Tetracyclic oxazepine compounds and their use

Abstract

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

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to International Patent Application PCT / CN2022 / 074435 filed on 27 January 2022 and International Patent Application PCT / CN2021 / 076369 filed on 9 February 2021, each of which is incorporated herein by reference in whole for all purposes.

[0002] Field of Invention Tetracyclic compounds useful for treating cancers containing KRas mutations, compositions of such compounds, and methods for treating cancers containing KRas mutations are provided herein. [Background technology]

[0003] background Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch in the central proliferation signaling pathway. In response to extracellular signals, Ras is catalyzed by guanine nucleotide exchange factors (GEFs), particularly the SOS1 protein, to GDP binding (Ras GDP ) state to GTP binding (Ras GTP ) is converted to the state of active Ras GTP Ras mediates its diverse growth-stimulating functions through direct interactions with effectors including Raf, PI3K, and the Ral guanine nucleotide dissociation stimulator. Next, Ras's intrinsic GTPase activity hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity can be further accelerated through interactions with GTPase-activating proteins (gap), including the neurofibromin-1 tumor suppressor.

[0004] Mutant Ras has reduced GTPase activity, which sustains the activated state of Ras, thereby promoting Ras-dependent signaling and cancer cell survival or proliferation. Mutations in Ras that interact with GAP or affect the ability to convert GTP back to GDP result in sustained protein activation, consequently sustained signals that signal continued proliferation and division. Because these signals lead to cell proliferation and division, excessively active RAS signaling can ultimately lead to cancer. Mutations in any one of the three main 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 of the P-loop, as well as at residue Q61. G12D is a frequent mutation in the KRas gene (glycine-12 to aspartate). Ras mutations in cancer are associated with poor prognosis. Inactivation of oncogenic Ras in mice results in tumor reduction. Therefore, Ras is widely considered an exceptionally important oncological target.

[0006] Therefore, there is an urgent need for treatments for G12D mutant KRas-mediated cancers. [Overview of the project]

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

[0008] In the first embodiment, the compound of formula (I) described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0009] In another embodiment, compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

[0010] In another embodiment, compounds of formulas (IIa), (IIb), (IIc), (IId), (IIe), (IIg), or (IIh) described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

[0011] In another embodiment, compounds of formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIg), or (IIIh) described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

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

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

[0014] In another embodiment, pharmaceutical compositions comprising the compounds, stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof described herein are provided herein.

[0015] In another embodiment, a method for treating a cancer containing a KRas mutation is provided herein, comprising administering to a patient having such cancer one of the compounds, stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof described herein.

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

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

[0018] In another embodiment, the present invention provides a method for inhibiting tumor metastasis, comprising administering to an individual in need of such inhibition 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, to the subject in need.

[0019] In another embodiment, a method for preparing a labeled KRas G12D mutant protein is provided herein, 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 a labeled KRas G12D mutant protein.

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

[0021] definition In certain embodiments, tetracyclic oxazepine compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof, which are inhibitors or modulators of mutant KRas, are disclosed herein. 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] While the disclosure herein provides the listed embodiments, it should be understood that they are not intended to limit the compounds and methods described herein to those embodiments. On the contrary, this disclosure is intended to cover all alternatives, modifications, and equivalents that may fall within the scope of this disclosure as defined by the claims.

[0023] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. All publications, patent applications, patents, and other references referenced herein are incorporated in their entirety by reference. The nomenclature used herein follows IUPAC systematic nomenclature unless otherwise indicated.

[0024] The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this 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. Furthermore, terms such as "haloalkyl" include monohaloalkyl, polyhaloalkyl, and perhaloalkyl.

[0026] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon radical. For example, an alkyl group consists of 1 to 18 carbon atoms (C1~18 ) It is. In other examples, 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 include 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(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, and 1-octyl, etc.

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

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

[0029] The terms "cyano" or "nitrile" refer to -C≡N or -CN.

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

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

[0032] The term "alkylidene" refers to a linear or branched monovalent hydrocarbon radical having the formula =CR'R'', where R' and R' may be the same or different. For example, an alkylidene radical has 1 to 6 carbon atoms (C 1~6 ) is. In another example, alkylidene radicals are 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" refers to a monovalent hydrocarbon, either linear or branched, having at least one carbon-carbon double bond, and includes groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. For example, an alkenyl group has 2 to 18 carbon atoms (C 2~18 ) is. In other examples, alkenyl radicals are 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=CH2), propa-1-enyl (-CH=CHCH3), propa-2-enyl (-CH2CH=CH2), 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl.

[0034] The term "alkynyl" refers to a monovalent hydrocarbon group, either linear or branched, that has at least one carbon-carbon triple bond. For example, an alkynyl radical has 2 to 18 carbon atoms (C 2~18 ) is. 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, ethinyl (-C≡CH), propa-1-inyl (-C≡CCH3), propa-2-inyl (propargyl, -CH2C≡CH), buta-1-inyl, buta-2-inyl, and buta-3-inyl.

[0035] The term "alkylene" refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, a divalent alkylene group has 1 to 18 carbon atoms (C 1~18 ) is. In other examples, 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-dimethylethanol-1,2-yl(-C(CH3)2CH2-), and 1,4-butyl(-CH2CH2CH2CH2-).

[0036] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyls include monocyclic, dicyclic, tricyclic, spirocyclic, and bridging saturated ring groups. For example, a cycloalkyl group has 3 to 12 carbon atoms (C 3~12 ) is. 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 other examples, a cycloalkyl group as a monocycle is C 3~4 , C 3~8 , C 3~6 , or C 5~6 In another example, a cycloalkyl group as a biring is 7-C 12 In another example, a 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, the [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary cross-linked 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 formula,” “heterocyclic,” “heterocyclic,” or “heterocyclo” are used interchangeably and refer to any mono, di, tricyclic, spiro, or bridging saturated, partially saturated, or unsaturated non-aromatic cyclic system having 3 to 20 ring atoms, where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any of the ring atoms in the cyclic system is a heteroatom, the system is a heterocycle regardless of the bond points of the cyclic system to the rest of the molecule. For example, a heterocyclil includes monocyclic, dicyclic, tricyclic, spiro, and bridging cyclic systems containing 3 to 10 ring atoms ("members"), where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclil contains 4 to 10 or 5 to 10 ring atoms. For example, a heterocyclil contains 1 to 4 heteroatoms. In one example, the heterocyclyl contains 1 to 3 heteroatoms. In another example, the heterocyclyl contains a 3 to 7-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In yet another example, the heterocyclyl contains a 4 to 6-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In yet another example, the heterocyclyl contains a 3-membered monoring. In yet another example, the heterocyclyl contains a 4-membered monoring. In yet another example, the heterocyclyl contains a 5 to 6-membered monoring. In some embodiments, the heterocycloalkyl contains at least one nitrogen. In one example, the heterocyclyl group contains 0 to 3 double bonds. Any nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatoms may optionally be quaternized (e.g., [NR4]). + Cl - [NR4] + OH -Exemplary heterocycles include oxyranil, azilidinil, thiranil, azetidinil, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, pyrrolidinil, dihydro-1H-pyrrolyl, dihydrofuranil, tetrahydrofuranil, dihydrothienyl, tetrahydrothienyl, imidazolidinil, piperidinil, piperazinil, isoquinolinil, tetrahydroisoquinolinil, morpholinil, thiomorpholinil, 1,1-dioxo-thiomorpholinil, dihydropyranil, tetrahydropyranil, hexahydrothiopyranil, hexa Dropyrimidinil, oxazinanil, thiadinil, thioxanil, homopiperazinil, homopiperidinil, azepanil, oxepanil, thiepanil, oxazepinil, oxazepanil, diazepanil, 1,4-diazepanil, diazepinil, thiazepinil, thiazepanil, tetrahydrothiopyranil, oxazolidinil, thiazolidinil, isothiazolidinil, 1,1-dioxoiisothiazolidinonil, 1,1-dioxoiisothiazolyl, oxazolidinonil, imidazolidinonil, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydro Benzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiadinyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinyl, pyrazolidinyl, dithianil, dithiolanil , pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, 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.These are [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-azapiro[4.5]decane-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl.

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

[0039] In certain embodiments, the heterocyclyl or heteroaryl group is nitrogen-bonded. Examples of nitrogen-bonded heterocyclyl or heteroaryl groups include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, the bond at position 1 of 1H-indazole, position 2 of isoindole or isoindoline, position 4 of morpholine, and the bond at position 9 of carbazole or β-carbolin.

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

[0041] The term "acyl" means a carbonyl compound containing a substituent represented by -C(=O)-R (wherein R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, and alkyl, cycloalkyl, aryl, and heterocyclyl are as defined herein). Examples of acyl groups include alkanoyl (e.g., acetyl), alloyl (e.g., benzoyl), and heteroaloyl (e.g., pyridinoyl).

[0042] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms are substituted with halogens. Examples of haloalkyls include trifluoromethyl, difluoromethyl, and fluoromethyl. A substituted haloalkyl refers to a haloalkyl that has a portion other than the halogen.

[0043] When used herein, a wavy line intersecting a bond in a chemical structure is used. "TIFF0007862413000001.tif3170" represents an atomic bond point in a chemical structure where a wave-like bond is attached to the remainder of a molecule or the remainder of a molecular fragment.

[0044] In certain embodiments, divalent groups are generally described without specific bonding structures. Unless otherwise specified, the general description is understood to include both bonding structures. For example, group R 1 -R 2 -R 3 In this case, base R 2 When written as -CH2C(O)-, unless otherwise specified, this group is R 1 -CH2C(O)-R 3 and R 1 -C(O)CH2-R 3 It is understood that they can be combined as both.

[0045] The term "pharmaceutically acceptable" refers to molecular entities and compositions that, when administered appropriately to animals, such as humans, do not produce side effects, allergic reactions, or other adverse reactions.

[0046] The compounds described herein may also be in the form of salts, such as pharmaceutically acceptable salts. "pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmacologically acceptable acid addition salts" means salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid that retain the biological efficacy and properties of the free base and are biologically or otherwise desirable. Organic acids can be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid categories 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, and salicylic acid.

[0047] The term "pharmaceutically acceptable base addition salt" 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 include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples of pharmaceutically acceptable salts derived from organic non-toxic bases include primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines containing basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and salts of polyamine resins. Specific examples of 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, saccharinate, adipine, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, phloate (e.g., 2-phloate or 3-phloate), 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-hydroxyethyl sulfonate), 2-mesitylene sulfonate, 2-naphthalene sulfonate, 2,5-dichlorobenzene sulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipine, esylate, malonate, mesicylate (2-mesitylene sulfonate), napsylate (2-naphtha Selected from lensulfonates, cansilates (camphor 10-sulfonates, e.g., (1S)-(+)-10-camphor-sulfonates), glutamates, glutarates, hippurates (2-(benzoylamino)acetate), orotates, xylates (p-xylene-2-sulfonates), and pamoates (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

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

[0050] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space. Stereoiomers include diastereomers, enantiomers, atropisomers, and conformational isomers.

[0051] The term "chiral" refers to molecules that have the property of not being able to be superimposed on their mirror image partners, while the term "achiral" refers to molecules that can be superimposed on those mirror image partners.

[0052] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0053] The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other but cannot be superimposed.

[0054] The term "atropisomer" refers to two conformational isomers arising from an obstructed rotation around a single bond where the steric strain barrier against rotation can be high enough to allow the isolation of each conformational isomer.

[0055] The definitions and conventions of stereochemistry used herein generally follow SP. 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, that is, 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 indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the sign of the rotation of plane-polarized light by the compound, with (-) or 1 meaning the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. In a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Furthermore, certain stereoisomers are sometimes called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to equimolar mixtures of two enantiomer species that are not optically active.

[0056] The term "tautomer" or "tautomer" refers to structural isomers with different energies that can be interconverted by a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton rearrangement, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of several bonding electrons.

[0057] Certain compounds described herein may exist in solvated forms, including non-solvated and hydrated forms. “Solvate” means 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 may exist in multiple crystalline or amorphous forms. Generally, all physical forms are construed 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 isotope-labeled compounds that are identical to those enumerated herein due to the fact that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. All isotopes of any specific atom or element designated, and their use, are contemplated herein. 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 I is an example. A specific isotope-labeled compound or a pharmaceutically acceptable salt thereof as described herein (e.g., 3 H and 14 Those labeled with 1C are useful in compound and / or substrate tissue distribution assays. Tritium-labeled ( 3 H) and carbon-14 ( 14C) Isotopes are useful due to their ease of preparation and detection. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), may result in certain therapeutic benefits derived from greater metabolic stability (e.g., extended in vivo half-life or reduced required dose), and therefore may be preferable in some environments. 15 O, 13 N, 11 C, and 18 Positron-emitting isotopes such as fluorine are useful for positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds described herein or their pharmaceutically acceptable salts can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents and following procedures similar to those described in the examples below.

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

[0060] As used herein, the term “carboxyl protecting group” means a group that is stable to the conditions of a subsequent reaction at another position in the molecule and can be removed at the appropriate location without destroying the rest of the molecule to give an unprotected carboxyl group. Examples of carboxyl protecting groups include ester groups and heterocyclyl groups. The carboxylic acid group may be blocked or protected using an ester derivative of the carboxylic acid group, while the reaction proceeds at another functional group of the compound. Examples of such ester groups include substituted arylalkyls containing substituted benzyls, 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-butylallyl or t-amyl, triphenylmethyl(trityl), 4- Examples of carboxy protecting groups include methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl, 2-phenylpropa-2-yl, thioesters, e.g., t-butylthioester, silyl esters, e.g., trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)propa-1-en-3-yl, and similar moieties. Another example of carboxy protecting groups is heterocyclyl groups such as 1,3-oxazole. Further examples of these groups can be found in TWGreene and PGMWuts, “Protecting Groups in Organic Synthesis, 3 rd This is found in ed., John Wiley & Sons, Inc., 1999. The term "protected carboxyl" refers to a carboxyl group substituted with one of the above carboxyl protecting groups.

[0061] The compounds described herein and their pharmaceutically acceptable salts may contain one or more chiral carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. For the synthesis of the compounds, racemic compounds, diastereomers, or enantiomers may be used as starting materials or intermediates. A mixture of specific diastereomer compounds may be separated or concentrated into one or more specific diastereomers by chromatography or crystallization. Similarly, an enantiomer mixture may be separated or enantiomerically concentrated using the same technique or other techniques known in the art. Each of the chiral carbon or nitrogen atoms may be in an R or S configuration, and both of these configurations are intended herein.

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

[0063] "Control," "individual," or "patient" are vertebrates and are used interchangeably herein. In certain embodiments, the vertebrate is a mammal. Examples of mammals include, but are not limited to, livestock (such as cattle), sports 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 the administration of a compound to a patient, the patient typically requires the administration of the compound.

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

[0065] The term “treatment” refers to a clinical intervention designed to alter the natural course of a patient or cells being treated during the course of a clinical lesion. Desired effects of treatment include a reduction in the rate of disease progression, recovery or mitigation of the disease state, and remission or improvement of prognosis. For example, a patient is said to have received a “treatment” if one or more of the cancer-related symptoms described herein are reduced or eliminated, including but not limited to: a reduction (or destruction) of cancerous cell proliferation, a reduction in symptoms caused by the disease, an improvement in the quality of life of the person affected, a reduction in the dose of other drug therapies required to treat the disease, and / or an extension of the patient’s survival.

[0066] The term “delay in disease progression” means delaying, preventing, slowing, postponing, stabilizing, and / or postponing the onset of the cancers described herein. This delay may be of varying lengths depending on the patient’s cancer history and / or the patient being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may substantially encompass prevention in that the patient does not develop or experience a recurrence of cancer.

[0067] "Mutant KRas-mediated diseases," etc., refer to diseases described herein (e.g., cancers described herein) that have the symptoms described herein or require treatment, and are associated with, as a result of, function of, or otherwise correlated with the mutant KRas activity described herein, in whole or in part. In such an embodiment, mutant KRas is KRas G12D That is the case.

[0068] The “effective dose” or “therapeutic effective dose” is the minimum amount necessary to achieve the measurable improvement or prevention of the cancer described herein. The effective dose as used herein may vary depending on factors such as the patient’s disease status, age, sex and weight, and the ability of the active ingredient to induce the desired response in the patient. The effective dose is also the amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the treatment. Beneficial or desired outcomes include the elimination or reduction of risk, reduction of severity, delay in the onset of the disease (including the biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes that appear during the onset of the disease), reduction of one or more symptoms caused by the disease, improvement in the quality of life of the person with the disease, reduction in the dose of other drugs necessary to treat the disease, enhancement of the effect of another drug, such as by targeting, delay in disease progression, and / or extension of survival. In some embodiments, an effective dose of the drug may be effective in reducing the number of cancer cells; shrinking tumor size; inhibiting (i.e., delaying or stopping) cancer cell invasion into peripheral organs; inhibiting (i.e., delaying or stopping) tumor metastasis; inhibiting (i.e., delaying or stopping) tumor growth; and / or alleviating one or more symptoms associated with the disorder. An effective dose may be administered in one or more doses.

[0069] "Administration period" or "cycle" means a period including the administration of one or more compounds described herein or pharmaceutically acceptable salts thereof, or additional therapeutic agents (i.e., chemotherapeutic agents), and any period not including the administration of one or more compounds described herein. "Relaxation period" means a period during which at least one of the compounds described herein is not administered. In one embodiment, a relaxation period means a period during which the compounds described herein are not administered. The relaxation periods provided herein may optionally include the administration of additional agents in the absence of the compounds described herein or pharmaceutically acceptable salts thereof, or vice versa. In such cases, the administration of any agent during the relaxation period should not interfere with or impair the administration of the compounds described herein or pharmaceutically acceptable salts thereof.

[0070] "Medication regimen" means a period of administration of one or more compounds described herein or pharmaceutically acceptable salts thereof, each cycle which may include administration of the compounds described herein or pharmaceutically acceptable salts thereof at different times or in different amounts.

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

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

[0073] The terms “simultaneous administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass the administration of two or more active substances to an animal, including a human, such that both active substances and / or their metabolites are present in the subject simultaneously. Simultaneous administration includes the simultaneous administration of different compositions, the administration of different compositions at different times (i.e., sequential administration), or the administration of a composition containing both active substances.

[0074] "1L therapy" refers to the first-line treatment administered to cancer patients who have not received prior treatment. Similarly, 2L, 3L, etc., refer to subsequent treatments administered to the patient.

[0075] The term “package insert” is used to refer to the instructions that are typically included in the commercial packaging of a therapeutic drug, including information about the indications, use, dosage, administration, contraindications, and / or warnings regarding its use.

[0076] The terms “antagonist” and “inhibitor” are used interchangeably and refer to compounds that have the ability to inhibit the biological function of a target protein, such as a variant 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. Preferred antagonists in this specification interact specifically with the target (e.g., by binding to the target), while compounds that inhibit the biological activity of the target protein by interacting with other elements of the signaling pathway in which the target protein is an element are also specifically included in this definition. Preferred biological activities inhibited by antagonists are associated with tumor progression, growth, or expansion.

[0077] As used herein, the term “agonist” means a compound that has the ability to initiate or enhance the biological function of a target protein, by whether or not it inhibits the activity or expression of the target protein. Therefore, the term “agonist” is defined in the context of the biological role of the target polypeptide. Preferred agonists as used herein are those that specifically interact with the target (e.g., by binding to the target), while compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other elements of a signaling pathway in which the target polypeptide is an element are also specifically included within this definition.

[0078] The terms “cancer,” “malignant,” “neoplasm,” and “tumor,” and related terms are used interchangeably herein and refer to or describe physiological conditions in mammals typically characterized by uncontrolled cell proliferation. A “tumor” includes one or more cancer cells. Examples of cancers include carcinomas, blastomas, sarcomas, seminomas, gliablastomas, melanomas, leukemias, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinoma) 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, pilocytic cell leukemia, oral cancer, pharyngeal 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, large intestine cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, liver cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer 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 cancer, brain cancer, head and neck cancer, Hodgkin's disease, and associated metastases. Other examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, myelofibrosis such as essential thrombocytosis and primary myelofibrosis, and chronic myeloid leukemia (CML).

[0079] A "chemotherapeutic agent" is a substance that is useful for treating a given disorder, such as cancer or inflammatory disorders. Examples of chemotherapeutic agents are well known in the art. Furthermore, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents, and combinations of two or more of these.

[0080] Unless otherwise indicated, the structures shown in this specification are also intended to include compounds that differ only in that one or more of the atoms are isotope-enriched. Exemplary isotopes that can be incorporated into the compounds and the pharmaceutically acceptable salts thereof described herein 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. Isotopically labeled compounds (e.g., 3 H and 14 C labeled compounds) can be useful in compound or substrate tissue distribution assays. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., [[ID=四十]] 14 C) isotopes can be useful because of the ease of preparation and detectability. Further, substitution with heavier isotopes, such as deuterium (i.e., 2 H), etc., can result in greater metabolic stability and, as a result, certain therapeutic advantages can be obtained (e.g., longer in vivo half-life or lower required dosage). In some embodiments, in the compounds and the pharmaceutically acceptable salts thereof described herein, one or more carbon atoms are replaced with carbon enriched in 13 C or 14 C. 15 O, 13 N, 11 C, and 18Positron-emitting isotopes such as 14F are useful for positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled compounds can generally be prepared by replacing unlabeled reagents with isotope-labeled reagents and following procedures similar to those described in the schemes or examples herein.

