Synthesis of quinazoline compounds

Abstract

This invention provides a method for synthesizing quinazoline compounds containing an atropisomer center. [Solution] In one embodiment, a crystalline cyclohexane solvate of formula (1) is provided, having substantially equal lattice dimensions a=9.83870Å; b=13.66880Å; c=33.36080Å; α=90°; β=90°; γ=90°; space group: P 21 21 21; measured at 90K. TIFF2026143404000371.tif53170

Description

Cross-reference of related applications

[0001] This application claims the interests of U.S. Provisional Patent Application No. 63 / 064,746, filed on 12 August 2020, which is incorporated herein by reference in its entirety for all purposes. [Technical Field]

[0002] Methods for synthesizing atrop isomers of quinazolinyl compounds via atrop-selective synthetic methods / techniques are provided herein. [Background technology]

[0003] The arrangement of biaryl axes often plays a crucial role in the pharmacological properties of bioactive compounds and is a fundamental basis for useful reagents and catalysts in asymmetric synthesis. Highly atroposelective cross-coupling, particularly heterocyclic cross-coupling for the synthesis of biheteroaryls, remains a challenging and unresolved problem. This disclosure provides an improved method for the atroposelective synthesis of aminopyridinyl-quinazolinyl compounds by Negishi coupling utilizing chiral ligands such as kylafites or valphos. [Overview of the project]

[0004] Solutions to the above-mentioned problems and other problems in the art are provided herein.

[0005] Compounds and methods for producing the compound of formula (I) described herein are disclosed herein.

[0006] In one embodiment, a method for synthesizing a compound of formula (I) described herein is provided, comprising (a) contacting a compound of formula (II) described herein with an organomagnesium compound and a zinc complex, and (b) contacting the mixture from step (a) with a compound of formula (III) described herein, a transition metal (e.g., Pd or Ni) catalyst precursor, and a chiral ligand, thereby synthesizing a compound of formula (I).

[0007] In one embodiment, compounds of formula (I) as described herein, or solvates, tautomers, stereoisomers, atropisomers, or salts thereof are provided herein. In one embodiment provided herein, the compounds of formula (I) have formulas Ia, Ib, Ib1, Ib2, Ib3, Ic1, Ic2, Id, 1a, 1b, 1c, or 1 as described herein.

[0008] In another embodiment, a method for preparing a compound of formula (I) is provided herein, comprising: (a) contacting a compound of formula (II) or its tautomer, stereoisomer, or salt described herein with an organomagnesium compound and a zinc complex; and (b) contacting the mixture from step (a) with a compound of formula (III) or its stereoisomer or salt described herein, a transition metal (e.g., Pd or Ni) catalyst precursor, and a chiral ligand to synthesize a compound of formula (I) or its solvate, tautomer, stereoisomer, atropisomer, or salt.

[0009] Methods (P2) described herein for the preparation of the compound of formula (II) described herein or its tautomers, stereoisomers, or salts thereof are further provided herein.

[0010] In another embodiment, a method (P3) described herein for preparing a compound of formula (III) or a salt thereof as described herein is provided herein.

[0011] In another embodiment, a method (P4) described herein for preparing a compound of formula (III) or a salt thereof as described herein is provided herein.

[0012] In another embodiment, a method (P5) described herein for preparing a compound of formula (III) or a salt thereof as described herein is provided herein.

[0013] In another embodiment, the method described herein (P6) for the preparation of a compound of formula (G) described herein or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof is provided herein.

[0014] In another embodiment, methods (P7) described herein for the preparation of a compound of formula (H) described herein or its tautomers, stereoisomers, atropisomers, or pharmaceutically acceptable salts thereof are provided herein.

[0015] In another embodiment, methods (P8) described herein for the preparation of a compound of formula (F) described herein or its tautomers, stereoisomers, atropisomers, or pharmaceutically acceptable salts thereof are provided herein.

[0016] In another embodiment, a method (P8) described herein for the preparation of a compound of formula (F) or a pharmaceutically acceptable salt thereof is provided herein. [Brief explanation of the drawing]

[0017] [Figure 1] The single-crystal structure of the cyclohexane crystalline solvate of compound 1 is shown.

[0018] [Figure 2] The single-crystal structure of the methylcyclohexane crystalline solvate of compound 1 is shown.

[0019] [Figure 3] The single-crystal structure of the chlorobenzene crystalline solvate of compound 1 is shown.

[0020] [Figure 4] The single-crystal structure of the ethylbenzene crystalline solvate of compound 1 is shown.

[0021] [Figure 5] The single-crystal structure of the m-xylene crystalline solvate of compound 1 is shown.

[0022] [Figure 6] The single-crystal structure of the toluene crystalline solvate of compound 1 is shown. [Modes for carrying out the invention]

[0023] definition The terms "halogen" and "halo" are used interchangeably herein and refer to F, Cl, Br, or I.

[0024] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. In one example, an alkyl group has 1 to 18 carbon atoms (C 1-18 ). In other examples, alkyl groups are C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , or C 1-3Examples of alkyl groups include methyl (Me, -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), and 2-butyl (s-Bu, s-butyl, -CH(C H3)CH2CH3), 2-methyl-2-propyl(t-Bu, t-butyl, -C(CH3)3), 1-pentyl(n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(- CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-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 Examples include )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.

[0025] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms are replaced by halogens. Examples of haloalkyls include trifluoromethyl, difluoromethyl, and fluoromethyl. "Fluoroalkyl" refers to an alkyl chain in which one or more hydrogen atoms are replaced by fluorine (F).

[0026] The term "amino" means -NH2.

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

[0028] The term "carboxy" means -C(=O)OH.

[0029] The term "alkoxy" means -O-alkyl.

[0030] The terms "cyano" and "nitrile" are used interchangeably herein and mean -C≡N or -CN.

[0031] The term "cyanoalkyl" means an alkyl substituted with one cyano substituent.

[0032] The term "haloalkoxy" means -O-haloalkyl.

[0033] The term "hydroxy" means -OH.

[0034] The term "hydroxyalkyl" means an alkyl substituted with one hydroxy substituent.

[0035] The term "aryl" means a carbocyclic aromatic group having the specified number of carbon atoms, or up to 14 carbon atoms if no number is specified, regardless of whether it is fused to one or more groups. One example is an aryl group having 6 to 14 carbon atoms. Another example is an aryl group having 6 to 10 carbon atoms. Another example is an aryl group having 5 to 7 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl and the like (see, for example, Lang’s Handbook of Chemistry (Dean, J.A., ed.) 13 thSee ed.Table 7-2

[1985] ). The specific aryl is phenyl.

[0036] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyls include monocyclic, dicyclic, tricyclic, spirocyclic, and bridging saturated ring systems. For example, a cycloalkyl group has 3 to 12 carbon atoms (C 3-12 ) is. In other examples, cycloalkyl is C 3-7 , C 3-8 , C 3-10 , or C 5-10 In other examples, a cycloalkyl group as a monocycle is C 3-8 , C 3-6 , or C 5-6 In another example, the cycloalkyl group as a biring is 7-C 12 In another example, the cycloalkyl group as a spiro system is C 5-12 Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary configurations of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, 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 bonding site of the cyclic system to the rest of the molecule. In one example, a heterocyclil includes monocyclic, dicyclic, tricyclic, spiro, and bridging cyclic systems containing 3 to 11 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. In one 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, hex Sahydropyrimidinyl, oxazinyl, thiadinyl, thioxanil, homopiperazinyl, homopiperidinyl, azepanil, oxepanil, thiepanil, oxazepinyl, oxazepanil, diazepanil, 1,4-diazepanil, diazepinyl, thiazepinyl, thiazepanil, tetrahydrothiopyranil, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoiisothiazolidinol, 1,1-dioxoiisothiazolyl, oxazolidinol, imidazolidinol, 4,5,6,7-tetrahydro[2H]indazolyl, tetra Hydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxadiadinyl, 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] The term "heteroaryl" refers to any monocyclic, dicyclic, or tricyclic aromatic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, where, in exemplary embodiments, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, JA, ed.) 13. th See ed.Table 7-2

[1985] . This definition includes any bicyclic group in which one of the heteroaryl rings is fused to an aryl ring, and the aryl ring or heteroaryl ring is bonded to the remainder of the molecule. In one embodiment, a heteroaryl includes a 5-6 member monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, triazinyl, tetradinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, and prinyl, as well as benzo-condensed derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl.

[0039] 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.

[0040] In certain embodiments, the heterocyclyl or heteroaryl group is nitrogen-bonded. For example, 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 1-position bond configuration of 1H-indazole, the 2-position bond configuration of isoindole or isoindli, the 4-position bond configuration of morpholine, and the 9-position bond configuration of carbazole or β-carbolin.

[0041] "Condensed" means any cyclic structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with a cyclic structure present in the compound of the present invention.

[0042] The term "acyl" refers to 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).

[0043] As used herein, “halogenating agent” refers to any reagent that adds one or more halogens to the compounds described herein. As used herein, “chlorinating agent” refers to any reagent that adds one or more chlorine (Cl) atoms to the compounds described herein. As used herein, “brominating” or “iodinating” agents refer to any reagent that adds one or more bromine (Br) or iodine (I) atoms, respectively, to the compounds described herein.

[0044] As used herein, “haloalkylating agent” refers to any reagent that adds one or more haloalkyl groups (e.g., CF3) to the compounds described herein. “Fluoroalkylating agent” refers to a reagent that adds one or more fluoroalkyl groups to the compounds described herein.

[0045] An "organomagnesium compound" is an organometallic compound in which the metal is magnesium.

[0046] "LDA" refers to lithium diisopropylamide.

[0047] "LiTMP" or "LTMP" refers to lithium tetramethylpiperidide.

[0048] "NCS" refers to N-chlorosuccinimide. "NBS" refers to N-bromosuccinimide. "NIS" refers to N-iodosuccinimide.

[0049] As used herein, "chiral ligand" refers to one or more compounds and / or catalysts that synthesize one chiral compound, such as an atropisomer, more than the other.

[0050] When used herein, a wavy line intersects a bond in the chemical structure. JPEG2026143404000001.jpg9170 shows atomic bonding points in a chemical structure where wavy bonds are attached to the remainder of a molecule or the remainder of a molecular fragment.

[0051] 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.

[0052] The term "pharmaceutically acceptable" means molecular elements and compositions that, when administered appropriately to animals, such as humans, do not produce adverse reactions, allergic reactions, or other adverse effects.

[0053] The compounds of the present invention may 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.

[0054] The term "pharmaceutically acceptable base addition salt" refers to 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 polyamine resin salts. Specific examples of organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0055] 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-disulfonic acid Salt, 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-na Selected from phthalene sulfonates, cansylates (camphor 10-sulfonates, e.g., (1S)-(+)-10-camphor-sulfonates), glutamates, glutarates, hippuric acid (2-(benzoylamino)acetate), orotinates, xylates (p-xylene-2-sulfonates), and pamoates (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylates).

[0056] The compounds of the present invention may contain one or more chiral carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. Racemic compounds, diastereomers, or enantiomers may be used as starting materials or intermediates in the synthesis of the compounds. A mixture of specific diastereomer compounds can be separated or concentrated into one or more specific diastereomers by chromatography or crystallization. Similarly, enantiomixtures can be separated or enantiomerically concentrated using the same technique or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms may be present in the R or S configuration, and both of these configurations are within the scope of the present invention.

[0057] In the structures shown herein, if the stereochemistry of any specific chiral atom is not specified, all stereoisomers are conceived and included as compounds of the present invention. 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, where solid wedges or dashed lines are used, relative stereochemistry is intended.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other but cannot be superimposed.

[0062] Atropisomers are stereoisomers resulting from rotations that are sterically hindered by a single bond or axis, where the energy difference due to steric strain or other factors creates a rotational barrier that is high enough to allow the isolation of individual conformational isomers.

[0063] The stereochemical definitions and conventions used in this specification generally follow those of 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. 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 l meaning that 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 method. The terms "racemic mixture" and "racemate" refer to equimolar mixtures of two enantiomer species that are not optically active.

[0064] 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.

[0065] 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), Cbz (carbobenzyloxy), Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, or DMB (dimethoxybenzyl). In some embodiments, the amino protecting group may be a group used to block or protect an amino group, arising from the cyclization of a group bonded to the amino group, but which can later be removed or substituted. Examples of such groups include 1,3,5-dioxazinane, 2,4-dimethyl-1,3,5-dioxazinane, 2,2,5,5-tetramethyl-1,2,5-azadisyloridine, and isoindoline-1,3-dione. Further exemplary amino protecting 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.

[0066] The term "leaving group" refers to a part of a first reactant that is replaced in a chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxys, and sulfonyloxy groups. Exemplary sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (e.g., methylsulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (e.g., p-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylate group)).

[0067] The terms “inhibit” and “reduce,” or any variation thereof, include any measurable reduction or complete inhibition to achieve the desired result. For example, there may be a reduction in the variable, a decrease in activity compared to normal, by about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range of these variables.

[0068] The terms “antagonist” and “inhibitor” are used interchangeably and refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as K-Ras, H-Ras, or N-Ras G12C. Therefore, 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 within this definition. Preferred biological activities inhibited by antagonists are those associated with tumor progression, growth, or expansion.

[0069] 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 that target protein. Therefore, the term “agonist” is defined in the context of the biological role of the target polypeptide. Preferred agonists in this specification interact specifically 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 the signaling pathway in which the target polypeptide is an element are also specifically included within this definition.

[0070] The terms “cancer,” “malignant,” “neoplasm,” and “tumor,” and related terms refer to or describe a physiological condition in mammals typically characterized by the uncontrolled growth of cells. A “tumor” includes one or more cancer cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, gliablastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer (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. Examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, myelofibrosis such as essential thrombocytosis and primary myelofibrosis, and chronic myeloid leukemia (CML).

[0071] A “chemotherapeutic agent” is an active substance useful for treating a given disorder, such as cancer or an inflammatory disorder. Examples of chemotherapeutic agents are known in the art and are incorporated herein by reference, such as those described in U.S. Patent Application Publication 2010 / 0048557. Furthermore, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents, and combinations of two or more thereof.

[0072] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include the 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. Isotope-labeled compounds (for example, 3 H and 14 Compounds labeled with 1C can be useful in compound or substrate tissue partitioning assays. Tritium labeling (i.e., 3 H) and carbon 14 (i.e.) 14 C) Isotopes can be useful due to their ease of preparation and detection. Furthermore, heavier isotopes, such as deuterium (i.e., 2 Substitution with H, etc., can lead to increased metabolic stability, potentially resulting in specific therapeutic benefits (e.g., longer in vivo half-life or reduced dosage). In some embodiments, one or more carbon atoms in the compound of the present invention are 13 C or 14It is replaced by carbon-enriched carbon. 15 O, 13 N, 11 C, and 18 Positron-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.

