene, R 9 Substituted or unsubstituted C 3~4Cycloalkyl or R containing N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle, R 8B are independently selected from halogen, oxo, -NH2, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 is alkylidene, R 3 and R 4 are each independently hydrogen, -CN, halogen, or unsubstituted C 1~3 alkyl, or unsubstituted cyclopropyl; Each R 5 are independently selected from halogen, oxo, and unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl, or 2 R's 5 taken together form a bridge between two carbon atoms of ring A, said bridge containing 1 to 3 carbons and optionally one heteroatom selected from O and N, or 2 R's 5 together form a bridge between two carbon atoms of ring A, said bridge being O or NR 11 including one of R 11 is hydrogen, C(O)CH3, or unsubstituted C 1~3 is alkyl, R 6 is hydrogen or 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- or 4-membered heterocycle, R 6A is halogen, CN, OR 6B , S.R. 6C , S(O)2R 6C, C(O) R6B , unsubstituted C 1~3 alkyl or unsubstituted C 1~3 Haloalkyl, R 6B a substituted or unsubstituted 3- or 4-membered heterocycle, R 6B and R 6C are each independently 1~3 Alkyl or C 1~3 haloalkyl) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0316] Embodiment 2. Each R 0 The compound of claim 1, wherein is hydrogen.

[0317] Embodiment 3.1 R 0 is hydrogen and one R 0 is methyl.

[0318] Embodiment 4. Structure: The compound of claim 3 having TIFF2024506029000121.tif34170.

[0319] Embodiment 5.R 1 But R 7 substituted or unsubstituted phenyl, R 7 Substituted or unsubstituted indazolyl, or R 7 2. The compound of claim 1, which is a substituted or unsubstituted pyridinyl.

[0320] Embodiment 6.R 1 But R 7 6. The compound according to claim 1, which is a substituted or unsubstituted phenyl.

[0321] Embodiment 7.R 1 But R 7 6. The compound according to claim 1, which is a substituted or unsubstituted indazolyl.

[0322] Embodiment 8.R1 But R 7 6. The compound according to claim 1, which is a substituted or unsubstituted pyridinyl.

[0323] Embodiment 9. Each R 7 are independently selected from halogen, NH2, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 The compound according to any one of claims 1 to 8, which is haloalkyl.

[0324] Embodiment 10.R 1 but, TIFF2024506029000122.tif21170 (in the formula, X 1 is N or CF, R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) The compound according to any one of claims 1 to 5, wherein

[0325] Embodiment 11.R 1 but, 11. The compound of any one of claims 1, 5, 8, or 10, which is TIFF2024506029000123.tif21170.

[0326] Embodiment 12.R 1 but, 12. The compound of any one of claims 1, 5, 8, 10 or 11, wherein the compound is TIFF2024506029000124.tif20170.

[0327] Embodiment 13.R 1 but, TIFF2024506029000125.tif25170 (in the formula, R 7 is hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) The compound according to any one of claims 1 to 6 or 10, wherein

[0328] Embodiment 14.R 1 but, 14. The compound of any one of claims 1 to 6, 10 or 13, which is TIFF2024506029000126.tif24170.

[0329] Embodiment 15.R 1 but, TIFF2024506029000127.tif27170 (in the formula, each R 7 are independently halogen, NH2, N(Me)2, or unsubstituted C 1~3 alkyl) The compound according to any one of claims 1 to 5, wherein

[0330] Embodiment 16.R 2 But, L 1 -OL 2 -R 8 , R 8A Substituted or unsubstituted C 1~3 Alkyl, or R 8B 16. The compound according to claim 1, which is a substituted or unsubstituted 4- to 6-membered heterocycle.

[0331] Embodiment 17.R 2 But, L 1 -OL 2 -R 8 The compound according to any one of claims 1 to 16, wherein

[0332] Embodiment 18.L 1 The compound according to any one of claims 1 to 17, wherein is a bond.

[0333] Embodiment 19.L 2 But unsubstituted C 1~3 19. The compound according to claim 16, which is alkylene.

[0334] Embodiment 20.R 8 20. The compound according to claim 16, wherein is a 4-10 membered heterocycle containing one N heteroatom.

[0335] Embodiment 21.R 8 but, TIFF2024506029000128.tif19170 (in the formula, 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 according to any one of claims 16 to 20, wherein

[0336] Embodiment 22. The compound of claim 21, wherein r is 0, 1, 2, or 3.

[0337] Embodiment 23.R 8 but, TIFF2024506029000129.tif33170 (in the formula, R 9 are independently a halogen or R 10 Substituted or unsubstituted C 1~3 is alkylidene, Each R 10 are independently hydrogen or halogen; r is 1 or 2) The compound according to any one of claims 16 to 22, wherein

[0338] Embodiment 24.R 8 but, TIFF2024506029000130.tif19170 (in the formula, R 9 are independently halogen, oxo, or unsubstituted C 1~3 is alkyl, r is 1 or 2) The compound according to any one of claims 16 to 20, wherein

[0339] Embodiment 25.R 8 but, TIFF2024506029000131.tif14170 (in the formula, R 9 is hydrogen or unsubstituted C 1~3 is alkyl, W is O, SO2, or NR 12 and R 12 is hydrogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) The compound according to any one of claims 16 to 20, wherein

[0340] Embodiment 26.R 8 26. The compound according to any one of claims 16 to 20 or 25, wherein is azetidinyl, oxetanyl, or thietanedioxide.

[0341] Embodiment 27.R 2 but, 27. The compound according to any one of claims 1 to 26, which is TIFF2024506029000132.tif65170.

[0342] Embodiment 28.R 9 is halogen or R 10 Substituted or unsubstituted C 1~3 28. The compound of claim 27, which is an alkylidene.

[0343] Embodiment 29.R 2 The compound according to any one of claims 1 to 15, wherein is hydrogen.

[0344] Embodiment 30.R 2 But R 8A Substituted or unsubstituted C 1~3 17. The compound according to any one of claims 1 to 16, which is alkyl.

[0345] Embodiment 31.R 8A But independently, R 9A substituted or unsubstituted alkoxy, or R 9A 30. The compound according to claim 29, which is a substituted or unsubstituted 4- to 6-membered heterocycle.

[0346] Embodiment 32.R 9A But R containing N 9 32. The compound according to claim 29 or 31, which is a substituted or unsubstituted 4- to 10-membered heterocycle.

[0347] Embodiment 33.R 9A are independently halogen, unsubstituted C 1~3 Alkyl, or R 10 Substituted or unsubstituted C 1~3 33. The compound of claim 31 or 32, which is an alkylidene.

[0348] Embodiment 34.R 3 34. The compound according to any one of claims 1 to 33, wherein is halogen.

[0349] Embodiment 35.R 4 35. The compound according to any one of claims 1 to 34, wherein is hydrogen.

[0350] Embodiment 36.R 4 35. The compound according to any one of claims 1 to 34, wherein is halogen.

[0351] Embodiment 37.R 5 are independently oxo or unsubstituted C 1~3 37. The compound according to any one of claims 1 to 36, wherein p is alkyl and p is 1.

[0352] Embodiment 38.2 R 5 together form a bridge between two carbon atoms of ring A, said bridge comprising 1 to 3 carbons.

[0353] Embodiment 39. The compound of claim 38, wherein the bridge comprises one carbon atom.

[0354] Embodiment 40. The compound of claim 38, wherein the bridge comprises two carbon atoms.

[0355] Embodiment 41. Formula: 10. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula: TIFF2024506029000133.tif35170.

[0356] Embodiment 42. Formula: 10. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula: TIFF2024506029000134.tif37170.

[0357] Embodiment 43. Formula: The compound of claim 1 having TIFF2024506029000135.tif37170.

[0358] Embodiment 44. Formula: 10. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula: TIFF2024506029000136.tif106170.

[0359] Embodiment 45. Formula: 10. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula: TIFF2024506029000137.tif106170.

[0360] Embodiment 46. Formula: 10. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula: TIFF2024506029000138.tif37170.

[0361] Embodiment 47. Formula: 10. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula: TIFF2024506029000139.tif37170.

[0362] Embodiment 48. Formula: 10. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula: TIFF2024506029000140.tif35170.

[0363] Embodiment 49. Formula: 10. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, having the formula: TIFF2024506029000141.tif35170.

[0364] Embodiment 50.R 8 but, 50. The compound of claim 1 or any one of claims 41 to 49, wherein the compound is TIFF2024506029000142.tif27170.

[0365] Embodiment 51.R 8 but, 43. The compound according to claim 1 or any one of claims 38 to 42, wherein the compound is TIFF2024506029000143.tif33170.

[0366] Embodiment 52.R 8 but, 50. The compound of claim 1 or any one of claims 41 to 49, wherein the compound is TIFF2024506029000144.tif19170.

[0367] Embodiment 53.X is NR 6 53. The compound according to any one of claims 1 to 52, wherein

[0368] Embodiment 54.R 6 But R 6A Substituted or unsubstituted C 1~3 54. The compound of claim 53, wherein the compound is alkyl.

[0369] Embodiment 55.R 6 But R 6A substitution C 1~3 54. The compound of claim 53, wherein the compound is alkyl.

[0370] Embodiment 56.R 6A But halogen, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1~3 56. The compound of claim 55, which is alkyl or a 4-membered heterocycle.

[0371] Embodiment 57.R 6 But R 6A Substituted or unsubstituted C 1~3 54. The compound of claim 53, which is haloalkyl.

[0372] Embodiment 58.R 6 But R 6A Substituted or unsubstituted C 1~3 54. The compound of claim 53, which is alkenyl.

[0373] Embodiment 59.R 6 But R 6A Substituted or unsubstituted C 1~3 54. The compound of claim 53, which is alkynyl.

[0374] Embodiment 60.R 6 54. The compound of claim 53, wherein is hydrogen.

[0375] Embodiment 61.R 6 54. The compound of claim 53, wherein is methyl.

[0376] Embodiment 62. A compound of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0377] Embodiment 63. A compound of Table 2, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0378] Embodiment 64. A compound of Table 3, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0379] Embodiment 65. A pharmaceutical composition comprising a compound of any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0380] Embodiment 66. A method for treating cancer, comprising administering an effective amount of a compound of any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 65.

[0381] Embodiment 67. The method of claim 66, wherein the cancer comprises a KRas mutation.

[0382] Embodiment 68. The KRas mutation is KRas G12D 68. The method of claim 67, which corresponds to a mutation.

[0383] Embodiment 69. A sample from a patient before administration is analyzed for KRas G12D 69. The method of claim 68, further comprising testing for the absence or presence of a mutation.

[0384] Embodiment 70. The compound, its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, or pharmaceutical composition is selected from the group consisting of: G12D 70. The method of claim 69, wherein the method is administered to the patient after indicating the presence of a mutation.

[0385] Embodiment 71. The method of any one of claims 66 to 70, wherein the cancer is tissue-crossing.

[0386] Embodiment 72. The method of any one of claims 66 to 70, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0387] Embodiment 73. The method of claim 72, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

[0388] Embodiment 74. The method of claim 72, wherein the cancer is pancreatic cancer.

[0389] Embodiment 75. The method of claim 72, wherein the cancer is colorectal cancer.

[0390] Embodiment 76. The method of any one of claims 66 to 75, further comprising administering at least one additional therapeutic agent.

[0391] Embodiment 77. The method of claim 76, 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.

[0392] Embodiment 78. A compound according to any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0393] Embodiment 79. KRas G12D 65. Use of a compound according to any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for the therapeutic treatment of cancers containing mutations.

[0394] Embodiment 80. KRas G12D 65. Use of a compound of any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of cancer containing a mutation.

[0395] Embodiment 81. Use of a compound according to any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer, or pharmaceutical salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0396] Embodiment 82. KRas G12D 65. A compound according to any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer or pharmaceutical salt thereof, for the therapeutic and / or prophylactic treatment of cancers that contain mutations.

[0397] Embodiment 83. A method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound of any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0398] Embodiment 84. A method for inhibiting proliferation of a cell population, comprising contacting the cell population with a compound of any one of claims 1-64, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0399] Embodiment 85. The method of claim 84, wherein said inhibition of proliferation is measured as a decrease in cell viability of said cell population.

[0400] Embodiment 86. Labeled KRas G12D A method for preparing a mutant protein comprising: G12D 65. The mutant protein is reacted with a labeled compound according to any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to produce the labeled KRas. G12D obtaining a mutant protein.

[0401] Embodiment 87. A method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 65.

[0402] Embodiment 88. A process for synthesizing a compound of formula (I) as described herein.

[0403] Example Intermediate 1: tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2024506029000145.tif66170

[0404] Step 1: tert-Butyl (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate TIFF2024506029000146.tif19170

[0405] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (50.0 g, 236 mmol) and K2CO3 (65.1 g, 472 mmol) in N,N-dimethylformamide (800 mL) was added BnBr (60.1 g, 354 mmol) at 0 °C. The reaction mixture was warmed to room temperature. After 2 h, ice water (1000 mL) was added. The resulting mixture was extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-10%) to afford the title compound (69 g, 97% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =303.

[0406] 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 TIFF2024506029000147.tif34170

[0407] To a solution of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (23.0 g, 76.1 mmol) and TMEDA (17.7 g, 153 mmol) in diethyl ether (500 mL) was added dropwise s-BuLi (1.3 M in hexanes) (117 mL, 152 mmol) under nitrogen at −78 °C. After 1.5 h, a solution of methyl chloroformate (17.9 g, 189 mmol) in 40 mL of EtO was added at −78 °C. The reaction was allowed to warm to room temperature. After 16 h, the reaction was quenched with saturated aqueous NaHCO and diluted with 500 mL of water. The resulting mixture was extracted with EtOAc (3×). The combined organic phase was dried over NaSO and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0–10%) to give 16 g of the product (cis mixture) as a yellow oil, which contained approximately 10% of the starting material tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, coeluting with the product. 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; 220 nm; RT1: 5.07; RT2: 5.57) to give 5.9 g of the faster peak (isomer 1) and 5.6 g of the slower peak (isomer 2) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =361.