[0081] Any limitations described in relation to one embodiment provided herein are particularly intended to apply to any other embodiment provided herein. Furthermore, any compound and its pharmaceutically acceptable salt, or any composition described herein, may be used in any manner provided herein, and any method provided herein may be used to produce or utilize any compound and its pharmaceutically acceptable salt, or any composition described herein.

[0082] Throughout this application, the term “approximately” is used to indicate that the value includes the standard deviation of errors in the device or method used to measure that value.

[0083] compound Provided herein are formulas (I * ): TIFF0007862413000002.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 either 1 or 2. n and m together form a ring A with 6, 7, or 8 members. Each R 0 These are independently hydrogen or methyl, R 1 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 These are independently hydrogen, halogen, -OH, NH2, N(Me)2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 It is a haloalkyl or unsubstituted cyclopropyl, Each R 7A These are independently hydrogen, halogen, NH2, N(Me)2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 It is a haloalkyl or unsubstituted cyclopropyl, R 2 is hydrogen, L 1 -OL 2 -R 8 , R 8A Substitute or non-substitute C 1~3 Alkyl, or R 8B A complex ring with 4 to 10 members, either substituted or unsubstituted. Here, R 2 is hydrogen, R 1 R 7 If it is a substituted indazolyl and n and m are 1, then p is not 0, and R 6 It is not H, L 1 is a combination or R L1 Substitute or non-substitute C 1~3 It is alkylene, R L1 is halogen or unsubstituted C 1~3 It is alkyl, L 2 is bonded or unsubstituted C 1~3 It is alkylene, R 8 R 9 Substitute or non-substitute C 1~3 R containing alkyl, N, S, or O 9 A substituted or unsubstituted 4-10 member complex ring, Each R 9These are independently halogen, oxo, -OCF3, -OCHF2, -OCH2F, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10 Substitute or non-substitute C 1~3 Alkyridene, or R 10 Substitute or non-substitute C 3~4 Cycloalkyl, or R 10 It is a substituted or non-substituted 3- or 4-membered heterogeneous ring, or 2 R 9 Together, R 10 Substitute or non-substitute C 3~5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substitute or non-substitute C 3~5 Forming a heterogeneous ring, R 10 is hydrogen, halogen, or unsubstituted C 1~3 It is alkyl, Each R 8A R is independent of R 9A Substitute or non-substitute C 1~3 Alkyl, R 9A Substitute or non-substitute C 1~3 Alkoxy, R 9A Substitute or non-substitute C 3~4 Cycloalkyl, or R 9A A complex ring with 4 to 6 members, either substituted or unsubstituted. Each R 9A These are, independently, halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 alkoxy, unsubstituted C 1~3 Alkyridene, R 9 Substitute or non-substitute C 3~4 Cycloalkyl, or R containing N, S, or O 9 A complex ring with 4 to 10 members, either substituted or unsubstituted. R 8B These are, independently, halogen, oxo, -NH2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3alkoxy or unsubstituted C 1~3 It is alkyridene, R 3 and R 4 These are, independently, hydrogen, -CN, halogen, and unsubstituted C. 1~3 Alkyl or unsubstituted cyclopropyl, Each R 5 These are, independently, halogen, oxo, and unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 It is a haloalkyl, or 2 R 5 Together, they form a bridge between two carbon atoms of ring A, and the bridge contains 1 to 3 carbon atoms and optionally one heteroatom selected from O and N, or 2 R 5 Together, they form a bridge between the two carbon atoms of ring A, and the bridge is O or NR 11 Includes one of the following: R 11 is hydrogen, C(O)CH3, or unsubstituted C 1~3 It is alkyl, R 6 is hydrogen or R 6A Substitute or non-substitute C 1~6 Alkyl, R 6A Substitute or non-substitute C 1~6 Haloalkyl, R 6A Substitute or non-substitute C 1~6 Alkenil, R 6A Substitute or non-substitute C 1~6 Alkinyl, or R 6A A complex ring with 3-4 members, either substituted or non-substituted. R 6A Halogen, CN, OR 6B , SR 6C S(O)2R 6C , C(O) R6B , unsubstituted C 1~3 Alkyl or R 6B A complex ring with 3-4 members, either substituted or non-substituted. R 6B and R 6C Each of them is independent of C 1~3 Alkyl or C 1~3(It is a haloalkyl) The compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[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 The following is described herein: q is 1, n and m are independently 1 or 2, and n and m together form a 6-membered ring or a 7-membered ring A.

[0085] In one embodiment, q is 1.

[0086] Provided herein is formula (I): TIFF0007862413000003.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 ring A with 6, 7, or 8 members. Each R 0 These are independently hydrogen or methyl, R 1 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 These are independently hydrogen, halogen, -OH, NH2, N(Me)2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 It is a haloalkyl or unsubstituted cyclopropyl, Each R 7A These are independently hydrogen, halogen, NH2, N(Me)2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 It is a haloalkyl or unsubstituted cyclopropyl, R 2 is hydrogen, L 1 -OL 2 -R 8 , R 8A Substitute or non-substitute C 1~3 Alkyl, or R 8B A complex ring with 4 to 10 members, either substituted or unsubstituted. Here, R 2 is hydrogen, R 1 R 7 If it is a substituted indazolyl and n and m are 1, then p is not 0, and R 6 It is not H, L 1 is a combination or R L1 Substitute or non-substitute C 1~3 It is alkylene, R L1 is halogen or unsubstituted C 1~3 It is alkyl, L 2 is bonded or unsubstituted C 1~3 It is alkylene, R 8 R 9 Substitute or non-substitute C 1~3 R containing alkyl, N, S, or O 9 A substituted or unsubstituted 4-10 member complex ring, Each R 9 These are independently halogen, oxo, -OCF3, -OCHF2, -OCH2F, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10Substitute or non-substitute C 1~3 Alkyridene, or R 10 Substitute or non-substitute C 3~4 Cycloalkyl, or R 10 It is a substituted or non-substituted 3- or 4-membered heterogeneous ring, or 2 R 9 Together, R 10 Substitute or non-substitute C 3~5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substitute or non-substitute C 3~5 Forming a heterogeneous ring, R 10 is hydrogen, halogen, or unsubstituted C 1~3 It is alkyl, Each R 8A R is independent of R 9A Substitute or non-substitute C 1~3 Alkyl, R 9A Substitute or non-substitute C 1~3 Alkoxy, R 9A Substitute or non-substitute C 3~4 Cycloalkyl, or R 9A A complex ring with 4 to 6 members, either substituted or unsubstituted. Each R 9A These are, independently, halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 alkoxy, unsubstituted C 1~3 Alkyridene, R 9 Substitute or non-substitute C 3~4 Cycloalkyl, or R containing N, S, or O 9 A complex ring with 4 to 10 members, either substituted or unsubstituted. R 8B These are, independently, halogen, oxo, -NH2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 alkoxy or unsubstituted C 1~3 It is alkyridene, R 3 and R 4 These are, independently, hydrogen, -CN, halogen, and unsubstituted C. 1~3Alkyl or unsubstituted cyclopropyl, Each R 5 These are, independently, halogen, oxo, and unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 It is a haloalkyl, or 2 R 5 Together, they form a bridge between two carbon atoms of ring A, and the bridge contains 1 to 3 carbon atoms and optionally one heteroatom selected from O and N, or 2 R 5 Together, they form a bridge between the two carbon atoms of ring A, and the bridge is O or NR 11 Includes one of the following: R 11 is hydrogen, C(O)CH3, or unsubstituted C 1~3 It is alkyl, R 6 is hydrogen or R 6A Substitute or non-substitute C 1~6 Alkyl, R 6A Substitute or non-substitute C 1~6 Haloalkyl, R 6A Substitute or non-substitute C 1~6 Alkenil, R 6A Substitute or non-substitute C 1~6 Alkinyl, or R 6A A complex ring with 3-4 members, either substituted or non-substituted. R 6A Halogen, CN, OR 6B , SR 6C S(O)2R 6C , C(O) R6B , unsubstituted C 1~3 Alkyl or R 6B A complex ring with 3-4 members, either substituted or non-substituted. R 6B and R 6C Each of them is independent of C 1~3 Alkyl or C 1~3 (It is a haloalkyl) The compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[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 The following is described herein, where n and m are independently 1 or 2, and together n and m form a 6-membered ring or a 7-membered ring A.

[0088] One embodiment, each R 0 is hydrogen, and as a result, the compound of formula (I) is: TIFF0007862413000004.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 (The formula (I) is as described herein.) It holds.

[0089] In one embodiment, one R 0 It is hydrogen, and one R 0 Since is methyl, the compound of formula (I) is: TIFF0007862413000005.tif34170 (in the formula, 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 (The formula (I) is as described herein.) It holds.

[0090] In one embodiment of the compound of formula (V) described herein or a pharmaceutically acceptable salt thereof, the compound of formula (V) is: TIFF0007862413000006.tif34170 (in the formula, 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 (As described herein) It holds.

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

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

[0093] In one embodiment, R 1 Equation (A): TIFF0007862413000007.tif22170(in the formula, 1 is CH, N, or CF, and R 7A (As described herein) It has or is a stereoisomer thereof. In one such embodiment, X 1 is N or CF. In one such embodiment, R 7AThis is hydrogen, halogen, and unsubstituted C. 1~3 Alkyl or unsubstituted C 1~3 It is a haloalkyl group.

[0094] In such one embodiment, X 1 is N or CF, and each R 7A These are independently hydrogen, halogen, and unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one such embodiment, R 7A Each is independently hydrogen, Cl, methyl, ethyl, or CF3, and there is one or fewer R 7A is hydrogen. In one embodiment, one R 7A It is cyclopropyl.

[0095] In such one embodiment, the part of formula (A1) is: It has TIFF0007862413000008.tif22170.

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

[0097] In such one embodiment, R 1 teeth, The filename is TIFF0007862413000009.tif21170.

[0098] In another such embodiment, R 1 teeth, The filename is TIFF0007862413000010.tif20170.

[0099] In one embodiment, R 1 teeth, The filename is TIFF0007862413000011.tif20170.

[0100] In another embodiment, part (A) is: TIFF0007862413000012.tif25170 (in the formula, each R 7A These are independently hydrogen, halogen, and unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 (It is a haloalkyl) It has. In one such embodiment, each R 7A R is independently hydrogen, F, methyl, ethyl, or CF3. In such embodiments, one or fewer R 7A is hydrogen. In another such embodiment, R 7A It is not hydrogen.

[0101] In such one embodiment, R 1 teeth, The filename is TIFF0007862413000013.tif24170.

[0102] In such one embodiment, R 1 teeth, TIFF0007862413000014.tif27170 (in the formula, each R 7 These are independently halogens, NH2, N(Me)2, or unsubstituted C 1~3 (It is alkyl.) That is the case.

[0103] In one embodiment, R 1 teeth, The filename is TIFF0007862413000015.tif27170.

[0104] In another embodiment, R 1 teeth, The filename is TIFF0007862413000016.tif58170.

[0105] In another embodiment, R 1 teeth, The filename is TIFF0007862413000017.tif24170.

[0106] In another embodiment, R 1 teeth, The filename is TIFF0007862413000018.tif24170.

[0107] In one embodiment, R 7 These are independently hydrogen, halogen, -OH, NH2, N(Me)2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 In another embodiment, R 7 These are, independently, halogens, NH2, or unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 It is a haloalkyl. In one embodiment of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, R 7 It is not -OH.

[0108] In one embodiment, R 1 R 7 However, independently, hydrogen, halogen, or unsubstituted C 1~3 The part of formula (B) or (C) is alkyl. In such an embodiment, R 7 These are independently hydrogen or unsubstituted C 1~3 It is alkyl (for example, methyl). In another such embodiment, R 7 These can be independently halogens (e.g., F) or unsubstituted C. 1~3 It is an alkyl group (for example, methyl).

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

[0110] In one embodiment, R 2 L1 -OL 2 -R 8 , R 8A Substitute or non-substitute C 1~3 Alkyl, or R 8B It is a substituted or unsubstituted 4-10 member complex ring. In one embodiment, R 2 is hydrogen or L 1 -OL 2 -R 8 In another embodiment, R 2 R 8A Substitute or non-substitute C 1~3 Alkyl, or R 8B It is a substituted or unsubstituted 4- to 10-membered heterogeneous ring. In another embodiment, R 2 R 8B It is a substituted or unsubstituted 4-6 member complex ring. In yet another embodiment, R 2 L 1 -OL 2 -R 8 And R 8A Substitute or non-substitute C 1~3 Alkyl or R containing one nitrogen heteroatom 8B It is a complex ring with 4 to 6 members, either substituted or non-substituted.

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

[0112] In one embodiment, the compound of formula I is: TIFF0007862413000019.tif35170 (in the formula, R 1 , R 3 , R 4 , R 5 (X and p are as described herein) It has, or is a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (Ia1) is of formula: It has TIFF0007862413000020.tif34170.

[0113] In another embodiment, the compound of formula (I) is: TIFF0007862413000021.tif78170 (in the formula, R 1 , R 3 , R 4 , R 5 (X and p are as described herein) The compound has, or is a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the compounds of formula (Ib1) and formula (Ic1) are each of formula: It has TIFF0007862413000022.tif37170.

[0114] In one embodiment, R 2 L 1 -OL 2 -R 8 In one embodiment, L 1 and L 2 One of them is a bond. In one embodiment, L 1 This is a bond. In another embodiment, L 2 This is a bond. In one embodiment, L 1 is non-substituted C 1~3 It is alkylene, L 2 is a bond. In another embodiment, L 1 and L 2 Each of them is independent of C 1~3 It is alkylene.

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

[0116] In one embodiment, the compound of formula (I) is: TIFF0007862413000023.tif35170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 (X, n, m, and p are as described herein.) It has, or is a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (II1) is: It has TIFF0007862413000024.tif34170.

[0117] In one such embodiment, the compound of formula (II) is: TIFF0007862413000025.tif78170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 (X and p are as described herein) It has, or is a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0118] In one such embodiment, the compound of formula (II1) is: TIFF0007862413000026.tif78170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 (X and p are as described herein) It has, or is a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0119] In one such embodiment, the compound of formula (II1) is: TIFF0007862413000027.tif78170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 (X and p are as described herein) It has, or is a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

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

[0121] Such an operating mechanism, each R 9 These are, independently, halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, or R 10Substitute or non-substitute C 1~3 In another such embodiment, each R 9 These are, independently, halogen, oxo, or R 10 Substitute or non-substitute C 1~3 It is alkylidene. In one embodiment, each R 9 Independently, non-substituted C 1~3 Alkyl or unsubstituted C 1~3 It is an alkoxy. In one embodiment, each R 9 R 10 Substitute or non-substitute C 3~4 Cycloalkyl, or R 10 It is a substituted or unsubstituted 3- or 4-membered complex ring. In one embodiment, two R 9 Together, R 10 Substitute or non-substitute C 3~5 A cycloalkyl group is formed. In one such embodiment, two R 9 together R 10 Form a substituted cyclopropyl. In one such embodiment, two R 9 But together, R 10 R is a halogen (e.g., F or Cl). 10 Forms a substituted cyclopropyl. Two R 9 together R 10 In one embodiment where a substituted cyclopropyl is formed, cyclopropyl is R 8 It is bonded to a single carbon. In one embodiment, two R 9 together R 10 A substituted cyclopropyl is formed, and the cyclopropyl is R 8 It is bonded to two separate carbon atoms. In another such embodiment, two R 9 Together, they form an unsubstituted C containing one or more oxygen atoms. 3~5 It forms 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 a halogen. In one such embodiment, R 10 It is F.

[0123] In one embodiment, R 2 L 1 -OL 2 -R 8 And R 8 teeth, TIFF0007862413000028.tif18170 (in the formula, R 9 These are halogen, -OCF3, -OCHF2, -OCH2F, R 10 Substitution or non-substitution 1~3 Alkylidene or two R 9 together R 10 Substitute or non-substitute C 3~5 Forming a cycloalkyl group, r is an integer between 0 and 12. j is 1, 2, or 3. k is either 1 or 2. It is either one of these, or a stereoisomer thereof.

[0124] In one embodiment, R 2 L 1 -OL 2 -R 8 And R 8 teeth, TIFF0007862413000029.tif18170 (in the formula, R 9 is halogen, or R 10 Substitute or non-substitute C 1~3 It is alkyridene, r is an integer between 0 and 12. j is 1, 2, or 3. k is either 1 or 2. It is either one of these, 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, TIFF0007862413000030.tif64170 (in the formula, R 9 , R 10 (and r are as described herein, and s is 1 or 2) It is either one of these, 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 It has formula D1, D2, or D3, and R 9 , R 10 And r are as described herein.

[0126] In such one embodiment, R 9 It is independently halogen, or R 10 Substitute or non-substitute C 1~3 It is alkylidene, and each R 10 is independently hydrogen or halogen, and r is 1 or 2.

[0127] In one embodiment, R 8 teeth, TIFF0007862413000031.tif23170 or its stereoisomer, where r is 0.

[0128] In another embodiment, R 8 teeth, TIFF0007862413000032.tif34170 or its stereoisomer, where r is 0 and each R 10 These are independently hydrogen or F. In one such embodiment, r is 0, and each R 10 is hydrogen. In another such embodiment, r is 0, and each R 10 is F. In another such embodiment, r is 0 and 1 R 10 It is hydrogen, and one R 10 is F. In another such embodiment, each R 10 is independently hydrogen or F, r is 1 or 2, R 9 It is F.

[0129] In another embodiment, R 8 teeth, TIFF0007862413000033.tif29170(In the formula, r is 0, and each R 9 (These are, independently, hydrogen or halogen.) or a stereoisomer thereof. In one such embodiment, each R 9 is F and r is 0. In such one embodiment, each R 9 is F, and r is 1.

[0130] R 2 is L 1 -OL 2 -R 8 In another embodiment, R 8 teeth, TIFF0007862413000034.tif15170 or its stereoisomer. In one such embodiment, r is 1, and R 9 is a halogen, oxo, or unsubstituted C1 alkylidene. In one such embodiment, two R 9 Together, R 10 Substitute or non-substitute C 3~5 It forms a cycloalkyl group.

[0131] In one embodiment, R 8 teeth, TIFF0007862413000035.tif19170 (in the formula, 10 (where is a halogen and s is 1 or 2) or a stereoisomer thereof. In one such embodiment, R 8 teeth, It is TIFF0007862413000036.tif25170 or its stereoisomer.

[0132] R 2 is L 1 -OL 2 -R 8 In another embodiment, R 8 teeth, TIFF0007862413000037.tif14170 (in the formula, R 9 is hydrogen or unsubstituted C 1~3 It is alkyl, W is O, SO2, or NR 12 And, R 12 is hydrogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 (It is a haloalkyl) It is either one of these, or a stereoisomer thereof.

[0133] In such one embodiment, W is O and R 9 is methyl. In another such embodiment, W is NR 12 And in the formula, R 12 is non-substituted C 1~3 It is a haloalkyl, R 9 is hydrogen. In another such embodiment, W is SO2 and R 9 It is hydrogen.

[0134] In one embodiment of the compounds described herein or their pharmaceutically acceptable salts, R 8 These are azetidinil, oxetanil, or thietanedioxide.

[0135] In further embodiments provided herein, R 8 The formula is: TIFF0007862413000038.tif19170 (in the formula, R 9 These are, independently, halogen, oxo, or unsubstituted C 1~3 It is alkyl, (r is either 1 or 2) It is a portion having [a certain characteristic], or a stereoisomer thereof.

[0136] In such one embodiment, R 8 This is the part having equation (G), where R 9 and r are as described herein. In one such embodiment, R 9 is an oxo, and r is 1. In another such embodiment, R 9is F, and r is either 1 or 2.

[0137] In another embodiment, R 8 The formula is: TIFF0007862413000039.tif16170 (in the formula, R 9 (and r are as described herein) It is a portion having [a certain characteristic], or a stereoisomer thereof.

[0138] In another embodiment, R 8 The formula is: TIFF0007862413000040.tif23170 (in the formula, R 9 (and r are as described herein) It is a portion having [a certain characteristic], or a stereoisomer thereof.

[0139] In another embodiment, R 8 The formula is: TIFF0007862413000041.tif17170 (in the formula, R 10 (where is a halogen and s is 1 or 2) It is a portion having [a certain characteristic], or a stereoisomer thereof.

[0140] In yet another embodiment, R 8 R 9 Substitute or non-substitute C 1~3 It is alkyl. In such one embodiment, R 8 The formula is: TIFF0007862413000042.tif13170 (in the formula, each R 9 Independently, non-substituted C 1~3 Alkyl or unsubstituted C 1~3 (It is an alkoxy) It is a portion having [a certain characteristic], or a stereoisomer thereof.