[0073] Any limitations discussed in relation to one embodiment of the present invention can be specifically conceived to apply to any other embodiment of the present invention. Furthermore, any compound or composition of the present invention can be used in any manner of the present invention, and any compound or composition of the present invention can be produced or utilized using any manner of the present invention.

[0074] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of errors in the device or method used to measure that value. compound

[0075] Provided herein are compounds of formula (I): JPEG2026143404000002.jpg55170 or its solvates, tautomers, stereoisomers, atropisomers, or salts, During the ceremony, X 0 is hydrogen, halogen, OR 5A , SR 5B , R 5 - Substitute or non-substitute C 1-6 Alkyl, R 5 - Substitute or non-substitute C 1-6 Haloalkyl, R 5 - Substitute or non-substitute C 5-7 Aryl, or R 5 - Substitute or non-substitute C 5-7 It is a heteroaryl; X 1 is hydrogen or halogen; X 3 is hydrogen, halogen, R 6 -substituted or unsubstituted C 1-3 alkyl, R 6 -substituted or unsubstituted C 1-3 haloalkyl, R 6 -substituted or unsubstituted C 1-3 alkoxy, or R 6 -substituted or unsubstituted cyclopropyl; R 1 is hydrogen or PG 1 ; each R 2 is independently halogen, cyano, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 cyanoalkyl, or unsubstituted C 1-6 haloalkyl; R 3 is hydrogen, halogen, R 3A -substituted or unsubstituted C 1-3 alkyl, R 3A -substituted or unsubstituted C 1-3 haloalkyl, or R 3A -substituted or unsubstituted C 3-6 cycloalkyl; R 3A is halogen, OH, CN, unsubstituted C 1-3 alkyl or unsubstituted C 1-3 haloalkyl; R 4 is R 4A -substituted or unsubstituted C 1-3 haloalkyl; R 4A is unsubstituted C 1-3 alkyl; R 5 is halogen, cyano, OH, NO2, R 5A -substituted or unsubstituted C 1-6 alkyl, R 5A -substituted or unsubstituted C 1-6 haloalkyl, R 5A -substituted or unsubstituted C 1-6 cyanoalkyl, R 5A -substituted or unsubstituted C 3-6 cycloalkyl, R 5A- Substitutive or unsubstituted 3- to 6-membered complex rings, R 5A - Substitutable or unsubstituted phenyl, or R 5A -It is a substituted or unsubstituted 6-membered heteroaryl; R 5A and R 5B Each of them is independent of R 5C - Substitute or non-substitute C 1-6 Alkyl, R 5C - Substitute or non-substitute C 1-6 Haloalkyl, R 5C - Substitute or non-substitute C 3-7 Cycloalkyl; R 5C - Substitutable or non-substitutable 3- to 7-membered complex rings; R 5C - Substitute or non-substitute C 5-7 Aryl, or R 5C - Substitute or non-substitute C 5-7 It is a heteroaryl; R 5C These are independently hydrogen, halogen, OH, CN, NO2, R 5D - Substitute or non-substitute C 1-6 Alkyl, R 5D - Substitute or non-substitute C 1-6 Haloalkyl, R 5D - Substitute or non-substitute C 3-7 Cycloalkyl; R 5D - Substitute or non-substitute C 3-7 Complex algebra; R 5D - Substitute or non-substitute C 5-7 Aryl, or R 5D - Substitute or non-substitute C 5-7 It is a heteroaryl; R 5D These are independently hydrogen, halogen, OH, CN, NO2, and unsubstituted C. 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl, unsubstituted C 3-7 Cycloalkyl; unsubstituted C 3-7 Heterogeneous algebra; non-substituted C 5-7 Aryl or unsubstituted C 5-7 It is a heteroaryl; R 6 These are hydrogen, halogen, OH, CN, NO2, and unsubstituted C. 1-6 Alkyl, unsubstituted C 1-6Haloalkyl or unsubstituted C 3-7 It is a cycloalkyl; n is either 1 or 2; Each PG is an amino protecting group independently, or two PGs together form a C 3-8 Forming a nitrogen heterocycle; and PG 1 This is an amino protecting group.

[0076] In one embodiment of the compound of formula (I) described herein, or its solvates, tautomers, stereoisomers, atropisomers, or salts, X 0 is halogen, OR 5A , SR 5B , R 5 - Substitute or non-substitute C 1-6 Alkyl, R 5 - Substitute or non-substitute C 1-6 Haloalkyl, R 5 - Substitute or non-substitute C 5-7 Aryl, or R 5 - Substitute or non-substitute C 5-7 It is a heteroaryl compound. In one embodiment of the compound of formula (I) described herein or its solvates, tautomers, stereoisomers, atropisomers, or salts, X 0 is hydrogen, halogen or OR 5A In another embodiment of the compound of formula (I) described herein or its solvates, tautomers, stereoisomers, atropisomers, or salts, X 0 , SR 5B , R 5 - Substitute or non-substitute C 1-6 Alkyl, R 5 - Substitute or non-substitute C 1-6 Haloalkyl, R 5 - Substitute or non-substitute C 5-7 Aryl, or R 5 - Substitute or non-substitute C 5-7 It is a heteroaryl compound. In another embodiment of the compound of formula (I) described herein or its solvates, tautomers, stereoisomers, atropisomers, or salts, X 0is hydrogen, halogen, CF3, CHF2, or CH2F. In a preferred embodiment, X 0 is a halogen. In one such embodiment of a compound of formula (I) described herein or its solvate, tautomer, stereoisomer, atropisomer or salt, X 0 It is F.

[0077] In yet another embodiment of the compound of formula (I) described herein or its solvates, tautomers, stereoisomers, atropisomers, or salts, X 0 This includes hydrogen, halogens, CF3, CHF2, CH2F, or the following structures: JPEG2026143404000003.jpg248170 or It is the portion containing JPEG2026143404000004.jpg23170, or its stereoisomer.

[0078] In one embodiment of the compound of formula (I) described herein, or its solvates, tautomers, stereoisomers, atropisomers, or salts, R 5 is a halogen, cyano, OH, or NO2. In one embodiment of the compound of formula (I) described herein or its solvates, tautomers, stereoisomers, atropisomers, or salts, R 5 is, R 5A - Substitute or non-substitute C 1-6 Alkyl, R 5A - Substitute or non-substitute C 1-6 Haloalkyl, or R 5A - Substitute or non-substitute C 1-6 It is a cyanoalkyl compound. In one embodiment of the compound of formula (I) described herein or its solvates, tautomers, stereoisomers, atropisomers, or salts, R 5 is, R 5A - Substitute or non-substitute C 3-6 Cycloalkyl, R 5A - Substitutive or unsubstituted 3- to 6-membered complex rings, R 5A - Substitutable or unsubstituted phenyl, or R 5A - It is a substituted or unsubstituted 6-membered heteroaryl.

[0079] In one embodiment, R 5A and R 5B Each of them is independent of R 5C - Substitute or non-substitute C 1-6 Alkyl or R 5C - Substitute or non-substitute C 1-6 In another embodiment, R 5A and R 5B Each of them is independent of R 5C - Substitute or non-substitute C 3-7 Cycloalkyl; R 5C - Substitutive or unsubstituted 3- to 7-membered complex rings, R 5C - Substitute or non-substitute C 5-7 Aryl, or R 5C - Substitute or non-substitute C 5-7 It is a heteroaryl compound. In one preferred embodiment, R 5A and R 5B Each of them is independent of R 5C - Substitute or non-substitute C 1-6 It is alkyl.

[0080] In one embodiment, R 5C These are independently halogen, OH, CN, or NO2. In one embodiment, R 5C R is independent of R 5D - Substitute or non-substitute C 1-6 Alkyl or R 5D - Substitute or non-substitute C 1-6 It is a haloalkyl. In one embodiment, R 5C R is independent of R 5D - Substitute or non-substitute C 3-7 Cycloalkyl or R 5D - Substitute or non-substitute C 3-7 It is a complex algebra. In one embodiment, R 5C R is independent of R 5D - Substitute or non-substitute C 5-7 aryl or R 5D - Substitute or non-substitute C 5-7 It is a heteroaryl. In another embodiment, R 5C R is independent of R 5D - Substitute or non-substitute C 3-7Heterogene or R 5D - Substitute or non-substitute C 5-7 It is a heteroaryl. In another embodiment, R 5C is, R 5D - This is a substituted pyrrolidinyl.

[0081] In one embodiment, R 5D In another embodiment, R is independently a halogen, OH, or CN. 5D is unsubstituted C 1-6 It is alkyl. In another embodiment, R 5D is unsubstituted C 1-6 In yet another embodiment, R 5D is unsubstituted C 3-7 Cycloalkyl, unsubstituted C 3-7 Heterogeneous algebras, non-substituted C 5-7 Aryl or unsubstituted C 5-7 It is a heteroaryl compound. In one embodiment, R 5D These are methyl, ethyl, or propyl.

[0082] In one embodiment, R 5A and R 5B Each of them operates independently. The filename is JPEG2026143404000005.jpg227170.

[0083] In one embodiment, R 5A and R 5B Each of them operates independently. The filename is JPEG2026143404000006.jpg228170.

[0084] In another embodiment, the compound of formula (Ia): JPEG2026143404000007.jpg53170 or its solvates, tautomers, stereoisomers, or salts are provided herein. During the ceremony, X 0 is hydrogen, halogen or OR 5A and; X 1 and X 3 These are independently halogens or methyl compounds; R 1 is hydrogen or PG 1 and; Each R 2 These are independently halogen, cyano, methyl, ethyl, propyl, -CH2CN, (CH2)2CN, CF3, CHF2, or CH2F; R 3 is hydrogen or methyl; R 5A teeth, The filename is JPEG2026143404000008.jpg227170; n is 0, 1, or 2; Each PG is an amino protecting group independently, or two PGs together form a C 3-8 Forming a nitrogen heterocycle; and PG 1 This is an amino protecting group.

[0085] Further provided herein are compounds of formula (Ib): JPEG2026143404000009.jpg55170 or its solvates, tautomers, stereoisomers, atropisomers, or salts, During the ceremony, X 1 is hydrogen or halogen; X 3 is hydrogen, halogen, R 6 - Substitute or non-substitute C 1-3 Alkyl, R 6 - Substitute or non-substitute C 1-3 Haloalkyl, R 6 - Substitute or non-substitute C 1-3 Alkoxy, or R 6 - Substituted or unsubstituted cyclopropyl; R 1 is hydrogen or PG 1 and; Each R 2 These are, independently, halogen, cyano, and unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 It is a haloalkyl; R3 is hydrogen, halogen, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 Haloalkyl, or R 3A - Substitute or non-substitute C 3-6 It is a cycloalkyl; R 3A This includes halogen, OH, CN, and unsubstituted C. 1-3 Alkyl or unsubstituted C 1-3 It is a haloalkyl; R 4 is, R 4A - Substitute or non-substitute C 1-3 It is a haloalkyl; R 4A is unsubstituted C 1-3 It is alkyl; R 6 These are hydrogen, halogen, OH, CN, NO2, and unsubstituted C. 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 It is a cycloalkyl; n is 0, 1, or 2; Each PG is an amino protecting group independently, or two PGs together form a C 3-8 Forming a nitrogen heterocycle; and PG 1 This is an amino protecting group.

[0086] In one embodiment, X 1 is hydrogen. In one embodiment, X 1 is a halogen. In one embodiment, X 1 is F or Cl. In another embodiment, X 1 If X is halogen, 3 is a halogen. In another embodiment, X 1 If X is F, 3 In another embodiment, X 1 If X is F, 3 It is Cl.

[0087] In one embodiment, X 3is hydrogen, halogen, R 6 - Substitute or non-substitute C 1-3 Alkyl, or R 6 - Substitute or non-substitute C 1-3 In another embodiment, X 3 is, R 6 - Substitute or non-substitute C 1-3 Alkoxy or R 6 - is substituted or unsubstituted cyclopropyl. In another embodiment, X 3 is hydrogen or halogen. In another embodiment, X 3 is halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3 In yet another embodiment, X 3 is halogen or unsubstituted C 1-3 In yet another embodiment, X 3 is unsubstituted C 1-3 It is an alkoxy or unsubstituted cyclopropyl. In one preferred embodiment, X 3 is a halogen. In one such embodiment, X 3 is Cl or F. In another embodiment, X 3 is Cl, F, CF3, CHF2, or CH2F. In yet another embodiment, X 3 These are CF3, CHF2, or CH2F.

[0088] In one embodiment, R 1 is hydrogen. In a preferred embodiment, R 1 is PG 1 In one such embodiment, PG 1 These are Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy). In another embodiment, PG 1 is Boc(tert-butyloxycarbonyl). In a preferred embodiment, R 1It is Boc(tert-butyloxycarbonyl).

[0089] One embodiment, each R 2 R is independently a halogen or a cyano. In one embodiment, each R 2 These are independently halogen or unsubstituted C 1-6 It is a cyanoalkyl. In another embodiment, each R 2 These are independent, non-substituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 It is a haloalkyl group. In one such embodiment, n is 1. In a preferred embodiment, each R 2 These are independent, non-substituted C 1-6 Alkyl or unsubstituted C 1-6 It is a cyanoalkyl. In such one embodiment, each R 2 is methyl or ethyl. In one such embodiment, n is 1. In another such embodiment, R 2 is methyl and n is 1. In another such embodiment, each R 2 is CF3, CHF2, or CH2F. In another such embodiment, R 2 is methyl, ethyl, CN, CH2CN, CF3, CHF2, or CH2F. In another embodiment, R 2 is methyl, ethyl, CN, or CH2CN. In such embodiments, n is 1. In another such embodiment, R 2 In one embodiment, n is CH2CN and n is 1. In another embodiment, n is 0.

[0090] In one embodiment, R 3 is hydrogen or halogen. In one embodiment, R 3 is hydrogen. In another embodiment, R 3 is hydrogen, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 In another embodiment, R 3 is, R 3A- Substitute or non-substitute C 1-3 Alkyl or R 3A - Substitute or non-substitute C 1-3 In another embodiment, R 3 is hydrogen or R 3A - Substitute or non-substitute C 1-3 It is alkyl. In yet another embodiment, R 3 is, R 3A - Substitute or non-substitute C 1-3 It is alkyl. In such one embodiment, R 3 is hydrogen or methyl. In another such embodiment, R 3 It is methyl.

[0091] In one embodiment, R 3 is, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 It is a haloalkyl, and in the formula, R 3A This is a halogen, OH, CN, or unsubstituted C 1-3 It is a haloalkyl. In one such embodiment, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 It is a haloalkyl, and in the formula, R 3A These are F, OH, CN, CF3, CHF2, or CH2F.