[0408] Step 3: tert-butyl (1R,2S,5S)-8-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate TIFF2024506029000148.tif19170

[0409] 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) in tetrahydrofuran (300 mL) cooled in an ice-salt bath under nitrogen, LiAlH (4.20 g, 111 mmol) was added portionwise at a rate that maintained the reaction temperature below 5 °C. The resulting solution was stirred at 0 °C for 30 min. The reaction was quenched with NaSO 10H O and filtered. The organics were concentrated in vacuo. The residue was purified by flash chromatography on silica gel 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.

[0410] Step 4: (6S,9R,9aS)-10-benzylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one TIFF2024506029000149.tif26170

[0411] NaH (1.35 g, 33.8 mmol) was added portionwise to a solution of tert-butyl 8-benzyl-4-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.10 g, 15.3 mmol) in tetrahydrofuran (100 mL) at 0 °C. The resulting suspension was allowed to warm to room temperature. After 3 h, the reaction mixture was quenched with saturated aqueous NH4Cl (30 mL). The resulting solution was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-40%) to afford the title compound (3.5 g, 88% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =259.

[0412] Step 5: (6S,9R,9aS)-Hexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one TIFF2024506029000150.tif25170

[0413] To a solution of (6S,9R,9aS)-10-benzylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one (10.0 g, 38.7 mmol) in methanol (200 mL) was added Pd / C (3.0 g, 10% dry) at room temperature. The resulting solution was stirred under hydrogen for 2 hours. The suspension was filtered, and the filtrate was concentrated to give 6 g of crude product, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =169.

[0414] Step 6: tert-Butyl (6S,9R,9aS)-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-10-carboxylate TIFF2024506029000151.tif22170

[0415] To a solution of (6S,9R,9aS)-hexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one (6.00 g, 35.7 mmol) and (Boc)2O (12.6 g, 57.8 mmol) in dichloromethane (100 mL) was added DIPEA (10.0 g, 77.5 mmol) at 0 °C. The solution was warmed to room temperature for 2 h. The solution was washed with saturated aqueous sodium chloride. The separated organic phase was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-40%) to afford the title compound (7.50 g, 78.4% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =269.

[0416] Step 7: tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2024506029000152.tif18170

[0417] To 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) in ethanol (200 mL) was added NaOH (16.8 g, 420 mmol) in water (70 mL). The resulting solution was heated at 80 °C for 16 h. EtOH was removed under reduced pressure, and the resulting aqueous solution was neutralized to pH 8 with HCl (1 M). The solution was extracted with EtOAc (3x). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with DCM / MeOH (5 / 1) to afford the title compound (5.0 g, 74% yield) as an off-white solid. LC-MS: (ESI, m / z): [M+H] + =243. 1H NMR(400MHz,DMSO-d6,ppm)δ 4.72-4.57(m,1H),4.02-3.90(m,2H),3.25-3.15(m,2H),2.82-2.68(m,2 H),2.64-2.53(m,1H),1.85-1.61(m,3H),1.61-1.47(m,1H),1.41(s,9H).

[0418] Intermediate 2: 7-Bromo-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one TIFF2024506029000153.tif47170

[0419] Step 1: 3-Bromo-2,5-difluoroaniline TIFF2024506029000154.tif20170

[0420] To a suspension of 1-bromo-2,5-difluoro-3-nitrobenzene (40.0 g, 168 mmol) and iron powder (28.4 g, 506 mmol) in water (10 mL) was added concentrated hydrochloric acid (40 mL, 36%) at room temperature. The suspension was heated to 100° C. After 1 h, the reaction was cooled to room temperature and filtered. The filter cake was washed with EtOAc. The combined filtrate was concentrated under reduced pressure to give the title compound (34.3 g, crude) as a brown oil, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =208.

[0421] Step 2: N-(3-bromo-2,5-difluorophenyl)-2-(hydroxyimino)acetamide TIFF2024506029000155.tif19170

[0422] To a solution of 2,2,2-trichloroethane-1,1-diol (40.9 g, 247 mmol), NaSO (187 g, 1.32 mol), and NHOH·HCl (39.8 g, 577 mmol) in water (680 mL) was added a solution of 3-bromo-2,5-difluoroaniline (34.3 g, 165 mmol) in ethanol (100 mL), hydrochloric acid (12.5 mL, 36%), and water (50 mL). The resulting solution was heated at 60 °C for 3 h. The reaction was cooled to room temperature and filtered. The solid was collected, rinsed with water (500 mL), and dried in an oven to give the title compound (32.8 g, crude) as a light brown solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =279.

[0423] Step 3: 6-Bromo-4,7-difluoroindoline-2,3-dione TIFF2024506029000156.tif19170

[0424] A solution of N-(3-bromo-2,5-difluorophenyl)-2-(hydroxyimino)acetamide (32.8 g, 118 mmol) in HSO (160 mL, 98%) was heated at 90° C. for 1 h. The reaction mixture was cooled to room temperature and added slowly to ice water. The precipitate was collected by filtration, washed with water, and dried in an oven to give the title compound (28.1 g, crude) as a brown solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =262.

[0425] Step 4: 2-Amino-4-bromo-3,6-difluorobenzoic acid TIFF2024506029000157.tif19170

[0426] A solution of 6-bromo-4,7-difluoroindoline-2,3-dione (28.1 g, 107 mmol) in NaOH (537 mL, 2 M in water) and HO (53.7 mL, 30%) was stirred at room temperature for 16 h. The mixture was poured into ice water and adjusted to pH = 2 with concentrated HCl. The solid was collected by filtration and rinsed with water. The crude product was purified by reverse-phase chromatography (gradient: 0-60% acetonitrile in water (0.1% formic acid)) to afford the title compound (13.4 g, 49.4% yield) as a light brown solid. LC-MS: (ESI, m / z): [M+H] + =252.

[0427] Step 5: 2-Amino-4-bromo-5-chloro-3,6-difluorobenzoic acid TIFF2024506029000158.tif19170

[0428] A solution of 2-amino-4-bromo-3,6-difluorobenzoic acid (10.9 g, 43.2 mmol) and N-chlorosuccinimide (6.32 g, 47.5 mmol) in DMF (100 mL) was stirred at 90° C. for 1 h. The mixture was cooled to room temperature and poured into water (500 mL). The solid was collected and dried in an oven to give the title compound (12.1 g, crude) as a brown solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =286.

[0429] Step 6: 2-amino-4-bromo-5-chloro-3,6-difluorobenzamide TIFF2024506029000159.tif19170

[0430] To a solution of 2-amino-4-bromo-5-chloro-3,6-difluorobenzoic acid (11.9 g, 41.6 mmol), NHCl (4.42 g, 83.4 mmol), and DIPEA (13.5 g, 104 mmol) in DMF (60 mL) was added HATU (17.43 g, 45.84 mmol) at room temperature. The resulting solution was stirred for 30 min. The mixture was poured into water (300 mL), and the resulting precipitate was collected by filtration. The solid was suspended in EtOAc / petroleum ether (1:4, 100 mL) and stirred for 3 h. The solid was collected by filtration and dried in an oven to give the title compound (8.85 g, crude) as a brown solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =285.

[0431] Step 7: 7-Bromo-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one TIFF2024506029000160.tif19170

[0432] A solution of 2-amino-4-bromo-5-chloro-3,6-difluorobenzamide (8.85 g, 31.0 mmol) and thiophosgene (10.7 g, 93.2 mmol) in 1,4-dioxane (175 mL) was stirred at room temperature for 1 hour. The mixture was then heated to 105° C. for 1 hour. The reaction was concentrated in vacuo, and the residue was suspended in EtOAc / petroleum ether (1:4, 60 mL) and stirred for 1 hour. The solid was collected by filtration and dried to give the title compound (7.08 g, crude) as a brown solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =330.

[0433] Intermediate 3 tert-Butyl (5aS,6S,9R)-2-bromo-3,13-dichloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000161.tif31170

[0434] Step 1: tert-butyl (1S,2S,5R)-2-(((7-bromo-2,6-dichloro-8-fluoro-4-hydroxyquinazolin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2024506029000162.tif33170

[0435] To an ice-cold solution of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.30 g, 9.49 mmol, Intermediate 1) in tetrahydrofuran (100 mL) was added NaH (3.20 g, 80.0 mmol) under nitrogen. The resulting solution was allowed to warm to room temperature. After 30 minutes, 7-bromo-2,6-dichloro-5,8-difluoroquinazolin-4-ol (4.40 g, 13.3 mmol, Intermediate 2) in tetrahydrofuran (50 mL) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NH4Cl and diluted with 200 mL of water. The resulting mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% MeOH / DCM) to give 3.6 g (48% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =551 / 553.

[0436] Step 2: tert-Butyl (5aS,6S,9R)-2-bromo-3,13-dichloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000163.tif35170

[0437] To a solution of tert-butyl (1S,2S,5R)-2-(((7-bromo-2,6-dichloro-8-fluoro-4-hydroxyquinazolin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.00 g, 14.5 mmol) and BOP-Cl (13.5 g, 53.0 mmol) in dichloromethane (150 mL) was added DIPEA (28.0 g, 217 mmol). The resulting solution was stirred at room temperature for 5 hours. The reaction mixture was washed with brine, and the organic layer was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 30% ethyl acetate / petroleum ether) followed by a slurry with ethyl acetate / petroleum ether = 1:10 to afford 3.50 g (45% yield) of the title compound as a pale yellow solid. LC-MS: (ESI, m / z): [M+H] + =533 / 535. 1 H NMR(400MHz,DMSO-d6,ppm)δ 4.90-4.80(m,1H),4.76-4.67(m,1H),4.55-4.46(m,1H),4.38-4.22(m,2 H),4.16-4.08(m,1H),3.20-3.12(m,1H),1.92-1.65(m,4H),1.45(s,9H).

[0438] Intermediate 4: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024506029000164.tif29170

[0439] To an ice-cold solution of 6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine (14.0 g, 54.9 mmol) in N,N-dimethylformamide (300 mL) was added 60% NaH (6.58 g, 165 mmol) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 h. PMB-Cl (21.4 g, 137 mmol) was then added at 0 °C and stirred at room temperature for 1 h. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc (3 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0–20% ethyl acetate / petroleum ether) to afford the title compound (23 g, 84.6% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =495 / 497; 1 H NMR (400 MHz, DMSO-d 6, ppm)δ 7.19(d,J=8.3Hz,4H),6.93-6.85(m,4H),6.65(s,1H),4.67(s,4H),3.73(s,6H),2.31(q,J=3.3Hz,3H).

[0440] Intermediate 5: tert-Butyl (5aS,6S,9R)-2-((R)-6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3,13-dichloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate ester and tert-butyl (5aS,6S,9R)-2-((S)-6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3,13-dichloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000165.tif47170

[0441] To a cold (−78° C.) solution of tert-butyl (5aS,6S,9R)-2-bromo-3,13-dichloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2′,1′:3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (6.50 g, 12.2 mmol, Intermediate 3) in tetrahydrofuran (25 mL) under nitrogen was added i-PrMgCl.LiCl (9.86 mL, 12.8 mmol) dropwise at −78° C. The solution was stirred at −78° C. for 1 h, and then ZnCl (6.72 mL, 13.4 mmol) was added dropwise to the cold solution. The solution was stirred at -78°C for 10 min, then the solution was slowly warmed to 25°C and stirred for 1 h. The resulting solution was divided into six portions, and each portion was transferred separately under nitrogen to the following solution: (6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (905 mg, 1.83 mmol, Intermediate 4) and PdCl(PPh) (57.1 mg, 0.0813 mmol) in tetrahydrofuran (4.6 mL). The reactions were stirred at 50 °C overnight, and all six reactions were run in parallel. The combined reaction mixture was diluted with water and extracted with EtOAc (3x). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 30% ethyl acetate / petroleum ether) to give 3.10 g of the title compound (29% yield, mixture of two atropisomers) as a yellow solid. The reaction was repeated to give a total of 7.1 g of the racemic compound. The racemic mixture was purified by SFC-HPLC (column: Lux 5 μm). Cellulose-2, 3 x 15 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 70 mL / min; Gradient: 50% B to 50% B in 24 min; 254 / 220 nm; R T1 :11.46;R T2 : 19.55) to give 2.30 g (later peak, desired isomer) and 2.40 g (faster peak) as yellow solids. 1.3 g of a mixture of atropisomers was also recovered. LC-MS: (ESI, m / z): [M+H] +=869.3. 1 H NMR(300MHz,DMSO-d6,ppm)δ 7.14(d,J=8.4Hz,4H),6.86(d,J=8.7Hz,4H),6.82(s,1H),4.92-4.81(m,1H),4.81-4.63(m,3H),4.62-4.47(m,3H),4. 41-4.24(m,2H),4.18-4.05(m,1H),3.72(s,6H),3.12(d,J=13.2Hz,1H),2.39(s,3H),2.00-1.63(m,4H),1.44(s,9H).

[0442] Intermediate 6: 7-Bromo-2-chloro-5,6,8-trifluoroquinazolin-4(3H)-one TIFF2024506029000166.tif56170

[0443] Step 1: (E)-N-(3-bromo-2,4,5-trifluorophenyl)-2-(hydroxyimino)acetamide TIFF2024506029000167.tif19170

[0444] To a solution of NaSO (207 g, 1438 mmol), hydroxylamine hydrochloride (44.7 g, 643.2 mmol), and hydrochloride (46.2 g, 279.32 mmol) in water (1000 mL) was added a solution of 3-bromo-2,4,5-trifluoroaniline (40.0 g, 177 mmol) in hydrochloric acid (30 mL, 37%), ethanol (80 mL), and water (100 mL). The resulting solution was stirred at 60 °C for 2 h. The precipitate was collected by filtration, washed with water, and dried under vacuum to give the title compound (43.2 g, 82.2% yield) as a light brown solid. LC-MS: (ESI, m / z): [MH] + =295.