[0141] In another embodiment, R 8 The formula is: This is the portion containing TIFF0007862413000043.tif13170.

[0142] In one embodiment, R 8 teeth, It is either TIFF0007862413000044.tif23170 or a stereoisomer thereof.

[0143] In one embodiment, R 8 teeth, It is either TIFF0007862413000045.tif22170 or a stereoisomer thereof.

[0144] In one embodiment, R 8 teeth, It is either TIFF0007862413000046.tif19170 or a stereoisomer thereof.

[0145] In one embodiment, R 8 teeth, The filename is TIFF0007862413000047.tif17170.

[0146] In another embodiment, R 8 teeth, It is either TIFF0007862413000048.tif27170 or a stereoisomer thereof.

[0147] In another embodiment, R 8 teeth, The filename is TIFF0007862413000049.tif27170.

[0148] In another embodiment, R 8 teeth, It is either TIFF0007862413000050.tif27170 or a stereoisomer thereof.

[0149] In another embodiment, R 8 teeth, The filename is TIFF0007862413000051.tif26170.

[0150] In yet another embodiment, R 8 teeth, It is either TIFF0007862413000052.tif23170 or a stereoisomer thereof.

[0151] In yet another embodiment, R 8 teeth, It is either TIFF0007862413000053.tif28170 or a stereoisomer thereof.

[0152] In yet another embodiment, R 8 teeth, The filename is TIFF0007862413000054.tif15170.

[0153] In yet another embodiment, R 8 teeth, The filename is TIFF0007862413000055.tif13170.

[0154] In yet another embodiment, R 2 teeth, TIFF0007862413000056.tif80170 (in the formula, R 9 , R 10 (r, j, and k are as described herein.) It is either or a stereoisomer thereof. In one embodiment, R 9 is halogen, or R 10 Substitute or non-substitute C 1~3 In another such embodiment, R 9 Halogen, oxo, R 10 Substitute or non-substitute C 1~3 It is an alkylidene, and r is independently 0, 1, or 2.

[0155] In one embodiment, R 2 teeth, It is either TIFF0007862413000057.tif19170 or a stereoisomer thereof.

[0156] In another embodiment, R 2 teeth, It is either TIFF0007862413000058.tif58170 or a stereoisomer thereof.

[0157] In another embodiment, R 2 teeth, It is either TIFF0007862413000059.tif27170 or a stereoisomer thereof.

[0158] In yet another embodiment, R 2 teeth, It is either TIFF0007862413000060.tif23170 or a stereoisomer thereof.

[0159] In yet another embodiment, R 2 teeth, It is either TIFF0007862413000061.tif27170 or a stereoisomer thereof.

[0160] In yet another embodiment, R 2 teeth, The filename is TIFF0007862413000062.tif15170.

[0161] In yet another embodiment, R 2 teeth, The filename is TIFF0007862413000063.tif13170.

[0162] In another embodiment, R 2 R 8A Substitute or non-substitute C 1~3 Alkyl, or R 8B It is a substituted or unsubstituted 4- to 10-membered heterocyclic ring. In one embodiment, each R 8A R is independent of R 9A Substitute or non-substitute C 1~3 Alkyl, or R 9A Substitute or non-substitute C 1~3 It is an alkoxy. In one embodiment, each R 8A R is independent of R 9A Substituted or unsubstituted alkoxy, or R 9AIt is a substituted or unsubstituted 4-6 member complex ring. In another embodiment, each R 8A R is independent of 9A Substitute or non-substitute C 3~4 Cycloalkyl, or R 9A It is a substituted or unsubstituted 4-6 member complex ring. In one embodiment, R 9A R containing N 9 It is a substituted or unsubstituted 4- to 10-membered heterocycle. In another embodiment, R 9 These are, independently, halogen and unsubstituted C 1~3 Alkyl, or R 10 Substitute or non-substitute C 1~3 It is Alkyridene.

[0163] In one embodiment, R 2 R 8A Substitute or non-substitute C 1~3 It is alkyl, R 8A R 9A Substitute or non-substitute C 1~3 Alkoxy, R 9A Substitute or non-substitute C 3~4 Cycloalkyl, or R 9A It is a complex ring with 4 to 6 members, either substituted or non-substituted.

[0164] In one embodiment, R 9A These are, independently, 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 These 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 complex ring with 4 to 10 members, either substituted or unsubstituted.

[0165] In one embodiment, R 2 R 8A Substitute or non-substitute C 1~3 It is alkyl, R 8A R 9ASubstitute or non-substitute C 1~3 It is alkyl.

[0166] In one embodiment, R 2 R 8A Substitute or non-substitute C 1~3 It is alkyl, R 8A R 9A Substitute or non-substitute C 1~3 It is an alkoxy. In one such embodiment, R 9A R is independent of R 9 Substitute or non-substitute C 3~4 Cycloalkyl or R containing one N heterocycle 9 It is a substituted or unsubstituted 4- to 10-membered heterogly ring. In another such embodiment, R 9A Independently, R contains one N-heterogenetic ring. 9 A substituted or unsubstituted 5 or 6-member monocyclic heteroring, or a 7 or 8-member fused bicyclic heteroring containing one N-heterocyclic ring. In such embodiments, R 9 These are, independently, halogen, oxo, and unsubstituted C 1~3 Alkyl, or R 10 Substitute or non-substitute C 1~3 It is an alkylidene, R 10 This is as described in this specification.

[0167] In another embodiment, R 2 R 8A Substitute or non-substitute C 1~3 It is alkyl, R 8A R 9A Substitute or non-substitute C 3~4 It is a cycloalkyl. In one embodiment, each R 8B These are, independently, 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 Alkyridene.

[0168] In one embodiment, R 2 R 8B It is a substituted or unsubstituted 4- to 10-membered heterogeneous ring. In one such embodiment, R8B This is a halogen, oxo, or unsubstituted C 1~3 It is alkylidene. In one embodiment, R 2 This is R containing one N heteroatom. 8B It is a substituted, or non-substituted, 4, 5, or 7-member complex ring.

[0169] In such one embodiment, R 2 teeth, The filename is TIFF0007862413000064.tif22170.

[0170] In such one embodiment, R 2 teeth, The filename is TIFF0007862413000065.tif18170.

[0171] In one embodiment, R 3 and R 4 These are, independently, hydrogen, -CN, halogen, and unsubstituted C. 1~3 It is alkyl or unsubstituted cyclopropyl. In one embodiment, R 3 and R 4 These are, independently, hydrogen, halogen, or unsubstituted C. 1~3 It is alkyl. In one embodiment, R 3 and R 4 Each is independently hydrogen or halogen. In one embodiment, R 3 and R 4 Neither of them is hydrogen. In another embodiment, R 3 and R 4 One of them is hydrogen, and the other is a halogen. In one embodiment, R 3 is a halogen. In one such embodiment, R 3 is F or Cl. In another embodiment, R 4 is hydrogen. In another embodiment, R 4 is a halogen. In one such embodiment, R 4 It is either F or Cl.

[0172] One embodiment, each R 5 These are, independently, halogen, oxo, and unsubstituted C1~3 Alkyl or unsubstituted C 1~3 It is a haloalkyl. In one embodiment, p is 1, and R 5 is a halogen, oxo, or unsubstituted C 1~3 It is alkyl. In another embodiment, R 5 These are independently oxo or unsubstituted C 1~3 It is alkyl and p is 1. In one such embodiment, n and m together form a 6 or 7-membered ring with p being 1. In another such embodiment, n and m together form a 7-membered ring with p being 0. In one embodiment, n and m together form a 6-membered ring. In one such embodiment, n and m together form a 6-membered ring with p being 0 or 1. In yet another embodiment, n and m together form a 7-membered ring. In one such embodiment, n and m together form a 7-membered ring with p being 0 or 1.

[0173] In one embodiment, p is 0.

[0174] In one embodiment, two R 5 Together, they form a bridge between two carbon atoms of ring A, and the bridge contains 1 to 3 carbon atoms. In one embodiment, two R 5 Together, they form a bridge between two carbon atoms of ring A, and this bridge contains one or two carbon atoms. In one embodiment, the bridge contains one carbon atom. In another embodiment, the bridge contains two carbon atoms. In such one embodiment, the compound of formula (I) is of formula: TIFF0007862413000066.tif75170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 (X and p are as described herein) It has, or is 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) is: TIFF0007862413000067.tif74170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 (X and p are as described herein) It has, or is 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) is: TIFF0007862413000068.tif74170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 (X and p are as described herein) It has, or is a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one such embodiment, p is 0.

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

[0178] In another such embodiment, the compound of formula (II) is: TIFF0007862413000069.tif70170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 8 (X and p are as described herein) is or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt. In such an embodiment, p is 0.

[0179] In another such embodiment, the compound of formula (II1) has the formula: TIFF0007862413000070.tif70170(where R 1 , R 3 , R 4 , R 5 , R 8 , X, and p are as described herein) is or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt. In such an embodiment, p is 0.

[0180] In another such embodiment, the compound of formula (II1) has the formula: TIFF0007862413000071.tif70170(where R 1 , R 3 , R 4 , R 5 , R 8 , X, and p are as described herein) is or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt. In such an embodiment, p is 0.

[0181] In such an 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 Together, they form a bridge between the two carbon atoms of ring A, and the bridge is O or NR 11 It includes one of the following. In one embodiment, the crosslinking includes O. In another such embodiment, the crosslinking includes NR 11 Includes R 11 This is hydrogen, C(O)CH3, or methyl.

[0183] In one embodiment of the compound of formula (I), or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, X is NR 6 In one embodiment, R 6 is hydrogen. In one embodiment, R 6 is R 6A Substitute or non-substitute C 1~6 It is alkyl. In one embodiment, R 6 is hydrogen, or R 6A Substitute or non-substitute C 1~6 Alkyl, R 6A Substitute or non-substitute C 1~6 Alkenyl, or R 6A Substitute or non-substitute C 1~6 It is alkynyl. In one embodiment, R 6 is hydrogen, or R 6A Substitute or non-substitute C 1~6 Alkyl, unsubstituted C 1~6 Alkenyl or unsubstituted C 1~6 In another embodiment, R 6 is hydrogen, or R 6A Substitute or non-substitute C 1~6 It is alkyl. In yet another embodiment, R 6 is hydrogen, or unsubstituted C 1~6 It is alkyl.

[0184] In such one embodiment, R 6 R 6A Substitute or non-substitute C 1~6 If it is Lukil, R 6A Halogen, CN, OR 6B S(O)2R 6C , unsubstituted C1~3 is alkyl or R 6B is a substituted or unsubstituted 4-membered heterocyclic ring. In another such embodiment, R 6 is R 6A substituted or unsubstituted C 1~6 When alkyl, R 6A is halogen, CN, OR 6B , unsubstituted C 1~3 alkyl or R 6B is a substituted or unsubstituted 4-membered heterocyclic ring. In another such embodiment, R 6 is R 6A substituted or unsubstituted C 1~6 When alkyl, R 6A is halogen, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1~3 alkyl or a 4-membered heterocyclic ring.

[0185] In another such embodiment, R 6 is R 6A substituted or unsubstituted C 1~6 When alkyl, R 6A is F, Cl, CN, CH3, OH, OCH3, OCF3, SCH3, SO2CH3, or a combination thereof. In one embodiment, R 6 is R 6A substituted or unsubstituted C 1~6 When alkyl, R 6A is halogen or oxetanyl. In another embodiment, R 6 is unsubstituted C 1~6 alkyl (e.g., methyl).

[0186] In another embodiment, R 6 is R 6A substituted or unsubstituted 3- to 4-membered heterocyclic ring. In such an 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 R 6A Substitute or non-substitute C 1~3 In another embodiment, R 6 R 6A Substitute or non-substitute C 1~3 It is alkynyl. In one embodiment, R 6 is hydrogen. In another embodiment, R 6 It is methyl.

[0188] In one embodiment of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, R 6 is hydrogen, methyl, or formula: The filename is TIFF0007862413000072.tif32170.

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

[0190] In another embodiment, R 6 teeth, TIFF0007862413000073.tif10170 (in the formula, R 6A (These are CH2F, CN, OH, OCH3, OCF3, SCH3, SO2CH3) That is the case.

[0191] In another embodiment, R 6 teeth, TIFF0007862413000074.tif10170 (in the formula, R 6A (These are independently F, CH3, or OCH3.) That is the case.

[0192] In another embodiment, R 6 teeth, TIFF0007862413000075.tif15170 (in the formula, R 6A (This is hydrogen, CH3, or F) That is the case.

[0193] In yet another embodiment, R 6 is hydrogen, methyl, or formula: The filename is TIFF0007862413000076.tif34170.

[0194] In one embodiment, R 6B and R 6C Each of them is independent of C 1~3 It is alkyl.

[0195] In one embodiment, the compound of formula (I) is: TIFF0007862413000077.tif35170 (in the formula, R 1 is the part of formula (A1), (A2), or (B), and R 8 is a part of equation (D1), (D2), (D3), (E), (G), or (G1), where X is NR 6 And R 6 (wherein this is hydrogen, methyl, or a part of formula (Q), (R), or (S)) It has, or is 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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl. 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, they form one or two carbon bridges as described herein.

[0196] In one embodiment, the compound of formula (I) is: TIFF0007862413000078.tif34170 (in the formula, R 1 is the part of formula (A1), (A2), or (B), and R 8is a part of equation (D1), (D2), (D3), (E), (G), or (G1), where X is NR 6 And R 6 (wherein this is hydrogen, methyl, or a part of formula (Q), (R), or (S)) It has, or is 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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl. 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, they form one to two carbon bridges as described herein. In one embodiment, the compound of formula (II1) is used as described herein. * ) has.

[0197] In one embodiment, the compound is given by formula: TIFF0007862413000079.tif78170 (in the formula, R 1 is the part of formula (A1), (A2), or (B), and R 8 is a part of formulas (D1), (D2), (D3), (D4), (D5), (E), (G), or (G1), where X is NR 6 And R 6 (wherein this is hydrogen, methyl, or a part of formula (Q), (R), or (S)) It has, or is 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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl. In yet another embodiment, two R 5 Together, they form one or two carbon bridges as described herein.

[0198] In one embodiment, the compound is given by formula: TIFF0007862413000080.tif78170 (in the formula, R 1 is the part of formula (A1), (A2), or (B), and R 8 is a part of formulas (D1), (D2), (D3), (D4), (D5), (E), (G), or (G1), where X is NR 6 And R 6 (wherein this is hydrogen, methyl, or a part of formula (Q), (R), or (S)) It has, or is 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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl.

[0199] In one embodiment, the compound is given by formula: TIFF0007862413000081.tif78170 (in the formula, R 1 is the part of formula (A1), (A2), or (B), and R 8 is a part of formulas (D1), (D2), (D3), (D4), (D5), (E), (G), or (G1), where X is NR 6 And R 6 (wherein this is hydrogen, methyl, or a part of formula (Q), (R), or (S)) It has, or is 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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl.

[0200] In one embodiment, the compound is given by formula: TIFF0007862413000082.tif78170 (in the formula, R 1 is the part of formula (A1), (A2), or (B), and R 8 is a part of formulas (D1), (D2), (D3), (D4), (D5), (E), (G), or (G1), where X is NR 6 And R 6 (wherein this is hydrogen, methyl, or a part of formula (Q), (R), or (S)) It has, or is 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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl.

[0201] In one embodiment, the compound is given by formula: TIFF0007862413000083.tif114170 (in the formula, R 1 is the part of formula (A1), (A2), (B), or (C), and R 2 is a part of formula (H), (J), (K), (L), (M), or (N), where X is NR 6 And R 6 (This is the part of equation (Q), (R), or (S)). It has, or is 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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl.

[0202] In one embodiment, the compound is given by formula: TIFF0007862413000084.tif114170 (in the formula, R 1 is the part of formula (A1), (A2), (B), or (C), and R 2is a part of formula (H), (J), (K), (L), (M), or (N), where X is NR 6 And R 6 (This is the part of equation (Q), (R), or (S)). It has, or is 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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl.

[0203] Formula (Id), (Ie), (Ig), (Ih), (Id1), (Ie1), (Ig1), (Ih1), (Id1 * ), (Ie1 * ), (Ig1 * ) and (Ih1 * In one embodiment, R is used to describe a compound of ) or a pharmaceutically acceptable salt thereof. 1 This is the part of equation (A1), where each R 7A R is independently hydrogen, halogen, methyl or CF3, as described herein. In one embodiment, the compounds of formula (Id), (Ie), (Ig) and (Ih) or pharmaceutically acceptable salts thereof, R 1 Each R 7 The part of formula (B) is a halogen or methyl as described herein. In such embodiments, R 2 is a part of formula (L), (M), or (N). In another such embodiment, R 2 is a part of formula (H1), (J), (K), or (O). In another such embodiment, R 2 This is part of equation (P). In such an embodiment, X is NR 6 And R 6 is a hydrogen atom, a methyl atom, or a component of formula (Q), (R), or (S). In one embodiment, the formulas (Id), (Ie), (Ig), (Ih), (Id1), (Ie1), (Ig1), (Ih1), (Id1 * ), (Ie1 * ), (Ig1* ), and (Ih1 * ) compounds, or pharmaceutically acceptable salts thereof, or stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof, R 1 is the formula (A1), (A2), (B), or (C), and R 8 is a part of equation (D), (D1), (D2), (D3), (E), or (G), where X is NR 6 , and R 6 is the part of equation (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 It is alkyl. In yet another embodiment, R 4 C 1~6 It is alkyl.

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

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

[0206] In one embodiment, R of the compound described herein 8 This is a part of formula D1, D2, or D3 as described herein.

[0207] In another embodiment, R of the compound described herein 8 This is the part of formula D6 as described in this specification.

[0208] In one embodiment, R of the compound described herein 8 teeth: The filename is TIFF0007862413000085.tif19170.

[0209] Further provided herein is the formula: TIFF0007862413000086.tif253170TIFF0007862413000087.tif203170 (in the formula, R 3 , R 4 , R 5 , R 7A X and P are as defined herein, and R 8 teeth, (This is TIFF0007862413000088.tif70170) It is a compound of the same, or a stereoisomer thereof.

[0210] In one embodiment, the compound of formula (I) described herein, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, is at least 5, 10, 25, 50, 100, 250, 500, 700, 1000, 1300, 1500, 2000, or 3000 times more selective than wild-type (WT) KRas protein for KRas G12D mutant protein.

[0211] In one embodiment, the compound of formula (I) or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts are the compounds listed in Table 1.

[0212] [Table 1] TIFF0007862413000090.tif184170TIFF0007862413000091.tif169170TIFF000 7862413000092.tif181170TIFF0007862413000093.tif176170TIFF00078624130 00094.tif213170TIFF0007862413000095.tif214170TIFF0007862413000096.t if176170TIFF0007862413000097.tif194170TIFF0007862413000098.tif174170 TIFF0007862413000099.tif178170TIFF0007862413000100.tif184170TIFF000 7862413000101.tif196170TIFF0007862413000102.tif163170TIFF00078624130 00103.tif186170TIFF0007862413000104.tif212170TIFF0007862413000105.t if188170TIFF0007862413000106.tif176170TIFF0007862413000107.tif221170

[0213] In one embodiment, the compound of formula (I) or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts are the compounds listed in Table 2.

[0214] [Table 2] TIFF0007862413000109.tif191170TIFF0007862413000110.tif126170TIFF0007862413000111.tif214170

[0215] In one embodiment, the compound of formula (I) or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts are the compounds listed in Table 3.

[0216] [Table 3] TIFF0007862413000113.tif186170TIFF0007862413000114.tif181170TIFF0007862413000115.tif193170TIFF00078624130 00116.tif199170TIFF0007862413000117.tif183170TIFF0007862413000118.tif179170TIFF0007862413000119.tif212170

[0217] Compound Synthesis The compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts can be prepared by various methods shown in the exemplary synthetic reaction schemes 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 from publications such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; RC La Rock, 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, ARKatritzky and CWRees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, ARKatritzky and CWRees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New The compounds are prepared by methods known to those skilled in the art, following the procedures described in references such as York, 1991, vol. 1-40. The following synthesis reactions are merely illustrative of several methods by which the compounds described herein or their pharmaceutically acceptable salts can be synthesized, and various modifications to these synthesis reaction schemes may be suggested to those skilled in the art who refer to the disclosures contained herein.

[0218] For useful synthetic chemical transformations and protecting group methodologies (protection and deprotection) for synthesizing the compounds and necessary reagents and intermediates described herein, see, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 3 rd This includes 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 their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be prepared individually or as a compound library containing at least two compounds, for example, 5 to 1,000 compounds or 10 to 100 compounds. A library of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be prepared by combinatorial split and mixed approaches, or by multiple parallel synthesis using either solution-phase or solid-phase chemistry, for example. Accordingly, in a further embodiment, a compound library containing at least two of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, is provided herein.