[0092] In a preferred embodiment, R 4 is non-substituted C 1-3 In one such embodiment, R 4 is CF3, CHF2, or CH2F. In one such embodiment, R 4 This is CF3.

[0093] In one embodiment, R 6 is a halogen. In another embodiment, R 6 OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C3-7 It is a cycloalkyl group.

[0094] In one embodiment, each PG is independently an amino protecting group. In one embodiment, each PG is the same. In such an embodiment, each PG is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy). In another embodiment, each PG is PMB, DMB, or Boc. In a preferred embodiment, each PG is PMB.

[0095] In yet another embodiment, two PGs come together as C 3-8 It forms a nitrogen heterocycle. In one embodiment, two PGs combine to form the following structure: It forms a portion containing JPEG2026143404000010.jpg25170.

[0096] In another embodiment, the compound of formula (Ib1): JPEG2026143404000011.jpg54170 or its solvates, tautomers, stereoisomers, atropisomers, or salts, During the ceremony, X 1 and X 3 These are independently halogens or methyl compounds; R 1 is hydrogen or PG 1 and; Each R 2 These are independently halogen, cyano, methyl, ethyl, propyl, -CH2CN, (CH2)2CN, CF3, CHF2, or CH2F; n is either 1 or 2; and PG 1 This is an amino protecting group.

[0097] In one embodiment, the compound of formula (I) described herein or its solvates, tautomers, stereoisomers, atropisomers, or salts is the compound of formula (Ib2): JPEG2026143404000012.jpg51170 or its solvates, tautomers, stereoisomers, atropisomers, or salts.

[0098] In one embodiment, the compound of formula (I) described herein, or its solvates, tautomers, stereoisomers, atropisomers, or salts thereof, is the compound of formula (Ib3): JPEG2026143404000013.jpg53170 or its solvates, tautomers, stereoisomers, or salts.

[0099] In one embodiment, the compound of formula (I) described herein, or its solvate, tautomer, stereoisomer, or salt, is a compound of the following formula: JPEG2026143404000014.jpg52170 or its solvates, tautomers, stereoisomers, or salts.

[0100] In one embodiment, the compound of formula (I) described herein or its solvate, tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000015.jpg50170 or its solvates, tautomers, stereoisomers, or salts.

[0101] In one embodiment, the compound of formula (I) described herein, or its solvate, tautomer, stereoisomer, or salt, is a compound of the following formula: JPEG2026143404000016.jpg51170 or its solvates, tautomers, stereoisomers, or salts.

[0102] In one embodiment, the compound of formula (I) described herein, or its solvate, tautomer, stereoisomer, or salt, is a compound of the following formula: JPEG2026143404000017.jpg52170 or its solvates, tautomers, stereoisomers, or salts.

[0103] In one embodiment, the compound of formula (I) described herein, or its solvate, tautomer, stereoisomer, or salt, is a compound of the following formula: JPEG2026143404000018.jpg50170 or its solvates, tautomers, stereoisomers, or salts.

[0104] In one embodiment, the compound of formula (I) described herein or its solvate, tautomer, stereoisomer, or salt is the compound of formula 1: JPEG2026143404000019.jpg51170 or its solvates, tautomers, stereoisomers, or salts.

[0105] Crystalline solvates of compounds of formula (I) are further provided herein. In one embodiment, the compound of formula (I) is cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene, or toluene solvate.

[0106] In one embodiment, the compound of formula (I) is the compound of formula 1: This is the crystalline solvate of JPEG2026143404000020.jpg51170.

[0107] In one embodiment, the compound of formula (1) is cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene, or toluene solvate. In one embodiment, the compound of formula (1) is crystalline cyclohexane solvate. In such an embodiment, the crystalline cyclohexane solvate of the compound of formula (1) is substantially as shown in Figure 1. In another embodiment, the compound of formula (1) is crystalline methylcyclohexane solvate. In such an embodiment, the crystalline methylcyclohexane solvate of the compound of formula (1) is substantially as shown in Figure 2. In another embodiment, the compound of formula (1) is crystalline chlorobenzene solvate. In such an embodiment, the crystalline chlorobenzene solvate of the compound of formula (1) is substantially as shown in Figure 3. In another embodiment, the compound of formula (1) is crystalline ethylbenzene solvate. In such an embodiment, the crystalline ethylbenzene solvate of the compound of formula (1) is substantially as shown in Figure 4. In another embodiment, the compound of formula (1) is crystalline m-xylene solvate. In one such embodiment, the crystalline m-xylene solvate of the compound of formula (1) is substantially as shown in Figure 5. In another embodiment, the compound of formula (1) is a crystalline toluene solvate. In one such embodiment, the crystalline toluene solvate of the compound of formula (1) is substantially as shown in Figure 6.

[0108] In another embodiment, a crystalline solvate solid form of compound (1) is provided herein. JPEG2026143404000021.jpg51170

[0109] In certain embodiments, the crystalline solvate is the crystalline cyclohexane solvate of compound 1. In one embodiment, the cyclohexane crystalline solvate of compound 1 is obtained from a hot cyclohexane solution cooled to approximately room temperature. In such an embodiment, the solution is cooled for about 72 hours. In one embodiment, the cyclohexane crystalline solvate of compound 1 is substantially as shown in Figure 1. In another embodiment, the cyclohexane crystalline solvate of compound 1 has the unit cell dimensions shown in Table 2.

[0110] In certain embodiments, the crystalline solvate is the crystalline methylcyclohexane solvate of compound 1. In one embodiment, the methylcyclohexane crystalline solvate of compound 1 is obtained from a hot methylcyclohexane solution cooled to approximately room temperature. In such an embodiment, the solution is cooled for about 48 hours. In one embodiment, the methylcyclohexane crystalline solvate of compound 1 is substantially as shown in Figure 2. In another embodiment, the methylcyclohexane crystalline solvate of compound 1 has the unit cell dimensions shown in Table 3.

[0111] In certain embodiments, the crystalline solvate is the crystalline chlorobenzene solvate of compound 1. In one embodiment, the chlorobenzene crystalline solvate of compound 1 is obtained from a saturated chlorobenzene solution, followed by slow vapor diffusion of heptane. In one embodiment, the chlorobenzene crystalline solvate of compound 1 is substantially as shown in Figure 3. In another embodiment, the chlorobenzene crystalline solvate of compound 1 has the unit cell dimensions shown in Table 4.

[0112] In certain embodiments, the crystalline solvate is the crystalline ethylbenzene solvate of compound 1. In one embodiment, the ethylbenzene crystalline solvate of compound 1 is obtained from a saturated ethylbenzene solution followed by slow vapor diffusion of heptane. In one embodiment, the ethylbenzene crystalline solvate of compound 1 is substantially as shown in Figure 4. In another embodiment, the ethylbenzene crystalline solvate of compound 1 has the unit cell dimensions shown in Table 5.

[0113] In certain embodiments, the crystalline solvate is the crystalline m-xylene solvate of compound 1. In one embodiment, the m-xylene crystalline solvate of compound 1 is obtained from a saturated m-xylene solution followed by slow vapor diffusion of heptane. In one embodiment, the m-xylene crystalline solvate of compound 1 is substantially as shown in Figure 5. In another embodiment, the m-xylene crystalline solvate of compound 1 has the unit cell dimensions shown in Table 6.

[0114] In certain embodiments, the crystalline solvate is the crystalline toluene solvate of compound 1. In one embodiment, the crystalline toluene solvate of compound 1 is obtained from a saturated toluene solution followed by slow vapor diffusion of heptane. In one embodiment, the crystalline toluene solvate of compound 1 is substantially as shown in Figure 6. In another embodiment, the crystalline toluene solvate of compound 1 has the unit cell dimensions shown in Table 7.

[0115] In another embodiment, the compound of formula (I) described herein, or its solvates, tautomers, stereoisomers, atropisomers, or salts, is a compound having the formula shown in Table 1, or its solvates, tautomers, stereoisomers, atropisomers, or salts.

[0116] [Table 1] JPEG2026143404000023.jpg211170JPEG2026143404000024.jpg201170JPEG2026143404000025.jpg23417 0JPEG2026143404000026.jpg220170JPEG2026143404000027.jpg238170JPEG2026143404000028.jpg62170

[0117] In one embodiment, the compound of formula (I) or its solvates, tautomers, stereoisomers, atropisomers, or salts include the compounds of formulas 103, 104, 105, 106, 107, 110, 113, 120, 121, 122, 125, 126, 127, 128, 129, 131, 137, 144, 145, 143, or 148. In another embodiment, the compound of formula (I) or its solvates, tautomers, stereoisomers, atropisomers, or salts are the compounds of formulas 105, 106, 120, 126, 128, 129, 131, 137, 143, or 148. In yet another embodiment, the compound of formula (I) or its solvate, tautomer, stereoisomer, atropisomer, or salt is a compound of formula 105, 126, 128, 129, 131, or 143. In a preferred embodiment, the compound is a compound of formula 105, 105, 126, 128, 129, 131, or 143 of Table 1, where R 1 It is Boc.

[0118] In another embodiment, the compound of formula (I) is a crystalline solvate of the compound of formula 103, 104, 105, 106, 107, 110, 113, 120, 121, 122, 125, 126, 127, 128, 129, 131, 137, 144, 145, 143, or 148. In yet another embodiment, the compound of formula (I) is a crystalline solvate of the compound of formula 105, 126, 128, 129, 131, or 143. In such embodiments, the solvate is a cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene, or toluene solvate of the compound of formula (I). In one embodiment, the compound of formula (I) is a crystalline solvate of the compound of formula 105, 126, 128, 129, 131, or 143, where R 1 is Boc. In one embodiment, the compound of formula (I) is a crystalline solvate of the compound of formula 105, where R 1 It is Boc. Preparation method

[0119] Furthermore, the compound of the following formula (I): Methods for preparing JPEG2026143404000029.jpg57170 or its solvates, tautomers, stereoisomers, atropisomers or salts are further provided herein, where X 0 , X 1 , X 3 , R 1 , R 2 , R 3 , R 4 n and PG are as described herein. In one embodiment, the compound of formula (I) synthesized according to the method described herein is a crystalline solvate. In one embodiment, the compound of formula (I) is cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene, or toluene solvate.

[0120] In one embodiment, a method (P1) for preparing a compound of formula (I) or its solvate, tautomer, stereoisomer, atropisomer, or salt thereof, (a) Compound of formula (II) JPEG2026143404000030.jpg45170 or its tautomers, stereoisomers, or salts (in the formula, X 0 , X 1 , X 3 , R 1 , and R 2 This is as described herein; and X 2 is halogen or ZnY 1 And in the formula, Y 1 is a halogen (e.g., Cl, Br, or I), OAc, TFA, OTf, or OPiv); Contacting with organomagnesium compounds and zinc complexes; and (b) The mixture from step (a) contains the compound of formula (III), JPEG2026143404000031.jpg28170 or its stereoisomer or salt (wherein X 4 It is a halogen; A method is provided herein for synthesizing a compound of formula (I) or its solvates, tautomers, stereoisomers, atropisomers, or salts, comprising contacting a transition metal (e.g., Pd or Ni) catalyst precursor with a chiral ligand.

[0121] In one preferred embodiment of the method (P1) described herein, X 0 is a halogen. In one such embodiment, X 0 In another embodiment, X 0 This is a part selected from the following group: JPEG2026143404000032.jpg227170JPEG2026143404000033.jpg26170

[0122] In one embodiment of the method described herein (P1), the organomagnesium compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate. In such an embodiment, the organomagnesium compound is isopropylmagnesium chloride, isopropylmagnesium bromide, or isopropylmagnesium iodide. In another embodiment, the organomagnesium compound is isopropylmagnesium chloride lithium chloride complex. In one embodiment, the reaction with the organomagnesium compound is carried out at a temperature of about -100 to about -40°C. In such an embodiment, the temperature is about -80 to about 60°C. In yet another embodiment, the temperature is about -70 ± 5°C.

[0123] In one embodiment of the method described herein (P1), the zinc complex is selected from the group consisting of ZnCl2, ZnBr2, ZnI2, Zn(OAc)2, Zn(TFA)2, Zn(OTf)2, and Zn(OPiv)2. In another embodiment, the zinc complex is ZnCl2, ZnBr2, or ZnI2. In one such embodiment, the zinc complex is ZnCl2. In yet another embodiment, the zinc complex is Zn(OAc)2, Zn(TFA)2, Zn(OTf)2, or Zn(OPiv)2.

[0124] In one embodiment of the method described herein (P1), the method is carried out in a polar aprotic solvent. In such an embodiment, the polar aprotic solvent is dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), ethyl acetate (Ã), acetonitrile (ACN or MeCN), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, or hexamethyltriamide phosphate (HMPA), or a combination thereof. In another embodiment, the method is carried out in THF. In yet another embodiment, the method is carried out in 2-MeTHF. In yet another embodiment, the method is carried out in THF and MeTHF.

[0125] In one embodiment of the method described herein (P1), the transition metal catalyst precursor is Pd or Ni catalyst precursor. In one embodiment of the method described herein (P1), the Pd or Ni catalyst precursor is Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl 2、The following are selected from the group consisting of Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(clotyl)]2, PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl2, NiBr2, Ni(OAc)2, and nickel(II) acetylacetonate.

[0126] In one such embodiment of the method described herein (P1), the Pd or Ni catalyst precursor is a Pd catalyst precursor. In one embodiment, the Pd catalyst precursor is Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(dba)2, Pd2(dba)3, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(clotyl)]2, PdCl(η5-cyclopentadienyl), or [(η3-allyl)(η5-cyclopentadienyl)palladium(II)]. In another embodiment of the method described herein (P1), the Pd catalyst precursor is Pd(OAc)2 or PdCl2. In another embodiment of the method described herein (P1), the Pd catalyst precursor is [PdCl(clotyl)]2, PdCl(η5-cyclopentadienyl), PdCl2(MeCN)2, Pd(dba)2, Pd2(dba)3, or Pd(TFA)2. In another embodiment of the method described herein (P1), the Pd catalyst precursor is [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, or (η3-allyl)(η5-cyclopentadienyl)palladium(II). In one embodiment, the Pd catalyst precursor is [Pd(allyl)Cl]2 or [Pd(cinnamyl)Cl]2. In one embodiment, the Pd catalyst precursor is [Pd(cinnamyl)Cl]2.