[0445] Step 2: 6-Bromo-4,5,7-trifluoroindoline-2,3-dione TIFF2024506029000168.tif19170

[0446] A solution of (2E)-N-(3-bromo-2,4,5-trifluorophenyl)-2-hydroxyimino-acetamide (43.2 g, 145 mmol) in triflic acid (120 mL, 1356 mmol) was stirred at 130° C. for 3 h. The solution was cooled to room temperature and added dropwise to ice water (1.2 L). The precipitate was collected by filtration and washed with petroleum ether / ethyl acetate (10:1) to give 10 g of the title compound. The filtrate was extracted with EtOAc, and the organic layer was washed with NaHCO (saturated) and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give an additional 7.8 g of the title compound. In total, 17.8 g (43.7% yield) of the title compound was obtained as a brown solid. No mass signal.

[0447] Step 3: 2-Amino-4-bromo-3,5,6-trifluorobenzoic acid TIFF2024506029000169.tif19170

[0448] To a solution of 6-bromo-4,5,7-trifluoro-indoline-2,3-dione (21.0 g, 75 mmol) in sodium hydroxide (2 M in water) (400 mL) was added dropwise with stirring hydrogen peroxide (30% in water) (40 mL). The solution was stirred at room temperature for 16 hours. The insoluble solid was filtered off. The filtrate was acidified to pH=2 with HCl (37% in water). The precipitate was collected by filtration and dried under vacuum to give the title compound (11.8 g, 58.3% yield) as a brown solid. LC-MS: (ESI, m / z): [M+H] + =290.

[0449] Step 4: 2-amino-4-bromo-3,5,6-trifluorobenzamide TIFF2024506029000170.tif19170

[0450] A solution of 2-amino-4-bromo-3,5,6-trifluorobenzoic acid (11.8 g, 43.7 mmol), NHCl (9.4 g, 175.7 mmol), DIPEA (16.7 g, 130 mmol), and HATU (19.1 g, 50.2 mmol) in N,N-dimethylformamide (60 mL) was stirred at room temperature for 2 hours. The resulting solution was poured into water with stirring. The precipitate was collected by filtration and dried under vacuum to give the title compound (6.1 g, 51.9% yield) as a brown solid. LC-MS: (ESI, m / z): [M+H] + =269.

[0451] Step 5: 7-Bromo-2-chloro-5,6,8-trifluoroquinazolin-4(3H)-one TIFF2024506029000171.tif19170

[0452] A solution of 2-amino-4-bromo-3,5,6-trifluorobenzamide (6.1 g, 22.7 mmol) and thiophosgene (5.4 mL, 70.5 mmol) in 1,4-dioxane (120 mL) was stirred at room temperature for 1 hour and then heated to reflux for 1 hour. The solution was cooled to room temperature and concentrated in vacuo. The solid was washed with petroleum ether / ethyl acetate (4:1) to give the title compound (5.9 g, 66.4% yield) as a brown solid. LC-MS: (ESI, m / z): [M+H] + =313.

[0453] Intermediate 7: tert-Butyl (5aS,6S,9R)-2-bromo-13-chloro-1,3-difluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000172.tif43170

[0454] Step 1: tert-butyl (1R,2S,5S)-2-(((7-bromo-2-chloro-6,8-difluoro-4-hydroxyquinazolin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2024506029000173.tif36170

[0455] To a solution of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (695 mg, 2.87 mmol, Intermediate 1) in THF (10 mL) under nitrogen, NaH (382 mg, 9.57 mmol) was added. The reaction was stirred at room temperature for 15 minutes. 7-Bromo-2-chloro-5,6,8-trifluoro-quinazolin-4-ol (1.00 g, 3.19 mmol, Intermediate 6) was then added at 0° C. and stirred at 0° C. for 2 hours. The reaction was then quenched by the addition of acetic acid. The resulting mixture was partitioned between water and DCM. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (gradient: 0-100% ACN in H2O (0.05% NH4HCO3)) to give 910 mg (crude) of the title compound as a brown solid. LC-MS: (ESI, m / z): [M+H] + =535.

[0456] Step 2: tert-Butyl (5aS,6S,9R)-2-bromo-13-chloro-1,3-difluoro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000174.tif30170

[0457] A solution of tert-butyl (1S,2S,5R)-2-[(7-bromo-2-chloro-6,8-difluoro-4-hydroxy-quinazolin-5-yl)oxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (915 mg, 1.71 mmol), DIPEA (3.31 g, 25.6 mmol), and BOP-Cl (1.31 g, 5.12 mmol) in DCM (10 mL) was stirred at room temperature for 3 h. The resulting mixture was partitioned between water and DCM. The collected organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-30% EtOAc in petroleum ether) to give a white solid (560 mg, 63% yield). LC-MS: (ESI, m / z): [M+H] + =517. 1 H NMR(300MHz,DMSO-d6)δ 4.89-4.78(m,1H),4.70(dd,J=13.4,2.8Hz,1H),4.50(dd,J=13.2,7.3Hz,1H),4.39-4.2 4(m,2H),4.10(d,J=7.0Hz,1H),3.16(d,J=13.3Hz,1H),1.89-1.76(m,4H),1.45(s,9H).

[0458] Intermediate 8: tert-Butyl (5aS,6S,9R)-2-bromo-3,13-dichloro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000175.tif35170

[0459] Step 1: tert-butyl (1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-hydroxyquinazolin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2024506029000176.tif29170

[0460] To an ice-cold solution of tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (463 mg, 1.91 mmol, Intermediate 1) in tetrahydrofuran (10 mL) under nitrogen was added NaH (191 mg, 4.78 mmol, 60% in mineral oil). After 0.5 h, 7-bromo-2,6-dichloro-5-fluoroquinazolin-4-ol (0.500 g, 1.61 mmol) was added, and the reaction mixture was heated to 65 °C for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0–10% methanol / DCM) to afford 460 mg (53% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =533.

[0461] Step 2: tert-Butyl (5aS,6S,9R)-2-bromo-3,13-dichloro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000177.tif27170

[0462] A solution of tert-butyl (1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-hydroxyquinazolin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (390 mg, 0.73 mmol), BOP-Cl (546 mg, 2.14 mmol), and DIPEA (1.49 g, 11.6 mmol) in dichloromethane (20 mL) under nitrogen was stirred at room temperature for 12 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-5% methanol / DCM) to afford 270 mg (71% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =515. 1 H NMR(400MHz,DMSO-d6,ppm)δ 7.75(s,1H),4.82(dd,J=13.5,2.4Hz,1H),4.74(dd,J=13.4,2.7Hz,1H),4.57(dd,J=13.3,7.4Hz,1H), 4.39-4.26(m,2H),4.11(dt,J=7.3,2.3Hz,1H),3.14(d,J=13.1Hz,1H),1.88-1.67(m,4H),1.45(s,9H).

[0463] Intermediate 9: tert-Butyl (5aS,6S,9R)-2-bromo-3-chloro-13-(((S)-2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000178.tif39170

[0464] To an ice-cold solution of (S)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (92.5 mg, 0.600 mmol, Intermediate 15) in tetrahydrofuran (13 mL) was added NaH (100 mg, 2.50 mmol, 60% in mineral oil). The solution was warmed to room temperature for 30 minutes and then recooled to 0° C. tert-Butyl (5aS,6S,9R)-2-bromo-3,13-dichloro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2′,1′:3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (250 mg, 0.48 mmol, Intermediate 8) was added, and the reaction mixture was heated to 40° C. for 3 hours. The reaction was cooled to 0 °C, diluted with water, and concentrated in vacuo. The residue was purified by pre-packed C18 column (solvent gradient: 0-100% ACN in water (0.05% NH4HCO3)) to give 230 mg (75% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =632.

[0465] Intermediate 10: 2,6-dichloro-5,8-difluoro-7-(6-fluoro-1-methyl-1H-indazol-7-yl)quinazolin-4(3H)-one TIFF2024506029000179.tif54170

[0466] Step 1: Methyl 2-amino-4-bromo-3,6-difluorobenzoate TIFF2024506029000180.tif19170

[0467] To an ice-cold solution of 2-amino-4-bromo-3,6-difluorobenzoic acid (2.72 g, 10.8 mmol, Step 4 of Intermediate 2) in ethyl acetate (13.5 mL) and methanol (13.5 mL) was added TMSCHN2 (10.8 mL, 21.6 mmol, 2 mol / L in n-hexane). The reaction was warmed to 25 °C. After 10 min, the mixture was concentrated in vacuo to give the title compound (2.8 g, crude) as a yellow solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H]+ =266.

[0468] Step 2: Methyl 2-amino-3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate TIFF2024506029000181.tif23170

[0469] A solution of methyl 2-amino-4-bromo-3,6-difluorobenzoate (2.87 g, 10.8 mmol), Pin2B2 (4.11 g, 16.2 mmol), Pd(dppf)Cl2 (788 mg, 1.08 mmol), and KOAc (3.17 g, 32.3 mmol) in 1,4-dioxane (72 mL) was stirred at 100 °C for 1 h under nitrogen. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0 to 20% ethyl acetate / petroleum ether) to give the crude product (containing 20% ​​Pin2B2). The crude material was stirred in 10 mL of petroleum ether for 10 min, and the solid was collected. The process was repeated three times to give 2.0 g (59% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+ = 314.

[0470] Step 3: Methyl 2-amino-3,6-difluoro-4-(6-fluoro-1-methyl-1H-indazol-7-yl)benzoate TIFF2024506029000182.tif26170

[0471] A solution of methyl 2-amino-3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.64 g, 5.24 mmol), 7-bromo-6-fluoro-1-methyl-indazole (1.44 g, 6.3 mmol), Pd(PPh)Cl (368 mg, 0.520 mmol), and KF (913 mg, 15.7 mmol) in acetonitrile (20 mL) and water (4 mL) was stirred at 80 °C for 1 h under nitrogen. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0-7% MeOH / DCM) to afford 1.25 g (71% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] = 336.

[0472] Step 4: Methyl 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-1H-indazol-7-yl)benzoate TIFF2024506029000183.tif26170

[0473] Under nitrogen, a solution of methyl 2-amino-3,6-difluoro-4-(6-fluoro-1-methyl-indazol-7-yl)benzoate (1.21 g, 3.60 mmol) and NCS (574 mg, 4.32 mmol) in N,N-dimethylformamide (12 mL) was stirred at 80 °C for 1 h. The reaction was quenched with saturated aqueous NaSO and diluted with ethyl acetate (100 mL). The resulting solution was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0–15% ethyl acetate / petroleum ether) to afford 1.1 g (83% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] = 370.

[0474] Step 5: 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-1H-indazol-7-yl)benzoic acid TIFF2024506029000184.tif26170

[0475] To a solution of methyl 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-indazol-7-yl)benzoate (1.10 g, 3.08 mmol) in tetrahydrofuran (12 mL) was added a solution of LiOH (212 mg, 9.23 mmol) in water (4 mL) at room temperature. After 18 h, the reaction mixture was acidified to pH 5-6 with 1 M aqueous HCl and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.0 g (crude) of the title compound. LC-MS: (ESI, m / z): [M+H]+ = 356. The crude material was used without further purification.

[0476] Step 6: 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-1H-indazol-7-yl)benzamide TIFF2024506029000185.tif26170

[0477] A solution of 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-1H-indazol-7-yl)benzamide (1 g, crude), NH₄Cl (830 mg, 15.4 mmol), HATU (1.75 g, 4.61 mmol), and DIPEA (2.78 g, 21.53 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 h. The solution was diluted with EtOAc (100 mL) and washed with saturated aqueous NH₄Cl. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0–4% MeOH / DCM) to afford 950 mg (87% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+ = 355.

[0478] Step 7: 2,6-Dichloro-5,8-difluoro-7-(6-fluoro-1-methyl-1H-indazol-7-yl)quinazolin-4(3H)-one TIFF2024506029000186.tif26170

[0479] A solution of 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-indazol-7-yl)benzamide (1.01 g, 2.85 mmol) and thiophosgene (0.65 mL, 8.55 mmol) in 1,4-dioxane (20 mL) was stirred at room temperature for 1 hour and then heated to reflux for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 5% MeOH / DCM) to afford the title compound (1.27 g, crude), 76% purity, as a brown solid. LC-MS: (ESI, m / z): [M+H] + =399. 1 H NMR(400MHz,DMSO-d6)δ 8.22(s,1H),8.04(dd,J=8.8,5.2Hz,1H),7.30-7.24(m,1H),3.56(s,3H).

[0480] Intermediate 11: (3-methylene-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2024506029000187.tif23170

[0481] Step 1: 1-(tert-butyl)2-methyl 2-(2-(chloromethyl)allyl)azetidine-1,2-dicarboxylate TIFF2024506029000188.tif16170

[0482] To a solution of 1-tert-butyl 2-methylazetidine-1,2-dicarboxylate (0.300 g, 1.39 mmol) in tetrahydrofuran (7 mL) under nitrogen was added LiHMDS (2.8 mL, 2.8 mmol, 1 M in THF) at −20° C. After 0.5 h, 3-chloro-2-chloromethyl-1-propene (349 mg, 2.79 mmol) was added at −20° C. The resulting solution was allowed to warm to room temperature for 1 h. The reaction was quenched with saturated aqueous NH4Cl, diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0% to 30% EtOAc / petroleum ether to afford the title compound (0.170 g, 40% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =304. 1 H NMR (300 MHz, chloroform-d) δ 5.42 (d, J = 1.3 Hz, 1H), 5.10 (d, J = 1.2 Hz, 1H), 4.26-4.02 (m, 2H), 4.01-3.94 (m, 1H), 3.78 (d, J = 5.4 Hz, 3H), 3.60 (s, 1H), 3.01 (dd, J = 14.9 Hz, 1.1 Hz, 1H), 2.64 (d, J = 14.8 Hz, 1H), 2.42-2.33 (m, 1H), 2.11 (d, J = 15.6 Hz, 1H), 1.43 (s, 9H).