[0220] The examples provide exemplary methods for preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Those skilled in the art will understand that the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be synthesized using other synthetic routes. While specific starting materials and reagents are described and discussed in the examples, various derivatives and / or reaction conditions can be provided by substituting other starting materials and reagents. Furthermore, many of the exemplary compounds prepared by the described methods can be further modified using conventional chemistry in consideration of this disclosure.

[0221] When preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, protection of distant functional groups (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection depends on the nature of the distant functional group and the conditions of the preparation method. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is easily determined. For a general description of protecting groups and their uses, see TW Greene, "Protective Groups in Organic Synthesis," John Wiley & Sons, New York (1991).

[0222] In methods for preparing the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, it may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products from each step or series of steps are separated and / or purified to a desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may 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 analysis, pseudo-moving bed (SMB) and preparative thin-layer or thick-layer chromatography, and small-scale thin-layer and flash chromatography techniques.

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

[0224] Diastereomer mixtures can be separated into their individual diastereomers based on their physicochemical differences, for example, by chromatography and / or fractionation crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or mossac acid chloride), separating the diastereomers, and converting the individual diastereoisomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, may also be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated using a chiral HPLC column.

[0225] By separating a racemic mixture using methods such as the generation of diastereomers with optically active resolving agents, a single stereoisomer substantially free of its stereoisomers, such as an enantiomer, can be obtained (Eliel, E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994; Lochmuller, CH, (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds or pharmaceutically acceptable salts thereof described herein can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomer salts with the chiral compound and separation by fractional recrystallization or other methods; (2) formation of diastereomer compounds with chiral derivatization reagents, separation of diastereomers and conversion to pure stereoisomers; and (3) separation of substantially pure or concentrated 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), diastereomer salts can be formed by the reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and α-methyl-β-phenylethylamine (amphetamine) with asymmetric compounds having acidic functional groups such as carboxylic acids and sulfonic acids. The diastereomer salts can be separated by fractional recrystallization or ion chromatography. Diastereomer salts can be formed by adding chiral carboxylic acids or sulfonic acids such as camphor sulfonic acid, tartaric acid, mandelic acid, or lactic acid to separate the optical isomers of amino compounds.

[0227] Alternatively, by method (2), the substrate to be separated is reacted with one enantiomer of the chiral compound to form a diastereomer pair (E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc. (1994), p. 322). Diastereomer compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing reagent such as a menthyl derivative, followed by separation of the diastereomer and hydrolysis to obtain a pure or concentrated enantiomer. Methods for determining optical purity include preparing a chiral ester such as a menthyl ester of a racemic mixture (e.g., (-)menthyl chloroformate) in the presence of a base or moscher ester, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem. (1982) 47:4165), and determining the presence of two atropisomer enantiomers or diastereomers. 1This includes analyzing the 1H NMR spectrum. Stable diastereomers of atropisomer compounds can be separated and isolated by normal-phase and reverse-phase chromatography following the method for separating atropisomer naphthyl-isoquinolines (International Publication No. 96 / 15111). Method (3) allows separation of a racemic mixture 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). Enantiomers can be distinguished by methods used to distinguish other chiral molecules with chiral carbon atoms, such as optical rotation and circular dichroism.

[0228] The chemical reactions described herein can be readily adapted to prepare other compounds and their pharmaceutically acceptable salts described herein. For example, the synthesis of compounds not exemplified herein and their pharmaceutically acceptable salts can be successfully carried out with modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by using other suitable reagents known in the art that are not described herein, or by making customary modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as applicable to preparing other compounds and their pharmaceutically acceptable salts described herein.

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

[0230] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be formulated as pharmaceutical compositions in accordance with standard pharmaceutical practices. Accordingly, pharmaceutical compositions comprising the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable additives are also provided herein.

[0231] Typical formulations are prepared by mixing the compounds described herein or their pharmaceutically acceptable salts with additives. Suitable carriers, diluents, and additives include, but are not limited to, carbohydrates, waxes, water-soluble and / or swelling polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water. The specific additives used depend on the means and purpose to which the compounds described herein or their pharmaceutically acceptable salts are applied. Solvents are generally selected based on solvents that are recognized as GRAS (Generally Recognized As Safe) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in water or miscible. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, flow enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, and other known additives to provide accurate presentation of a drug (i.e., a compound or pharmaceutical composition thereof) or to assist in the manufacture of a pharmaceutical (i.e., a pharmaceutical).

[0232] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the active pharmaceutical ingredient (bulk drug substance) (i.e., the 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 complex-forming agent)) is dissolved in a suitable solvent in the presence of one or more of the additives described above. The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are typically formulated into pharmaceutical dosage forms to provide easily controllable drug doses and enable patient compliance in a given 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, dispensing articles include containers in which the pharmaceutical formulation is placed in a suitable form. Suitable containers include bottles (plastic and glass), pouches, ampoules, plastic bags, and metal cylinders. Containers may also include tamper-evident assemblies to prevent unintentional access to the contents of the package. In addition, containers have labels on them that describe the contents of the container. Labels 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 of desired purity, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, may optionally be mixed with one or more pharmaceutically acceptable additives (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.) in the form of a lyophilized formulation, a pulverized powder, or an aqueous solution. The formulation may be prepared by mixing at ambient temperature, at a suitable pH, and to a desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to the recipient at the dose and concentration used. The pH of the formulation may be in the range of about 3 to about 8, but mainly depends on the specific application and the concentration of the compound. For example, a formulation in acetate buffer at pH 5 may be a preferred embodiment.

[0235] Pharmaceutical compositions can usually be stored as solid compositions, lyophilized preparations, or aqueous solutions.

[0236] The pharmaceutical compositions described herein may be formulated, prescribed, and administered in a manner that is appropriate for sufficient medical utility, i.e., in terms of quantity, concentration, schedule, course, vehicle, and route of administration. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical symptoms of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration scheduling, and other factors known to the physician. The effective amount of the compound administered, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, is controlled by such considerations and is the minimum amount necessary to improve or treat the hyperproliferative disorder.

[0237] As a general suggestion, the initial pharmaceutically effective dose of a parenterally administered compound, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, would be approximately 0.01–100 mg / kg of the patient's body weight per day, i.e., in the range of approximately 0.1–20 mg / kg, with a typical initial range of 0.3–15 mg / kg / day for the compound used. In another embodiment, the pharmaceutical composition described herein contains an effective amount of the compound described herein, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable Br salts, in amounts of approximately: 1 mg to 10 mg; 10 mg to 25 mg; 20 mg to 50 mg; 50 mg to 75 mg; 70 mg to 100 mg; 100 mg to 150 mg; 100 mg to 200 mg; 100 mg to 500 mg; 200 mg to 500 mg; 250 mg to 500 mg; 500 mg to 1000 mg; or 750 mg to 1000 mg.

[0238] Acceptable pharmaceutically acceptable additives are non-toxic to the recipient at the dosage and concentration used and include buffers (such as phosphoric acid, citrate, and other organic acids); antioxidants and preservatives including ascorbic acid and methionine (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens (such as methyl or propylparaben); catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than approximately 10 residues) polypeptides; and proteins (such as serum albumin). This includes 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 nonionic surfactants (such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG)). The active pharmaceutical ingredient may also be incorporated into colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsifies, nanoparticles, and nanocapsules) or macroemulsifies, for example, in microcapsules prepared by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively. 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 pharmaceutically acceptable salts thereof may be prepared. A preferred example of a sustained-release formulation is a semipermeable matrix of a solid hydrophobic polymer containing the compounds described herein or pharmaceutically acceptable salts thereof, the matrix being, for example, in the form of a molded article such as a film or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactide (US Patent No. 3773919), copolymers of L-glutamic acid and ethyl γ-L-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 be conveniently presented in unit dosage forms 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 associating an active ingredient with a carrier constituting one or more minor components. Generally, formulations are prepared by homogeneously and closely associating an active ingredient with a liquid carrier or a micronized solid carrier, 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 separate units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of such compound, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed optionally with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be produced by molding a mixture of moistened powdered active ingredient and an inert liquid diluent in a suitable machine. Tablets may optionally be coated or grooved and formulated to optionally provide a slowed or controlled release of the active ingredient therefrom. Tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsifiers, hard or soft capsules, such as gelatin capsules, syrups, or elixirs may be prepared for oral use. Preparations of the compounds described herein or pharmaceutically acceptable salts thereof intended for oral use may be prepared according to any method for producing pharmaceutical compositions, 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 the manufacture of tablets may be acceptable. These additives may include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques, including microencapsulation, to slow their disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

[0242] For the treatment of the eyes or other external tissues, such as the mouth and skin, the formulation is preferably applied as a topical ointment or cream containing an amount of the active ingredient in the range 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 may contain polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG400), and mixtures thereof. Topical formulations may optionally contain compounds that enhance the 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 analogs. The oily phase of the emulsifier of the compositions provided herein may consist of known components in known forms. The phase may simply contain an emulsifier, but preferably contains a mixture of at least one emulsifier with a fat or oil, or both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferable to include both oil and fat. In summary, emulsifiers with or without stabilizers constitute a so-called emulsifying wax, and the wax together with oil and fat constitutes a so-called emulsifying ointment base that forms the oily dispersion phase of the cream formulation. Suitable emulsifiers and emulsifying 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 active materials mixed with additives suitable for the preparation of aqueous suspensions. Such additives include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersants or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide and partial esters derived from fatty acids and anhydrous hexitol (e.g., polyethylene sorbitan monooleate). The aqueous suspension also contains one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

[0244] Pharmaceutical compositions of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, may also be in the form of sterile injectable preparations, such as aqueous or oily sterile injectable suspensions. These suspensions may be formulated using the appropriate dispersants or wetting agents and suspending agents described above. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or may be prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterilization fixatives may conventionally be used as solvents or suspensions. For this purpose, any non-irritating, non-volatile oil, including synthetic monoglycerides or synthetic diglycerides, may be used. In addition, fatty acids such as oleic acid may similarly be used in the preparation of injectable preparations.

[0245] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific 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, combined with a suitable and convenient amount of carrier material, which can vary from approximately 5 to approximately 95% (by weight) of the total composition. Pharmaceutical compositions may be prepared to provide an amount that is easily measurable for administration. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 to 500 μg of active ingredient per milliliter of solution so that a suitable volume is injected at a rate of approximately 30 mL / hour.

[0246] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the preparation isotonic with the blood of the target recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0247] Formulations suitable for topical administration to the eye include ophthalmic solutions, in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at 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 oral administration include flavored bases, lozenges typically containing the active ingredient in sucrose and acacia or tragacanth, inert bases such as gelatin and glycerin, or flavored tablets containing the active ingredient in sucrose and acacia, and mouthwashes containing the active ingredient in a suitable liquid carrier.

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

[0250] Formulations suitable for intrapulmonary or nasal administration have particle sizes ranging from 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in units of microns such as 0.5, 1, 30, and 35 microns), and are administered by rapid inhalation through the nostrils or by inhalation through the mouth to reach the alveolar sacs. 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 for the treatment or prevention of the disorders described below.

[0251] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations, and may include an active ingredient along with a suitable carrier.

[0252] The formulations may be packaged in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as water, for injection immediately before use. Instantaneous injectable solutions and suspensions are prepared from the aforementioned types of sterile powders, granules, and tablets. Preferred unit-dose formulations contain the daily dose or daily unit secondary dose of the active ingredient as described herein, or appropriate fractions 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 a compound or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt. A prodrug as defined herein includes a derivative comprising 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 properties, and is converted into a bioactive substance or a more bioactive substance provided herein. In one embodiment, the prodrug herein does not have biological activity until the release of the compound or its pharmaceutically acceptable salt.

[0254] Method of administration The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, may be administered by any route appropriate to the condition being treated. Preferred routes include oral, parenteral (including subcutaneous, intramuscular, intravenous (IV), intra-arterial, intradermal, intrathecal, and epidural), percutaneous, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal administration. In one embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are administered orally or IV. For topical immunosuppressive treatment, the compounds may be administered intralesion, including perfusion of the graft with the inhibitor or other means prior to transplantation. It will be understood that preferred routes may vary, for example, with the recipient's condition. When a compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, is administered orally, it may be formulated as pills, capsules, tablets, etc., together with a pharmaceutically acceptable carrier or excipient. When a compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, is administered parenterally, it may be formulated as injectable unit dosages together with a pharmaceutically acceptable parenteral vehicle, as detailed below.

[0255] Accordingly, in one embodiment, a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives is provided herein. In one embodiment, a 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. A 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 in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion, or otherwise suspended.

[0256] Oral administration can facilitate patient compliance when taking the compound (e.g., formulated as a pharmaceutical composition), thereby enhancing compliance and efficacy. Oral pharmaceutical compositions containing the compounds described herein include, but are not limited to, tablets (e.g., coated, uncoated, chewable) and capsules (e.g., rigid 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 containing the compounds described herein can be formulated for delayed-release or long-release.

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

[0258] Treatment method and use The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as Ras inhibitors. In one embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as KRas inhibitors. In another embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as NRas inhibitors. In yet another embodiment, 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] This specification provides a method for inhibiting Ras activity (e.g., KRas activity) in cells, such as ex vivo cells, by contacting them 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] A method for treating cancer containing a KRas mutation is further provided herein, comprising administering an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition, to a patient having such cancer. In one embodiment, the KRas mutation is KRas G12D It is a mutation.

[0261] In one embodiment, the method is KRas G12D This further includes testing a sample from a patient (for example, as described herein) for the absence or presence of mutations before administration of the compound described herein or a pharmaceutically acceptable salt thereof. In one such embodiment, the compound described herein, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, or pharmaceutical composition thereof, is tested if the patient sample is KRasG12D It is administered to the patient after they have tested positive for a mutation (for example, for the presence of a mutation).

[0262] The methods for treating cancer described herein include acute myeloid leukemia, adolescent cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astroglioma, atypical malformation / rhabdoid tumors, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, embryonic tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CM). L) Chronic myeloproliferative disorders, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancers, endometrial 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, trophoblastic tumors of pregnancy, pilocytic cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic Neuroendocrine tumors, kidney cancer, laryngeal cancer, lip cancer and oral cancer, non-invasive lobular carcinoma (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, median line carcinoma, oral cancer, multiple endocrine neoplastic syndrome, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, oropharyngeal This relates to the treatment of cancers such as cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblast tumor, childhood abnormal cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers.

[0263] In some embodiments, the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendiceal cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. The lung cancer may 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 are also KRas G12D The presence or absence of mutations may include testing a sample from a patient before administration of the compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the compound, its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, or pharmaceutical composition, is used to determine if the patient sample is KRas G12D It is administered to the patient after the presence of the mutation is indicated. In one embodiment, the compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered to the patient sample if the KRas 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 trans-historical (KRas G12D (Including mutations).

[0266] KRas G12DFurther provided herein are methods for treating lung cancer containing mutations in a patient having such lung cancer, comprising administering to the patient an effective amount of the compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt (or a pharmaceutical composition containing them). In one embodiment, the lung cancer is non-small cell lung carcinoma (NSCLC). NSCLC may be, for example, adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma. In another embodiment, the lung cancer is small cell lung carcinoma. In yet another embodiment, the lung cancer is an adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. One method provided herein is to administer 1 L of the compound as a treatment.

[0267] KRas G12D A method for treating a mutated pancreatic cancer in a patient having such pancreatic cancer is further provided herein, 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 are methods for treating a mutated 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 II. In another embodiment, the colon cancer is stage III or IV.

[0269] KRas G12D Methods for treating trans-tissue cancers, including mutations, are further provided herein. In one embodiment of such a method, the method is (a)(a) KRas in samples taken from patients diagnosed with suspected cancer G12D Measuring the absence or presence of a mutation, (b) (b) administering to a patient an effective amount of the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

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

[0271] Compounds for use as therapeutically active substances, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are also provided herein. In one such embodiment, the compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, is KRas G12D It may be for the therapeutic treatment of cancer, including mutations. KRas G12D Compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, for therapeutic and / or prophylactic treatment of cancers including mutations are further provided herein. In one embodiment, the compound, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof are KRas G12DIt is used in the preparation of pharmaceuticals for the therapeutic treatment of cancers, including mutations. The use of the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts in the manufacture of pharmaceuticals for inhibiting tumor metastasis is further provided herein.

[0272] Methods for inhibiting tumor metastasis are further provided herein, comprising administering a therapeutically effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to a patient having a tumor. In one embodiment, inhibition is performed by KRas G12D This involves inhibition of tumors, including mutations. In another embodiment, inhibition of tumor metastasis in the patient described herein results in a reduction in tumor size. In another embodiment, inhibition of tumor metastasis in the patient described herein results in stabilization of tumor size (e.g., no further growth). In another embodiment, inhibition of tumor metastasis in the patient described herein results in remission of cancer and / or its symptoms.

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

[0274] A method for inhibiting KRas in a patient requiring treatment is further provided herein, 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 to be inhibited is KRas G12D In another embodiment, inhibiting KRas reduces tumor size. In yet another embodiment, inhibiting KRas leads to remission of cancer and / or its symptoms.

[0275] Furthermore, methods for regulating the activity of KRas mutant proteins are provided herein, 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 KRas G12D This includes mutations. In one embodiment, the activity of KRas decreases after contact with the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. In another embodiment, downregulation of the activity of a KRas mutant protein treats the cancer described herein in the patient described herein. In another embodiment, downregulation of the activity of a KRas mutant protein results in a reduction of tumor size. In another embodiment, downregulation of the activity of a KRas mutant protein results in remission of the cancer and / or its symptoms described herein.

[0276] In some embodiments, the methods provided herein involve treating cells as KRas in those cells. G12D By contacting the cells with a sufficient amount of the compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the activity of KRas can be inhibited. G12D This includes inhibiting activity. In some embodiments, the methods provided herein involve treating a tissue as a KRas G12D By contacting the tissue with a sufficient amount of the compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the activity of KRas can be inhibited. G12D This includes inhibiting activity. In some embodiments, the methods provided herein involve treating a patient described herein as having KRas G12D Contacting the patient with a sufficient amount of the compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to inhibit the activity of KRas G12D This includes inhibiting activity.

[0277] Labeled KRas G12D A method for preparing mutant proteins, and KRas G12D The mutant protein is reacted with a labeled compound described herein, or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt, to produce labeled KRas G12D Methods for obtaining mutant proteins are further provided herein. In one embodiment, the label is a contrast agent. In one embodiment, labeled KRas G12D This method can be used to detect the presence or absence of G12D variant KRas in patient samples, thereby detecting the presence or absence of cancer mediated by the variant KRas.

[0278] Methods for inhibiting Ras-mediated cellular signaling are further provided herein. In one embodiment, the method involves contacting cells with an effective amount of one or more compounds disclosed herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Inhibition of Ras-mediated signaling can be assessed and demonstrated by various methods known in the art. Non-limiting examples include (a) a decrease in Ras GTPase activity, (b) a decrease in GTP binding affinity or an increase in GDP binding affinity, (c) an increase in GTP Koff or a decrease in GDP Koff, (d) a decrease in pMEK levels, a decrease in the amount of signaling molecules downstream of the Ras pathway, and / or (e) a decrease in the binding of the Ras complex to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays can be used to measure one or more of the above.

[0279] KRas mutations, including the G12D variant, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, certain embodiments relate to the administration (e.g., in the form of pharmaceutical compositions) of the compounds disclosed herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, to patients requiring treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds disclosed herein can be used to treat diseases such as acute lymphoblastic 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 lymphomas such as Hodgkin lymphoma or all subtypes of non-Hodgkin lymphoma.

[0280] Tumor or cancer is KRas G12D Determining whether or not a mutation is present can be done by evaluating the nucleotide sequence encoding the KRas protein, by evaluating the amino acid sequence of the KRas protein, or by evaluating the characteristics of the predicted KRas mutant protein. The sequence of wild-type human KRas (e.g., accession number NP203524) is publicly known in the art.

[0281] Methods for detecting mutations in the KRas nucleotide sequence 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 higher-order structure 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 thawing assays, and microarray analysis. In some embodiments, a sample is evaluated for the G12D KRas mutation by real-time PCR. In real-time PCR, a fluorescent probe specific to 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 a specific region of the KRas gene (e.g., exon 2 and / or exon 3). This method identifies all possible mutations within the sequenced region.

[0282] Tumor or cancer is KRas G12D Methods for determining whether a sample contains mutations can utilize 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 treated with a cell lysate. In some embodiments, the sample is treated with DNA or RNA.

[0283] The use of the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts in the manufacture of pharmaceuticals for treating cancer is further provided herein. In some embodiments, the pharmaceutical is formulated for oral administration. In some embodiments, the pharmaceutical is formulated for injection (e.g., IV administration). In some embodiments, cancer is treated with KRas G12D This includes mutations. In some embodiments, the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, 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 the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts in the manufacture of a pharmaceutical product for inhibiting tumor metastasis.