[0127] In another embodiment of the method described herein (P1), the Pd or Ni catalyst precursor is a Ni catalyst precursor. In one embodiment, the Ni catalyst precursor is NiCp(allyl), bis(1,5-cyclooctadiene)nickel(0), NiCl2, NiBr2, Ni(OAc)2, or nickel(II) acetylacetonate. In one embodiment, the Ni catalyst precursor is NiCl2, NiBr2, or Ni(OAc)2. In another embodiment, the Ni catalyst precursor is NiCp(allyl), bis(1,5-cyclooctadiene)nickel(0), or nickel(II) acetylacetonate.

[0128] In one embodiment, step 1 of method P1 is carried out using a continuous flow mode including one or more continuous stirring reactors (CSTRs). In one embodiment, the Pd precursor described herein and the chiral ligand described herein are brought into contact to form a Pd ligand complex in situ. In another embodiment, the Pd precursor described herein can be treated with the chiral ligand described herein to form a Pd ligand complex, which can then be isolated before use in the method described herein.

[0129] In one embodiment of the method (P1) described herein, the chiral ligand is The filename is JPEG2026143404000034.jpg81170. During the ceremony, Y is O or NR 7 and; Z is either O or N; Each R 7 and R 8 Independently, non-substituted C 1-6 It is an alkyl or unsubstituted phenyl compound; Alternatively, in the formula, R 7 and R 8 They come together as non-substituted C 5-6 Cycloalkyl or unsubstituted C 6-10 Form an aryl group; Alternatively, in the formula, R 8 It combines with the adjacent methylene group, R 8A - Substitute or non-substitute C 5-8Cycloalkyl or R containing at least one oxygen atom 8A - Substitutable or unsubstituted 5-8 member heterocycles can be formed, in the formula R 8A is C 1-3 It is an unsubstituted alkyl group; R 9 and R 10 R is independent of R 10A - Substitute or non-substitute C 5-6 Cycloalkyl or R 10A - Substituted or unsubstituted phenyl; Each R 10A These are, independently, hydrogen and C 1-6 Unsubstituted alkyl, or C 1-6 It is an unsubstituted haloalkyl; R 11 is C 1-4 It is an unsubstituted alkyl group; R 12 and R 13 Each of them is independent of R 14 - Substitute or non-substitute C 1-6 Alkyl, R 14 - Substitute or non-substitute C 3-7 Cycloalkyl, R 14 - Substitutable or non-substitutable aryl, or R 14 - Substitute or non-substitute C 5-7 It is a heteroaryl; and Each R 14 Independently, non-substituted C 1-4 It is alkyl.

[0130] In one embodiment of the method (P1) described herein, the chiral ligand comprises a compound of the following formula: JPEG2026143404000035.jpg51170In formula, Y, R 7 and R 8 This is as described in this specification.

[0131] In such one embodiment, each Y is O. In such one embodiment, each Y is O, and R 7 and R 8 R is independently ethyl or phenyl. In one such embodiment, R 7 and R8 They are the same. In such one embodiment, each Y is NR 7 And each R 7 Y is independently methyl, ethyl, or propyl. In another embodiment, each Y is NR 7 And each R 7 It is methyl.

[0132] In one such embodiment of the L1 compound, R 7 and R 8 They are the same. In another such embodiment of the L1 compound, R 7 and R 8 These are methyl, ethyl, or propyl, respectively. In another such embodiment, R 7 and R 8 Together, they form an unsubstituted cyclopentyl, cyclohexyl, or indenyl moiety. In another such embodiment, R 8 It combines with the adjacent methylene group to form a tetrahydrophlodioxolyl moiety.

[0133] In one such embodiment of the method (P1) described herein, the chiral ligand is The files are JPEG2026143404000036.jpg (255170) and JPEG2026143404000037.jpg (108170).

[0134] In one such embodiment of the method (P1) described herein, the chiral ligand is The filename is JPEG2026143404000038.jpg130170.

[0135] In one such embodiment of the method (P1) described herein, the chiral ligand is The filename is JPEG2026143404000039.jpg47170.

[0136] In another embodiment of the method (P1) described herein, the chiral ligand comprises a compound of the following formula: JPEG2026143404000040.jpg28170In formula, R 12 and R 13 This is as described in this specification.

[0137] In one such embodiment of the L2 compound, R 12 and R 13 Each is independent of R 14 - Substitute or non-substitute C 1-6 It is alkyl. In another embodiment of the L2 compound, R 12 and R 13 Each is independent of R 14 - Substitute or non-substitute C 3-7 Cycloalkyl or R 14 - It is a substituted or unsubstituted aryl compound. In one embodiment of the L2 compound, R 12 and R 13 Each of these is independently phenyl or unsubstituted C 3-7 It is cycloalkyl. In another embodiment of the L2 compound, each R 12 Phenyl and each R 13 is non-substituted C 3-7 It is cycloalkyl. In one embodiment of the L2 compound, R 13 This is norbornanil.

[0138] In one such embodiment of the method (P1) described herein, the chiral ligand is L2 having the following structure: JPEG2026143404000041.jpg237170JPEG2026143404000042.jpg249170JPEG2026143404000043.jpg231170 or JPEG2026143404000044.jpg38170 or its stereoisomer.

[0139] In one embodiment of the method (P1) described herein, the chiral ligand is L2 having the following structure: JPEG2026143404000045.jpg163170JPEG2026143404000046.jpg196170

[0140] In another embodiment of the method (P1) described herein, the chiral ligand is L2 having the following structure: JPEG2026143404000047.jpg87170

[0141] In one embodiment of the method (P1) described herein, the chiral ligand is The filename is JPEG2026143404000048.jpg38170.

[0142] In one embodiment of the method (P1) described herein, the reaction with the chiral ligand is carried out at temperatures of about 30°C to about 65°C; about 35°C to about 55°C; about 40°C to about 50°C; about 35°C to about 45°C; or about 40°C to about 55°C. In another embodiment, the reaction with the chiral ligand is carried out at temperatures of about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50°C. In yet another embodiment, the reaction with the chiral ligand is carried out at temperatures of about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50°C. In yet another embodiment, the reaction with the chiral ligand is carried out at temperatures of about 50, 52, 54, 56, 58, 60, 62 or 64°C.

[0143] In one embodiment of the method (P1) described herein, the reaction with the chiral ligand takes place over a period of about 1 to about 15 hours; about 1 to about 10 hours; about 2 to about 10 hours; about 4 to about 10 hours; about 10 to about 30 hours; about 15 to about 30 hours; about 15 to about 25 hours; about 10 to about 20 hours; about 16 to about 24 hours; or about 16 to about 20 hours. In one embodiment of the method (P1) described herein, the reaction with the chiral ligand takes place over a period of about 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, or 16 hours.

[0144] In one embodiment of the method (P1) described herein, the compound of formula (II) or its tautomers, stereoisomers, or salts, and the compound of formula (III) or its stereoisomers or salts are present in approximately equal molar equivalents. In another embodiment of the method (P1) described herein, the compound of formula (II) or its tautomers, stereoisomers, or salts, and the compound of formula (III) or its stereoisomers or salts are present in approximately 1:1, 1.1:1, or 1.2:1 equivalents.

[0145] In one embodiment of the method described herein (P1), the method is carried out using the Pd catalyst precursor described herein in a molar ratio of about 0.1 to about 1; about 0.5 to about 1.1; about 1:1 to about 1:5; about 1:1 to about 1:4; about 1:1 to about 1:3; or about 1:1 to about 1:2 with respect to the chiral ligand. In one embodiment, the method is carried out using the Pd catalyst precursor described herein in a molar ratio of about 0.5:1 with respect to the chiral ligand. In another embodiment, the method is carried out using the Pd catalyst precursor described herein in a molar ratio of about 1:2 with respect to the chiral ligand. In yet another embodiment, the method is carried out using the Pd catalyst precursor described herein in a molar ratio of about 1:1.1 with respect to the chiral ligand.

[0146] In one embodiment of the method described herein (P1), the method is carried out using a Pd catalyst precursor described herein, and the catalytic load (e.g., with respect to the limiting reagent of the reaction) is about: 0.1 mol% to 10 mol%, 0.1 mol% to 5 mol%, 0.1 mol% to 2 mol%, 0.1 mol% to 1.5 mol%, 0.1 mol% to 1 mol%, 0.5 mol% to 10 mol%, 0.5 mol% to 5 mol%, 0.5 mol% to 2 mol%, 0.7 mol% to 10 mol%, 0.7 mol% to 5 mol%, 0.7 mol% to 2 mol%, or 0.7 mol% to 1.5 mol%. In one such embodiment, the catalytic load is about 0.1 mol% to 10 mol%. In another embodiment, the catalytic load is about 0.5 mol% to 2 mol%. In yet another embodiment, the catalytic load is about 0.7 to 1.5 mol%.

[0147] In one embodiment, method (P1) further includes adding a salt additive during step 2. In one embodiment, the additive is NaTFA, NaOAc, or NaOTf.

[0148] In another embodiment of the method (P1) described herein, the chiral ligand comprises a compound of the following formula: JPEG2026143404000049.jpg33170In formula, R 9 , R 10 and R 11 This is as described in this specification.

[0149] In one embodiment of the L3 compound, R 9 and R 10 They are the same. In one such embodiment of the L3 compound, R 9 and R 10 is, R 10A - Substitute or non-substitute C 5-6 It is cycloalkyl. In one such embodiment of the L3 compound, R 9 and R 10 Each of these is an unsubstituted cyclohexyl. In another embodiment of the compound L3, R 9 and R 10 is, R 10A - is a substituted or unsubstituted phenyl. In one such embodiment of the L3 compound, R 9 and R 10 is an unsubstituted phenyl compound. In another such embodiment of the L3 compound, R 9 and R 10 is, R 10A -substituted phenyl, where R 10A These are methyl, ethyl, tert-butyl, or CF3.

[0150] In one embodiment of the L3 compound, Z is O, and R 11 is methyl, ethyl, or tert-butyl. In another embodiment of the L3 compound, Z is N and R 11 It is dimethyl, diethyl, or di-tertbutyl.

[0151] In one embodiment, the chiral ligand is a compound of the following formula: JPEG2026143404000050.jpg123170

[0152] In another embodiment of the method (P1) described herein, the chiral ligand is a compound of the following formula: JPEG2026143404000051.jpg73170

[0153] In one embodiment, the compound of formula (II) JPEG2026143404000052.jpg45170 or its tautomers, stereoisomers, or salts are prepared according to a method (P2) comprising the following steps: (a) Equation (IVa) The compound of JPEG2026143404000053.jpg28170, or its stereoisomer or salt, is defined by formula JPEG2026143404000054.jpg27170(in the formula, 3 When contacted with a halogenating agent having (which is a halogen), formula (IVb) To produce the compound JPEG2026143404000055.jpg27170 or its stereoisomer or salt; (c) Compound of formula (IVb) Cyclization of the compound JPEG2026143404000056.jpg27170, or its stereoisomer or salt; (d) When the compound of formula (V) is brought into contact with a chlorinating agent, formula (Va) To produce the compound JPEG2026143404000057.jpg27170 or its stereoisomer or salt; (e) Compound of formula (Va) By bringing the piperazinyl moiety containing JPEG2026143404000058.jpg28170 into contact, formula (IIa) To produce the compound JPEG2026143404000059.jpg47170 or its stereoisomer or salt; and (f) Compound of formula (IIa) X0 To form a compound of formula (II) or its tautomers, stereoisomers, or salts by contacting it with a salt of [formula].

[0154] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000060.jpg47170 or its tautomers, stereoisomers, or salts.

[0155] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: This includes JPEG2026143404000061.jpg46170 or its tautomers, stereoisomers, or salts.

[0156] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000062.jpg45170 or its tautomers, stereoisomers, or salts.

[0157] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000063.jpg46170 or its tautomers, stereoisomers, or salts.

[0158] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: This includes JPEG2026143404000064.jpg45170 or its tautomers, stereoisomers, or salts.

[0159] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: This includes JPEG2026143404000065.jpg46170 or its tautomers, stereoisomers, or salts.

[0160] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: This includes JPEG2026143404000066.jpg45170 or its tautomers, stereoisomers, or salts.

[0161] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000067.jpg47170 or its tautomers, stereoisomers, or salts.

[0162] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000068.jpg45170 or its tautomers, stereoisomers, or salts.

[0163] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: This includes JPEG2026143404000069.jpg45170 or its tautomers, stereoisomers, or salts.

[0164] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000070.jpg46170 or its tautomers, stereoisomers, or salts.

[0165] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000071.jpg46170 or its tautomers, stereoisomers, or salts.

[0166] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: This includes JPEG2026143404000072.jpg45170 or its tautomers, stereoisomers, or salts.

[0167] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000073.jpg45170 or its tautomers, stereoisomers, or salts.

[0168] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000074.jpg45170 or its tautomers, stereoisomers, or salts.

[0169] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000075.jpg46170 or its tautomers, stereoisomers, or salts.

[0170] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000076.jpg45170 or its tautomers, stereoisomers, or salts.

[0171] In one embodiment, the compound of formula (II) or its tautomer, stereoisomer, or salt is a compound of the following formula: JPEG2026143404000077.jpg45170 or a salt thereof.

[0172] In one embodiment, the compound of formula (II) is contacted with an organomagnesium compound and a zinc complex as described herein (Method P1), thereby obtaining the compound of formula (IIz): This creates the file JPEG2026143404000078.jpg46170.

[0173] In one embodiment, a compound of formula (IIb), (IIb1), (IIb2), (IIb3), (IIc), (IIc1), (IIc2), (IIc3), (IId), (IId1), (IId2), (IId3), (IIa1), (IIa2), or (IIa3) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby forming a compound of the formula: JPEG2026143404000079.jpg125170In formula, Y 1 These are halogens (e.g., Cl, Br, or I), OAc, TFA, OTf, or OPiv.

[0174] In one embodiment, Y 1 is Cl. In one embodiment, the compound of step a described herein in method P1, which is carried over to step b described herein, is a compound of formula IIz1, IIz2, IIz3, IIz4, IIz5, IIz6, IIz7, IIz8, IIz9, IIz10, IIz11, IIz12, IIz13, IIz14, IIz15, 2az, 2bz, 2cz, or 2z.

[0175] In another embodiment, the compound of formula (2a) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby obtaining the compound of formula: This creates the file JPEG2026143404000080.jpg46170.

[0176] In another embodiment, the compound of formula (2b) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby obtaining the compound of formula: This creates the file JPEG2026143404000081.jpg45170.

[0177] In another embodiment, the compound of formula (2c) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby obtaining the compound of formula: This creates the file JPEG2026143404000082.jpg47170.

[0178] In another embodiment, the compound of formula (2) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby obtaining the compound of formula: This creates the file JPEG2026143404000083.jpg44170.

[0179] In such embodiments, Y 1 is a halogen (e.g., Cl, Br, or I), OAc, TFA, OTf, or OPiv. In one such embodiment, Y 1 is Cl. In one such embodiment, Y 1 This is OPiv.