[0483] Step 2: Methyl 2-(2-(chloromethyl)allyl)azetidine-2-carboxylate TIFF2024506029000189.tif15170

[0484] A solution of 1-(tert-butyl) 2-methyl 2-(2-(chloromethyl)allyl)azetidine-1,2-dicarboxylate (170 mg, 0.560 mmol) in 2,2,2-trifluoroacetic acid (0.4 mL) and dichloromethane (1.6 mL) was stirred at room temperature for 0.5 h. The resulting mixture was concentrated in vacuo to give the title compound as a TFA salt (110 mg, crude yellow solid). LC-MS: (ESI, m / z): [M+H] += 204. The crude product was used without further purification.

[0485] Step 3: Methyl 3-methylene-1-azabicyclo[3.2.0]heptane-5-carboxylate TIFF2024506029000190.tif14170

[0486] A mixture of methyl 2-[2-(chloromethyl)allyl]azetidine-2-carboxylate TFA salt (110 mg, 0.540 mmol) and K2CO3 (225 mg, 1.63 mmol) in acetonitrile (4 mL) was stirred at room temperature for 3 h. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with (MeOH / DCM = 0-10%) to give the title compound (48 mg, 20% yield over three steps) as a pale yellow oil. LC-MS: (ESI, m / z): [M+H] + = 168. The crude product was used without further purification. 1 H NMR (300 MHz, chloroform-d) δ 5.22-5.14 (m, 1H), 5.13-5.04 (m, 1H), 3.78 (d, J = 2.6 Hz, 3H), 3.62-3.44 (m, 2H), 3.22-3.10 (m, 1H), 3.02-2.84 (m, 2H), 2.84-2.73 (m, 2H), 2.25-2.14 (m, 1H).

[0487] Step 4: (3-methylene-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2024506029000191.tif13170

[0488] To an ice-cold solution of methyl 3-methylene-1-azabicyclo[3.2.0]heptane-5-carboxylate (40.1 mg, 0.240 mmol) in tetrahydrofuran (1 mL) was added LiAlH (0.5 mL, 0.5 mmol, 1 M in THF). After 0.5 h, the reaction was quenched with NaSO 10H O and diluted with ether (10 mL). The solid was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (21.1 mg, crude) as a colorless oil. LC-MS: (ESI, m / z): [M+H] + =140. The crude product was used without further purification.

[0489] Intermediate 12: (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol TIFF2024506029000192.tif27170

[0490] To an ice-cold solution of K2CO3 (0.500 g, 3.62 mmol) in acetonitrile (5 mL) and (S)-azetidin-2-ylmethanol hydrochloride (200 mg, 1.63 mmol) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.360 g, 1.68 mmol). The reaction mixture was allowed to warm to room temperature. After 24 h, the reaction was diluted with water (30 mL), and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-60% ethyl acetate / petroleum ether) to afford 0.090 g (36% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + =152.

[0491] Intermediate 13: (2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000193.tif23170

[0492] To a solution of ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.20 g, 0.96 mmol) in tetrahydrofuran (20 mL) under nitrogen was added LiAlH (2.87 mL, 1 M in THF) at -40 °C. The resulting solution was allowed to warm to room temperature for 3 h. The reaction mixture was quenched with NaSO 10H O. The solid was filtered and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give the crude product (150 mg). The crude product was used without purification. LC-MS: (ESI, m / z): [M+H] + =154.2.

[0493] Intermediates 14 and 15: (R)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol and (S)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000194.tif41170

[0494] Step 1: Ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate and Ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024506029000195.tif36170

[0495] Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (19.9 g) was 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; run number: 122) to give ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.61 g, early peak) and (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.29 g, late peak). 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 spectra of the two isomers are identical.

[0496] Step 2: (S)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000196.tif14170

[0497] To an ice-cold solution of ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (110 mg, 0.51 mmol) in tetrahydrofuran (5 mL) under nitrogen, LiAlH (1.1 mL, 1 M in THF) was added. The mixture was heated at 70 °C for 0.5 h. The mixture was cooled to room temperature, quenched with NaSO 10H O, and filtered. The solvent was removed by blowing with nitrogen (low boiling point of the product) to give the title compound (62.8 mg, crude). LC-MS: (ESI, m / z): [M+H] + = 154. The crude material was used without further purification.

[0498] The enantiomer (R)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (Intermediate 14) was synthesized in a similar manner as described in step 2.

[0499] Intermediate 16: (S)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000197.tif38170

[0500] Step 1: Ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate and ethyl (R)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024506029000198.tif36170

[0501] Ethyl 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (20.0 g, 94.6 mmol) was separated using a column (AD 2.12 × 25 cm, 5 μm; mobile phase A: CO, 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) to give ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (8.21 g, early peak) as a yellow oil and ethyl (R)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.92 g, late peak) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =212. 1 H NMR (400 MHz, chloroform-d) δ 4.22 (q, J = 7.2 Hz, 2H), 4.14-4.05 (m, 1H), 3.54 (d, J = 18.6 Hz, 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 = 7.1 Hz, 3H).

[0502] Step 2: Ethyl (S)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024506029000199.tif23170

[0503] To an ice-cold solution of ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.20 g, 0.95 mmol) in dichloromethane (30 mL) under nitrogen, DAST (378 mg, 2.35 mmol) was added. The mixture was allowed to warm to room temperature. After 3 h, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-2% MeOH / DCM) to afford 98.3 mg (44.4% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =234. 1 H NMR (400 MHz, chloroform-d) δ 4.28 (q, J = 7.1 Hz, 2H), 4.20-4.07 (m, 1H), 3.54-3.39 (m, 1H), 3.08-2.5 (m, 1H), 2.82-2.60 (m, 2H), 2.51-2.12 (m, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0504] Step 3: (S)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000200.tif14170

[0505] To an ice-cold solution of ethyl (S)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (95.3 mg, 0.410 mmol) in tetrahydrofuran (10 mL) under nitrogen, LiAlH (2.0 mL, 1 M in THF) was added. The mixture was heated to 70 °C for 3 h. The mixture was quenched with NaSO 10H O and filtered. The solvent was removed by gentle bubbling with nitrogen (low boiling point) to give 70.5 mg (crude). LC-MS: (ESI, m / z): [M+H] + = 178. The crude product was used without further purification.

[0506] Intermediate 17: (R)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000201.tif17170

[0507] The title compound was prepared from ethyl (R)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate in a manner similar to that described in Intermediate 16. LC-MS: (ESI, m / z): [M+H] + =178. The crude was used in the next step without further purification.

[0508] Intermediate 18: (Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (mixture of trans isomers) TIFF2024506029000202.tif64170

[0509] Step 1: Diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (mixture of trans) TIFF2024506029000203.tif35170

[0510] 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 flash chromatography on silica gel (gradient: 0-15% ethyl acetate / petroleum ether) to afford 1.27 g (14% yield) of the title compound as a pale 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)δ 7.32-7.20(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).

[0511] Step 2: (1-benzylpyrrolidine-2,5-diyl)dimethanol (mixture of trans) TIFF2024506029000204.tif21170

[0512] To an ice-cold solution of diethyl trans-1-benzylpyrrolidine-2,5-dicarboxylate (2.30 g, 7.53 mmol) in tetrahydrofuran (30 mL) under nitrogen, LiAlH4 (716 mg, 18.8 mmol) was added portionwise. 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 flash chromatography on silica gel (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)δ 7.38-7.15(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).

[0513] Step 3: Pyrrolidine-2,5-diyldimethanol (mixture of trans) TIFF2024506029000205.tif14170

[0514] 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 h. The catalyst was filtered off and the filtrate was concentrated to give 405 mg (crude) of the title compound as a pale yellow oil. LC-MS: (ESI, m / z): [M+H] + =132.1. The crude product was used without further purification.

[0515] Step 4: 1-(2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-2-bromoethan-1-one (mixture of trans) TIFF2024506029000206.tif18170

[0516] 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 flash chromatography on silica gel (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)δ 5.03(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).

[0517] Step 5: 6-(Hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (mixture of trans isomers) TIFF2024506029000207.tif16170

[0518] 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 1 mL of THF. 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 flash chromatography on silica gel (gradient: 0-10% MeOH / DCM) to afford the title compound as an oil (37.0 mg, 42% yield). LC-MS: (ESI, m / z): [M+H] + =172.2. 1 H NMR(400MHz,DMSO-d6,ppm)δ 4.88-4.82(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).

[0519] Step 6: (Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (mixture of trans forms) TIFF2024506029000208.tif15170

[0520] To an ice-cold suspension of LiAlH4 (27.3 mg, 0.720 mmol) in tetrahydrofuran (5 mL) under nitrogen was added 6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (60.0 mg, 0.350 mmol) in 0.5 mL THF. The resulting solution was warmed to 60 °C for 2 h. The reaction was cooled to room temperature and quenched with Na2SO4·10H2O. The solid was filtered, and the filtrate was concentrated to give the title compound as a pale yellow oil (60 mg, crude). LC-MS: (ESI, m / z): [M+H] + =158.1. The crude product was used without further purification.

[0521] Intermediate 19: (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000209.tif30170

[0522] Step 1: Ethyl (S)-2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024506029000210.tif24170

[0523] To a solution of ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.20 g, 0.95 mmol, Intermediate 16, Step 1, earlier peak) and 2-((difluoromethyl)sulfonyl)pyridine (237 mg, 1.23 mmol) in N,N-dimethylformamide (6 mL) under nitrogen at −50° C., t-BuOK (191 mg, 1.71 mmol) in DMF (2 mL) was added slowly. The reaction was warmed to −40° C. for 1 h, and the reaction was quenched with saturated aqueous ammonium chloride (2 mL) and 3 M HCl (2 mL). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc. The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-40% EtOAc / DCM) to give the title compound as a yellow oil (28.0 mg, 12% yield). LC-MS: (ESI, m / z): [M+H] + =246.1.

[0524] Step 2: (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000211.tif20170

[0525] To an ice-cold solution of ethyl (S)-2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (28.0 mg, 0.110 mmol) in tetrahydrofuran (2 mL) under nitrogen, DIBAL-H (1.12 mL, 1.12 mmol) was added. The reaction mixture was allowed to warm to room temperature. After 1 h, the solution was quenched with NaSO. 10H. The solid was filtered and the filtrate was concentrated under reduced pressure. LC-MS: (ESI, m / z): [M+H] + =190.1. The crude product was used for further purification.

[0526] Intermediate 20: (R)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000212.tif21170

[0527] The title compound was prepared from (R)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (Intermediate 16, Step 1, later peak) and 2-((difluoromethyl)sulfonyl)pyridine in a manner similar to that described for Intermediate 19. LC-MS: (ESI, m / z): [M+H] + =190.1. The crude material was used without further purification.

[0528] Intermediate 21: (S)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (mixture of Z / E) TIFF2024506029000213.tif38170

[0529] Step 1: Ethyl (S)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024506029000214.tif37170

[0530] To a solution of 2-((fluoromethyl)sulfonyl)pyridine (177 mg, 1.01 mmol) in tetrahydrofuran (10 mL) under nitrogen was added KHMDS (1.2 mL, 1.20 mmol) at −78° C. After 30 min, ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.20 mg, 0.95 mmol, Intermediate 16, Step 1, earlier peak) in THF (5 mL) was added slowly at −78° C. After 3 h, the reaction was allowed to warm to room temperature for 1 h. The reaction was quenched with saturated aqueous ammonium chloride (1 mL) followed by 3 M HCl (2 mL). The mixture was stirred at room temperature for 1 h, diluted with water, and extracted with EtOAc. The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-30% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (65 mg, 30% yield). LC-MS: (ES, m / z): [M+1] + =228.1. 1 H NMR(400MHz,chloroform-d1,ppm)δ 6.75-6.65(m,1H),6.55-6.44(m,1H),4.45-4.32(m,2H),4.27-4.20(m,4H),3.90(d,J=16Hz,1H),3.73(d,J=16Hz,1H),3.32(d,J =16Hz,1H),3.04(d,J=16Hz,1H),2.89-2.75(m,2H),2.72-2.56(m,2H),2.53-2.35(m,4H),2.25-2.08(m,2H),1.33-1.28(m,6H).

[0531] Step 2: (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol and (S,E)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000215.tif30170

[0532] To an ice-cold solution of ethyl (S,Z / E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.060 g, 0.26 mmol) in tetrahydrofuran (5 mL) was added DIBAL-H (2.64 mL, 2.64 mmol). The resulting solution was allowed to warm to room temperature for 1 h. The reaction was quenched with NaSO·10H₂O. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0–20% MeOH / DCM (0.1% Et₃N)) to afford the title compound as a yellow oil (26 mg, 57% yield). LC-MS: (ESI, m / z): [M+H] + =172.1. 1 H NMR (300 MHz, chloroform-d1, ppm) δ 6.79-6.38 (m, 2H), 3.92-3.70 (m, 2H), 3.61-3.20 (m, 8H), 2.79-2.44 (m, 5H), 2.36-2.26 (m, 1H), 2.14-1.66 (m, 8H). (The resulting diploid H is a Z / E mixture.)

[0533] On a larger scale, 9.7 g of ethyl (S,Z / E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate gave 2.20 g (Z isomer, first fraction) and 2.70 g (E isomer, second fraction) following the same procedure and purification method as above.

[0534] Z isomer:LC-MS:(ESI,m / z):[M+H] + =172. 1 H NMR (300 MHz, chloroform-d1, ppm) δ 6.64-6.29 (m, 1H), 3.79-3.65 (m, 1H), 3.48-3.37 (m, 1H), 3.35-3.23 (m, 2H), 3.14-3.03 (m, 1H), 2.69-2.58 (m, 1H), 2.46-2.35 (m, 1H), 2.30-2.17 (m, 1H), 2.03-1.59 (m, 4H).