[0284] Compounds described herein or pharmaceutically acceptable salts thereof for use in methods of treating cancer are further provided herein. In one embodiment, cancer is treated with KRas G12D This includes mutations. In one such embodiment, the cancer is 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, may be used alone or in combination with other therapeutic agents for the treatment of the diseases or disorders described herein. The second compound in a combination drug formulation or drug regimen preferably has complementary activity to the compounds described herein or their pharmaceutically acceptable salts, such that they do not adversely affect each other. Combination therapy provides a “synergistic effect,” meaning that the effect achieved is “synergistic,” i.e., greater than the combined effect of the active ingredients used together than the combined effect of the compounds used individually.

[0286] Combination therapy may be administered as a concurrent regimen or a sequential regimen. When administered sequentially, the combination is administered in two or more doses. Combination administration may include co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in either order, preferably allowing time for both (or all) activators to exert their biological activity simultaneously.

[0287] The combination therapy described herein involves the administration of the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and the use of at least one other treatment method. The amounts and relative timing of administration of the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and other pharmaceutically active agents(s) will be selected to achieve the desired combined therapeutic effect.

[0288] In various embodiments of the method, additional therapeutic agents include epidermal growth factor receptor (EGFR) inhibitors, phosphatidylinositol kinase (PI3K) inhibitors, insulin-like growth factor receptor (IGF1R) inhibitors, Janus kinase (JAK) inhibitors, Met kinase inhibitors, SRC family kinase inhibitors, mitogen-activated protein kinase (MEK) inhibitors, extracellular signal-regulated kinase (ERK) inhibitors, topoisomerase inhibitors (such as irinotecan, etoposide, or doxorubicin), taxanes (such as anti-microtubule inhibitors including paclitaxel and docetaxel), antimetabolites (such as 5-FU, or gemcitabine), or alkylating agents (such as cisplatin, or cyclophosphamide), or taxanes.

[0289] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as erlotinib or afatinib. In some embodiments, the additional therapeutic agent is gefitinib, osimertinib, or dacomitinib. In some embodiments, the additional therapeutic agent is a monoclonal antibody, such as cetuximab (erbitux) or panitumumab (vectibix). In some embodiments, the GFR inhibitor is a bipolar or pan-HER inhibitor. In other embodiments, the additional therapeutic agent is a phosphatidylinositol-3-kinase (PI3K) inhibitor, such as GDC-0077, GDC-0941, MLN1117, BYL719 (alpelisib), or BKM120 (buparlicib). GDC-0941 means 2-(1H-indazole-4-yl)-6-(4-methanesulfonylpiperazine-1-ylmethyl)-4-morpholine-4-ylthieno[3,2-d]pyrimidine, or a salt thereof (e.g., bismesylate salt).

[0290] In further 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 (lincitinib) or BMS-754807. Alternatively, in other embodiments, the additional therapeutic agent is an IGF1R-specific neutralizing monoclonal antibody, such as AMG-479 (ganitumab), CP-751, 871 (physitumumab), IMC-A12 (sixtumumab), MK-0646 (darotuzumab), or R-1507 (lovatumumab).

[0291] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, restaurtinib, momerotinib, 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 codolituzumab.

[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. In some embodiments, the MDM2 antagonist is idasanuturin.

[0295] In some other embodiments, the additional therapeutic agent is an agonist antibody against CD40. In some embodiments, the agonist antibody against CD40 is sericrelumab (RG7876).

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

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

[0298] In some other embodiments, the additional therapeutic agent is an antibody that targets the colony-stimulating factor 1 receptor (CSF-1R). In some embodiments, the CSF-1R antibody is emuctuzumab.

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

[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 onaltubumab.

[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. An exemplary inhibitor in this regard is dasatinib. Other examples in this regard include ponatinib, salakatinib, and bosutinib.

[0305] In yet another embodiment, 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 another embodiment, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0306] In yet another embodiment, 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 inhibitors include tasericib, ipatasericib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, atezolizumab, bevacizumab, vosututinib, cetuximab, crizotinib, dasatinib, and These include rulotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, or vemurafenib. In still further embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some further embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include taxol and docetaxel.

[0308] In addition to the additional therapeutic agents described above, other chemotherapeutic agents currently known in the art may 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 mitotic inhibitors, alkylating agents, antimetabolites, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, bioresponse modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0309] Non-limiting examples include chemotherapeutic agents, cytotoxic agents, non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and Adriamycin, as well as hosts for chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocon, metsuredopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; chloramb Nitrogen mustards such as chlornafadin, cyclophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobenbitin, fenestrine, prednimastine, trophosphamide, uracil mustard; nitrosoureas such as carmastine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; acrasinomycin, actinomycin, anthramycin, azaserine, b Rheomycin, kactinomycin, calicheamycin, carabicin, carminomycin, cardinophilin, Casodex (trademark), chromomycin, dactinomycin, daunorubicin, detrubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, keratin Antibiotics such as mycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folate analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur,Pyrimidine analogs such as cytarabine, dideoxyuridinene, doxifluridine, enocitabine, and fulociuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal agents such as aminoglutethimide, mitothein, and trilostane; folic acid supplements such as folinic acid; acegraton; aldofasphamide glycoside; aminolevulinic acid; amsacrin; bestrabusil; bisantren; edatrexate; defofamine; demecoltin; diazicone; elfomitin; eriptinium acetate; etogluside; gallium nitrate; hydroxyurea; Lentinan; Ronidamin; Mitoguazone; Mytoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide K; Lazoxane; Schizophyllan; Spirogermanium; Tenuazonic acid; Triadiquan; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxane (e.g., Paclitaxel (TAXOL®, Bristol-Myers) Examples of suitable chemotherapeutic cytomodulators include, for example, tamoxifen (Nolvadex®), raloxifen, aromatase inhibitor 4(5)imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and toremifene (Fairston); flutamide, nilutamide, bicalutamide, leuprolide,Other examples include anti-androgens such as 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); topoisomerase inhibitor RFS 2000; and anti-estrogens including difluoromethylornithine (DMFO), which have the effect of regulating or inhibiting hormonal activity in tumors. If desired, the compounds described herein or their pharmaceutically acceptable salts, or pharmaceutical compositions may be used as Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxot ere(registered trademark), ABVD, AVICINE, avagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfarazine, arbocidib, 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone, amonafide, anthracendione, anti-CD22 immunotoxin, antitumor drug, tumor-inhibiting herb, apadiquon, atiprimod, azathioprine, berotecan, bendamustine, BIBW 2992, Bilicodal, Brostarisin, Briostatin, Butionine sulfoximine, CBV (chemotherapy), Kalikrin, Cell cycle nonspecific anti-cancer drug, Dichloroacetate, Discodermolide, Elsamitrusine, Enocitabine, Epothiron, Eribulin, Everolimus, Exatecan, Exrind, Ferginol, Forodesine, Phosfestol, ICE chemotherapy regimen, IT-101, Imexone, Imiquimod, Indocarbazole, Ilofluben, Lanikidal, Lalotaxel, Lenalidomide, Lucanson, Lulutotecan, Mafosfamide,It can be used in combination with commonly prescribed anticancer drugs such as mitozolomide, napoximide, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, reximod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swinesonin, talaporfin, talikidal, tegafur-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, bajimezan, vinflunin, ZD6126, or zoskidal.

[0310] The precise method for administering the compound and additional therapeutic agents will be apparent to those skilled in the art. In some exemplary embodiments, the compound and additional therapeutic agents are administered simultaneously. In other embodiments, the compound and additional therapeutic agents are administered separately.

[0311] In some embodiments, the compound and the additional therapeutic agent are administered simultaneously with the second agent or individually. These combinations include simultaneous administration of the two active agents in the same dose formulation, simultaneous administration of separate dose formulations, and individual administration. That is, the compound and any of the additional therapeutic agents described herein can be formulated together in the same dose formulation and administered simultaneously. Alternatively, the compound and any of the additional therapeutic agents described herein can be administered simultaneously, in which case both active agents are present in separate formulations. In another alternative form, 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 individual administration protocol, the compound and any of the additional therapeutic agents described herein are administered at intervals of several minutes, several hours, or several days.

[0312] manufactured goods Products or “kits” containing materials useful for the treatment of cancer, as provided herein, are also 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 accompanying documentation on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, and blister packs. Containers may be formed from a variety of materials, such as glass or plastic. Containers may have a sterile access port and may hold a compound described herein or a pharmaceutically acceptable salt thereof, or a formulation thereof, that is effective in treating a symptom (for example, the container may be an intravenous solution bag or a vial with a stopper that can be pierced with a subcutaneous needle). At least one activator in the composition is a compound described herein or a pharmaceutically acceptable salt thereof. Alternatively, the product may further include a second container containing a pharmaceutical diluent such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution. The product may further include other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0313] In another embodiment, the kit is suitable for the delivery of a solid oral form (e.g., a tablet or capsule) of the compounds described herein or pharmaceutically acceptable salts thereof. Such a kit may contain a large number of unit doses. An example of such a kit is a "blister pack," which is well known in the packaging industry and is widely used for packaging unit dose forms of pharmaceuticals. Embodiment

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

[0315] Embodiment 1. Formula (I): TIFF0007862413000120.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 ring A with 6, 7, or 8 members. Each R 0 These are independently hydrogen or methyl, R 1 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 These are independently hydrogen, halogen, -OH, NH2, N(Me)2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 It is a haloalkyl or unsubstituted cyclopropyl, Each R 7A These are independently hydrogen, halogen, NH2, N(Me)2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 It is a haloalkyl or unsubstituted cyclopropyl, R 2 is hydrogen, L 1 -OL 2 -R 8 , R 8A Substitute or non-substitute C 1~3 Alkyl, or R 8B A complex ring with 4 to 10 members, either substituted or unsubstituted. Here, R 2 is hydrogen, R 1 R 7 If it is a substituted indazolyl and n and m are 1, then p is not 0, and R 6 It is not H, L 1 is a combination or R L1 Substitute or non-substitute C 1~3 It is alkylene, R L1 is halogen or unsubstituted C1~3 It is alkyl, L 2 is bonded or unsubstituted C 1~3 It is alkylene, R 8 R containing N, S, or O 9 A substituted or unsubstituted 4-10 member complex ring, Each R 9 These are independently halogen, oxo, -OCF3, -OCHF2, -OCH2F, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10 Substitute or non-substitute C 1~3 Alkyridene, or R 10 Substitute or non-substitute C 3~4 Cycloalkyl, or R 10 It is a substituted or non-substituted 3- or 4-membered heterogeneous ring, or 2 R 9 Together, R 10 Substitute or non-substitute C 3~5 Cycloalkyl, or R containing one or more oxygen atoms 10 Forming substituted or unsubstituted C3-5 heterorings, R 10 is hydrogen, halogen, or C 1~3 It is an unsubstituted alkyl group, Each R 8A R is independent of R 9A Substitute or non-substitute C 1~3 Alkyl, R 9A Substitute or non-substitute C 1~3 Alkoxy, R 9A Substitute or non-substitute C 3~4 Cycloalkyl, or R 9A A complex ring with 4 to 6 members, either substituted or unsubstituted. Each R 9A These are, independently, halogen, oxo, and unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 alkoxy, unsubstituted C 1~3 Alkyridene, R 9 Substitute or non-substitute C 3~4Cycloalkyl, or R containing N, S, or O 9 A complex ring with 4 to 10 members, either substituted or unsubstituted. R 8B These are, independently, halogen, oxo, -NH2, and unsubstituted C. 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 alkoxy or unsubstituted C 1~3 It is alkyridene, R 3 and R 4 These are, independently, hydrogen, -CN, halogen, and unsubstituted C. 1~3 Alkyl or unsubstituted cyclopropyl, Each R 5 These are, independently, halogen, oxo, and unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 It is a haloalkyl, or 2 R 5 Together, they form a bridge between two carbon atoms of ring A, the bridge comprising 1 to 3 carbon atoms and optionally 1 heteroatom selected from O and N, or 2 R 5 Together, they form a bridge between two carbon atoms of ring A, and the bridge is O or NR 11 Includes one of the following: R 11 is hydrogen, C(O)CH3, or unsubstituted C 1~3 It is alkyl, R 6 is hydrogen or R 6A Substitute or non-substitute C 1~6 Alkyl, R 6A Substitute or non-substitute C 1~6 Haloalkyl, R 6A Substitute or non-substitute C 1~6 Alkenil, R 6A Substitute or non-substitute C 1~6 Alkinyl, or R 6A A complex ring with 3-4 members, either substituted or non-substituted. R 6A Halogen, CN, OR 6B , SR 6C S(O)2R 6C, C(O) R6B , unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 Haloalkyl, R 6B A complex ring with 3-4 members, either substituted or non-substituted. R 6B and R 6C Each of them is independent of C 1~3 Alkyl or C 1~3 (It is a haloalkyl) Compounds having, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof.

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

[0317] Embodiment 3.1 R 0 However, it is hydrogen, and one R 0 The compound according to claim 1, wherein the compound is methyl.

[0318] Embodiment 4. Structure: The compound according to claim 3, having TIFF0007862413000121.tif34170.

[0319] Embodiment 5.R 1 However, R 7 Substituted or unsubstituted phenyl, R 7 Substituted or unsubstituted indazolyl, or R 7 The compound according to claim 1, which is a substituted or unsubstituted pyridinyl.

[0320] Embodiment 6.R 1 However, R 7 The compound according to any one of claims 1 to 5, wherein it is a substituted or unsubstituted phenyl.

[0321] Embodiment 7.R 1 However, R 7 The compound according to any one of claims 1 to 5, wherein it is substituted or unsubstituted indazolyl.

[0322] Embodiment 8.R1 However, R 7 The compound according to any one of claims 1 to 5, which is a substituted or unsubstituted pyridinyl.

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

[0324] Embodiment 10.R 1 but, TIFF0007862413000122.tif21170 (in the formula, X 1 is N or CF, R 7A This is hydrogen, halogen, and unsubstituted C. 1~3 Alkyl or unsubstituted C 1~3 (It is a haloalkyl) The compound according to any one of claims 1 to 5.

[0325] Embodiment 11.R 1 but, The compound according to any one of claims 1, 5, 8, or 10, which is TIFF0007862413000123.tif21170.

[0326] Embodiment 12.R 1 but, The compound according to any one of claims 1, 5, 8, 10, or 11, which is TIFF0007862413000124.tif20170.

[0327] Embodiment 13.R 1 but, TIFF0007862413000125.tif25170 (in the formula, R 7 This is hydrogen, halogen, and unsubstituted C. 1~3 Alkyl or unsubstituted C 1~3 (It is a haloalkyl) The compound according to any one of claims 1 to 6 or 10.

[0328] Embodiment 14.R 1 but, The compound according to any one of claims 1 to 6, 10, or 13, which is TIFF0007862413000126.tif24170.

[0329] Embodiment 15.R 1 but, TIFF0007862413000127.tif27170 (in the formula, each R 7 These are independently halogens, NH2, N(Me)2, or unsubstituted C 1~3 (It is alkyl.) The compound according to any one of claims 1 to 5.

[0330] Embodiment 16.R 2 However, L 1 -OL 2 -R 8 , R 8A Substitute or non-substitute C 1~3 Alkyl, or R 8B The compound according to any one of claims 1 to 15, which is a substituted or unsubstituted 4- to 6-membered heterocycle.

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

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

[0333] Embodiment 19.L 2 However, non-substituted C 1~3 The compound according to any one of claims 16 to 18, which is an alkylene.

[0334] Embodiment 20.R 8 The compound according to any one of claims 16 to 19, wherein the compound is a 4- to 10-membered heterocycle containing one N heteroatom.

[0335] Embodiment 21.R 8 but, TIFF0007862413000128.tif19170 (in the formula, R 9 is halogen, or R 10 Substitute or non-substitute C 1~3 It is alkyridene, r is an integer between 0 and 12. j is 1, 2, or 3. k is either 1 or 2. The compound according to any one of claims 16 to 20.

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

[0337] Embodiment 23.R 8 but, TIFF0007862413000129.tif33170 (in the formula, R 9 It is independently halogen, or R 10 Substitute or non-substitute C 1~3 It is alkyridene, Each R 10 These are independently hydrogen or halogen, (r is either 1 or 2) The compound according to any one of claims 16 to 22.

[0338] Embodiment 24.R 8 but, TIFF0007862413000130.tif19170 (in the formula, R 9 These are, independently, halogen, oxo, or unsubstituted C 1~3 It is alkyl, (r is either 1 or 2) The compound according to any one of claims 16 to 20.

[0339] Embodiment 25.R 8 but, TIFF0007862413000131.tif14170 (in the formula, R 9 is hydrogen or unsubstituted C 1~3 It is alkyl, W is O, SO2, or NR 12 And, R 12 is hydrogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 (It is a haloalkyl) The compound according to any one of claims 16 to 20.

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

[0341] Embodiment 27.R 2 but, The compound according to any one of claims 1 to 26, which is TIFF0007862413000132.tif65170.

[0342] Embodiment 28.R 9 However, halogen, or R 10 Substitute or non-substitute C 1~3 The compound according to claim 27, which is an alkylidene.

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

[0344] Embodiment 30.R 2 However, R 8A Substitute or non-substitute C 1~3 A compound according to any one of claims 1 to 16, wherein it is alkyl.

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

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

[0347] Embodiment 33.R 9A However, independently, halogen, unsubstituted C 1~3 Alkyl, or R 10 Substitute or non-substitute C 1~3 The compound according to claim 31 or 32, which is an alkylidene.

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

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

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

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

[0352] Embodiment 38.2 R 5 The compound according to any one of claims 1 to 36, wherein together they form a bridge between two carbon atoms of ring A, and the bridge contains 1 to 3 carbon atoms.

[0353] Embodiment 39. The compound according to claim 38, wherein the crosslink comprises one carbon atom.

[0354] Embodiment 40. The compound according to claim 38, wherein the crosslink comprises two carbon atoms.

[0355] Embodiment 41. Formula: The compound according to claim 1, having TIFF0007862413000133.tif35170, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0356] Embodiment 42. Formula: The compound according to claim 1, having TIFF0007862413000134.tif37170, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0357] Embodiment 43. Formula: The compound according to claim 1, having TIFF0007862413000135.tif37170.

[0358] Embodiment 44. Formula: The compound according to claim 1, having TIFF0007862413000136.tif106170, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0359] Embodiment 45. Formula: The compound according to claim 1, having TIFF0007862413000137.tif106170, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0360] Embodiment 46. Formula: The compound according to claim 1, having TIFF0007862413000138.tif37170, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0361] Embodiment 47. Formula: The compound according to claim 1, having TIFF0007862413000139.tif37170, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0362] Embodiment 48. Formula: The compound according to claim 1, having TIFF0007862413000140.tif35170, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0363] Embodiment 49. Formula: The compound according to claim 1, having TIFF0007862413000141.tif35170, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0364] Embodiment 50.R 8 but, The compound according to claim 1 or any one of claims 41 to 49, which is TIFF0007862413000142.tif27170.

[0365] Embodiment 51.R 8 but, The compound according to claim 1 or any one of claims 38 to 42, which is TIFF0007862413000143.tif33170.

[0366] Embodiment 52.R 8 but, The compound according to claim 1 or any one of claims 41 to 49, which is TIFF0007862413000144.tif19170.

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

[0368] Embodiment 54.R 6 However, R 6A Substitute or non-substitute C 1~3 The compound according to claim 53, wherein it is alkyl.

[0369] Embodiment 55.R 6 However, R 6A substitution C 1~3 The compound according to claim 53, wherein it is alkyl.

[0370] Embodiment 56.R 6A However, halogens, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1~3 The compound according to claim 55, which is alkyl or a four-membered heterocycle.

[0371] Embodiment 57.R 6 However, R 6A Substitute or non-substitute C 1~3 The compound according to claim 53, which is a haloalkyl compound.

[0372] Embodiment 58.R 6 However, R 6A Substitute or non-substitute C 1~3 The compound according to claim 53, which is an alkenyl.

[0373] Embodiment 59.R 6 However, R 6A Substitute or non-substitute C 1~3 The compound according to claim 53, which is an alkynyl.

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

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

[0376] Embodiment 62. Compounds of Table 1, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0377] Embodiment 63. Compounds of Table 2, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0378] Embodiment 64. Compounds of Table 3, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

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

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

[0381] Embodiment 67. The method according to claim 66, characterized in that the cancer contains a KRas mutation.

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

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

[0384] Embodiment 70. The compound, its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions, wherein the patient sample is KRas G12D The method according to claim 69, administered to the patient after the presence of the mutation has been indicated.

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

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

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

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

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

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

[0391] Embodiment 77. The method according to 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 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 cancer including mutations.

[0394] Embodiment 80.KRas G12D 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 preparation of a pharmacopoeia for the therapeutic treatment of cancer including mutations.

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

[0396] Embodiment 82. KRas G12D A compound according to any one of claims 1 to 64, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for therapeutic and / or prophylactic treatment of cancer including mutations.

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

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

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

[0400] Embodiment 86. Labeled KRas G12D A method for preparing mutant proteins, and KRas G12D 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 obtain the labeled KRas G12D A method, including obtaining a mutant protein.