[0180] In one embodiment of the method described herein (P2), the method is (a0) Equation (IV) in the presence of CO2 gas The compound in JPEG2026143404000084.jpg20170 is brought into contact with a base, and the compound is aminated to form formula (IVa). Further includes forming the compound JPEG2026143404000085.jpg28170.

[0181] In one embodiment of the method (P2) described herein, the base in step (a0) is n-butyllithium, LDA, or LiTMP. In another embodiment, the base is LDA.

[0182] In one embodiment of the method (P2) described herein, the halogenating agent in step (b) is of the formula The file JPEG2026143404000086.jpg21170 is included, and in the formula, X 3 is Cl, Br, or I. In one such embodiment, X 3In another embodiment, X 3 In yet another embodiment, X 3 It is I.

[0183] In one embodiment of the method (P2) described herein, the halogenating agent in step (b) is of the formula The file JPEG2026143404000087.jpg25170 is included, and in the formula, each X 3 The same, and is Cl, Br, or I. In one embodiment, each X 3 is Cl. In another embodiment, each X 3 is Br. In yet another embodiment, each X 3 It is I.

[0184] In one embodiment of the method described herein (P2), the halogenating agent in step (b) is NCS or 1,3-dichloro-5,5-dimethylhydantoin. In another embodiment, the halogenating agent is NCS. In yet another embodiment, the halogenating agent is 1,3-dichloro-5,5-dimethylhydantoin.

[0185] In one embodiment of the method described herein (P2), the cyclization of the compound of formula (IVb) to the compound of formula (V) in step (c) is carried out by using KOCN in an aqueous solution of a base (e.g., NaOH or KOH) followed by contact with an acid (e.g., HCl).

[0186] In one embodiment of the method described herein (P2), the chlorinating agent in step (d) is POCl3, PCl3, PCl5, or SOCl2. In another embodiment, the chlorinating agent is POCl3.

[0187] In one embodiment of the method described herein (P2), X of the compound of formula (II) 0 F is F, and step (f) is to contact the compound of formula (IIa) with CsF to obtain the compound of formula (IIa1): This includes producing JPEG2026143404000088.jpg44170 or its tautomers, stereoisomers, or salts.

[0188] In one embodiment of the method described herein (P2), X is a compound of formula (II) or its tautomer, stereoisomer, or salt. 0 F is F, and step (f) is to contact the compound of formula (IIa) with CsF to obtain the compound of formula (IIa2): This includes producing JPEG2026143404000089.jpg45170 or its tautomers, stereoisomers, or salts.

[0189] In one embodiment of the method described herein (P2), X is a compound of formula (II) or its tautomer, stereoisomer, or salt. 0 F is F, and step (f) is to contact the compound of formula (IIa) with CsF to obtain the compound of formula (IIa3): This includes producing JPEG2026143404000090.jpg44170 or its tautomers, stereoisomers, or salts.

[0190] In one embodiment of the method described herein (P2), the compound of formula (IV) has the following formula: JPEG2026143404000091.jpg21170

[0191] In one embodiment of the method described herein (P2), the compound of formula (IVa) has the following formula: JPEG2026143404000092.jpg27170 or its salt.

[0192] In one embodiment of the method described herein (P2), the compound of formula (IVa) has the following formula: JPEG2026143404000093.jpg27170 or its salt.

[0193] In one embodiment of the method described herein (P2), the compound of formula (IVb) has the following formula: JPEG2026143404000094.jpg28170 or its salt.

[0194] In one embodiment of the method described herein (P2), the compound of formula (IVb) has the following formula: JPEG2026143404000095.jpg28170 or its salt.

[0195] In one embodiment of the method described herein (P2), the compound of formula (IVb) has the following formula: JPEG2026143404000096.jpg27170 or its salt.

[0196] In one embodiment of the method described herein (P2), the compound of formula (V) has the following formula: JPEG2026143404000097.jpg27170 or its salt.

[0197] In one embodiment of the method described herein (P2), the compound of formula (V) has the following formula: JPEG2026143404000098.jpg28170 or its salt.

[0198] In one embodiment of the method described herein (P2), the compound of formula (V) has the following formula: JPEG2026143404000099.jpg28170 or a salt thereof.

[0199] In one embodiment, the compound of formula (III) JPEG2026143404000100.jpg29170 or the salt thereof of the method described herein is prepared according to method (P3), which includes: (a) Equation (VII) Compound of JPEG2026143404000101.jpg21170 (where X is in the formula) 4 (is a halogen) is brought into contact with a compound having the formula NH2(PG), thereby producing (VIIa) To produce the compound JPEG2026143404000102.jpg26170; (b) Compound of formula (VIIa) a PG(in the formula, X aWhen a compound having (which is a halogen) is brought into contact with the compound of formula (VIIb) To produce the compound JPEG2026143404000103.jpg27170; (c) Compound of formula (VIIb), JPEG2026143404000104.jpg27170(in the formula, 5 When contacted with a halogenating agent having (which is a halogen), formula (VIIc) To produce the compound JPEG2026143404000105.jpg27170; (d) The compound of formula (VIIc) is haloalkylated with a haloalkylating agent to obtain formula (VIId). To generate the compound JPEG2026143404000106.jpg27170 (e) Brominate the compound of formula (VIId) to obtain formula (VIIe) To produce the compound JPEG2026143404000107.jpg21170; and (f) Compound of formula (VIIe) X a To produce a compound of formula (III) or a salt thereof by contacting it with PG.

[0200] In one embodiment of the method described herein (P3), each PG is the same. In one embodiment, each PG is the same and is PMB, DMB, or Boc. In another embodiment, each PG is PMB (p-methoxybenzyl). In one embodiment, X a is Cl or Br. In another embodiment, X a It is Cl.

[0201] In one embodiment of the method described herein (P3), the halogenating agent in step (c) is This is JPEG2026143404000108.jpg21170. In one such embodiment, X 5 is Cl, Br, or I. In another embodiment, X 5 In another embodiment, X 5 In yet another embodiment, X 5 It is Br.

[0202] In one embodiment of the method described herein (P3), the halogenating agent in step (c) is This is JPEG2026143404000109.jpg25170. In one such embodiment, X 5 is Cl, Br, or I. In another embodiment, X 5 In another embodiment, X 5 In yet another embodiment, X 5 It is Br.

[0203] In another embodiment of the method described herein (P3), the halogenating agent in step (c) is NIS or 1,3-diiodo-5,5-dimethylhydantoin. In one such embodiment, the halogenating agent is NIS. In another embodiment, the halogenating agent is 1,3-diiodomo-5,5-dimethylhydantoin.

[0204] In one embodiment of the method described herein (P3), the haloalkylating agent in step (d) is a fluoroalkylating agent. In such an embodiment, the haloalkylating agent is methyl 2,2-difluoro-2-(fluorosulfonyl)acetate.

[0205] In one embodiment of the method described herein (P3), the bromination step (e) further comprises contacting a compound of formula (VIId) with HBr.

[0206] In one such embodiment of the method described herein (P3), the bromination step (e) further comprises contacting the compound of formula (VIId) with AcBr to produce the compound of formula (VIIe).

[0207] In one embodiment, X of the compound of formula (VII) 4 is Cl or I. In another embodiment, X of the compound of formula (VII) 4 It is Cl.

[0208] In one embodiment, the compound of formula (VII) has the following formula: JPEG2026143404000110.jpg24170

[0209] In one embodiment, the compound of formula (VII) has the following formula: JPEG2026143404000111.jpg21170

[0210] In one embodiment, the compound of formula (VIIa) has the following formula: JPEG2026143404000112.jpg28170 or its salt.

[0211] In one embodiment, the compound of formula (VIIa) has the following formula: JPEG2026143404000113.jpg28170 or its salt.

[0212] In one embodiment, the compound of formula (VIIa) has the following formula: JPEG2026143404000114.jpg27170 or its salt.

[0213] In one embodiment, the compound of formula (VIIb) has the following formula: JPEG2026143404000115.jpg28170 or its salt.

[0214] In one embodiment, the compound of formula (VIIb) has the following formula: JPEG2026143404000116.jpg28170 or its salt.

[0215] In one embodiment, the compound of formula (VIIb) has the following formula: JPEG2026143404000117.jpg27170 or its salt.

[0216] In one embodiment, the compound of formula (VIIc) has the following formula: JPEG2026143404000118.jpg28170 or its salt.

[0217] In one embodiment, the compound of formula (VIIc) has the following formula: JPEG2026143404000119.jpg28170 or its salt.

[0218] In one embodiment, the compound of formula (VIIc) has the following formula: JPEG2026143404000120.jpg28170 or its salt.

[0219] In one embodiment, the compound of formula (VIIc) has the following formula: JPEG2026143404000121.jpg27170 or its salt.

[0220] In one embodiment, the compound of formula (VIId) has the following formula: JPEG2026143404000122.jpg29170 or its salt.

[0221] In one embodiment, the compound of formula (VIId) has the following formula: JPEG2026143404000123.jpg30170 or its salt.

[0222] In one embodiment, the compound of formula (VIId) has the following formula: JPEG2026143404000124.jpg29170 or its salt.

[0223] In one embodiment, the compound of formula (VIId) has the following formula: JPEG2026143404000125.jpg27170 or its salt.

[0224] In one embodiment, the compound of formula (VIIe) has the following formula: JPEG2026143404000126.jpg22170 or a salt thereof.

[0225] In one embodiment, the compound of formula (VIIe) has the following formula: JPEG2026143404000127.jpg22170 or a salt thereof.

[0226] In another embodiment, the compound of formula (III) JPEG2026143404000128.jpg29170 or the salt of the method described herein is prepared according to method (P4), which includes: (a) Equation (VIII) Compound of JPEG2026143404000129.jpg23170 (where X is in the formula) 6 (where is Cl or I) is brought into contact with a halogenating agent, and formula (VIIIa) To form the compound JPEG2026143404000130.jpg22170; (b) Brominate the compound of formula (VIIIa) to obtain formula (VIIIb) To form the compound JPEG2026143404000131.jpg21170; and (c) Contacting a compound of formula (VIII) with a compound having formula NH(PG)2 to produce a compound of formula (III) or a salt thereof.

[0227] In one embodiment of the method described herein (P4), each X 6 They are the same. In such one embodiment, each X 6 is Cl. In another embodiment, each X 6 It is I.

[0228] In yet another embodiment, the compound of formula (III) JPEG2026143404000132.jpg29170 or the salt of the method described herein is prepared according to method (P5), which includes: (a) Equation (VIIIc) When the compound in JPEG2026143404000133.jpg22170 is brought into contact with a brominating agent, formula (VIIId) To form the compound JPEG2026143404000134.jpg22170; (b) The compound of formula (VIIId) is brought into contact with a halogenating agent to form formula (VIIIb) To form the compound JPEG2026143404000135.jpg21170; (c) Contacting a compound of formula (VIIIb) with a compound having formula NH(PG)2 to produce a compound of formula (III).

[0229] In one embodiment of the method described herein (P4) or (P5), the halogenating agent is SF4 in HF.

[0230] In one such embodiment, the compound of formula (VIII) has the following formula: JPEG2026143404000136.jpg23170 or its salt.

[0231] In one such embodiment, the compound of formula (VIII) has the following formula: JPEG2026143404000137.jpg24170 or its salt.

[0232] In one such embodiment, the compound of formula (VIIIa) has the following formula: JPEG2026143404000138.jpg24170 or its salt.

[0233] In one such embodiment, the compound of formula (VIIIa) has the following formula: JPEG2026143404000139.jpg24170 or a salt thereof.

[0234] In one such embodiment, the compound of formula (VIIIa) has the following formula: JPEG2026143404000140.jpg22170 or its salt.

[0235] In one such embodiment, the compound of formula (VIIIb) has the following formula: JPEG2026143404000141.jpg24170 or its salt.

[0236] In one such embodiment, the compound of formula (VIIIb) has the following formula: JPEG2026143404000142.jpg21170 or a salt thereof.

[0237] In one such embodiment, the compound of formula (VIIIc) has the following formula: JPEG2026143404000143.jpg23170 or a salt thereof.

[0238] In one such embodiment, the compound of formula (VIIId) has the following formula: JPEG2026143404000144.jpg23170 or its salt.

[0239] In one such embodiment, the compound of formula (III) has the following formula: JPEG2026143404000145.jpg29170 or its salt.

[0240] In one such embodiment, the compound of formula (III) has the following formula: JPEG2026143404000146.jpg30170 or its salt.

[0241] In one such embodiment, the compound of formula (III) has the following formula: JPEG2026143404000147.jpg29170 or its salt.

[0242] In one such embodiment, the compound of formula (III) has the following formula: JPEG2026143404000148.jpg26170 or its salt.

[0243] In one embodiment of the method described herein, X 1 is hydrogen. In one embodiment of the method described herein, X 1 is a halogen. In one embodiment, X 1 is F or Cl. In another embodiment of the method described herein, X 1 If X is halogen, 3 is a halogen. In another embodiment of the method described herein, X 1 If X is F, 3 is not F. In another embodiment of the method described herein, X 1 If X is F, 3 is Cl. In another embodiment of the method described herein, X 1 If X is H, 3 It is Cl.

[0244] In one embodiment of the method described herein, X 2 is Br. In one embodiment of the method described herein, X 2 is ZnCl, ZnBr, ZnI, ZnOAc, ZnTFA, ZnOTf, or ZnOPiv. In one embodiment of the method described herein, X 2 It is ZnCl.

[0245] In one embodiment of the method described herein, X 3 is hydrogen, halogen, R 6 - Substitute or non-substitute C 1-3 Alkyl, or R 6 - Substitute or non-substitute C 1-3 It is a haloalkyl. In another embodiment of the method described herein, X 3 is, R 6 - Substitute or non-substitute C 1-3 Alkoxy or R 6 - is a substituted or unsubstituted cyclopropyl. In another embodiment of the method described herein, X 3 X is hydrogen or halogen. In another embodiment of the method described herein, X 3 is halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3It is a haloalkyl. In yet another embodiment of the method described herein, X 3 is halogen or unsubstituted C 1-3 It is a haloalkyl. In yet another embodiment of the method described herein, X 3 is unsubstituted C 1-3 It is an alkoxy or an unsubstituted cyclopropyl. In one preferred embodiment of the method described herein, X 3 is a halogen. In one such embodiment of the method described herein, X 3 is Cl or F. In another embodiment, X 3 is Cl, F, CF3, CHF2, or CH2F. In yet another embodiment of the method described herein, X 3 These are CF3, CHF2, or CH2F.