[0535] E isomer:LC-MS:(ESI,m / z):[M+H] + =172. 1 H NMR (300 MHz, chloroform-d1, ppm) δ 6.76-6.42 (m, 1H), 3.75-3.65 (m, 1H), 3.48-3.34 (m, 2H), 3.33-3.18 (m, 2H), 2.73-2.40 (m, 3H), 2.09-1.65 (m, 4H).

[0536] Intermediate 22: 6-Bromo-5-chloro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine TIFF2024506029000216.tif41170

[0537] Step 1: 6-Bromo-5-chloro-4-methylpyridin-2-amine TIFF2024506029000217.tif21170

[0538] A solution of 6-bromo-4-methylpyridin-2-amine (500 mg, 2.67 mmol) and NCS (360 mg, 2.69 mmol) in DMF (5 mL) was stirred at 60 °C for 1 h. The resulting solution was cooled to room temperature, diluted with EtOAc, and washed with water (3x). The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 30% ethyl acetate / petroleum ether) to afford 370 mg (62% yield) of the title compound as a white solid. LC-MS (ESI, m / z): [M+H] + =221.

[0539] Step 2: 6-Bromo-5-chloro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine TIFF2024506029000218.tif44170

[0540] To a solution of 6-bromo-5-chloro-4-methyl-pyridin-2-amine (370 mg, 1.67 mmol) in DMF (5 mL) under nitrogen was added 60% NaH (202 mg, 5.05 mmol) at 0 °C. The reaction was stirred at room temperature. After 30 min, 1-(chloromethyl)-4-methoxybenzene (656 mg, 4.21 mmol) was added, and the reaction was maintained at room temperature for 1 h. The reaction was quenched with water, and the resulting solution was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 30% ethyl acetate / petroleum ether) to afford 550 mg (71% yield) of the title compound as a white solid. LC-MS (ESI, m / z): [M+H] + =461.

[0541] Intermediates 23 and 24: (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol and ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000219.tif60170

[0542] Step 1: Ethyl (7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024506029000220.tif23170

[0543] To a solution of ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.22 g, 5.68 mmol) in tetrahydrofuran (100 mL) under nitrogen was added NaBH4 (70.3 mg, 1.85 mmol) at 0 °C. After 30 min, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 6% MeOH / DCM) to afford the title compound (0.631 g, 62% yield) as a pale yellow oil. LC-MS: (ESI, m / z): [M+H] + =214.

[0544] Step 2: 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 TIFF2024506029000221.tif31170

[0545] Under nitrogen, to a solution of ethyl (7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (809 mg, 3.80 mmol) was added DAST (923 mg, 5.74 mmol, dissolved in 20 mL of DCM) at −15° C. The mixture was allowed to warm to room temperature for 3 hours. The mixture was quenched with EtOH and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0% to 100% EtOAc / petroleum) to afford 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.

[0546] Ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (early peak). 1 H NMR (400 MHz, chloroform-d) δ 5.32 (d, J = 19.2 Hz, 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 = 7.1 Hz, 3H).

[0547] Ethyl (2S,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (later peak). 1 H NMR (400 MHz, chloroform-d) δ 5.47-5.32 (m, 1H), 4.29-4.24 (m, 2H), 4.08-3.96 (m, 1H), 3.46-3.35 (m, 1H), 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 = 7.1 Hz, 3H).

[0548] Step 3: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000222.tif14170

[0549] 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, LiAlH (3.1 mL, 1 M in THF) was added at 0 °C. The mixture was heated to 70 °C for 30 min. After cooling to room temperature, the mixture was quenched with NaSO.10H0 under vigorous stirring. The solid was filtered, and the filtrate was evaporated by gentle bubbling with N to give the title compound (124 mg, crude). LC-MS: (ESI, m / z): [M+H] + =160. The crude material was used without further purification.

[0550] Step 4: ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000223.tif14170

[0551] The title compound was prepared from ethyl (2S,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate in a similar manner to that described in step 3. LC-MS: (ESI, m / z): [M+H]+ =160. The crude material was used without further purification.

[0552] Intermediate 25: 6-Bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine TIFF2024506029000224.tif27170

[0553] To a solution of 6-bromo-5-(trifluoromethyl)pyridin-2-amine (500 mg, 2.08 mmol) in N,N-dimethylformamide (5 mL) under nitrogen at 0 °C was added 60% NaH (416 mg, 10.4 mmol). The resulting solution was allowed to warm to room temperature. After 30 min, 1-(chloromethyl)-4-methoxybenzene (812 mg, 5.20 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NH4Cl, and the resulting mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (gradient: 0% to 20% EtOAc / petroleum ether) to afford 645 mg (64% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =481 / 483.

[0554] Intermediate 26[2]: 6-Bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine TIFF2024506029000225.tif21170

[0555] To a solution of 2-amino-4-bromo-5-chloro-3,6-difluorobenzamide (5.00 g, 17.5 mmol, Intermediate 2, Step 6) in triethyl orthoformate (100 mL) was added AcOH (10 mL). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed in vacuo. The residue was diluted with EtOAc / DCM (1 / 5, 150 mL). The solid was collected by filtration and dried under vacuum to give the title compound (4 g, crude) as a white solid, which was used in the next reaction without further purification. LC-MS: (ESI, m / z): [M+H] + =295. 1 H NMR(400MHz,DMSO-d6)δ 12.76(s,1H),8.22(s,1H).

[0556] Intermediate 27: 6-Bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine TIFF2024506029000226.tif23170

[0557] Step 1: 6-Bromo-5-(trifluoromethyl)pyridin-2-amine

[0558] Under nitrogen, 6-chloro-5-(trifluoromethyl)pyridin-2-amine (1000 mg, 5.09 mmol) and a solution of HBr in acetic acid (10 mL, 33% w / w) were stirred at 130 °C (steel tank) for 48 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with HO (30 mL), adjusted to pH = 8-9 with NaCO (aq), and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0%-10% EtOAc / petroleum ether) to give the title compound (1106 mg, 86.8% yield). LC-MS: (ESI, m / z): [M+H] + =241 / 243.

[0559] Step 2: 6-Bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine TIFF2024506029000227.tif16170

[0560] To a solution of 6-bromo-5-(trifluoromethyl)pyridin-2-amine (500 mg, 2.08 mmol) in DMF (5 mL) under nitrogen was added NaH (416 mg, 10.4 mmol, 60% suspension in oil) at 0 °C. The resulting solution was warmed to room temperature and stirred for 0.5 h. 1-(chloromethyl)-4-methoxybenzene (812 mg, 5.20 mmol) was then added dropwise at room temperature. The resulting solution was stirred at room temperature for 3 h. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 20% EtOAc / petroleum ether) to afford 645 mg (64% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =481 / 483.

[0561] Intermediate 28[5]: 7-Bromo-6-fluoro-1-methyl-1H-indazole TIFF2024506029000228.tif21170

[0562] 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 for 2 h under microwave irradiation. The reaction was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-10%) to afford the title compound (333.2 mg, 64.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =229 / 231; 1H NMR(400MHz,DMSO-d6)δ 8.13(s,1H),7.80(dd,J=8.7,5.0Hz,1H),7.15(t,J=8.9Hz,1H),4.31(s,3H).

[0563] Intermediate 29: tert-butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2024506029000229.tif70170

[0564] Step 1: tert-Butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate TIFF2024506029000230.tif18170

[0565] 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) under nitrogen, K2CO3 (6.51 g, 47.1 mmol) and (bromomethyl)benzene (6.01 g, 35.1 mmol) were added 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 flash chromatography on silica gel (gradient: 0-30% EtOAc / petroleum ether) to afford 7 g (98.3% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =303.

[0566] Step 2: (1S,6S,9R,9aS)-10-benzyl-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one TIFF2024506029000231.tif38170

[0567] 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) under nitrogen, s-BuLi (35.6 mL, 46.3 mmol, 1.3 M in hexanes) was added dropwise at −78°C. The resulting solution was stirred at −78°C for 1.5 h. 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 extracted with NH4Cl (aq) and EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0–50% EtOAc in petroleum ether) to give 5.1 g of a mixture of four diastereoisomers. Separation by prep-SFC (column: CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: CO; mobile phase B: IPA (0.5% 2M NH3-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; number of runs: 50) gave compound a (1.39 g, 22% yield) (first peak) and compound d (1.47 g, 23.3% yield) (third peak), as well as a mixture of compounds b and c (second peak). The mixture of compounds b and c was re-separated by Prep-SFC (column: CHIRALPAK IH, 5 × 25 cm, 5 μm; mobile phase A: CO , mobile phase B: IPA (0.5% 2M NH -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; number of runs: 6) to give compound b (0.500 g, 7.9% yield) (fast peak) and compound c (0.430 g, 6.8% yield) (slow peak) as yellow solids. LC-MS: (ESI, m / z): [M+H] + =273. Compound a is the desired isomer.

[0568] Step 3: (1S,6S,9R,9aS)-1-Methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one TIFF2024506029000232.tif22170

[0569] 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 under a hydrogen gas atmosphere for 1 hour. 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.

[0570] Step 4: tert-Butyl (1S,6S,9R,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-10-carboxylate TIFF2024506029000233.tif23170

[0571] 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)O (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 minutes. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (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.

[0572] Step 5: tert-butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2024506029000234.tif19170

[0573] 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. 1 H NMR(300MHz,DMSO-d6)δ 4.54(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).

[0574] Intermediate 30: tert-Butyl (2R,5S,5aS,6S,9R)-2-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3,13-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000235.tif91170

[0575] Step 1: tert-butyl (1S,2S,5R)-2-((S)-1-((7-bromo-2,6-dichloro-8-fluoro-4-hydroxyquinazolin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF2024506029000236.tif32170

[0576] To a solution of tert-butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.00 g, 23.4 mmol, Intermediate 29) in tetrahydrofuran (200 mL) under nitrogen, NaH (5.00 g, 125 mmol, 60% oil suspension) was added at 0 °C. The resulting solution was stirred at 0 °C for 30 min. Then, 7-bromo-2,6-dichloro-5,8-difluoro-quinazolin-4-ol (15.4 g, 46.6 mmol, Intermediate 2) was added. The reaction was stirred at room temperature for 1 h. The mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give 17.7 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] + =565.

[0577] Step 2: tert-Butyl (5S,5aS,6S,9R)-2-bromo-3,13-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000237.tif29170

[0578] A solution of tert-butyl (1S,2S,5R)-2-((S)-1-((7-bromo-2,6-dichloro-8-fluoro-4-hydroxyquinazolin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (17.7 g, 31.2 mmol), BOPCl (31.8 g, 125.5 mmol), and DIPEA (60.7 g, 470 mmol) in dichloromethane (200 mL) was stirred at room temperature overnight. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-30% EtOAc / petroleum ether) to afford 7.2 g (42% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =547.

[0579] Step 3: tert-Butyl (2R,5S,5aS,6S,9R)-2-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3,13-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000238.tif47170

[0580] To a solution of tert-butyl (5S,5aS,6S,9R)-2-bromo-3,13-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (510 mg, 0.930 mmol) in tetrahydrofuran (3.2 mL) under nitrogen, iPrMgCl.LiCl (0.93 mL, 1.3 M in THF) was added at −78° C. The resulting solution was stirred at −78° C. for 10 minutes. Then, ZnCl (2 M in 2-MeTHF) (0.93 mL, 1.86 mmol) was added at −78° C. and stirred for 10 minutes. The mixture was warmed to room temperature and stirred at this temperature for 20 minutes. The mixture was added to a solution of 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (461 mg, 0.930 mmol, Intermediate 4) and Pd(PPh3)2Cl2 (32.8 mg, 0.0500 mmol) in tetrahydrofuran (5 mL). The resulting solution was stirred at 50 °C overnight. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0 to 40% EtOAc / petroleum ether) to afford 350 mg of the title compound (a mixture of two atropisomers) as a yellow solid. The mixture was separated by PREP_CHIRAL_HPLC (Column: CHIRAL ART Cellulose-SB, 2 x 25 cm, 5 μm; Mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 10% B to 10% B in 22 min; Wavelength: 220 / 254 nm; RT1 (min): 14.03; RT2 (min): 16.79; Sample solvent: EtOH-HPLC; Injection volume: 0.3 mL; Run number: 15) to give 80 mg of the fast peak and 110 mg of the slow peak as yellow solids. LC-MS: (ESI, m / z): [M+H] + =883.

[0581] Faster peak: 1H NMR(300MHz,DMSO-d6)δ 7.19-7.08(m,4H),6.90-6.78(m,5H),5.11(d,J=13.1Hz,1H),4.77(d,J =15.9Hz,2H),4.59(s,1H),4.48(d,J=15.8Hz,2H),4.31(s,1H),4.14(s ,1H),4.02(d,J=9.5Hz,1H),3.72(s,6H),3.09(d,J=13.1Hz,1H),2.40( d,J=2.1Hz,3H),1.99-1.68(m,4H),1.54(d,J=6.2Hz,3H),1.46(s,9H).

[0582] Later peak: 1 H NMR(300MHz,DMSO-d6)δ 7.21-7.09(m,4H),6.92-6.80(m,5H),5.13(d,J=13.2Hz,1H),4.79-4.51(m,5H),4.31(d,J=5.2Hz,1H),4.12(s,1H),4.05(d,J =9.6Hz,1H),3.73(s,6H),3.14(d,J=13.2Hz,1H),2.38(d,J=2.2Hz,3H),1.99-1.68(m,4H),1.53(d,J=6.2Hz,3H),1.47(s,9H).