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

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

[0403] Examples Intermediate 1: tert-butyl(1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF0007862413000145.tif66170

[0404] Step 1: tert-butyl(1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate TIFF0007862413000146.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), BnBr (60.1 g, 354 mmol) was added at 0°C. The reaction mixture was warmed to room temperature. After 2 hours, ice water (1000 mL) was added. The resulting mixture was extracted with dimethylethanol (3×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted with dimethylethanol / petroleum ether (0-10%) to obtain 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 TIFF0007862413000147.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), s-BuLi (1.3 M in hexane) (117 mL, 152 mmol) was added dropwise under nitrogen at -78 °C. After 1.5 hours, a solution of methyl chloroformate (17.9 g, 189 mmol) in 40 mL of Et2O was added at -78 °C. The reaction mixture was warmed to room temperature. After 16 hours, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and diluted with 500 mL of water. The resulting mixture was extracted with SiO(3×). The combined organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel eluted with siRNA / petroleum ether (0-10%), yielding 16 g of the product (cis mixture) as a yellow oily substance, which contained approximately 10% of the starting material tert-butyl8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate co-eluted 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), yielding 5.9 g of the faster peak (isomer 1) and 5.6 g of the slower peak (isomer 2) as a yellow oily substance. 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 TIFF0007862413000148.tif19170

[0409] In 300 mL of tetrahydrofuran cooled in an ice salt bath, 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) was added in fractions 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) under nitrogen at a rate that maintained the reaction temperature below 5°C. The resulting solution was stirred at 0°C for 30 minutes. The reaction product was quenched with Na2SO4·10H2O and filtered. The organic matter was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted with siRNA / petroleum ether (0-20%) to obtain the title compound (14.3 g, yield 77.5%) 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]azepine-3-one TIFF0007862413000149.tif26170

[0411] NaH (1.35 g, 33.8 mmol) was gradually added at 0°C 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). The resulting suspension was warmed to room temperature. After 3 hours, the reaction mixture was quenched with saturated NH4Cl aqueous solution (30 mL). The resulting solution was extracted with ethyl acetate (3 ×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted with ethyl acetate / petroleum ether (0-40%) to obtain the title compound (3.5 g, yield 88%) 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]azepine-3-one TIFF0007862413000150.tif25170

[0413] To a solution of (6S,9R,9aS)-10-benzylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-3-one (10.0 g, 38.7 mmol) in methanol (200 mL), Pd / C (3.0 g, 10% dry) was added at room temperature. The resulting solution was stirred under hydrogen for 2 hours. The suspension was filtered, and the filtrate was concentrated to obtain 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 TIFF0007862413000151.tif22170

[0415] A solution of (6S,9R,9aS)-hexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-3-one (6.00 g, 35.7 mmol) and (Boc)2O (12.6 g, 57.8 mmol) in dichloromethane (100 mL) was mixed with DIPEA (10.0 g, 77.5 mmol) at 0°C. The solution was warmed to room temperature for 2 hours. The solution was washed with saturated sodium chloride aqueous solution. The separated organic phase was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted with siRNA / petroleum ether (0-40%) to obtain the title compound (7.50 g, yield 78.4%) 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 TIFF0007862413000152.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), NaOH (16.8 g, 420 mmol) in water (70 mL) was added. The resulting solution was heated at 80°C for 16 hours. EtOH was removed under reduced pressure, and the resulting aqueous solution was neutralized to approximately pH 8 with HCl (1 M). The solution was extracted with ELISA (3 ×). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with DCM / MeOH (5 / 1) to obtain the title compound (5.0 g, yield 74%) as a grayish-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-difluoroquinazoline-4(3H)-one TIFF0007862413000153.tif47170

[0419] Step 1: 3-bromo-2,5-difluoroaniline TIFF0007862413000154.tif20170

[0420] 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 mixed with concentrated hydrochloric acid (40 mL, 36%) at room temperature. The suspension was heated to 100 °C. After 1 hour, the reaction system was cooled to room temperature and filtered. The filtrate was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to obtain the title compound (34.3 g, crude) as a brown oily substance, 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 TIFF0007862413000155.tif19170

[0422] To a solution of 2,2,2-trichloroethane-1,1-diol (40.9 g, 247 mmol), Na2SO4 (187 g, 1.32 mol), and NH2OH·HCl (39.8 g, 577 mmol) in water (680 mL), 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) were added. The resulting solution was heated at 60 °C for 3 hours. The reaction system was cooled to room temperature and filtered. The solid was collected, rinsed with water (500 mL), and dried in an oven to obtain 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 TIFF0007862413000156.tif19170

[0424] A solution of N-(3-bromo-2,5-difluorophenyl)-2-(hydroxyimino)acetamide (32.8 g, 118 mmol) in H2SO4 (160 mL, 98%) was heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature and slowly added to ice water. The precipitate was collected by filtration, washed with water, and dried in an oven to obtain 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 TIFF0007862413000157.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 H2O2 (53.7 mL, 30%) was stirred at room temperature for 16 hours. The mixture was poured into ice water and the pH was adjusted to 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 obtain the title compound (13.4 g, yield 49.4%) 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 TIFF0007862413000158.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 hour. The mixture was cooled to room temperature and poured into water (500 mL). The solid was collected and dried in an oven to obtain 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 TIFF0007862413000159.tif19170

[0430] HATU (17.43 g, 45.84 mmol) was added at room temperature to a solution of 2-amino-4-bromo-5-chloro-3,6-difluorobenzoic acid (11.9 g, 41.6 mmol), NH4Cl (4.42 g, 83.4 mmol), and DIPEA (13.5 g, 104 mmol) in DMF (60 mL). The resulting solution was stirred for 30 minutes. The mixture was poured into water (300 mL), and the resulting precipitate was collected by filtration. The solid was suspended in SiO2 / petroleum ether (1:4, 100 mL) and stirred for 3 hours. The solid was collected by filtration and dried in an oven to obtain 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-difluoroquinazoline-4(3H)-one TIFF0007862413000160.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 product was concentrated under vacuum, and the residue was suspended in SiO2 / petroleum ether (1:4, 60 mL) and stirred for 1 hour. The solid was collected by filtration and dried to obtain 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 TIFF0007862413000161.tif31170

[0434] Step 1: tert-butyl(1S,2S,5R)-2-(((7-bromo-2,6-dichloro-8-fluoro-4-hydroxyquinazoline-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF0007862413000162.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), NaH (3.20 g, 80.0 mmol) was added under nitrogen. The resulting solution was warmed 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 mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution and diluted with 200 mL of water. The resulting mixture was extracted with ELISA. The combined organic extract was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~10% MeOH / DCM), yielding 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 TIFF0007862413000163.tif35170

[0437] To a solution of tert-butyl(1S,2S,5R)-2-(((7-bromo-2,6-dichloro-8-fluoro-4-hydroxyquinazoline-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), DIPEA (28.0 g, 217 mmol) was added. The resulting solution was stirred at room temperature for 5 hours. The reaction mixture was washed with brine, and the organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~30% ethyl acetate / petroleum ether), followed by a slurry using ethyl acetate / petroleum ether = 1:10, yielding 3.50 g (yield 45%) 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)pyridine-2-amine TIFF0007862413000164.tif29170

[0439] To an ice-cold solution of 6-bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine (14.0 g, 54.9 mmol) in N,N-dimethylformamide (300 mL), 60% NaH (6.58 g, 165 mmol) was added under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 hour. Then, PMB-Cl (21.4 g, 137 mmol) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride and extracted with RINKAN (3 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-20% ethyl acetate / petroleum ether) to obtain the title compound (23 g, yield 84.6%) as a white solid. LC-MS: (ESI, m / z): [M + H] + =495 / 497; 1 1H NMR (400MHz, 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)pyridine-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 tert-butyl(5aS,6S,9R)-2-((S)-6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-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 TIFF0007862413000165.tif47170

[0441] Under nitrogen, i-PrMgCl.LiCl (9.86 mL, 12.8 mmol) was added dropwise at -78°C 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). The solution was stirred at -78°C for 1 hour, and then ZnCl2 (6.72 mL, 13.4 mmol) was added dropwise to the cold solution. The solution was stirred at -78°C for 10 minutes, then slowly heated to 25°C and stirred for 1 hour. The obtained solution was divided into six parts, and each part was separately transferred under nitrogen to the following solution ((6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (905 mg, 1.83 mmol, intermediate 4) and PdCl2(PPh3)2 (57.1 mg, 0.0813 mmol) in tetrahydrofuran (4.6 mL)). The reaction system was stirred overnight at 50 °C, and all six reactions were carried out in parallel. The combined reaction mixtures were diluted with water and extracted with RINKAN (3×). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~30% ethyl acetate / petroleum ether) to obtain 3.10 g of the title compound (yield 29%, mixture of two atropisomers) as a yellow solid. The reaction was repeated to obtain a total of 7.1 g of the racemic compound. The racemic mixture was subjected to 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 Separation was performed using LC-MS (19.55), yielding 2.30 g (later peak, desired isomer) and 2.40 g (faster peak) as yellow solids. Additionally, 1.3 g of a mixture of atropisomers was 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-trifluoroquinazoline-4(3H)-one TIFF0007862413000166.tif56170

[0443] Step 1: (E)-N-(3-bromo-2,4,5-trifluorophenyl)-2-(hydroxyimino)acetamide TIFF0007862413000167.tif19170

[0444] To a solution of Na2SO4 (207 g, 1438 mmol), hydroxylamine hydrochloride (44.7 g, 643.2 mmol), and hydroxylamine hydrochloride (46.2 g, 279.32 mmol) in water (1000 mL), a solution of hydrochloric acid (30 mL, 37%), ethanol (80 mL), and 3-bromo-2,4,5-trifluoroaniline (40.0 g, 177 mmol) in water (100 mL) was added. The resulting solution was stirred at 60°C for 2 hours. The precipitate was collected by filtration, washed with water, and dried under vacuum to obtain the title compound (43.2 g, yield 82.2%) as a light brown solid. LC-MS:(ESI,m / z):[MH] + =295.

[0445] Step 2: 6-Bromo-4,5,7-trifluoroindoline-2,3-dione TIFF0007862413000168.tif19170

[0446] A solution of (2E)-N-(3-bromo-2,4,5-trifluorophenyl)-2-hydroxyiminoacetamide (43.2 g, 145 mmol) in triflic acid (120 mL, 1356 mmol) was stirred at 130°C for 3 hours. 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 obtain 10 g of the title compound. The filtrate was extracted with phenylethylamine, the organic layer was washed with NaHCO3 (saturated) and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a further 7.8 g of the title compound. In total, 17.8 g (yield 43.7%) of the title compound was obtained as a brown solid. No mass signal was obtained.

[0447] Step 3: 2-amino-4-bromo-3,5,6-trifluorobenzoic acid TIFF0007862413000169.tif19170

[0448] To a solution of 6-bromo-4,5,7-trifluoroindoline-2,3-dione (21.0 g, 75 mmol) in 2M sodium hydroxide (400 mL), hydrogen peroxide (30% in water) (40 mL) was added dropwise while stirring. 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 obtain the title compound (11.8 g, yield 58.3%) as a brown solid. LC-MS:(ESI,m / z):[M+H] + =290.

[0449] Step 4: 2-amino-4-bromo-3,5,6-trifluorobenzamide TIFF0007862413000170.tif19170

[0450] A solution of 2-amino-4-bromo-3,5,6-trifluorobenzoic acid (11.8 g, 43.7 mmol), NH4Cl (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 while stirring. The precipitate was collected by filtration and dried under vacuum to obtain the title compound (6.1 g, yield 51.9%) as a brown solid. LC-MS:(ESI,m / z):[M+H] + =269.

[0451] Step 5: 7-Bromo-2-chloro-5,6,8-trifluoroquinazoline-4(3H)-one TIFF0007862413000171.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 under reflux for 1 hour. The solution was cooled to room temperature and concentrated under vacuum. Washing the solid with petroleum ether / ethyl acetate (4:1) yielded the title compound (5.9 g, yield 66.4%) 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 TIFF0007862413000172.tif43170

[0454] Step 1: tert-butyl(1R,2S,5S)-2-(((7-bromo-2-chloro-6,8-difluoro-4-hydroxyquinazoline-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF0007862413000173.tif36170

[0455] Under nitrogen, NaH (382 mg, 9.57 mmol) was added 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). The reaction mixture was stirred at room temperature for 15 minutes. Then, 7-bromo-2-chloro-5,6,8-trifluoroquinazolin-4-ol (1.00 g, 3.19 mmol, intermediate 6) was added at 0°C and the mixture was stirred at 0°C for 2 hours. The reaction was then quenched by adding acetic acid. The resulting mixture was partitioned into water and DCM. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography (gradient: 0-100% ACN (0.05% NH4HCO3) in H2O) to obtain 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 TIFF0007862413000174.tif30170

[0457] A solution of tert-butyl(1S,2S,5R)-2-[(7-bromo-2-chloro-6,8-difluoro-4-hydroxyquinazolin-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 hours. The resulting mixture was partitioned into water and DCM. The collected organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-30% ethyl ether in petroleum ether) to obtain a white solid (560 mg, yield 63%). 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 TIFF0007862413000175.tif35170

[0459] Step 1: tert-butyl(1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-hydroxyquinazoline-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF0007862413000176.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), NaH (191 mg, 4.78 mmol, 60% in mineral oil) was added under nitrogen. After 0.5 hours, 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 hours. The reaction product was quenched with saturated NH4Cl aqueous solution and extracted by DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-10% methanol / DCM) to obtain 460 mg (yield 53%) 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 TIFF0007862413000177.tif27170

[0462] Under nitrogen, a solution of tert-butyl(1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-hydroxyquinazoline-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) was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-5% methanol / DCM) to obtain 270 mg (yield 71%) 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-pyrrolidine-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 TIFF0007862413000178.tif39170

[0464] To an ice-cold solution of (S)-(2-methylenetetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (92.5 mg, 0.600 mmol, intermediate 15) in tetrahydrofuran (13 mL), NaH (100 mg, 2.50 mmol, 60% in mineral oil) was added. The solution was heated 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 mixture was cooled to 0°C, diluted with water, and concentrated under vacuum. Purification of the residue using a packed C18 column (solvent gradient: 0-100% ACN (0.05% NH4HCO3) in water) yielded 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-indazole-7-yl)quinazoline-4(3H)-one TIFF0007862413000179.tif54170

[0466] Step 1: Methyl 2-mino-4-bromo-3,6-difluorobenzoate TIFF0007862413000180.tif19170

[0467] TMSCHN2 (10.8 mL, 21.6 mmol, 2 mol / L in n-hexane) was added 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). The reaction mixture was heated to 25°C. After 10 minutes, the mixture was concentrated under vacuum to obtain 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 TIFF0007862413000181.tif23170

[0469] Under nitrogen, 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 hour. 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% ethyl acetate / petroleum ether) to obtain the crude product (containing 20% ​​Pin2B2). The crude substance was stirred in 10 mL of petroleum ether for 10 minutes, and the solid was collected. The process was repeated three times to obtain 2.0 g (yield 59%) 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-indazole-7-yl)benzoate TIFF0007862413000182.tif26170

[0471] Under nitrogen, solutions 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(PPh3)2Cl2 (368 mg, 0.520 mmol), and KF (913 mg, 15.7 mmol) in acetonitrile (20 mL) and water (4 mL) were stirred at 80°C for 1 hour. 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 obtain 1.25 g (yield 71%) 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-indazole-7-yl)benzoate TIFF0007862413000183.tif26170

[0473] Under nitrogen, a solution of methyl 2-amino-3,6-difluoro-4-(6-fluoro-1-methyl-indazole-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 hour. The reaction mixture was quenched with saturated Na2S2O3 aqueous solution 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 under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-15% ethyl acetate / petroleum ether) to obtain 1.1 g (yield 83%) 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-indazole-7-yl)benzoic acid TIFF0007862413000184.tif26170

[0475] A solution of methyl 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-indazole-7-yl)benzoate (1.10 g, 3.08 mmol) in tetrahydrofuran (12 mL) was mixed with a solution of LiOH (212 mg, 9.23 mmol) in water (4 mL) at room temperature. After 18 hours, 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 under vacuum to obtain 1.0 g (crude) of the title compound. LC-MS: (ESI, m / z): [M+H]+=356. The crude substance was used without further purification.

[0476] Step 6: 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-1H-indazole-7-yl)benzamide TIFF0007862413000185.tif26170

[0477] A solution of 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-1H-indazole-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 hours. The solution was diluted with  (100 mL) and washed with saturated NH4Cl aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-4% MeOH / DCM) to obtain 950 mg (yield 87%) 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-indazole-7-yl)quinazoline-4(3H)-one TIFF0007862413000186.tif26170

[0479] A solution of 2-amino-5-chloro-3,6-difluoro-4-(6-fluoro-1-methyl-indazole-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 under reflux for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~5% MeOH / DCM) to obtain the title compound (1.27 g, crude), purity 76%, 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 TIFF0007862413000187.tif23170

[0481] Step 1: 1-(tert-butyl)2-methyl 2-(2-(chloromethyl)allyl)azetidine-1,2-dicarboxylate TIFF0007862413000188.tif16170

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

[0483] Step 2: Methyl 2-(2-(chloromethyl)allyl)azetidine-2-carboxylate TIFF0007862413000189.tif15170

[0484] A solution of 1-(tert-butyl)2-methyl2-(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 hours. The resulting mixture was concentrated under vacuum to obtain the title compound as 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 TIFF0007862413000190.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 hours. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with (MeOH / DCM = 0-10%) to obtain the title compound (48 mg, 20% yield in 3 steps) as a pale yellow oil. LC-MS: (ESI, m / z): [M + H] + =168. The crude product was used without further purification. 1 ¹H 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 TIFF0007862413000191.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), LiAlH4 (0.5 mL, 0.5 mmol, 1 M in THF) was added. After 0.5 hours, the reaction product was quenched with Na2SO4·10H2O and diluted with ether (10 mL). The solid was filtered, and the filtrate was concentrated under reduced pressure to obtain 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)azetidine-2-yl)methanol TIFF0007862413000192.tif27170

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

[0491] Intermediate 13: (2-methylenetetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000193.tif23170

[0492] Under nitrogen, a solution of ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.20 g, 0.96 mmol) in tetrahydrofuran (20 mL) was mixed with LiAlH4 (2.87 mL, 1 M in THF) at -40°C. The resulting solution was warmed at room temperature for 3 hours. The reaction mixture was quenched with Na2SO4·10H2O. The solid was filtered and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain 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-pyrrolidine-7a(5H)-yl)methanol and (S)-(2-methylenetetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000194.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 TIFF0007862413000195.tif36170

[0495] Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (19.9g) was separated by chiral SFC (column: CHIRALPAK IH, 50×250mm; mobile phase A: CO2, mobile phase B: EtOH; flow rate: 150mL / min; gradient: 26%B; 220nm; RT1: 4.8; RT2: 6.43; injection volume: 1.8ml; run number: 122) to obtain ethyl(R)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.61g, faster peak) and (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.29g, slower peak). LC-MS:(ESI,m / z):[M+H]+ =210. 1 ¹H NMR (400MHz, chloroform-d)δ 5.12-5.00 (m, 2H), 4.32-4.28 (m, 1H), 4.21 (q, J=7.1Hz, 2H), 3.73 (d, J=15.7Hz, 1H), 3.06 (d, J=15.7Hz, 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=7.1Hz, 3H). The ¹H NMR of the two isomers is the same.

[0496] Step 2: (S)-(2-methylenetetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000196.tif14170

[0497] Under nitrogen, 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) was mixed with LiAlH4 (1.1 mL, 1 M in THF). The mixture was heated at 70 °C for 0.5 hours. The mixture was cooled to room temperature, quenched with Na2SO4·10H2O, and filtered. The solvent was removed by blowing in nitrogen (low boiling point of the product) to obtain the title compound (62.8 mg, crude). LC-MS:(ESI,m / z):[M+H] + =154. The crude material was used without further refinement.

[0498] Enantiomer(R)-(2-methylenetetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (intermediate 14) was synthesized in the same manner as described in step 2.

[0499] Intermediate 16: (S)-(2,2-difluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000197.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 TIFF0007862413000198.tif36170

[0501] When ethyl 2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (20.0 g, 94.6 mmol) was separated by (column: AD 2.12 × 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: EtOH:ACN = 1:1; flow rate: 200 mL / min; gradient: 50% B; 220 nm; RT1: 2.44; RT2: 3.58; injection volume: 10 ml; number of runs: 15), ethyl(S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (8.21 g, faster peak) was obtained as a yellow oily substance, and ethyl(R)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.92 g, slower peak) was obtained as a yellow oily substance. LC-MS:(ESI,m / z):[M+H] + =212. 1 ¹H NMR (400MHz, chloroform-d)δ 4.22 (q, J=7.2Hz, 2H), 4.14-4.05 (m, 1H), 3.54 (d, J=18.6Hz, 1H), 3.02-2.91 (m, 2H), 2.87-2.72 (m, 1H), 2.60-2.38 (m, 2H), 2.23-2.11 (m, 1H), 1.28 (t, J=7.1Hz, 3H).