[0246] In one embodiment of the method described herein, R 1 R is hydrogen. In preferred embodiments of the method described herein, R 1 is PG 1 In such an embodiment of the method described herein, PG 1 These are Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy). In another embodiment of the method described herein, PG 1 is Boc(tert-butyloxycarbonyl). In preferred embodiments of the methods described herein, R 1 This is Boc(tert-butyloxycarbonyl).

[0247] One embodiment of the method described herein, each R 2 R is independently a halogen or a cyano. In another embodiment of the method described herein, each R 2 Independently, non-substituted C 1-6 Alkyl, unsubstituted C 1-6Cyanoalkyl or unsubstituted C 1-6 It is a haloalkyl. In another embodiment of the method described herein, each R 2 Independently, non-substituted C 1-6 Alkyl or unsubstituted C 1-6 It is a cyanoalkyl group. In one such embodiment of the method described herein, n is 1. In one preferred embodiment of the method described herein, each R 2 Independently, non-substituted C 1-6 Alkyl or unsubstituted C 1-6 It is a cyanoalkyl. In one such embodiment of the method described herein, each R 2 is methyl or ethyl. In one such embodiment of the method described herein, n is 1. In another such embodiment of the method described herein, R 2 is methyl and n is 1. In another such embodiment of the method described herein, each R 2 is CF3, CHF2, or CH2F. In another such embodiment of the method described herein, R 2 R is methyl, ethyl, CN, CH2CN, CF3, CHF2, or CH2F. In another embodiment of the method described herein, R 2 is methyl, ethyl, CN, or CH2CN. In such embodiments of the method described herein, n is 1. In another such embodiment of the method described herein, R 2 In one embodiment, n is CH2CN and n is 1. In yet another embodiment, n is 0.

[0248] In one embodiment of the method described herein, R 3 R is hydrogen or halogen. In one embodiment of the method described herein, R 3 R is hydrogen. In another embodiment of the method described herein, R 3 is, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 Haloalkyl, cyclopropyl. In another embodiment of the method described herein, R 3 is, R3A - Substitute or non-substitute C 1-3 Alkyl, or R 3A - Substitute or non-substitute C 1-3 It is a haloalkyl. In yet another embodiment of the method described herein, R 3 R 3A - Substitute or non-substitute C 1-3 It is alkyl. In one such embodiment of the method described herein, R 3 R is hydrogen or methyl. In another such embodiment of the method described herein, R 3 It is methyl.

[0249] In one embodiment of the method described herein, R 3 R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 It is a haloalkyl, and in the formula, R 3A This is a halogen, OH, CN, or unsubstituted C 1-3 It is a haloalkyl. In one such embodiment of the method described herein, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 It is a haloalkyl, and in the formula, R 3A These are F, OH, CN, CF3, CHF2, or CH2F.

[0250] In preferred embodiments of the methods described herein, R 4 is non-substituted C 1-3 It is a haloalkyl. In one such embodiment of the method described herein, R 4 These are CF3, CHF2, or CH2F.

[0251] In one embodiment, R 5 is a halogen, cyano, or OH. In another embodiment, R 5 R 5A - Substitute or non-substitute C 1-6 Alkyl, R 5A - Substitute or non-substitute C1-6 Haloalkyl, or R 5A - Substitute or non-substitute C 1-6 It is a cyanoalkyl. In another embodiment, R 5 is, R 5A - Substitute or non-substitute C 3-6 Cycloalkyl, R 5A - Substitutive or unsubstituted 3- to 6-membered complex rings, R 5A - Substitutable or unsubstituted phenyl, or R 5A - It is a substituted or unsubstituted 6-membered heteroaryl.

[0252] In one embodiment of the method described herein, R 5A and R 5B Each of them is independent of R 5C - Substitute or non-substitute C 1-6 Alkyl or R 5C - Substitute or non-substitute C 1-6 It is a haloalkyl. In another embodiment of the method described herein, R 5A and R 5B Each of them is independent of R 5C - Substitute or non-substitute C 3-7 Cycloalkyl; R 5C - Substitutive or unsubstituted 3- to 7-membered complex rings, R 5C - Substitute or non-substitute C 5-7 Aryl, or R 5C - Substitute or non-substitute C 5-7 It is a heteroaryl compound. In one preferred embodiment of the method described herein, R 5A and R 5B Each of them is independent of R 5C - Substitute or non-substitute C 1-6 It is alkyl.

[0253] In one embodiment of the method described herein, R 5C R is independently a halogen, OH, CN, or NO2. In one embodiment of the method described herein, R 5C R is independent of R 5D - Substitute or non-substitute C 1-6 Alkyl or R 5D - Substitute or non-substitute C 1-6It is a haloalkyl. In one embodiment of the method described herein, R 5C R is independent of R 5D - Substitute or non-substitute C 3-7 Cycloalkyl or R 5D - Substitute or non-substitute C 3-7 It is a complex algebra. In one embodiment, R 5C R is independent of R 5D - Substitute or non-substitute C 5-7 aryl or R 5D - Substitute or non-substitute C 5-7 It is a heteroaryl compound. In another embodiment of the method described herein, R 5C R is independent of R 5D - Substitute or non-substitute C 3-7 Heterogene or R 5D - Substitute or non-substitute C 5-7 It is a heteroaryl. In another embodiment of the method described herein, R 5C is, R 5D - This is a substituted pyrrolidinyl.

[0254] In one embodiment of the method described herein, R 5D R is independently a halogen, OH, or CN. In another embodiment, R 5D is unsubstituted C 1-6 It is alkyl. In another embodiment of the method described herein, R 5D is unsubstituted C 1-6 It is a haloalkyl. In yet another embodiment of the method described herein, R 5D is unsubstituted C 3-7 Cycloalkyl, unsubstituted C 3-7 Heterogeneous algebras, non-substituted C 5-7 Aryl or unsubstituted C 5-7 It is a heteroaryl compound. In one embodiment of the method described herein, R 5D These are methyl, ethyl, or propyl.

[0255] In one embodiment of the method described herein, R 5A and R 5B Each is independent: The filename is JPEG2026143404000149.jpg231170.

[0256] In one embodiment of the method described herein, R 6 is a halogen. In another embodiment of the method described herein, R 6 OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 It is a cycloalkyl group.

[0257] In one embodiment of the method described herein, each PG is independently an amino protecting group. In one embodiment, each PG is the same. In one such embodiment of the method described herein, each PG is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy). In another embodiment, each PG is PMB, DMB, or Boc. In one preferred embodiment of the method described herein, each PG is PMB.

[0258] In yet another embodiment of the method described herein, two PGs come together as C 3-8 It forms a nitrogen heterocycle. In one embodiment of the method described herein, two PGs combine to form the following structure: It forms a portion containing JPEG2026143404000150.jpg26170.

[0259] In one embodiment of the method described herein, X 0 is hydrogen, halogen or OR 5A In another embodiment of the method described herein, X 0 , SR 5B , R 5 - Substitute or non-substitute C 1-6 Alkyl, R 5- Substitute or non-substitute C 1-6 Haloalkyl, R 5 - Substitute or non-substitute C 5-7 Aryl, or R 5 - Substitute or non-substitute C 5-7 It is a heteroaryl compound. In another embodiment of the method described herein, X 0 is hydrogen, halogen, CF3, CHF2, or CH2F. In one preferred embodiment of the method described herein, X 0 is a halogen. In one such embodiment of the method described herein, X 0 is F. In yet another embodiment of the method described herein, X 0 This includes hydrogen, halogens, CF3, CHF2, CH2F, or the following structures: This is the portion containing JPEG2026143404000151.jpg228170 and JPEG2026143404000152.jpg54170.

[0260] In one embodiment of the method described herein (P1), the compound of formula (III) has formulas (III1), (III2), (III3), or (3) as described herein.

[0261] In one embodiment of the method described herein (P2), the method includes: JPEG2026143404000153.jpg74170, X 1 , X 2 , X 3 , R 1 , R 2 , and n are as described herein. In one such embodiment, R 1 is PG 1 And R 2 It is methyl.

[0262] In one embodiment of the method described herein (P3), the method includes: JPEG2026143404000154.jpg55170, X 4 , X 5 , R 3And PG are as described herein.

[0263] In one embodiment of the method described herein (P4), the method includes: JPEG2026143404000155.jpg25170, X 6 , R 3 , R 4 And PG are as described herein.

[0264] In one embodiment of the method described herein (P5), the method includes: JPEG2026143404000156.jpg25170In formula, R 3 , R 4 And PG are as described herein.

[0265] A method (P6) for synthesizing the compound of formula (G) is further provided herein, and the method includes: JPEG2026143404000157.jpg56170 or its tautomers, stereoisomers, atropisomers, or pharmaceutically acceptable salts (wherein X 1 , X 3 , R 2 , R 3 , R 4 And n are as described herein; R Alk The following: A portion selected from the group consisting of JPEG2026143404000158.jpg42170; and X A teeth, Selected from the group consisting of JPEG2026143404000159.jpg228170); (a) Contacting a compound of formula (II) or its tautomer, stereoisomer, or salt synthesized according to the method described herein with a compound of formula (III) or its salt synthesized according to the method described herein to produce a compound of formula (I) or its solvate, tautomer, stereoisomer, atropisomer, or salt described herein; (b) A compound of formula (I) or its solvate, tautomer, stereoisomer, atropisomer or salt, X A The part containing the compound of formula (G1) is brought into contact with the compound of formula (G1); To synthesize JPEG2026143404000160.jpg55170 or its solvates, tautomers, stereoisomers, atropisomers or salts (wherein PG and R 1 This is as described herein; (c) Removing the PG group from the compound of formula (G1); and (d)R Alk To synthesize the compound of formula (G) or its tautomers, stereoisomers, atropisomers, or pharmaceutically acceptable salts by introducing a group.

[0266] In one such embodiment, X in step (b) A The part that includes: The filename is JPEG2026143404000161.jpg233170.

[0267] In one such embodiment, step (d) of method (P6) further comprises a base and an activator. In one embodiment, the activator is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), isobutyl chloroformate, ethyl chloroformate, or propylphosphonic anhydride.

[0268] In one embodiment of the method described herein (P6), R Alk teeth This is JPEG2026143404000162.jpg16170. In one embodiment of the method described herein (P6), R Alk teeth The image is JPEG2026143404000163.jpg17170. In such embodiments, the method includes the base and activator described herein.

[0269] In one embodiment of the method described herein (P6), R 2 is C 1-3 Alkyl or C 1-3It is a cyanoalkyl, and n is 1. In one embodiment of the method described herein (P6), each PG is PMB. In one embodiment of the method described herein (P6), X 1 and X 3 These are halogens in their own right.

[0270] Further provided herein is method (P7), which involves a compound of formula (H): JPEG2026143404000164.jpg57170 or its tautomers, stereoisomers, atropisomers, or pharmaceutically acceptable salts (wherein X 1 , X 3 , R 2 , R 3 , R 4 A method for the synthesis of PG and n (where n is as described herein), the method comprising: (a) Contacting a compound of formula (II) or its tautomer, stereoisomer, or salt synthesized according to the method described herein with a compound of formula (III) or its salt synthesized according to the method described herein to produce a compound of formula (I) or its solvate, tautomer, stereoisomer, atropisomer, or salt described herein; (b) A compound of formula (I) or its solvate, tautomer, stereoisomer, atropisomer, or salt is prepared in the presence of a base, and then prepared in the presence of a base, the compound of formula HO-X A The process involves contacting the compound with the following: Selected from the group consisting of JPEG2026143404000165.jpg232170, thereby a compound of formula (G1); To synthesize JPEG2026143404000166.jpg55170 or its solvates, tautomers, stereoisomers, atropisomers, or salts, (In the formula, PG and R 1 This is as described herein; and (c) Removing the PG group from the compound of formula (G1); (d) The compound from step (c) is prepared in the presence of a base and optionally an activator. To bring into contact with JPEG2026143404000167.jpg23170, thereby producing a compound of formula (H) or its tautomers, stereoisomers, atropisomers, or pharmaceutically acceptable salts.

[0271] In one embodiment of the method described herein (P7), R 1 PG 1 The method involves step (b1): before performing step (d), the compound of G1 is converted to PG. 1 This further includes removing.

[0272] In one embodiment of the method described herein (P7), the compound of step (d) is The filename is JPEG2026143404000168.jpg17170.

[0273] In one embodiment of the method described herein (P7), the compound in step (d) The image is JPEG2026143404000169.jpg15170, and step (d) is carried out in the presence of the base and the activator described herein. In one such embodiment, the activator is EDCI.

[0274] In one embodiment of the method described herein (P7), the compound in step (d) The image is JPEG2026143404000170.jpg15170, and step (d) is carried out in the presence of only the bases described herein.

[0275] In one embodiment of the method described herein (P7), the compound in step (d) The image is JPEG2026143404000171.jpg14170, and step (d) is carried out in the presence of only the bases described herein.

[0276] In one embodiment of the method described herein (P7), the compound in step (d) The image is JPEG2026143404000172.jpg22170, and step (d) is carried out in the presence of the base and the activator described herein. In one such embodiment, the activator is EDCI.

[0277] In one embodiment of the method described herein (P7), the base in step (d) is N-ethylmorpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), N,N-diisopropylethylamine (DIPEA), or pyridine. In one embodiment of the method described herein (P7), the base in step (d) is diisopropylethylamine (DIPEA). In one embodiment of the method described herein (P7), R 2 is C 1-3 Alkyl or C 1-3 It is a cyanoalkyl, and n is 1. In one embodiment of the method described herein (P7), each PG is PMB. In one embodiment, R 1 is PG 1 And, PG 1 is Boc. In one embodiment of the method described herein (P7), X 1 and X 3 These are halogens in their own right.

[0278] In one embodiment of the method described herein (P7), the activator is a carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)). In one embodiment of the method described herein (P7), the activator is a benzo-triazole hexafluorophosphate compound (e.g., (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), or BOP-Cl).

[0279] In one embodiment of the method described herein (P7), the activator is a uronium compound (e.g., 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBT) In yet another embodiment, the activator is O-(N-Suc-siminimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximide)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU), and O-(1,2-dihydro-2-oxo-1-pyridyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU)). In yet another embodiment, the coupling agent is 3-(diethylphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT).

[0280] In one embodiment of the method described herein (P7), the activator is EDCI, isobutyl chloroformate, ethyl chloroformate, or propylphosphonic anhydride. In such one embodiment, the activator is EDCI. In another such embodiment, the activator is isobutyl chloroformate or ethyl chloroformate. In yet another such embodiment, the activator is propylphosphonic anhydride.

[0281] In one embodiment of the method described herein (P7), X A The part that includes, The filename is JPEG2026143404000173.jpg157170.

[0282] In one embodiment of the method described herein (P7), X A The part that includes, The filename is JPEG2026143404000174.jpg19170.