[0583] Intermediate 31: tert-butyl (2R,5S,5aS,6S,9R)-2-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-3,13-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate TIFF2024506029000239.tif47170

[0584] To a solution of tert-butyl (5S,5aS,6S,9R)-2-bromo-3,13-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-15-carboxylate (1.70 g, 3.10 mmol, Intermediate 30, Step 2) in tetrahydrofuran (10 mL) under nitrogen at −78° C. was added iPrMgCl.LiCl (3.1 mL, 4.03 mmol, 1.3 M in THF) and the resulting solution was stirred at −78° C. for 10 min. Then, ZnCl (3.1 mL, 6.20 mmol, 2 M in 2-Me THF) was added at −78° C. The solution was stirred at −78° C. for 10 minutes, warmed to room temperature, and added with stirring at room temperature for 20 minutes. The mixture was added to a solution of 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyridin-2-amine (1.50 g, 3.12 mmol, Intermediate 27) and Pd(PPh)Cl (109 mg, 0.160 mmol) in tetrahydrofuran (17 mL) at room temperature. The resulting solution was stirred at 50° C. overnight and then concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (gradient: 0–30% EtOAc / petroleum ether) to afford 1.2 g of the title compound (a mixture of two atropisomers). The mixture was separated by PREP_SFC (Column: Lux 5um Cellulose-4, 3 x 25cm, 5µm; Mobile phase A: CO2, Mobile phase B: MeOH:ACN = 1:1 (0.1% 2M NH3-MeOH); Flow rate: 70mL / min; Gradient: Isocratic 40% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220nm; RT1 (min): 4.34; RT2 (min): 5.16; Sample solvent: MeOH ----- Prep; Injection volume: 1mL; Run number: 75) to give 537mg of the fast peak and 460mg of the slow peak as yellow solids. LC-MS: (ESI, m / z): [M+H] + =869.

[0585] Intermediate 32: ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol TIFF2024506029000240.tif16170

[0586] To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (60.0 g, 257 mmol) in tetrahydrofuran (1000 mL) under nitrogen, LiAlH (19.6 g, 515 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 h and then at 60 °C for 2 h. The reaction mixture was cooled in an ice bath, and the reaction was quenched by the slow addition of water (20 mL), followed by the addition of 20% aqueous NaOH (20 mL) and 20 mL of water. The solids were 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 flash chromatography on silica gel (gradient: 0% to 15% MeOH (0.1% TEA) in DCM) to afford 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)δ 5.25-4.97(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).

[0587] Intermediate 33: ((3S)-3-Fluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2024506029000241.tif33170

[0588] Step 1: 1-(tert-butyl) 2-methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-1,2-dicarboxylate TIFF2024506029000242.tif27170

[0589] To 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) under nitrogen, LiHMDS in THF (60.7 mL, 60.7 mmol, 1 M) was added 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 extracted with NH4Cl (aq) and EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (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.

[0590] Step 2: Methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-2-carboxylate TIFF2024506029000243.tif22170

[0591] To a solution of 1-(tert-butyl) 2-methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-1,2-dicarboxylate (1.26 g, 3.87 mmol) in dichloromethane (10 mL) was added TFA (5 mL). The resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo to give the title compound 2 g (crude) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =210.

[0592] Step 3: Methyl (3S)-3-fluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate TIFF2024506029000244.tif15170

[0593] 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.

[0594] Step 4: ((3S)-3-Fluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2024506029000245.tif12170

[0595] 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) under nitrogen was added LiAlH in THF (16.7 mL, 16.7 mmol, 1 M) 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 blowing with N (volatile) 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.

[0596] Intermediate 34: ((3S)-2',2'-Difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropan]-5-yl)methanol (two single unknown isomers) and ((3R)-2',2'-Difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropan]-5-yl)methanol (two single unknown isomers) TIFF2024506029000246.tif70170

[0597] Step 1: 5-(tert-butyl) 6-methyl (3S,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate and 5-(tert-butyl) 6-methyl (3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate TIFF2024506029000247.tif32170

[0598] To a solution of 1-(tert-butyl) 2-methyl (S)-4-methylenepyrrolidine-1,2-dicarboxylate (5.00 g, 20.7 mmol) in tetrahydrofuran (70 mL) under nitrogen, TMSCF (10.3 g, 72.5 mmol) and NaI (1.55 g, 10.3 mmol) were added at room temperature. The resulting solution was stirred at 60 °C for 2 h. The reaction was concentrated in vacuo. The residue was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0 to 20% EtOAc / petroleum ether) to afford 4.6 g of the title compounds as a yellow oil. The mixture was purified by Chiral Prep-HPLC (column: CHIRALPAK IH, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 5% B to 5% B in 8 min; wavelength: 220 / 254 nm; R T1 (minutes):6.313;R T2 (min): 7.224; Sample solvent: EtOH-HPLC; Injection volume: 0.5 mL; Run number: 32.) gave 1.14 g (fast peak) and 600 mg (slow peak) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =292.

[0599] Faster peak: 1H NMR(400MHz,DMSO-d6)δ 4.44-4.31(m,1H),3.67(d,J=9.2Hz,3H),3.59-3.49(m,1H),3.45-3.36(m,1H), 2.61-2.47(m,1H),2.02-1.85(m,1H),1.71-1.49(m,2H),1.37(d,J=22.9Hz,9H).

[0600] Later peak: 1 H NMR(400MHz,DMSO-d6)δ 4.42-4.31(m,1H),3.64(d,J=9.2Hz,3H),3.50-3.36(m,2H),2.61-2.51(m,1H),1.93-1.78(m,1H),1.71-1.41(m,2H),1.37(d,J=25.2Hz,9H).

[0601] Step 2: 5-(tert-butyl) 6-methyl(3S)-6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (two unknown single isomers) and 5-(tert-butyl) 6-methyl(3R)-6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (two unknown single isomers) TIFF2024506029000248.tif81170

[0602] To a solution of 5-(tert-butyl) 6-methyl(3S,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (1.14 g, 3.91 mmol) (from the earlier peak from the previous step) in tetrahydrofuran (25 mL) under nitrogen, HMPA (910 mg, 5.09 mmol) was added at room temperature. LiHMDS (5.00 mL, 5.00 mmol) was then added at −40° C. The resulting solution was stirred at −40° C. for 0.5 hours. 1-Bromo-2-chloroethane (2.80 g, 19.5 mmol) was then added at −40° C. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-30% EtOAc / petroleum ether) to give 420 mg (30% yield) of the title compound as a yellow oil (Intermediate 3a) and 530 mg of a mixture of the starting material and another isomer (Compound 3b). The 530 mg mixture was repurified on a C18 column (solvent gradient: 0-100% ACN in water (10 M NH4HCO3)) to give 117 mg (8% yield) of the title compound as a yellow oil (Intermediate 3b). LC-MS: (ESI, m / z): [M+H] + =354.

[0603] Intermediate 3a: 1 H NMR(400MHz,DMSO-d6)δ 3.91-3.75(m,1H),3.71-3.44(m,6H),2.61-2.52(m,2H),2.44-2.31(m,1H),2.13-2.03(m,1H),1.75-1.52(m,2H),1.37(d,J=19.6Hz,9H).

[0604] Intermediate 3b: 1 H NMR(300MHz,DMSO-d6)δ 3.81-3.62(m,4H),3.61-3.44(m,3H),2.46-2.17(m,4H),1.81-1.51(m,2H),1.37(d,J=13.8Hz,9H).

[0605] To a solution of 5-(tert-butyl) 6-methyl(3R,6S)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (600 mg, 2.06 mmol) (from the later peak of the previous step) in tetrahydrofuran (15 mL) under nitrogen, HMPA (479 mg, 2.67 mmol) was added at room temperature. The reaction was then cooled to -40 °C, and LiHMDS (2.67 mL, 2.67 mmol) was added. The resulting solution was stirred at -40 °C for 0.5 h. 1-Bromo-2-chloroethane (1.48 g, 10.3 mmol) was then added at -40 °C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-30% EtOAc / petroleum ether) to give 200 mg (27% yield) of the title compound as a yellow oil (Intermediate 3c) and 200 mg of a mixture of the starting material and another isomer (Compound 3d). The 200 mg mixture was repurified on a C18 column (solvent gradient: 0-100% ACN in water (10 M NH4HCO3)) to give 63 mg (8% yield) of the title compound as a yellow oil (Intermediate 3d). LC-MS: (ESI, m / z): [M+H] + =354.

[0606] Intermediate 3c: 1 H NMR(400MHz,DMSO-d6)δ 3.91-3.75(m,1H),3.71-3.44(m,6H),2.61 _ 2.52(m,2H),2.44-2.31(m,1H),2.13-2.03(m,1H),1.75-1.52(m,2H),1.37(d,J=19.6Hz,9H)

[0607] Intermediate 3D: 1 H NMR(300MHz,DMSO-d6)δ 3.81-3.62(m,4H),3.61-3.44(m,3H),2.46 _ 2.17(m,4H),1.81-1.51(m,2H),1.37(d,J=13.8Hz,9H)

[0608] Step 3: Methyl (3S)-6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (two single unknown isomers) and methyl (3R)-6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (two single unknown isomers) TIFF2024506029000249.tif23170

[0609] A solution of 5-(tert-butyl) 6-methyl(3S)-6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (260 mg, 0.736 mmol) (compound 3a) and TFA (0.6 mL) in dichloromethane (3 mL) was stirred at room temperature for 1 hour. The solvent was concentrated in vacuo to give the crude product, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =254.

[0610] The other three isomers were prepared from the relevant Boc starting materials in a similar manner to that described above.

[0611] Step 4: Methyl (3S)-2',2'-difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropane]-5-carboxylate (two single unknown atropisomers) and methyl (3R)-2',2'-difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropane]-5-carboxylate (two single unknown atropisomers) TIFF2024506029000250.tif22170

[0612] A solution of methyl (3S)-6-(2-chloroethyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (186 mg, 0.735 mmol) and EtN (371 mg, 3.67 mmol) in acetonitrile (10 mL) was stirred at 85 °C for 4 h. The solvent was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-10% MeOH / DCM) to give 90 mg (56% yield, Intermediate 5a) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =218. 1 H NMR(300MHz,DMSO-d6)δ 3.64(s,3H),3.42-3.33(m,1H),3.27 _ 3.16(m,1H),3.04(d,J=12.6Hz,1H),2.76-2.67(m,1H),2.65-2.54(m,1H),2.40-2.31(m,1H),2.32-2.21(m,2H),1.85-1.75(m,2H).

[0613] The other three isomers were prepared from related starting materials in a similar manner to that described above.

[0614] Intermediate 5b: 1 H NMR(400MHz,DMSO-d6)δ 3.67(s,3H),3.42-3.33(m,1H),3.09-2.97(m,1H),2.79(d,J=8.8Hz,1H),2.71-2.58( m,2H),2.33(d,J=7.6Hz,1H),2.19-2.05(m,2H),1.73-1.65(m,1H),1.62-1.52(m,1H).

[0615] Intermediate 5c: 1 H NMR(300MHz,DMSO-d6)δ 3.64(s,3H),3.42-3.33(m,1H),3.27-3.16(m,1H),3.04(d,J=12.6Hz,1H),2.76-2.6 7(m,1H),2.65-2.54(m,1H),2.40-2.31(m,1H),2.32-2.21(m,2H),1.85-1.75(m,2H).

[0616] Intermediate 5d: 1 H NMR (400 MHz, chloroform-d) δ 3.87-3.77 (m, 3H), 3.75-3.65 (m, 1H), 3.30-3.20 (m, 1H), 3.12-3.00 (m, 1H), 2.87-2.76 (m, 2H), 2.49-2.37 (m, 1H), 2.36-2.21 (m, 2H), 1.60-1.39 (m, 2H).

[0617] Step 5: ((3S)-2',2'-Difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropan]-5-yl)methanol (two single unknown atropisomers) and ((3R)-2',2'-Difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropan]-5-yl)methanol (two single unknown atropisomers) TIFF2024506029000251.tif29170

[0618] To a solution of methyl (3S)-2',2'-difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropane]-5-carboxylate (97.0 mg, 0.450 mmol) in tetrahydrofuran (7 mL) under nitrogen, LiAlH4 (0.9 mL, 0.900 mmol) was added at 0 °C. The resulting solution was stirred at room temperature for 0.5 h. The reaction was quenched with Na2SO4.10H2O. After filtration, the filtrate was concentrated under reduced pressure to give the product (100 mg, crude, Intermediate 6a) as a yellow oil. The crude product was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =190. 1 H NMR(400MHz,DMSO-d6)δ 3.42-3.33(m,1H),3.31-3.22(m,2H),3.21-3.10(m,2H),3.04-2.91(m,1H),2.61-2.5 5(m,1H),2.25-2.11(m,2H),2.10-2.01(m,1H),1.91-1.81(m,1H),1.78-1.70(m,2H).

[0619] The other three isomers were prepared from related starting materials in a similar manner to that described above.

[0620] Intermediate 6b: 1 H NMR(400MHz,DMSO-d6)δ 4.75-4.61(m,1H),3.40-3.20(m,5H),2.95-2.81(m,1H),2.80-2.70(m,1H),2.25-2.1 3(m,1H),2.07-1.95(m,1H),1.92-1.83(m,1H),1.61-1.50(m,1H),1.49-1.40(m,1H).

[0621] Intermediate 6c: 1 H NMR(400MHz,DMSO-d6)δ 3.42-3.33(m,1H),3.31-3.22(m,2H),3.21-3.10(m,2H),3.04-2.91(m,1H),2.61-2.5 5(m,1H),2.25-2.11(m,2H),2.10-2.01(m,1H),1.91-1.81(m,1H),1.78-1.70(m,2H).