[0502] Step 2: Ethyl(S)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF0007862413000199.tif23170

[0503] Under nitrogen, DAST (378 mg, 2.35 mmol) was added 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). The mixture was warmed to room temperature. After 3 hours, the reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-2% MeOH / DCM) to obtain 98.3 mg (yield 44.4%) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =234. 1 ¹H NMR (400MHz, chloroform-d) δ 4.28 (q, J=7.1Hz, 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=7.1Hz, 3H).

[0504] Step 3: (S)-(2,2-difluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000200.tif14170

[0505] Under nitrogen, 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) was mixed with LiAlH4 (2.0 mL, 1 M in THF). The mixture was heated to 70°C for 3 hours. The mixture was quenched with Na2SO4·10H2O and filtered. The solvent was removed by gently blowing in nitrogen (low boiling point) to obtain 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-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000201.tif17170

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

[0508] Intermediate 18: (Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (trans mixture) TIFF0007862413000202.tif64170

[0509] Step 1: Diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (trans mixture) TIFF0007862413000203.tif35170

[0510] To a solution of diethyl cis-1-benzylpyrrolidine-2,5-dicarboxylate (8.60 g, 28.2 mmol) in tetrahydrofuran (120 mL), LiHMDS (43.4 mL, 56.4 mmol) was added at -35°C. After 1 hour, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-15% ethyl acetate / petroleum ether) to obtain 1.27 g (yield 14%) of the title compound as a pale yellow oily substance. 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 (trans mixture) TIFF0007862413000204.tif21170

[0512] Under nitrogen, LiAlH4 (716 mg, 18.8 mmol) was added in several portions to an ice-cold solution of diethyl trans-1-benzylpyrrolidine-2,5-dicarboxylate (2.30 g, 7.53 mmol) in tetrahydrofuran (30 mL). The reaction mixture was warmed to room temperature. After 2 hours, the mixture was quenched with Na2SO4·10H2O. The solid was filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-10% MeOH / DCM) to obtain 1.65 g (99% yield) of the title compound as a yellow oily substance. 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 (trans mixture) TIFF0007862413000205.tif14170

[0514] Under hydrogen (1 atm), 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 at room temperature for 2 hours. The catalyst was filtered, and the filtrate was concentrated to obtain 405 mg (crude) of the title compound as a pale yellow oily substance. 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)pyrrolidine-1-yl)-2-bromoethane-1-one (trans mixture) TIFF0007862413000206.tif18170

[0516] 2-bromoacetyl bromide (539 mg, 2.67 mmol) was added 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). After 1 hour, the reaction product was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-10% MeOH / DCM) to obtain 130 mg (yield 19%) of the title compound as a yellow oily substance. 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]oxazine-4(3H)-one (trans mixture) TIFF0007862413000207.tif16170

[0518] A solution of 1-(2,5-bis(hydroxymethyl)pyrrolidine-1-yl)-2-bromoethane-1-one (130 mg, 0.517 mmol) in 1 mL of THF was added to an ice-cold suspension of NaH (65.0 mg, 1.63 mmol, 60%) in tetrahydrofuran (5 mL). After 1 hour, the resulting solution was warmed to room temperature for 3 hours. The reaction was diluted with water and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-10% MeOH / DCM) to obtain the title compound as an oil (37.0 mg, yield 42%). 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 (trans mixture) TIFF0007862413000208.tif15170

[0520] To an ice-cold suspension of LiAlH4 (27.3 mg, 0.720 mmol) in tetrahydrofuran (5 mL) under nitrogen, 6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (60.0 mg, 0.350 mmol) in 0.5 mL of THF was added. The resulting solution was heated to 60°C for 2 hours. The reaction mixture was cooled to room temperature and quenched with Na2SO4·10H2O. The solid was filtered, and the filtrate was concentrated to obtain the title compound as a pale yellow oily substance (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-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000209.tif30170

[0522] Step 1: Ethyl(S)-2-(difluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF0007862413000210.tif24170

[0523] Under nitrogen, t-BuOK (191 mg, 1.71 mmol) in DMF (2 mL) was slowly added at -50°C to a solution of ethyl(S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.20 g, 0.95 mmol, intermediate 16, step 1, faster peak) and 2-((difluoromethyl)sulfonyl)pyridine (237 mg, 1.23 mmol) in N,N-dimethylformamide (6 mL). The reaction mixture was heated to -40°C for 1 hour, and then quenched with saturated ammonium chloride aqueous solution (2 mL) and 3 M HCl (2 mL). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate. The combined organic matter was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-40% Â1 / DCM), yielding the title compound as a yellow oily substance (28.0 mg, yield 12%). LC-MS:(ESI,m / z):[M+H] + =246.1.

[0524] Step 2: (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000211.tif20170

[0525] Under nitrogen, DIBAL-H (1.12 mL, 1.12 mmol) was added 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). The reaction mixture was warmed to room temperature. After 1 hour, the solution was quenched with Na2SO4·10H2O. 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 further purified and used.

[0526] Intermediate 20: (R)-(2-(difluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000212.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, similar to the method described in 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-pyrrolidine-7a(5H)-yl)methanol (mixture of Z / E) TIFF0007862413000213.tif38170

[0529] Step 1: Ethyl(S)-2-(fluoromethylene)-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF0007862413000214.tif37170

[0530] Under nitrogen, KHMDS (1.2 mL, 1.20 mmol) was added at -78°C to a solution of 2-((fluoromethyl)sulfonyl)pyridine (177 mg, 1.01 mmol) in tetrahydrofuran (10 mL). After 30 minutes, ethyl(S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (0.20 mg, 0.95 mmol, intermediate 16, step 1, faster peak) in THF (5 mL) was slowly added at -78°C. After 3 hours, the reaction system was warmed to room temperature for 1 hour. The reactants were quenched with saturated ammonium chloride aqueous solution (1 mL), followed by 3 M HCl (2 mL). The mixture was stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate. The combined organic matter was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-30% ethyl acetate / petroleum ether), yielding the title compound as a yellow oily substance (65 mg, yield 30%). 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-pyrrolidine-7a(5H)-yl)methanol and (S,E)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000215.tif30170

[0532] DIBAL-H (2.64 mL, 2.64 mmol) was added 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). The resulting solution was warmed to room temperature for 1 hour. The reaction product was quenched with Na2SO4·10H2O. 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 obtain the title compound as a yellow oily substance (26 mg, yield 57%). LC-MS: (ESI, m / z): [M+H] + =172.1. 1 ¹H 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 mixture of Z / E).

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

[0534] Z isomer:LC-MS:(ESI,m / z):[M+H] + = 172. 1 ¹H NMR (300MHz, 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 ¹H 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-methylpyridine-2-amine TIFF0007862413000216.tif41170

[0537] Step 1: 6-Bromo-5-chloro-4-methylpyridine-2-amine TIFF0007862413000217.tif21170

[0538] A solution of 6-bromo-4-methylpyridine-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 hour. The resulting solution was cooled to room temperature, diluted with ethyl acetate, and washed with water (3 ×). The organic layer was dried over anhydrous sodium 2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~30% ethyl acetate / petroleum ether) to obtain 370 mg (yield 62%) 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-methylpyridine-2-amine TIFF0007862413000218.tif44170

[0540] Under nitrogen, 60% NaH (202 mg, 5.05 mmol) was added at 0°C to a solution of 6-bromo-5-chloro-4-methylpyridine-2-amine (370 mg, 1.67 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature. After 30 minutes, 1-(chloromethyl)-4-methoxybenzene (656 mg, 4.21 mmol) was added, and the reaction mixture was maintained at room temperature for 1 hour. The reaction mixture was quenched with water, and the resulting solution was extracted with RINKAN (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~30% ethyl acetate / petroleum ether) to obtain 550 mg (yield 71%) 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-pyrrolidine-7a(5H)-yl)methanol and ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000219.tif60170

[0542] Step 1: Ethyl(7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF0007862413000220.tif23170

[0543] Under nitrogen, NaBH4 (70.3 mg, 1.85 mmol) was added at 0°C to a solution of ethyl(S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.22 g, 5.68 mmol) in tetrahydrofuran (100 mL). After 30 minutes, the reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~6% MeOH / DCM) to obtain the title compound (0.631 g, yield 62%) 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 TIFF0007862413000221.tif31170

[0545] Under nitrogen, DAST (923 mg, 5.74 mmol, dissolved in 20 mL of DCM) was added to a solution of ethyl(7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (809 mg, 3.80 mmol) at -15°C. The mixture was warmed at room temperature for 3 hours. The mixture was quenched with EtOH and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient: 0%~100% ethyl / petroleum) on silica gel, yielding 425 mg (yield 52%) of ethyl(2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate as a colorless oil, and 219 mg (yield 26.9%) 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 (faster peak). 1 ¹H NMR (400MHz, chloroform-d) δ 5.32 (d, J=19.2Hz, 1H), 4.26-4.11 (m, 3H), 3.25-3.12 (m, 1H), 2.85-2.59 (m, 3H), 2.48-2.39 (m, 1H), 2.37-2.07 (m, 2H), 1.30 (t, J=7.1Hz, 3H).

[0547] Ethyl(2S,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (later peak). 1 ¹H NMR (400MHz, 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=7.1Hz, 3H).

[0548] Step 3: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000222.tif14170

[0549] Under nitrogen, a solution of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (310 mg, 1.44 mmol) in tetrahydrofuran (7 mL) was mixed with LiAlH4 (3.1 mL, 1 M in THF) at 0°C. The mixture was heated to 70°C for 30 minutes. After cooling to room temperature, the mixture was quenched with Na2SO4.10H2O while vigorously stirring. The solid was filtered, and the filtrate was evaporated by gently blowing N2 to obtain the title compound (124 mg, crude). LC-MS:(ESI,m / z):[M+H] + =160. The crude material was used without further refinement.

[0550] Step 4: ((2S,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol TIFF0007862413000223.tif14170

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

[0552] Intermediate 25: 6-bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridine-2-amine TIFF0007862413000224.tif27170

[0553] Under nitrogen, 60% NaH (416 mg, 10.4 mmol) was added at 0°C to a solution of 6-bromo-5-(trifluoromethyl)pyridine-2-amine (500 mg, 2.08 mmol) in N,N-dimethylformamide (5 mL). The resulting solution was warmed to room temperature. After 30 minutes, 1-(chloromethyl)-4-methoxybenzene (812 mg, 5.20 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution, and the resulting mixture was extracted with ethyl acetate (3×). 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%~20% ethyl acetate / petroleum ether) to obtain 645 mg (yield 64%) 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)pyridine-2-amine TIFF0007862413000225.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), AcOH (10 mL) was added. The resulting mixture was stirred at 80°C for 1 hour. The solvent was removed under vacuum. The residue was diluted with siRNA / DCM (1 / 5, 150 mL). The solid was collected by filtration and dried under vacuum to obtain 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)pyridine-2-amine TIFF0007862413000226.tif23170

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

[0558] Under nitrogen, a solution of 6-chloro-5-(trifluoromethyl)pyridine-2-amine (1000 mg, 5.09 mmol) and HBr in acetic acid (10 mL, 33% w / w) was stirred at 130°C (steel tank) for 48 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with H2O (30 mL), adjusted to pH 8-9 with Na2CO3 (aqueous solution), and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%-10% ethyl acetate / petroleum ether) to obtain the title compound (1106 mg, yield 86.8%). LC-MS: (ESI, m / z): [M+H] + = 241 / 243.

[0559] Step 2: 6-Bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridine-2-amine TIFF0007862413000227.tif16170

[0560] Under nitrogen, a solution of 6-bromo-5-(trifluoromethyl)pyridine-2-amine (500 mg, 2.08 mmol) in DMF (5 mL) was mixed with 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 hours. Then, 1-(chloromethyl)-4-methoxybenzene (812 mg, 5.20 mmol) was added dropwise at room temperature. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~20% ethyl acetate / petroleum ether) to obtain 645 mg (yield 64%) 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 e TIFF0007862413000228.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 hours under microwave irradiation. The reaction system was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted with ethyl acetate / petroleum ether (0-10%) to obtain the title compound (333.2 mg, yield 64.3%) 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 TIFF0007862413000229.tif70170

[0564] Step 1: tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate TIFF0007862413000230.tif18170

[0565] Under nitrogen, a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.00 g, 23.5 mmol) in N,N-dimethylformamide (50 mL) was mixed with K2CO3 (6.51 g, 47.1 mmol) and (bromomethyl)benzene (6.01 g, 35.1 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-30% ethyl acetate / petroleum ether) to obtain 7 g (yield 98.3%) 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]azepine-3-one TIFF0007862413000231.tif38170

[0567] Under nitrogen, 7.0 g, 23.1 mmol of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and 5.38 g, 46.3 mmol of TMEDA were added dropwise to a solution of these in 70 mL of diethyl ether with s-BuLi (35.6 mL, 46.3 mmol, 1.3 M in hexane) at -78°C. The resulting solution was stirred at -78°C for 1.5 hours. Then, 2.55 g, 57.8 mmol of acetaldehyde was added at -78°C. The reaction mixture was gradually warmed to room temperature and stirred overnight. The mixture was extracted with NH4Cl (aqueous solution) and HCl. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% HCl in petroleum ether) to obtain a mixture of 5.1 g of four diastereoisomers. The compounds were separated using Prep-SFC (column: CHIRALPAK IH, 3 × 25 cm, 5 μm; mobile phase A: CO2, 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; run number: 50), yielding compound a (1.39 g, yield 22%) (first peak), compound d (1.47 g, yield 23.3%) (third peak), and a mixture of compounds b and c (second peak). A mixture of compounds b and c was re-separated by Prep-SFC (column: CHIRALPAK IH, 5 × 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3-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 obtain compound b (0.500 g, yield 7.9%) (faster peak) and compound c (0.430 g, yield 6.8%) (slower 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]azepine-3-one TIFF0007862413000232.tif22170

[0569] A solution of (1S,6S,9R,9aS)-10-benzyl-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-3-one (1.00 g, 3.67 mmol) (compound a from the previous step) and Pd / C (500 mg, 10%) in methyl alcohol (15 mL) was stirred at room temperature for 1 hour under a hydrogen gas atmosphere. The catalyst was filtered off. The filtrate was concentrated under vacuum to obtain 658 mg (crude) of the title compound as a yellow oily substance, 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 TIFF0007862413000233.tif23170

[0571] A solution of (1S,6S,9R,9aS)-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine-3-one (658 mg, 3.61 mmol), (Boc)2O (1.18 g, 5.41 mmol), and DIPEA (1.4 g, 10.8 mmol) in dichloromethane (10 mL) was stirred at room temperature for 30 minutes. The reaction system was quenched with water and extracted by DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (gradient: 0-100% siRNA / petroleum ether) on silica gel to obtain the title compound (920 mg, yield 90.2%) 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 TIFF0007862413000234.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 hour. The reaction solution was cooled to room temperature, diluted with water, and extracted by DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to obtain 815 mg (crude) of 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)pyridine-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 TIFF0007862413000235.tif91170

[0575] Step 1: tert-butyl(1S,2S,5R)-2-((S)-1-((7-bromo-2,6-dichloro-8-fluoro-4-hydroxyquinazoline-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate TIFF0007862413000236.tif32170

[0576] Under nitrogen, 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) was mixed with NaH (5.00 g, 125 mmol, 60% oil suspension) at 0°C. The resulting solution was stirred at 0°C for 30 minutes. Then, 7-bromo-2,6-dichloro-5,8-difluoroquinazolin-4-ol (15.4 g, 46.6 mmol, intermediate 2) was added. The reaction system was stirred at room temperature for 1 hour. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to obtain 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 TIFF0007862413000237.tif29170

[0578] A solution of tert-butyl(1S,2S,5R)-2-((S)-1-((7-bromo-2,6-dichloro-8-fluoro-4-hydroxyquinazoline-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 overnight at room temperature. The solid was filtered off. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-30% siRNA / petroleum ether) to obtain 7.2 g (yield 42%) 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)pyridine-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 TIFF0007862413000238.tif47170

[0580] Under nitrogen, 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) was mixed with iPrMgCl.LiCl (0.93 mL, 1.3 M in THF) at -78°C. The resulting solution was stirred at -78°C for 10 minutes. Then, ZnCl2 (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)pyridine-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 overnight at 50°C. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-40% Â / petroleum ether) to obtain 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, 2×25cm, 5μm; 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 mins; wavelength: 220 / 254 nm; RT1 (min): 14.03; RT2 (min): 16.79; sample solvent: EtOH-HPLC; injection volume: 0.3 mL; number of runs: 15), and the faster peak of 80 mg and the slower peak of 110 mg were obtained as yellow solids. LC-MS: (ESI, m / z): [M+H] + =883.

[0581] The earlier 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] The 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)pyridine-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 TIFF0007862413000239.tif47170

[0584] Under nitrogen, iPrMgCl.LiCl (3.1 mL, 4.03 mmol, 1.3 M in THF) was added 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) at -78°C. The resulting solution was stirred at -78°C for 10 minutes. Then, ZnCl2 (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 while stirring at room temperature for 20 minutes. The mixture was added at room temperature to a solution of 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyridine-2-amine (1.50 g, 3.12 mmol, intermediate 27) and Pd(PPh3)2Cl2 (109 mg, 0.160 mmol) in tetrahydrofuran (17 mL). The resulting solution was stirred overnight at 50°C and then concentrated under vacuum. The crude substance was purified by flash chromatography on silica gel (gradient: 0-30% siRNA / petroleum ether) to obtain 1.2 g of the title compound (a mixture of two atropisomers). The mixture was separated by PREP_SFC (column: Lux 5um Cellulose-4, 3×25cm, 5μm; mobile phase A: CO2, mobile phase B: MeOH:ACN=1:1 (0.1% 2M NH3-MeOH); flow rate: 70 mL / min; gradient: isocratic 40% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 4.34; RT2 (min): 5.16; sample solvent: MeOH-----preparative; injection volume: 1 mL; run number: 75), and the faster peak of 537 mg and the slower peak of 460 mg were obtained as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =869.

[0585] Intermediate 32: ((2S,4R)-4-fluoro-1-methylpyrrolidine-2-yl)methanol TIFF0007862413000240.tif16170

[0586] Under nitrogen, LiAlH4 (19.6 g, 515 mmol) was added at 0°C to a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (60.0 g, 257 mmol) in tetrahydrofuran (1000 mL). The reaction mixture was stirred at room temperature for 1 hour, then stirred at 60°C for 2 hours. The reaction mixture was cooled in an ice bath, and the reaction was quenched by slowly adding water (20 mL), followed by the addition of 20% NaOH aqueous solution (20 mL) and 20 mL of water. The solid was filtered off, and the filtrate was concentrated under vacuum. The residue was redissolved in DCM, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~15% MeOH (0.1% TEA) in DCM) to obtain 12.4 g (yield 36%) of the title compound as a yellow oily substance. LC-MS:(ESI,m / z):[M+H] + =134. 1 1H NMR (300MHz, 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 TIFF0007862413000241.tif33170

[0588] Step 1: 1-(tert-butyl)2-methyl(4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-1,2-dicarboxylate TIFF0007862413000242.tif27170

[0589] Under nitrogen, LiHMDS in THF (60.7 mL, 60.7 mmol, 1 M) was added at -78°C 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). The resulting solution was stirred at -78°C for 1 hour. Then, 1-bromo-2-chloroethane (8.36 mL, 100 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. The mixture was extracted with NH4Cl (aqueous solution) and ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~100% ethyl acetate / petroleum ether) to obtain 1.26 g (yield 20.1%) 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 TIFF0007862413000243.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), TFA (5 mL) was added. The resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated under vacuum, yielding 2 g (crude) of the title compound as a yellow oily substance, 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 TIFF0007862413000244.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 hour. The solid was filtered off. The filtrate was concentrated under vacuum to obtain 2.9 g (crude) of the title compound as a yellow oily substance, 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 TIFF0007862413000245.tif12170

[0595] Under nitrogen, LiAlH4 in THF (16.7 mL, 16.7 mmol, 1 M) was added at 0°C 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). The resulting solution was stirred at 0°C for 30 minutes. The mixture was quenched with Na2SO4₄₀H₂O and filtered. The solvent was removed by blowing in N₂ (volatile) to obtain 2 g (crude) as a yellow oily substance, 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'-cyclopropane]-5-yl)methanol (two single unknown isomers) and ((3R)-2',2'-difluoro-1-azaspiro[bicyclo[3.2.0]heptane-3,1'-cyclopropane]-5-yl)methanol (two single unknown isomers) TIFF0007862413000246.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 TIFF0007862413000247.tif32170

[0598] Under nitrogen, a solution of 1-(tert-butyl)2-methyl(S)-4-methylenepyrrolidine-1,2-dicarboxylate (5.00 g, 20.7 mmol) in tetrahydrofuran (70 mL) was mixed with TMSCF3 (10.3 g, 72.5 mmol) and NaI (1.55 g, 10.3 mmol) at room temperature. The resulting solution was stirred at 60 °C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with water and extracted by DCM. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-20% siRNA / petroleum ether) to obtain a mixture of the title compound as a yellow oily substance of 4.6 g. The mixture was subjected to 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 mins; wavelength: 220 / 254 nm; R T1 (minutes):6.313;R T2 The sample was separated by (minutes: 7.224; sample solvent: EtOH-HPLC; injection volume: 0.5 mL; number of runs: 32) to obtain 1.14 g (faster peak) and 600 mg (slower peak) as a yellow oily substance. LC-MS: (ESI, m / z): [M+H] + =292.