[0283] In one embodiment of the method described herein (P7), X A The part that includes, The filename is JPEG2026143404000175.jpg103170.

[0284] In one embodiment of the method described herein (P7), X A The part that includes, The filename is JPEG2026143404000176.jpg24170.

[0285] In one embodiment of the method described herein (P6) or (P7), the compound of formula (G1) or its solvate, atropisomer, tautomer, stereoisomer, or salt is a compound of Table 1. In one embodiment of the method described herein (P6) or (P7), the compound of formula (G1) or its solvate, tautomer, stereoisomer, atropisomer, or salt is a compound of formula 5, 33, 35, 37, 40, 44, 46, or 69 of Table 1. In a preferred embodiment of the method described herein (P6) or (P7), the compound of formula (G1) or its solvate, atropisomer, tautomer, stereoisomer, or salt is a compound of formula 5 of Table 1.

[0286] In another embodiment, a Rothes (P8) for the synthesis of a compound of formula (F) or its tautomers, stereoisomers, atropisomers or pharmaceutically acceptable salts is provided herein. JPEG2026143404000177.jpg56170In formula, R 2 and n are as described herein, and the method includes: Formula (a) The compound or salt thereof of JPEG2026143404000178.jpg25170 is given by formula Contact the compound of JPEG2026143404000179.jpg46170 or its tautomer, stereoisomer, or salt with the compound of formula (1a) To synthesize JPEG2026143404000180.jpg53170 or its solvates, tautomers, stereoisomers, atropisomers, and salts. (b) Compounds of formula (1a) or their solvates, tautomers, stereoisomers, and atropisomers, of formula HO-X A (In the formula, X A is an expression The compound (containing JPEG2026143404000181.jpg25170) is brought into contact with the compound of formula (F1); Synthesizing JPEG2026143404000182.jpg50170 or its solvates, tautomers, stereoisomers, or salts; (c) Contacting a compound of formula (F1) or its solvate, tautomer, stereoisomer, or salt with methanesulfonic acid (MsOH) in an acid to obtain a compound of formula (F2); Synthesizing JPEG2026143404000183.jpg52170 or its solvates, tautomers, stereoisomers, or salts; and (d) A compound of formula (F2) or its solvate, tautomer, stereoisomer, or salt, Contacting the compound of JPEG2026143404000184.jpg20170 with the compound of formula (F) to produce the compound of formula (F) or its tautomers, stereoisomers, or pharmaceutically acceptable salts.

[0287] In one embodiment of the method described herein (P8), the acid in step (c) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid, or trifluoromethanesulfonic acid. In one such embodiment, the acid in step (c) is AcOH, trifluoroacetic acid, or chlorosulfonic acid. In another such embodiment, the acid in step (c) is AcOH.

[0288] In one embodiment of the method described herein (P8), X A teeth This is JPEG2026143404000185.jpg16170. In one embodiment of the method described herein, X A teeth The filename is JPEG2026143404000186.jpg16170.

[0289] In one embodiment of method (P8), step (d) further comprises a base and optionally an activator. In such an embodiment, step (d) of method (P8) further comprises only the bases described herein. In another such embodiment, step (d) of method (P8) further comprises the bases and activators described herein.

[0290] In one embodiment of the method described herein (P8), the compound of step (d) is JPEG2026143404000187.jpg15170 and a base.

[0291] In one embodiment of the method described herein (P8), the compound of step (d) is JPEG2026143404000188.jpg14170 and bases.

[0292] In one embodiment of the method described herein (P8), the compound of step (d) is JPEG2026143404000189.jpg21170 and the bases and activators described herein.

[0293] In one embodiment of the method described herein (P8), each R 2 R is independently a halogen or a cyano. In one embodiment of the method described herein (P8), each R 2 These are, independently, halogen or unsubstituted C 1-6 It is a cyanoalkyl. In one embodiment of the method described herein (P8), each R 2 Independently, non-substituted C 1-6Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 It is a haloalkyl. In one embodiment of the method described herein (P8), n is 1. In one embodiment of the method described herein (P8), each R 2 Independently, non-substituted C 1-6 Alkyl or unsubstituted C 1-6 It is a cyanoalkyl. In one embodiment of the method described herein (P8), each R 2 is methyl or ethyl. In one such embodiment, n is 1. In one embodiment of the method described herein (P8), R 2 is methyl and n is 1. In one embodiment of the method described herein (P8), each R 2 is CF3, CHF2, or CH2F. In one embodiment of the method described herein (P8), R 2 is methyl, ethyl, CN, CH2CN, CF3, CHF2, or CH2F. In another embodiment, R 2 is methyl, ethyl, CN, or CH2CN. In one embodiment of the method described herein (P8), n is 1. In one embodiment of the method described herein (P8), R 2 is CH2CN, and n is 1. In one embodiment of the method described herein (P8), n is 0.

[0294] In one embodiment, the compound of formula (F) has formula (F4): JPEG2026143404000190.jpg55170 or its tautomers, stereoisomers, or pharmaceutically acceptable salts.

[0295] In one embodiment, the compound of formula (F) has formula (F5) JPEG2026143404000191.jpg56170 or its tautomers, stereoisomers, or pharmaceutically acceptable salts.

[0296] In one embodiment of the method described herein (P8), compound (F1) or its tautomers, stereoisomers, or pharmaceutically acceptable salts are the compounds of Table 1. In one embodiment of the method described herein (P8), the compound of formula (F1) or its tautomers, stereoisomers, or pharmaceutically acceptable salts are the compounds of formulas 105, 133, 135, 137, 140, 144, 146, or 169 of Table 1. In a preferred embodiment of the method described herein (P8), the compound of formula (F1) or its tautomers, stereoisomers, or pharmaceutically acceptable salts is the compound of formula 105 of Table 1.

[0297] Further provided herein is a method (P9) comprising a compound of formula (A): A method for preparing JPEG2026143404000192.jpg57170 or a pharmaceutically acceptable salt thereof, (a) Formula (2) The compound or salt thereof of JPEG2026143404000193.jpg43170 is brought into contact with i-PrMgCl·LiCl and ZnCl2, followed by NaTFA and formula (3) Contacting the compound in JPEG2026143404000194.jpg23170, (b) Contact the mixture from step (a) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand as described herein, thereby obtaining the compound of formula (1). To synthesize JPEG2026143404000195.jpg50170 or its solvates or salts, (c) A compound of formula (1) or its solvate or salt, formula HO-X A (In the formula, X A is an expression Contact the compound (containing JPEG2026143404000196.jpg16170) with a base to obtain the compound of formula (1d); To synthesize JPEG2026143404000197.jpg47170 or its solvates or pharmaceutically acceptable salts; (d) Contact the compound of formula (1d) with MsOH in an acid to obtain the compound of formula (1e); Synthesizing JPEG2026143404000198.jpg42170 or its solvates or pharmaceutically acceptable salts; and (e) A compound of formula (1e) or its solvate or pharmaceutically acceptable salt, This involves contacting JPEG2026143404000199.jpg20170 with a base and optionally an activator as described herein, thereby producing a compound of formula (A) or a pharmaceutically acceptable salt thereof.

[0298] In one embodiment, step (b) of method (P9) further comprises crystallization. In such an embodiment, crystallization is carried out in toluene / n-heptane.

[0299] In one embodiment, step (c) of method (P9) further comprises washing with potassium carbonate and filtration (e.g., abrasive filtration). In such an embodiment, step (c) of method (P9) further comprises solvent exchange to 1-PrOH. In such an embodiment, crystallization is carried out from 1-PrOH / water after solvent exchange. In another embodiment, crystallization is carried out from isopropanol / water, acetonitrile, acetonitrile / water, or acetone / water.

[0300] In one embodiment of the method described herein, the base in step (c) is selected from the group consisting of LiOt-Am, NaOt-Am, KOt-Am, KDMO (potassium 3,7-dimethyl-3-octanoxide), LiOt-Bu, NaOt-Bu, or KOt-Bu. In such an embodiment, the base is one of the bases in the following table: [Table 2]

[0301] In such an embodiment, the base is NaOt-Am or NaOt-Bu. In such an embodiment, the base may be present in an amount of about 1.1 to about 1.35 equivalents relative to compound 1.

[0302] In one embodiment of the method described herein (P9), the acid in step (d) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, formic acid, p-toluenesulfonic acid, or trifluoromethanesulfonic acid. In one such embodiment, the acid in step (d) is AcOH, trifluoroacetic acid, or chlorosulfonic acid. In another such embodiment, the acid in step (d) is AcOH, formic acid, trifluoroacetic acid, or chlorosulfonic acid.

[0303] In one embodiment of the method described herein (P9), the activator is EDCI, isobutyl chloroformate, ethyl chloroformate, or propylphosphonic anhydride. In such one embodiment, the activator is EDCI. In another such embodiment, the activator is isobutyl chloroformate or ethyl chloroformate. In yet another such embodiment, the activator is propylphosphonic anhydride.

[0304] In one embodiment, step (d) of method (P9) further comprises quenching with a base (e.g., a hydroxide base, e.g., NaOH) and washing with the same base (e.g., NaOH). In another such embodiment, step (d) of method (P9) further comprises polishing filtration. In yet another embodiment, step (d) of method (P9) further comprises a crystallization step (e.g., using toluene / n-heptane).

[0305] In one embodiment of the method described herein (P9), the MsOH in step (d) may be present in an amount of about 10–30 equivalents, 15–30 equivalents, 15–27 equivalents, 15–25 equivalents, 15–23 equivalents, or about 20–30 equivalents relative to the compound of formula (1d). In such an embodiment, the MsOH may be present in an amount of about 15–27 equivalents relative to the compound of formula (1d). In another embodiment of the method described herein (P9), the AcOH may be present in an amount of about 1–4 volumes, 1.5–3.5 volumes, 1.6–3.4 volumes, or 1.8–3.3 volumes. In one embodiment of the method described herein (P9), step d further comprises toluene as a cosolvent. In such an embodiment, the volume of toluene is 0–7 volumes.

[0306] In one embodiment of the method described herein (P9), step (e) is to use a compound of formula (1e) or a solvate or pharmaceutically acceptable salt thereof. This includes contacting JPEG2026143404000201.jpg21170 with a base and optionally an activator as described herein.

[0307] In one embodiment of the method described herein (P9), step (e) is to add a compound of formula (1e) or its solvate or pharmaceutically acceptable salt in the presence of a base. This includes contact with JPEG2026143404000202.jpg14170.

[0308] In one embodiment of the method described herein (P9), step (e) is to add a compound of formula (1e) or its solvate or pharmaceutically acceptable salt in the presence of a base. This includes contact with JPEG2026143404000203.jpg15170.

[0309] In one embodiment of the method described herein (P9), step (e) is to use a compound of formula (1e) or its solvate or pharmaceutically acceptable salt in the presence of a base and activator as described herein. This includes contacting JPEG2026143404000204.jpg15170.

[0310] In one embodiment of the method described herein (P9), step (e) is to use a compound of formula (1e) or its solvate or pharmaceutically acceptable salt in the presence of a base and activator as described herein. This includes contact with JPEG2026143404000205.jpg21170. In one such embodiment, the reaction is carried out in a solvent such as 2-Me-THF or toluene. In one embodiment, the activator is EDCI. In another embodiment, the activator includes pivaloyl chloride (PivCl).

[0311] In one embodiment of the method described herein, the base in step (e) is NaOH, KOH, LiOH, triethylamine, or pyridine. In such an embodiment, the base is NaOH.

[0312] In one embodiment of the method described herein (P9), the compound of formula (1) is cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene, or toluene solvate. In one embodiment of the method described herein (P9), the compound of formula (1) is crystalline cyclohexane solvate. In such an embodiment of the method described herein (P9), the crystalline cyclohexane solvate of the compound of formula (1) is substantially as shown in Figure 1. In another embodiment of the method described herein (P9), the compound of formula (1) is crystalline methylcyclohexane solvate. In such an embodiment of the method described herein (P9), the crystalline methylcyclohexane solvate of the compound of formula (1) is substantially as shown in Figure 2. In another embodiment of the method described herein (P9), the compound of formula (1) is crystalline chlorobenzene solvate. In such an embodiment of the method described herein (P9), the crystalline chlorobenzene solvate of the compound of formula (1) is substantially as shown in Figure 3. In another embodiment of the method described herein (P9), the compound of formula (1) is a crystalline ethylbenzene solvate. In one such embodiment of the method described herein (P9), the crystalline ethylbenzene solvate of the compound of formula (1) is substantially as shown in Figure 4. In another embodiment of the method described herein (P9), the compound of formula (1) is a crystalline m-xylene solvate. In one such embodiment of the method described herein (P9), the crystalline m-xylene solvate of the compound of formula (1) is substantially as shown in Figure 5. In another embodiment of the method described herein (P9), the compound of formula (1) is a crystalline toluene solvate. In one such embodiment of the method described herein (P9), the crystalline toluene solvate of the compound of formula (1) is substantially as shown in Figure 6.

[0313] In one embodiment of the method described herein, method (P9) further comprises step (f): contacting a compound of formula (A) with adipic acid in a solvent (e.g., methyl ethyl ketone (MEK), 2-Me-THF, 2-butanol, or 2-Me-THF / 2-butanol) to form a compound of formula (B). In one embodiment, step (f) comprises scheme 1. In another embodiment, step (f) comprises scheme 2. In yet another embodiment, step (f) comprises scheme 3. In one embodiment, scheme 3 further comprises n-heptane. Scheme 1: JPEG2026143404000206.jpg57170 Scheme 2: JPEG2026143404000207.jpg57170 Scheme 3: JPEG2026143404000208.jpg57170 Treatment Method

[0314] The methods described herein are useful for preparing compounds useful for the treatment of cancer. In one embodiment, KRas is administered by administering an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, synthesized according to any of the methods described herein. G12C A method for treating mutation-mediated cancer is provided herein. In one embodiment, KRas is treated by administering an effective amount of compound (B), which is synthesized according to one of the methods described herein. G12C A method for treating mutation-mediated cancer is provided herein. In one preferred embodiment of the method described herein, compound (A) or a pharmaceutically acceptable salt thereof is synthesized according to the method described herein P9. In one preferred embodiment of the method described herein, compound (B) or a pharmaceutically acceptable salt thereof is synthesized according to the method described herein P9.

[0315] Tumor or cancer is KRas G12CWhether or not a mutation is present can be determined by evaluating the nucleotide sequence encoding the K-Ras protein, by evaluating the amino acid sequence of the K-Ras protein, or by evaluating the characteristics of the predicted K-Ras mutant protein. The sequence of wild-type human K-Ras (e.g., accession number NP 203524) is known in the art.