[0622] Intermediate 6d: HNMR not performed due to small amount

[0623] Intermediate 35: (3,3-Difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2024506029000252.tif33170

[0624] Step 1. 1-(tert-butyl) 2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate TIFF2024506029000253.tif26170

[0625] 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) under nitrogen, LiHMDS (10 mL, 10 mmol) was added 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 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 flash chromatography on silica gel 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

[0626] Step 2. Methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate TIFF2024506029000254.tif22170

[0627] 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) under nitrogen, TFA (1 mL) was added 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

[0628] Step 3. Methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate TIFF2024506029000255.tif17170

[0629] To a solution of methyl 2-(2-chloroethyl)-4,4-difluoro-pyrrolidine-2-carboxylate (300 mg, 1.32 mmol) in acetonitrile (5 mL) under nitrogen, EtN (1 mL) was added at room temperature and stirred at 85 °C for 12 h. The solvent was concentrated in vacuo. The residue was purified by flash chromatography on silica gel 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

[0630] Step 4. (3,3-Difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF2024506029000256.tif14170

[0631] 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) under nitrogen 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. The solvent was removed by blowing nitrogen through to give 110 mg (crude) of the title compound as a yellow oil, which was used in the next reaction without further purification. LC-MS: (ESI, m / z): [M+H] + =164.Refined.

[0632] Intermediate 36: ((7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol TIFF2024506029000257.tif38170

[0633] Step 1: Ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate and ethyl (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024506029000258.tif37170

[0634] Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (19.9 g) was 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; run number: 122) to give ethyl (R)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.61 g, early peak) and (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.29 g, late peak). 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 spectra of the two isomers are identical.

[0635] Step 2: Ethyl (7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate TIFF2024506029000259.tif39170

[0636] To 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) under nitrogen, TMSCF (476 mg, 3.35 mmol) was added 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 Na SO . The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 35% ethyl acetate / petroleum ether) to give 95.0 mg (38.3% yield) of the earlier peak as a yellow solid, and 108 mg (43.6% yield) of the later peak by (gradient: 35% to 90% ethyl acetate / petroleum ether). LC-MS: (ESI, m / z): [M+H] + =260. Faster peak: 1 H NMR(300MHz,DMSO-d6,ppm)δ 4.25-4.19(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)δ 4.24-4.08(m,2H),3.61(d,J=11.7,2.7Hz,1H),3.11(d,J=11.6Hz,1H),2.7 2-2.54(m,1H),2.44-2.13(m,5H),1.79-1.58(m,2H),1.22(t,J=7.1Hz,3H).

[0637] Step 2: ((7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol TIFF2024506029000260.tif18170

[0638] 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 the previous step) in THF (2.5 mL) under nitrogen, LiAlH4 (1.1 mL, 1 M in THF) was added. The solution was stirred at 65 °C for 1 h. The reaction was cooled to room temperature and quenched with Na2SO4·10H2O. After filtration, the filtrate was concentrated under reduced pressure to afford 42.0 mg (56.4% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =204.

[0639] Intermediate 37: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one TIFF2024506029000261.tif84170

[0640] Step 1: 3-Bromo-2,5-difluoroaniline TIFF2024506029000262.tif21170

[0641] To a solution of 1-bromo-2,5-difluoro-3-nitrobenzene (40.0 g, 168 mmol) and iron powder (28.4 g, 506 mmol) in water (10 mL) was added concentrated hydrochloric acid (40 mL, 36%) at room temperature. The solution was heated to 100° C. for 1 h. The reaction was cooled to room temperature. The solid was filtered off and washed with EtOAc. The combined filtrate was concentrated under reduced pressure to give the title compound (34.3 g, crude) as a brown oil. LC-MS: (ESI, m / z): [M+H] + = 208. The crude was used in the next step without further purification.

[0642] Step 2: N-(3-bromo-2,5-difluorophenyl)-2-(hydroxyimino)acetamide TIFF2024506029000263.tif19170

[0643] To a solution of 2,2,2-trichloroethane-1,1-diol (40.9 g, 247 mmol), NaSO (187 g, 1.32 mol), and NHOH·HCl (39.8 g, 577 mmol) in water (680 mL) was added a solution of 3-bromo-2,5-difluoroaniline (34.3 g, 165 mmol) in ethanol (100 mL), hydrochloric acid (12.5 mL, 36%), and water (50 mL). The resulting solution was heated at 60 °C for 3 h. The reaction was cooled to room temperature and filtered. The solid was collected, washed with water (500 mL), and dried in an oven to give the title compound (32.8 g, crude) as a light brown solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =279.

[0644] Step 3: 6-Bromo-4,7-difluoroindoline-2,3-dione TIFF2024506029000264.tif21170

[0645] A solution of N-(3-bromo-2,5-difluorophenyl)-2-(hydroxyimino)acetamide (32.8 g, 118 mmol) in HSO (160 mL, 98%) was heated at 90° C. for 1 h. The reaction mixture was cooled to room temperature and added slowly to ice water. The precipitate was collected by filtration, washed with water, and dried in an oven to give the title compound (28.1 g, crude) as a brown solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =262.

[0646] Step 4: 2-Amino-4-bromo-3,6-difluorobenzoic acid TIFF2024506029000265.tif21170

[0647] A solution of 6-bromo-4,7-difluoroindoline-2,3-dione (28.1 g, 107 mmol) in NaOH (537 mL, 2 M in water) and HO (53.7 mL, 30%) was stirred at room temperature for 16 h. The mixture was poured into ice water and adjusted to pH = 2 with concentrated HCl. The solid was collected by filtration and washed with water. The crude product was purified by reverse-phase chromatography (gradient: 0-60% acetonitrile in water (0.1% formic acid)) to afford the title compound (13.4 g, 49.4% yield) as a light brown solid. LC-MS: (ESI, m / z): [M+H] + =252.

[0648] Step 5: Methyl 2-amino-4-bromo-3,6-difluorobenzoate TIFF2024506029000266.tif18170

[0649] To a solution of 2-amino-4-bromo-3,6-difluorobenzoic acid (50.0 g, 198 mmol) in dichloromethane (75 mL) and methyl alcohol (75 mL) was added TMSCHN2 (100 mL, 2.0 mol / L in hexane) at 0 °C. The resulting solution was stirred at room temperature for 2 h. The solvent was concentrated in vacuo to give 52 g (crude) of the title compound as a yellow solid. The crude product was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =266.

[0650] Step 6: Methyl 2-amino-3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate TIFF2024506029000267.tif22170

[0651] Under nitrogen, a solution of methyl 2-amino-4-bromo-3,6-difluorobenzoate (25.0 g, 93.9 mmol), Pin2B2 (35.8 g, 141 mmol), KOAc (27.6 g, 282 mmol), and PdCl2(dppf) (6.88 g, 9.40 mmol) in 1,4-dioxane (300 mL) was stirred at 90 °C for 2 h. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 35 g (crude) as a brown solid. The crude product was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =314.

[0652] Step 7: Methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3,6-difluorobenzoate TIFF2024506029000268.tif38170

[0653] Under nitrogen, a solution of methyl 2-amino-3,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (58.0 g, 185 mmol), 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (73.4 g, 148 mmol, Intermediate 4), KF (20.4 g, 352 mmol), and Pd(PPh)Cl (13.0 g, 18.5 mmol) in acetonitrile (500 mL) and water (100 mL) was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo to give 75 g (crude) as a brown solid. The crude product was used in the next step without purification. LC-MS: (ESI, m / z): [M+H] + =602.

[0654] Step 8: Methyl 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3,6-difluorobenzoate TIFF2024506029000269.tif38170

[0655] A solution of methyl 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-3,6-difluorobenzoate (15.0 g, 24.9 mmol) and NCS (4.99 g, 37.4 mmol) in 1-methyl-2-pyrrolidinone (350 mL) was stirred at 25° C. for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over NaSO, and concentrated in vacuo to give 15.8 g (crude) of the title compound as a brown solid. The crude product was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =636.

[0656] Step 9: 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3,6-difluorobenzoic acid TIFF2024506029000270.tif38170

[0657] To a solution of methyl 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-5-chloro-3,6-difluorobenzoate (16.0 g, 25.2 mmol) in tetrahydrofuran (150 mL), water (50 mL), and methyl alcohol (50 mL) was added NaOH (15.1 g, 377 mmol). The solution was stirred at 50 °C for 3 hours. The reaction was cooled to room temperature, and the pH was adjusted to about 4 with citric acid. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na SO and concentrated in vacuo to give 15.8 g (crude) of the title compound as a brown solid. The crude product was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =622.

[0658] Step 10: 2-amino-4-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-3,6-difluorobenzamide TIFF2024506029000271.tif38170

[0659] A solution of 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-5-chloro-3,6-difluorobenzoic acid (14.5 g, 23.3 mmol), NHCl (3.74 g, 69.9 mmol), DIPEA (9.04 g, 69.9 mmol), and HATU (17.7 g, 46.6 mmol) in DMF (150 mL) was stirred at room temperature for 2 hours. The reaction solution was poured into water, and the solid was collected by filtration and washed with water to give 13.5 g (crude) of the title compound as a brown solid. The crude product was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =621.

[0660] Step 11: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6-dichloro-5,8-difluoroquinazolin-4(3H)-one TIFF2024506029000272.tif38170

[0661] A solution of 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-5-chloro-3,6-difluoro-benzamide (30.0 g, 48.3 mmol) and thiophosgene (7.74 mL, 101 mmol) in 1,4-dioxane (250 mL) was stirred at 105 °C for 1 h. The reaction was cooled to room temperature and poured into saturated NaHCO . The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over Na SO and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-8% EtOAc / DCM) to afford 11 g (34.2% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =665. 1 H NMR(300MHz,DMSO-d6,ppm):δ 7.25-7.06(m,4H),6.88(d,J=8.0Hz,5H),4.88-4.49(m,4H),3.35(s,6H),2.40(d,J=2.3Hz,3H).

[0662] Intermediate 38: tert-butyl (1R,2S,5R)-2-(hydroxymethyl)-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate TIFF2024506029000273.tif94170

[0663] Step 1: 3-benzyl 6-(tert-butyl)(1S,5R)-3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate TIFF2024506029000274.tif19170

[0664] A solution of tert-butyl 3,6-diazabicyclo[3.2.2]nonane-6-carboxylate (500 mg, 2.21 mmol), CbzCl (492 mg, 2.88 mmol), and DIPEA (1.42 g, 11.1 mmol) in dichloromethane (10 mL) was stirred at room temperature under nitrogen for 1 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-100% EtOAc / petroleum ether) to afford 800 mg of the title compound as a colorless oil. The two enantiomers were separated by Prep-SFC using the following conditions: (Column: CHIRALPAK IG, 3 x 25 cm, 5 μm; Mobile phase A: CO, Mobile phase B: IPA (0.5% 2M NH-MeOH); Flow rate: 70 mL / min; Gradient: 30% B; Column temperature: 35 °C; Back pressure: 100 bar; 215 nm; RT1: 6.86; RT2: 7.89; Injection volume: 1.5 ml; Number of runs: 20) to give 330 mg of the fast peak and 340 mg of the slow peak as a white oil. The fast peak is the desired isomer. LC-MS: (ESI, m / z): [M+H] + =361.

[0665] Step 2: Benzyl (1R,5R)-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate TIFF2024506029000275.tif16170

[0666] A solution of 3-benzyl 6-(tert-butyl)(1S,5R)-3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate (10.0 g, 27.7 mmol) in dichloromethane (60 mL) and 4 M HCl / dioxane (20 mL) was stirred at room temperature for 2 hours. The solvent was concentrated in vacuo to give 11.2 g (crude) of the title compound as a yellow solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =261.

[0667] Step 3: Benzyl (1R,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate TIFF2024506029000276.tif23170

[0668] A solution of benzyl (1R,5R)-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate (11.4 g, 43.7 mmol), benzyl bromide (8.99 g, 52.5 mmol), and DIPEA (11.3 g, 87.5 mmol) in N,N-dimethylformamide (50 mL) was stirred at 80 °C for 3 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-40% EtOAc in petroleum ether) to give 8.30 g of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =351

[0669] Step 4: (1S,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane (2,2,2-trifluoroacetate) TIFF2024506029000277.tif23170

[0670] A solution of benzyl (1R,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate (8.30 g, 23.6 mmol) in TFA (60 mL) was stirred at 70° C. for 2 h. The solvent was concentrated in vacuo to give 5.80 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] + =217.

[0671] Step 5: tert-butyl (1R,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate TIFF2024506029000278.tif23170

[0672] A solution of (1S,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane (2,2,2-trifluoroacetate) (5.80 g, crude), BocO (8.60 g, 39.4 mmol), and DIPEA (10.3 g, 79.8 mmol) in dichloromethane (120 mL) was stirred at room temperature for 2 h. The solvent was concentrated in vacuo, and the resulting residue was purified by reverse-phase chromatography (gradient: 0-100% acetonitrile in water (0.05% NH4HCO3)) to afford 6.30 g of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =317.

[0673] Step 6: 3-(tert-butyl) 2-methyl (1R,2S,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane-2,3-dicarboxylate TIFF2024506029000279.tif23170

[0674] Under nitrogen, to a solution of tert-butyl (1R,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate (6.09 g, 19.2 mmol) and TMEDA (2.72 g, 23.4 mmol) in diethyl ether (46 mL) was added s-BuLi (18.8 mL, 1.3 M in hexane) at −78° C. The resulting solution was stirred at −78° C. for 1.5 h. Then, methyl chloroformate (1.77 mL, 22.8 mmol) in diethyl ether (4.5 mL) was added and stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO solution. The resulting solution was extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-50% EtOAc in petroleum ether) to give 1.50 g (desired isomer (isomer a), later peak in the column, contains traces b and d) and 2.6 g (undesired isomer (isomer c), earlier peak in the column, pure) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =375.