[0599] The earlier 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] The 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 single unknown isomers) TIFF0007862413000248.tif81170

[0602] Under nitrogen, HMPA (910 mg, 5.09 mmol) was added at room temperature 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 faster peak in the previous step) in tetrahydrofuran (25 mL). Then, LiHMDS (5.00 mL, 5.00 mmol) was added at -40°C. The resulting solution was stirred at -40°C for 0.5 hours. Then, 1-bromo-2-chloroethane (2.80 g, 19.5 mmol) was added at -40°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-30% SiO2 / petroleum ether) to obtain 420 mg (30% yield) of the title compound as a yellow oily substance (intermediate 3a), and 530 mg of a mixture of the starting material and another isomer (compound 3b) was obtained. The 530 mg mixture was re-purified by C18 column chromatography (solvent gradient: 0-100% ACN (10M NH4HCO3) in water) to obtain 117 mg (8% yield) of the title compound as a yellow oily substance (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] Under nitrogen, HMPA (479 mg, 2.67 mmol) was added at room temperature 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 in the previous step) in tetrahydrofuran (15 mL). The reaction system 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 hours. Then, 1-bromo-2-chloroethane (1.48 g, 10.3 mmol) was added at -40°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-30% SiO2 / petroleum ether) to obtain 200 mg (yield 27%) of the title compound as a yellow oily substance (intermediate 3c), and 200 mg of a mixture of the starting material and another isomer (compound 3d) was obtained. The 200 mg mixture was re-purified by C18 column chromatography (solvent gradient: 0-100% ACN (10M NH4HCO3) in water) to obtain 63 mg (yield 8%) of the title compound as a yellow oily substance (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) TIFF0007862413000249.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 under vacuum to obtain the crude product, which was used in the next step without further purification. LC-MS:(ESI,m / z):[M+H] + =254.

[0610] Similar to the method described above, the other three isomers were prepared from the relevant Boc starting materials.

[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) TIFF0007862413000250.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 Et3N (371 mg, 3.67 mmol) in acetonitrile (10 mL) was stirred at 85°C for 4 hours. The solvent was concentrated under vacuum. The residue was purified by flash chromatography (gradient: 0-10% MeOH / DCM) on silica gel to obtain 90 mg (yield 56%, intermediate 5a) as a yellow oily substance. 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 the corresponding starting materials using the same method as 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 ¹H 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]heptan-3,1'-cyclopropane]-5-yl)methanol (two single unknown atropisomers) and ((3R)-2',2'-difluoro-1-azaspiro[bicyclo[3.2.0]heptan-3,1'-cyclopropane]-5-yl)methanol (two single unknown atropisomers) TIFF0007862413000251.tif29170

[0618] Under nitrogen, 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) was mixed with LiAlH4 (0.9 mL, 0.900 mmol) at 0°C. The resulting solution was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with Na2SO4.10H2O. After filtration, the filtrate was concentrated under reduced pressure to obtain the product (100 mg, crude, intermediate 6a) as a yellow oily substance. 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 the corresponding starting materials using the same method as 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 was not performed due to the small quantity.

[0623] Intermediate 35: (3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol TIFF0007862413000252.tif33170

[0624] Step 1. 1-(tert-butyl)2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate TIFF0007862413000253.tif26170

[0625] Under nitrogen, 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) was mixed with LiHMDS (10 mL, 10 mmol) at -78°C, and the mixture was stirred at -78°C for 0.5 hours. Then, 1-chloro-2-iodoethane (2.87 g, 15.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction product was quenched with NH4Cl (aqueous solution) and extracted with ethyl acetate. The combined organic layer was dried over NaSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted with ethyl acetate / petroleum ether (0-60%) to obtain 900 mg of the title compound (yield 36.4%) as a yellow solid. LC-MS:(ESI,m / z):[M+H] + =328

[0626] Step 2. Methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate TIFF0007862413000254.tif22170

[0627] Under nitrogen, a solution of 1-(tert-butyl)2-methyl2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (470 mg, 1.43 mmol) in dichloromethane (5 mL) was mixed with TFA (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The solvent was concentrated under vacuum to obtain 300 mg (crude) of the title compound as a yellow oily substance, 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 TIFF0007862413000255.tif17170

[0629] Under nitrogen, a solution of methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate (300 mg, 1.32 mmol) in acetonitrile (5 mL) was mixed with Et3N (1 mL) at room temperature and stirred at 85 °C for 12 hours. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted with DCM / MeOH (0-6%) to obtain 150 mg of the title compound (yield 59.5%) 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 TIFF0007862413000256.tif14170

[0631] Under nitrogen, a solution of methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate (150 mg, 0.780 mmol) in tetrahydrofuran (3 mL) was mixed with LiAlH4 (2.4 mL, 2.4 mmol, 1 M in THF) at 0°C. The solution was stirred at 0°C for 0.5 hours. After removing the solvent by blowing in nitrogen, 110 mg (crude) of the title compound was obtained as a yellow oily substance, which was used in the next reaction without further purification. LC-MS:(ESI,m / z):[M+H] + =164. Purification.

[0632] Intermediate 36: ((7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-yl)methanol TIFF0007862413000257.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 TIFF0007862413000258.tif37170

[0634] Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (19.9g) was separated by chiral SFC (column: CHIRALPAK IH, 50×250mm; mobile phase A: CO2, mobile phase B: EtOH; flow rate: 150mL / min; gradient: 26%B; 220nm; RT1: 4.8; RT2: 6.43; injection volume: 1.8ml; run number: 122) to obtain ethyl(R)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.61g, faster peak) and (S)-2-methylene-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.29g, slower peak). LC-MS:(ESI,m / z):[M+H] + =210. 1 ¹H NMR (400MHz, chloroform-d): δ 5.12-5.00 (m, 2H), 4.32-4.28 (m, 1H), 4.21 (q, J=7.1Hz, 2H), 3.73 (d, J=15.7Hz, 1H), 3.06 (d, J=15.7Hz, 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=7.1Hz, 3H). The ¹H NMR of the two isomers is the same.

[0635] Step 2: Ethyl(7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine]-7a'(5'H)-carboxylate TIFF0007862413000259.tif39170

[0636] Under nitrogen, TMSCF3 (476 mg, 3.35 mmol) was added at room temperature 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). The resulting solution was stirred at 65 °C for 2.5 hours. The solution was diluted with DCM, washed with sodium thiosulfate solution, and dried over Na₂SO₄. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0%~35% ethyl acetate / petroleum ether), yielding a yellow solid with a fast peak of 95.0 mg (yield 38.3%) and a slow peak of 108 mg (yield 43.6%) obtained by flash chromatography (gradient: 35%~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 TIFF0007862413000260.tif18170

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

[0639] Intermediate 37: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-2,6-dichloro-5,8-difluoroquinazoline-4(3H)-one TIFF0007862413000261.tif84170

[0640] Step 1: 3-bromo-2,5-difluoroaniline TIFF0007862413000262.tif21170

[0641] 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 mixed with concentrated hydrochloric acid (40 mL, 36%) at room temperature. The solution was heated to 100 °C for 1 hour. The reaction system was cooled to room temperature. The solid was filtered off and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to obtain the title compound (34.3 g, crude) as a brown oily substance. LC-MS: (ESI, m / z): [M+H] + =208. The crude product was used in the next process without further purification.

[0642] Step 2: N-(3-bromo-2,5-difluorophenyl)-2-(hydroxyimino)acetamide TIFF0007862413000263.tif19170

[0643] To a solution of 2,2,2-trichloroethane-1,1-diol (40.9 g, 247 mmol), Na2SO4 (187 g, 1.32 mol), and NH2OH·HCl (39.8 g, 577 mmol) in water (680 mL), 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) were added. The resulting solution was heated at 60 °C for 3 hours. The reaction system was cooled to room temperature and filtered. The solid was collected, washed with water (500 mL), and dried in an oven to obtain 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 TIFF0007862413000264.tif21170

[0645] A solution of N-(3-bromo-2,5-difluorophenyl)-2-(hydroxyimino)acetamide (32.8 g, 118 mmol) in H2SO4 (160 mL, 98%) was heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature and slowly added to ice water. The precipitate was collected by filtration, washed with water, and dried in an oven to obtain 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 TIFF0007862413000265.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 H2O2 (53.7 mL, 30%) was stirred at room temperature for 16 hours. 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 obtain the title compound (13.4 g, yield 49.4%) as a light brown solid. LC-MS:(ESI,m / z):[M+H] + =252.

[0648] Step 5: Methyl 2-amino-4-bromo-3,6-difluorobenzoate TIFF0007862413000266.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), TMSCHN2 (100 mL, 2.0 mol / L in hexane) was added at 0°C. The resulting solution was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum, yielding 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 TIFF0007862413000267.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 hours. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain 35 g (crude) of 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)pyridine-2-yl)-3,6-difluorobenzoate TIFF0007862413000268.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)pyridine-2-amine (73.4 g, 148 mmol, intermediate 4), KF (20.4 g, 352 mmol), and Pd(PPh3)2Cl2 (13.0 g, 18.5 mmol) in acetonitrile (500 mL) and water (100 mL) was stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was concentrated under vacuum to obtain 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)pyridine-2-yl)-5-chloro-3,6-difluorobenzoate TIFF0007862413000269.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 Na2SO4, and concentrated under vacuum to obtain 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)pyridine-2-yl)-5-chloro-3,6-difluorobenzoic acid TIFF0007862413000270.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), NaOH (15.1 g, 377 mmol) was added. The solution was stirred at 50°C for 3 hours. The reaction system was cooled to room temperature, and the pH was adjusted to approximately 4 with citric acid. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain 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)pyridine-2-yl)-5-chloro-3,6-difluorobenzamide TIFF0007862413000271.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), NH4Cl (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, the solid was collected by filtration, and washed with water to obtain 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)pyridine-2-yl)-2,6-dichloro-5,8-difluoroquinazoline-4(3H)-one TIFF0007862413000272.tif38170

[0661] A solution of 2-amino-4-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-5-chloro-3,6-difluorobenzamide (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 hour. The reaction system was cooled to room temperature and poured into saturated NaHCO₃. The resulting solution was extracted with ethyl acetate. The combined organic layer was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by flash chromatography (gradient: 0-8% HCl / DCM) on silica gel to obtain 11 g (yield 34.2%) 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 TIFF0007862413000273.tif94170

[0663] Step 1: 3-benzyl 6-(tert-butyl)(1S,5R)-3,6-diazabicyclo[3.2.2]nonane-3,6-dicarboxylate TIFF0007862413000274.tif19170

[0664] Under nitrogen, 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 for 1 hour. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-100% siRNA / petroleum ether) to obtain 800 mg of the title compound as a colorless oil. The two enantiomers were separated by Prep-SFC under the following conditions: (Column: CHIRALPAK IG, 3×25cm, 5μm; Mobile phase A: CO2, Mobile phase B: IPA (0.5% 2M NH3-MeOH); Flow rate: 70 mL / min; Gradient: 30%B; Column temperature: 35℃; Back pressure: 100 bar; 215 nm; RT1: 6.86; RT2: 7.89; Injection volume: 1.5 ml; Number of runs: 20). The faster peak at 330 mg and the slower peak at 340 mg were obtained as a white oily substance. The faster 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 TIFF0007862413000275.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 4M HCl / dioxane (20 mL) was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum to obtain 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 TIFF0007862413000276.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 hours. The reaction mixture was diluted with SiO2 and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-40% SiO2 in petroleum ether) to obtain 8.30 g of the title compound as a yellow oily substance. 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) TIFF0007862413000277.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 hours. The solvent was concentrated under vacuum to obtain 5.80 g (crude) of the title compound as a yellow oily substance, 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 TIFF0007862413000278.tif23170

[0672] A solution of (1S,5R)-6-benzyl-3,6-diazabicyclo[3.2.2]nonane (2,2,2-trifluoroacetate) (5.80 g, crude), Boc2O (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 hours. The solvent was concentrated under vacuum, and the resulting residue was purified by reverse-phase chromatography (gradient: 0-100% acetonitrile (0.05% NH4HCO3) in water) to obtain 6.30 g of the title compound as a yellow oily substance. 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 TIFF0007862413000279.tif23170

[0674] Under nitrogen, s-BuLi (18.8 mL, 1.3 M in hexane) was added at -78°C 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). The resulting solution was stirred at -78°C for 1.5 hours. Then, methyl chloroformate (1.77 mL, 22.8 mmol) in diethyl ether (4.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction product was quenched with saturated NaHCO3 solution. The resulting solution was extracted with SiO2. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-50% SiO2 in petroleum ether), yielding 1.50 g (the desirable isomer (isomer a), represented by the slower peak in the column, containing traces b and d) and 2.6 g (the undesirable isomer (isomer c), represented by the faster peak in the column, pure) as a yellow oily substance. 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 TIFF0007862413000280.tif22170

[0676] Under nitrogen, 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) was mixed with LiAlH4 (3.2 mL, 1 M in THF) at 0°C. The resulting solution was stirred at 0°C for 2 hours. The reaction mixture was quenched with N...

Claims

1. Equation (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 ring A with 6, 7, or 8 members. Each R ０ It is, independently, hydrogen, R １ is a substituted or unsubstituted naphthyl, R ７ substituted or unsubstituted isoquinolinyl, R ７ substituted or unsubstituted indazolyl, R ７ substituted or unsubstituted benzothiazolyl, R ７ substituted or unsubstituted phenyl, or R ７Ａ substituted or unsubstituted pyridinyl, and ７Ａ is Each R ７ These are independently hydrogen, halogen, -OH, and NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ It is a haloalkyl or unsubstituted cyclopropyl, Each R ７Ａ These are, independently, hydrogen, halogen, and NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ It is a haloalkyl or unsubstituted cyclopropyl, R ２ is, L １ -O-L ２ -R ８ , or R ８Ａ Substitute or non-substitute C １～３ It is alkyl, L １ is a combination or R Ｌ１ Substitute or non-substitute C １～３ It is alkylene, R Ｌ１ is halogen or unsubstituted C １～３ It is alkyl, L ２ is bonded or unsubstituted C １～３ It is alkylene, R ８ R includes N, S, or O. ９ A substituted or unsubstituted 4- to 10-member complex ring, Each R ９ These are, independently, halogen, oxo, and -OCF ３ , -OCHF ２ , -OCH ２ F, unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ Alkoxy, R １０ Substitute or non-substitute C １～３ Alkyriden, R １０ Substitute or non-substitute C ３～４ Cycloalkyl, or R １０ It is a substituted or non-substituted 3 or 4-member complex ring, or Two R ９ Together, R １０ Substitute or non-substitute C ３～５ Cycloalkyl, or R containing one or more oxygen atoms １０ Substitute or non-substitute C ３～５ Forming a heterogeneous ring, R １０ is hydrogen, halogen, or C １～３ It is an unsubstituted alkyl group, Each R ８Ａ R is independent of R ９Ａ Substitute or non-substitute C １～３ Alkyl, R ９Ａ Substitute or non-substitute C １～３ Alkoxy, R ９Ａ Substitute or non-substitute C ３～４ Cycloalkyl, or R ９Ａ A complex ring with 4 to 6 members, either substituted or unsubstituted. Each R ９Ａ These are, independently, halogen, oxo, and unsubstituted C. １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ alkoxy, unsubstituted C １～３ Alkyriden, R ９ Substitute or non-substitute C ３～４ Cycloalkyl, or R containing N, S, or O ９ A substituted or unsubstituted 4- to 10-member complex ring, R ３ and R ４ These are, independently, hydrogen, -CN, halogen, and unsubstituted C. １～３ Alkyl or unsubstituted cyclopropyl, Each R ５ These are, independently, halogen, oxo, and unsubstituted C. １～３ Alkyl or unsubstituted C １～３ It is a haloalkyl, or Two R ５ Together, they form a bridge between two carbon atoms of ring A, and the bridge comprises one to three carbon atoms and optionally one heteroatom selected from O and N, or Two R ５ Together, they form a bridge between the two carbon atoms of ring A, and the bridge is O or NR １１ Including one of the following, R １１ is hydrogen, C(O)CH ３ , or non-substituted C １～３ It 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 is a substituted or unsubstituted 3- to 4-membered heterocyclic ring, R ６Ａ is halogen, CN, OR ６Ｂ , SR ６Ｃ , S(O) ２ R ６Ｃ , C(O) Ｒ６Ｂ , unsubstituted C １～３ alkyl, or unsubstituted C １～３ haloalkyl, or R ６Ｂ is a substituted or unsubstituted 3- to 4-membered heterocyclic ring, R ６Ｂ and R ６Ｃ Each of them is independent of C １～３ Alkyl or C １～３ (It is a haloalkyl) A compound having the structure, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

2. R １ However, R ７Ａ Substituted or unsubstituted phenyl, R ７ Substituted or unsubstituted indazolyl, or R ７Ａ The compound according to claim 1, which is a substituted or unsubstituted pyridinyl, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

3. Each R ７ However, independently, halogen, NH ２ , unsubstituted C １～３ Alkyl or unsubstituted C １～３ A compound according to claim 1 or 2, which is a haloalkyl compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

4. R １ but, (In the formula, X １ is N or CF, Each R ７Ａ These are independently hydrogen, halogen, and unsubstituted C. １～３ Alkyl or unsubstituted C １～３ (It is a haloalkyl) The compound according to claim 1, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

5. R １ but, The compound according to claim 1, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

6. R １ but, The compound according to claim 1, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

7. R １ but, (In the formula, each R ７ These are, independently, halogen, NH ２ , N(Me) ２ , or non-substituted C １～３ (It is alkyl.) The compound according to claim 1, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

8. R ２ However, L １ -O-L ２ -R ８ And L １ However, it is a bond, L ２ The compound according to any one of claims 1 to 7, wherein the compound is methylene, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

9. R ８ but, (In the formula, R ９ is halogen, or R １０ Substitute or non-substitute C １～３ It is alkyridene, r is an integer between 0 and 12. j is 1, 2, or 3. k is either 1 or 2. A compound according to any one of claims 1 to 8, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

10. R ８ but, (In the formula, R ９ It is independently halogen, or R １０ Substitute or non-substitute C １～３ It is alkyridene, Each R １０ These are independently hydrogen or halogen, (r is either 1 or 2) A compound according to any one of claims 1 to 8, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

11. R ８ but, (In the formula, R ９ These are, independently, halogen, oxo, or unsubstituted C １～３ It is alkyl, (r is either 1 or 2) A compound according to any one of claims 1 to 8, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

12. R ８ but, (In the formula, R ９ is hydrogen or unsubstituted C １～３ It 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 (It is a haloalkyl) A compound according to any one of claims 1 to 8, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

13. R ３ A compound according to any one of claims 1 to 12, wherein is a halogen, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

14. R ４ A compound according to any one of claims 1 to 13, wherein is hydrogen, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

15. R ４ A compound according to any one of claims 1 to 13, wherein is a halogen, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

16. Two R ５ However, together they form a bridge between two carbon atoms of ring A, and the bridge contains 1 to 3 carbon atoms, the compound according to any one of claims 1 to 15, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

17. formula: A compound according to any one of claims 1 to 7, 9 to 16, having the structure of, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

18. formula: A compound according to any one of claims 1 to 7, 9 to 16, having the structure of, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

19. X is NR ６ And R ６ A compound according to any one of claims 1 to 18, wherein is hydrogen, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

20. X is NR ６ And R ６ However, R ６Ａ Substitute or non-substitute C １～３ It is alkyl, and each R ６Ａ However, independently, halogen, CN, OMe, OEt, OCF ３ A compound according to any one of claims 1 to 18, or a four-membered heterocycle, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. A compound selected from the group consisting of

21. . A pharmaceutically acceptable salt of

22. . A compound selected from the group consisting of

23. . A pharmaceutically acceptable salt of

24. . A compound selected from the group consisting of

25. . A pharmaceutically acceptable salt of

26. .

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives.

28. A composition comprising a compound according to any one of claims 1 to 26, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of cancer, or the pharmaceutical composition according to claim 27.

29. The aforementioned cancer, KRas Ｇ１２Ｄ A composition for use or pharmaceutical composition according to claim 28, comprising a mutation.

30. The composition for use or pharmaceutical composition according to claim 28 or 29, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

31. The composition for use or pharmaceutical composition according to claim 30, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

32. The composition for use or pharmaceutical composition according to claim 30, wherein the cancer is pancreatic cancer.

33. The composition for use or pharmaceutical composition according to claim 30, wherein the cancer is colorectal cancer.

34. A composition comprising a compound according to any one of claims 1 to 26, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis, or the pharmaceutical composition according to claim 27.

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