[0675] Step 7: tert-butyl (1R,2S,5R)-6-benzyl-2-(hydroxymethyl)-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate TIFF2024506029000280.tif22170

[0676] To a solution of 3-(tert-butyl) 2-methyl(1R,2S,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane-2,3-dicarboxylate (580 mg, 1.54 mmol) under nitrogen was added LiAlH (3.2 mL, 1 M in THF) at 0 °C. The resulting solution was stirred at 0 °C for 2 h. The reaction was quenched with NaSO.10H O. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0-100% EtOAc in petroleum ether) to afford 520 mg of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =347. 1 H NMR(400MHz,DMSO-d6)δ 7.37-7.16(m,5H),4.59(d,J=42.8Hz,1H),4.39-4.19(m,2H),3.74-3.56(m,2H),3.46(dt,J=28.9,10.3 Hz,2H),2.84(s,1H),2.78-2.61(m,3H),2.21(s,1H),1.89(dq,J=29.0,15.0,13.0Hz,2H),1.46(s,11H).

[0677] Step 8: (6R,9R,9aS)-11-benzylhexahydro-1H,3H-6,9-(epiminomethano)oxazolo[3,4-a]azepin-3-one TIFF2024506029000281.tif27170

[0678] To a solution of tert-butyl (1R,2S,5R)-6-benzyl-2-(hydroxymethyl)-3,6-diazabicyclo[3.2.2]nonane-3-carboxylate (480 mg, 1.39 mmol) in tetrahydrofuran (15 mL) under nitrogen at 0 °C was added NaH (112 mg, 2.82 mmol, 60% suspension in oil). The reaction was stirred at room temperature for 12 h. The reaction was quenched by the addition of aqueous NH4Cl. The solvent was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0-60% EtOAc in petroleum ether) to afford 360 mg of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =273.

[0679] Step 9: tert-Butyl (6R,9R,9aS)-3-oxohexahydro-1H,3H-6,9-(epiminomethano)oxazolo[3,4-a]azepine-11-carboxylate TIFF2024506029000282.tif22170

[0680] A solution of (6R,9R,9aS)-11-benzylhexahydro-1H,3H-6,9-(epiminomethano)oxazolo[3,4-a]azepin-3-one (330 mg, 1.20 mmol), 10% Pd / C (99.0 mg, dry), and BocO (530 mg, 2.45 mmol) in methyl alcohol (70 mL) under H2 (3 atm) was stirred at room temperature for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (gradient: 0-100% EtOAc in petroleum ether) to afford 350 mg of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =283.

[0681] Step 10: tert-butyl (1R,2S,5R)-2-(hydroxymethyl)-3,6-diazabicyclo[3.2.2]nonane-6-carboxylate TIFF2024506029000283.tif18170

[0682] A solution of tert-butyl (6R,9R,9aS)-3-oxohexahydro-1H,3H-6,9-(epiminomethano)oxazolo[3,4-a]azepine-11-carboxylate (275 mg, 0.972 mmol) and NaOH (585 mg, 14.6 mmol) in ethanol (9 mL) and water (3 mL) was stirred at 80 °C for 12 h. The solvent was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography on a pre-packed C18 column (gradient: 0-100% CHCN in water (0.05% NHHCO)) to give 250 mg of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =257. 1 H NMR(300MHz,DMSO-d6)δ 4.60(br,1H),3.91-4.08(m,1H),3.40-3.01(m,4H),3.00-2.90(m,1H),2.60-2.45(m,2 H),2.00(br,1H),1.95-1.85(m,1H),1.80-1.55(m,3H),1.35(s,9H),1.30-1.20(m,1H).

[0683] Intermediate 39: (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000284.tif41170

[0684]

[0685] Step 1: Ethyl (S,Z / E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024506029000285.tif33170

[0686] To a solution of 2-((fluoromethyl)sulfonyl)pyridine (177 mg, 1.01 mmol) in tetrahydrofuran (10 mL) under N was added KHMDS (1.2 mL, 1.20 mmol) at −78° C. The reaction was stirred at −78° C. for 30 minutes, and ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (200 mg, 0.950 mmol, Intermediate 23, Step 1, earlier peak) in THF (5 mL) was added slowly at −78° C. After stirring at −78° C. for 3 hours, the reaction was allowed to warm to room temperature and stirred at room temperature for an additional hour. The reaction was quenched with saturated aqueous ammonium chloride (1 mL) followed by 3 M HCl (2 mL). The solution was stirred at room temperature for 1 hour. The reaction was 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 flash chromatography on silica gel (gradient: 0% to 30% ethyl acetate / petroleum ether) to give 65.0 mg (30% yield) of the title compound as a yellow oil. LC-MS: (ES, m / z): [M+1] + =228.1. 1 H NMR (400 MHz, chloroform-d1, ppm) δ 6.75-6.65 (m, 1H), 6.55-6.44 (m, 1H), 4.45-4.32 (m, 2H), 4.27-4.20 (m, 4H), 3.90 (d, J = 16 Hz, 1H), 3.73 (d, J = 16 Hz, 1H), 3.32 (d, J = 16 Hz, 1H), 3.04 (d, J = 16 Hz, 1H), 2.89-2.75 (m, 2H), 2.72-2.56 (m, 2H), 2.53-2.35 (m, 4H), 2.25-2.08 (m, 2H), 1.33-1.28 (m, 6H). (The resulting diploid H is a Z / E mixture.)

[0687] Step 2: (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol and (S,E)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024506029000286.tif28170

[0688] To a solution of ethyl (S,Z / E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (60.0 mg, 0.260 mmol) in tetrahydrofuran (5 mL) under nitrogen, DIBAL-H (2.64 mL, 2.64 mmol) was added at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction was quenched with NaSO.10H0. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0% to 20% MeOH / DCM (0.1% EtN)) to afford 26.0 mg (mixture of Z / E, two peaks on flash but collected together) (57% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =172.1. 1 H NMR (300 MHz, chloroform-d1, ppm) δ 6.79-6.38 (m, 2H), 3.92-3.70 (m, 2H), 3.61-3.20 (m, 8H), 2.79-2.44 (m, 5H), 2.36-2.26 (m, 1H), 2.14-1.66 (m, 8H). (The resulting diploid H is a Z / E mixture.)

[0689] For the scaled-up batch, following the same procedure and purification methods as above, 9.7 g of ethyl (S,Z / E)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate gave 2.20 g (Z, desired isomer) and 2.70 g (E, undesired isomer), both as yellow oils.

[0690] Isomers:LC-MS:(ESI,m / z):[M+H] + =172. 1 H NMR (300 MHz, chloroform-d1, ppm) δ 6.64-6.29 (m, 1H), 3.79-3.65 (m, 1H), 3.48-3.37 (m, 1H), 3.35-3.23 (m, 2H), 3.14-3.03 (m, 1H), 2.69-2.58 (m, 1H), 2.46-2.35 (m, 1H), 2.30-2.17 (m, 1H), 2.03-...

Claims

1. Formula (I): (In the formula, X is O or NR ６ and n is 1, 2 or 3; m is 1, 2, or 3; p is 0, 1 or 2; n and m together form a 6-, 7- or 8-membered ring A; Each R ０ are independently hydrogen or methyl; 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 benzothiazolyl, R ７Ａ Substituted or unsubstituted phenyl, or R ７Ａ substituted or unsubstituted pyridinyl, Each R ７ are independently hydrogen, halogen, —OH, NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ haloalkyl, or unsubstituted cyclopropyl; Each R ７Ａ are independently hydrogen, halogen, NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ haloalkyl, or unsubstituted cyclopropyl; R ２ L １ -O-L ２ -R ８ , R ８Ａ Substituted or unsubstituted C １～３ Alkyl, or R ８Ｂ a substituted or unsubstituted 4- to 10-membered heterocycle; L １ is a bond or R Ｌ１ Substituted or unsubstituted C １～３ is alkylene, R Ｌ１ is halogen or unsubstituted C １～３ is alkyl, L ２ is a bond or an unsubstituted C １～３ is alkylene, R ８ R containing N, S or O ９ a substituted or unsubstituted 4-10 membered heterocycle; Each R ９ are independently halogen, oxo, -OCF ３ , -OCHF ２ , -OCH ２ F, unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ Alkoxy, R １０ Substituted or unsubstituted C １～３ Alkylidene, R １０ Substituted or unsubstituted C ３～４ Cycloalkyl, or R １０ a substituted or unsubstituted 3- or 4-membered heterocycle; or Two R's ９ Together, R １０ Substituted or unsubstituted C ３～５ Cycloalkyl or R containing one or more oxygen atoms １０ forming a substituted or unsubstituted C3-5 heterocycle, R １０ is hydrogen, halogen, or C １～３ is an unsubstituted alkyl; Each R ８Ａ are independently R ９Ａ Substituted or unsubstituted C １～３ Alkyl, R ９Ａ Substituted or unsubstituted C １～３ Alkoxy, R ９Ａ Substituted or unsubstituted C ３～４ Cycloalkyl, or R ９Ａ a substituted or unsubstituted 4- to 6-membered heterocycle; Each R ９Ａ are independently halogen, oxo, unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ Alkoxy, unsubstituted C １～３ Alkylidene, R ９ Substituted or unsubstituted C ３～４ Cycloalkyl or R containing N, S or O ９ a substituted or unsubstituted 4- to 10-membered heterocycle; R ８Ｂ are independently halogen, oxo, -NH ２ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ Alkoxy or unsubstituted C １～３ is alkylidene, R ３ and R ４ are each independently hydrogen, —CN, halogen, unsubstituted C １～３ alkyl, or unsubstituted cyclopropyl; Each R ５ are independently halogen, oxo, unsubstituted C １～３ Alkyl or unsubstituted C １～３ haloalkyl, or Two R's ５ taken together form a bridge between two carbon atoms of ring A, said bridge containing 1-3 carbons and, optionally, one heteroatom selected from O and N; or Two R's ５ taken together form a bridge between two carbon atoms of ring A, said bridge being O or NR １１ one of R １１ is hydrogen, C(O)CH ３ , or unsubstituted C １～３ is alkyl, R ６ is hydrogen or 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) ２ R ６Ｃ , C(O) Ｒ６Ｂ , unsubstituted C １～３ Alkyl or 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 １～３ Alkyl or C １～３ haloalkyl) or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

2. Each R ０ is hydrogen, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

3. One R ０ is hydrogen, and one R ０ is methyl, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

4. Formula (V*):

4. The compound of claim 3 having the structure: or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

5. R １ But, R ７ substituted or unsubstituted phenyl, R ７ Substituted or unsubstituted indazolyl, or R ７ 5. The compound of any one of claims 1 to 4, which is a substituted or unsubstituted pyridinyl, or a stereoisomer, atropisomer, tautomer or pharma- ceutically acceptable salt thereof.

6. Each R ７ are independently halogen, NH ２ , unsubstituted C １～３ Alkyl or unsubstituted C １～３ 6. The compound of any one of claims 1 to 5, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, which is haloalkyl.

7. R １ but, (In the formula, X １ is N or CF, Each R ７Ａ are independently hydrogen, halogen, unsubstituted C １～３ Alkyl or unsubstituted C １～３ haloalkyl) 5. The compound according to any one of claims 1 to 4, wherein:

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

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

10. R １ but, (In the formula, each R ７ are independently halogen, NH ２ , N(Me) ２ , or unsubstituted C １～３ is alkyl) 5. The compound according to any one of claims 1 to 4, wherein:

11. R ２ But, L １ -O-L ２ -R ８ 11. The compound of any one of claims 1 to 10, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein: L 1 is a bond and L 2 is methylene.

12. R ８ but, (In the formula, R ９ is 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.

12. The compound of any one of claims 1 to 11, wherein:

13. R ８ but, (In the formula, R ９ are independently halogen or R １０ Substituted or unsubstituted C １～３ is alkylidene, Each R １０ are independently hydrogen or halogen; r is 1 or 2.

12. The compound of any one of claims 1 to 11, wherein:

14. R ８ but, (In the formula, R ９ are independently halogen, oxo, or unsubstituted C １～３ is alkyl, r is 1 or 2.

12. The compound of any one of claims 1 to 11, wherein:

15. R ８ but, (In the formula, R ９ is hydrogen or unsubstituted C １～３ is alkyl, W is O, SO ２ , or NR １２ and R １２ is hydrogen, unsubstituted C １～３ Alkyl or unsubstituted C １～３ haloalkyl) 12. The compound of any one of claims 1 to 11, wherein:

16. R ３ 16. The compound of any one of claims 1 to 15, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein is halogen.

17. R ４ 17. The compound of any one of claims 1 to 16, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein is hydrogen.

18. R ４ 17. The compound of any one of claims 1 to 16, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein is halogen.

19. Two R's ５ taken together form a bridge between two carbon atoms of ring A, said bridge containing 1 to 3 carbons, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

20. formula:

20. The compound of any one of claims 1, 5-10, 12-19, having the structure:

21. formula:

20. The compound of any one of claims 1, 5-10, 12-19, having the structure:

22. formula:

20. The compound of any one of claims 1, 5-10, 12-19, having the structure:

23. formula:

20. The compound of any one of claims 1, 5-10, 12-19, having the structure:

24. X is NR ６ and R 6 is hydrogen; or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. Claim 25: X is NR 6 and R ６ But, R ６Ａ Substituted or unsubstituted C １～３ 24. The compound of any one of claims 1 to 23, wherein R 6A is alkyl and each R 6A is independently halogen, CN, OMe, OEt, OCF 3 , or a 4-membered heterocycle, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

26. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

27. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

28. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

29. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a stereoisomer, atropisomer, tautomer or pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

30. A composition comprising a compound according to any one of claims 1 to 28, or a stereoisomer, atropisomer, tautomer or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29, for use in the therapeutic treatment of cancer.

31. The composition or pharmaceutical composition for use according to claim 30, wherein the cancer comprises a KRas G12D mutation.

32. A composition or pharmaceutical composition for use according to claim 30 or 31, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

33. The composition or pharmaceutical composition for use according to claim 32, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

34. A composition or pharmaceutical composition for use according to claim 32, wherein the cancer is pancreatic cancer.

35. The composition or pharmaceutical composition for use according to claim 32, wherein the cancer is colorectal cancer.

36. A composition comprising a compound according to any one of claims 1 to 28, or a stereoisomer, atropisomer, tautomer or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29, for use in inhibiting tumour metastasis.

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