[0316] In certain embodiments, the method includes the treatment of lung cancer. In one embodiment, KRas G12C A method for treating lung cancer containing mutations in a patient having such lung cancer, comprising administering to the patient a therapeutically effective amount of compound (A) synthesized according to the method described herein P9, or a pharmaceutically acceptable salt thereof. In one embodiment, KRas G12C A method for treating lung cancer containing mutations in a patient having such lung cancer, comprising administering to the patient a therapeutically effective amount of compound (B) synthesized according to the method described herein P9, or a pharmaceutically acceptable salt thereof.

[0317] In certain embodiments, the lung cancer is non-small cell lung carcinoma (NSCLC), such as adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma. In some embodiments, the cancer is lung adenocarcinoma. In other embodiments, the lung cancer is small cell lung carcinoma. NSCLC can be, for example, adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma. In yet 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 can be stage I or II. In one embodiment, the lung cancer can be stage III or IV.

[0318] 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 administration of any therapeutic agent. In another embodiment of such a method, the sample is taken before administration of a pharmaceutically acceptable salt of the compound described herein and after administration of another chemotherapeutic agent. In another embodiment of such a method, the compound described herein or a pharmaceutically acceptable salt thereof is administered as provided herein (e.g., orally).

[0319] KRas G12C A method for treating pancreatic cancer containing mutations in a patient having such pancreatic cancer is further provided herein, comprising administering to the patient a therapeutically effective amount of compound (A) synthesized according to Method P9 herein or a pharmaceutically acceptable salt thereof. G12C There exists a method for treating pancreatic cancer containing mutations in a patient having such pancreatic cancer, comprising administering to the patient a therapeutically effective amount of compound (B) or a pharmaceutically acceptable salt thereof, synthesized according to the method described herein P9.

[0320] In one embodiment, the patient has previously received radiation and / or chemotherapy. 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.

[0321] KRas G12C A method for treating mutated colon cancer in a patient having such colon cancer is further provided herein, comprising administering to the patient a therapeutically effective amount of compound (A) synthesized according to Method P9 herein or a pharmaceutically acceptable salt thereof. G12CFurther provided herein are methods for treating mutated colon cancer in a patient having such colon cancer, comprising administering to the patient a therapeutically effective amount of compound (B) synthesized according to Method P9 herein or a pharmaceutically acceptable salt thereof.

[0322] In one embodiment, the colorectal cancer is stage I or II. In another embodiment, the colorectal cancer is stage III or IV.

[0323] KRas G12C Hematological cancers including mutations or KRas G12C Further provided herein are methods for treating MYH-associated polyposis cancer, including mutations, by administering a therapeutically effective amount of compound (A), synthesized according to Method P9 of the Specified Method, or a pharmaceutically acceptable salt thereof, to a subject having such disease. G12C Hematological cancers including mutations or KRas G12C This specification further provides a method for treating MYH-associated polyposis cancer, including mutations, by administering a therapeutically effective amount of compound (B), synthesized according to the method described herein (P9), to a subject having such disease.

[0324] KRas G12C Methods for treating tumor-independent cancers, including mutations, are further provided herein. In one embodiment of such a method, the method includes: (a) KRas in samples taken from patients diagnosed with suspected cancer G12C Measuring the presence or absence of mutations; and (b) Administering to a subject having such disease a therapeutically effective amount of compound (A) or a pharmaceutically acceptable salt thereof, synthesized according to method P9 as described herein.

[0325] KRas G12C Methods for treating tumor-independent cancers, including mutations, are further provided herein. In one embodiment of such a method, the method includes: (a) KRas in samples taken from patients diagnosed with suspected cancerG12C Measuring the presence or absence of mutations; and (b) Administering a therapeutically effective amount of compound (B), synthesized according to method P9 as described herein, to a subject having such disease.

[0326] The patients described herein may be human. In some embodiments, the administration of the compounds described herein in the methods provided herein is by oral route. In some embodiments, the administration is by injection. One method provided herein is to administer the compound as a 1 L treatment. Embodiment

[0327] The following are exemplary embodiments.

[0328] Embodiment 1. A method for preparing a compound of formula (I), JPEG2026143404000209.jpg57170In formula, X 0 is hydrogen, halogen, OR 5A , SR 5B , R 5 - Substitute or non-substitute C 1-6 Alkyl, R 5 - Substitute or non-substitute C 1-6 Haloalkyl, R 5 - Substitute or non-substitute C 5-7 Aryl, or R 5 - Substitute or non-substitute C 5-7 It is a heteroaryl; X 1 is hydrogen or halogen; X 3 is hydrogen, halogen, R 6 - Substitute or non-substitute C 1-3 Alkyl, R 6 - Substitute or non-substitute C 1-3 Haloalkyl, R 6 - Substitute or non-substitute C 1-3 Alkoxy, or R 6 - Substituted or unsubstituted cyclopropyl; R1 is hydrogen or PG 1 and; Each R 2 These are, independently, halogen, cyano, and unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 It is a haloalkyl; R 3 is hydrogen, halogen, R 3A - Substitute or non-substitute C 1-3 Alkyl, R 3A - Substitute or non-substitute C 1-3 Haloalkyl, or R 3A - Substitute or non-substitute C 3-6 It is a cycloalkyl; R 3A This includes halogen, OH, CN, and unsubstituted C. 1-3 Alkyl or unsubstituted C 1-3 It is a haloalkyl; R 4 is, R 4A - Substitute or non-substitute C 1-3 It is a haloalkyl; R 4A is unsubstituted C 1-3 It is alkyl; R 5 Halogen, cyano, OH, NO2, R 5A - Substitute or non-substitute C 1-6 Alkyl, R 5A - Substitute or non-substitute C 1-6 Haloalkyl, R 5A - Substitute or non-substitute C 1-6 Cyanoalkyl, R 5A - Substitute or non-substitute C 3-6 Cycloalkyl, R 5A - Substitutive or unsubstituted 3- to 6-membered complex rings, R 5A - Substitutable or unsubstituted phenyl, or R 5A -It is a substituted or unsubstituted 6-membered heteroaryl; R 5A and R 5B Each of them is independent of R 5C - Substitute or non-substitute C 1-6 Alkyl, R 5C - Substitute or non-substitute C1-6 haloalkyl, R 5C -substituted or unsubstituted C 3-7 cycloalkyl; R 5C -substituted or unsubstituted 3- to 7-membered heterocycle; R 5C -substituted or unsubstituted C 5-7 aryl, or R 5C -substituted or unsubstituted C 5-7 heteroaryl; R 5C is independently halogen, OH, CN, NO2, R 5D -substituted or unsubstituted C 1-6 alkyl, R 5D -substituted or unsubstituted C 1-6 haloalkyl, R 5D -substituted or unsubstituted C 3-7 cycloalkyl; R 5D -substituted or unsubstituted C 3-7 heterocycle; R 5D -substituted or unsubstituted C 5-7 aryl, or R 5D -substituted or unsubstituted C 5-7 heteroaryl; R 5D is independently halogen, OH, CN, NO2, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 haloalkyl, unsubstituted C 3-7 cycloalkyl; unsubstituted C 3-7 heterocycle; unsubstituted C 5-7 aryl or unsubstituted C 5-7 heteroaryl; R 6 is halogen, OH, CN, NO2, unsubstituted C 1-6 alkyl, unsubstituted C 1-6 haloalkyl, or unsubstituted C 3-7 cycloalkyl; n is 0, 1 or 2; each PG is independently an amino protecting group, or two PGs together form a C 3-7 nitrogen-containing heterocycle; and PG 1 is an amino protecting group; (a) the compound of formula (II), JPEG2026143404000210.jpg45170(in the formula, 2 It is a halogen; Contacting with organomagnesium compounds and zinc complexes; and The mixture from step (a) is a compound of formula (III), JPEG2026143404000211.jpg30170(in the formula, 4 It is a halogen; A method for synthesizing a compound of formula (I), comprising contacting a transition metal (e.g., Pd or Ni) catalyst precursor with a chiral ligand.

[0329] Embodiment 2. The method according to Embodiment 1, wherein the compound of formula (II) is obtained by the following method: (a) Equation (IVa) The compound in JPEG2026143404000212.jpg30170, formula JPEG2026143404000213.jpg27170(in the formula, 3 When contacted with a halogenating agent having (which is a halogen), formula (IVb) To produce the compound JPEG2026143404000214.jpg27170; (d) Compound of formula (IVb) Cyclization of the compound in JPEG2026143404000215.jpg29170; (d) When the compound of formula (V) is brought into contact with a chlorinating agent, formula (Va) To produce the compound JPEG2026143404000216.jpg31170; and (d) Compound of formula (Va) By bringing the piperazinyl portion containing JPEG2026143404000217.jpg28170 into contact, formula (IIa) To produce the compound JPEG2026143404000218.jpg47170; and (f) The compound of formula (IIa) X 0 A method for preparing a compound of formula (II) by bringing it into contact with a portion containing the compound.

[0330] Embodiment 3. The method according to Embodiment 2, further comprising the following steps: (a0) Equation (IV) in the presence of CO2 gas The compound in JPEG2026143404000219.jpg21170 is brought into contact with a base, and the compound is aminated to form formula (IVa). A method comprising forming the compound JPEG2026143404000220.jpg30170.

[0331] Embodiment 4. A method according to any one of Embodiments 1 to 3, wherein the compound of formula (III) is obtained by the following method: (a) Equation (VII) The compound in JPEG2026143404000221.jpg26170 is brought into contact with a compound having the formula NH2(PG), thereby producing formula (VIIa). To produce compound (VIIa); (b) Compound of formula (VIIa) a PG(in the formula, X a When a compound having (which is a halogen) is brought into contact with the compound of formula (VIIb) To produce the compound JPEG2026143404000222.jpg27170; (c) Compound of formula (VIIb), JPEG2026143404000223.jpg26170(in the formula, 5 When contacted with a halogenating agent having (which is a halogen), formula (VIIc) To produce the compound JPEG2026143404000224.jpg27170; (d) Haloalkylation of the compound of formula (VIIc) with a haloalkylating agent to produce the compound of formula (VIId). JPEG2026143404000225.jpg29170(e) Brominate the compound of formula (VIId) to obtain formula (VIIe) To produce the compound JPEG2026143404000226.jpg23170; and (f) Compound of formula (VIIe) Xa A method for preparing a compound of formula (III) by contacting it with PG.

[0332] Embodiment 5 The method according to Embodiment 1, wherein the compound of formula (III) is obtained by the following method: (a) Equation (VIII) Compound of JPEG2026143404000227.jpg25170 (where X is in the formula) 6 (where is Cl or I) is brought into contact with a halogenating agent, and formula (VIIIa) To form the compound JPEG2026143404000228.jpg23170; (b) Brominate the compound of formula (VIIIa) to obtain formula (VIIIb) To form the compound of JPEG2026143404000229.jpg22170; and (c) A method for preparing a compound by contacting a compound of formula (VIIIb) with a compound having formula NH(PG)2 to produce a compound of formula (III).

[0333] Embodiment 6. The method according to Embodiment 1, wherein the compound of formula (III) is obtained by the following method: (a) Equation (VIIIc) When the compound in JPEG2026143404000230.jpg23170 is brought into contact with a brominating agent, formula (VIIId) To form the compound JPEG2026143404000231.jpg22170; (b) The compound of formula (VIIId) is brought into contact with a halogenating agent to form formula (VIIIb) To form the compound JPEG2026143404000232.jpg22170; (c) A method for preparing a compound by contacting a compound of formula (VIIIb) with a compound having formula NH(PG)2 to produce a compound of formula (III).

[0334] Embodiment 7.X 1 The method according to any one of embodiments 1 to 6, wherein is a halogen.

[0335] Embodiment 8.X 1 The method according to any one of Embodiments 1 to 7, wherein is F or Cl.

[0336] Embodiment 9.X 1 The method according to any one of Embodiments 1 to 6, wherein is hydrogen or halogen.

[0337] Embodiment 10.X 3 However, halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3 The method according to any one of Embodiments 1 to 8, wherein the material is a haloalkyl.

[0338] Embodiment 11.X 3 is halogen or unsubstituted C 1-3 The method according to any one of Embodiments 1 to 8, wherein the material is a haloalkyl.

[0339] Embodiment 12.X 3 is non-substituted C 1-3 The method according to any one of Embodiments 1 to 8, wherein the hydroxyl molecule is an alkoxy or an unsubstituted cyclopropyl molecule.

[0340] Embodiment 13.X 3 The method according to any one of Embodiments 1 to 8, wherein is a halogen.

[0341] Embodiment 14.X 3 The method according to any one of Embodiments 1 to 8, wherein is Cl or F.

[0342] Embodiment 15.X 3 The method according to any one of Embodiments 1 to 8, wherein is Cl, F, CF3, CHF2, or CH2F.

[0343] Embodiment 16.X 3 The method according to any one of Embodiments 1 to 8, wherein is CF3, CHF2, or CH2F.

[0344] Embodiment 17.R 1PG 1 The method according to any one of embodiments 1 to 16.

[0345] Embodiment 18.PG 1 The method according to Embodiment 17, wherein the compound is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy).

[0346] Embodiment 19.R 1 The method according to any one of Embodiments 1 to 16, wherein is Boc(tert-butyloxycarbonyl).

[0347] Embodiment 20.R 2 The method according to any one of Embodiments 1 to 19, wherein is a halogen or cyano.

[0348] Embodiment 21.R 2 However, non-substituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 The method according to any one of Embodiments 1 to 19, wherein the material is a haloalkyl.

[0349] Embodiment 22.R 2 is non-substituted C 1-6 Alkyl or unsubstituted C 1-6 The method according to any one of Embodiments 1 to 19, wherein the material is a cyanoalkyl group.

[0350] Embodiment 23.R 2 is non-substituted C 1-6 Alkyl or unsubstituted C 1-6 The method according to any one of Embodiments 1 to 19, wherein the material is a haloalkyl.

[0351] Embodiment 24.R 2 The method according to any one of Embodiments 1 to 19, wherein is methyl or ethyl.

[0352] Embodiment 25. R 2 is methyl. The method according to any one of Embodiments 1 to 19.

[0353] Embodiment 26. R 2 is CF3, CHF2 or CH2F. The method according to any one of Embodiments 1 to 19.

[0354] Embodiment 27. R 2 is CH2. The method according to any one of Embodiments 1 to 19.

[0355] Embodiment 28. R 3 is hydrogen or R 3A -substituted or unsubstituted C 1-3 alkyl. The method according to any one of Embodiments 1 to 27.

[0356] Embodiment 29. R 3 is R 3A -substituted or unsubstituted C 1-3 alkyl, R 3A -substituted or unsubstituted C 1-3 haloalkyl, or cyclopropyl. The method according to any one of Embodiments 1 to 27.

[0357] Embodiment 30. R 3 is R 3A -substituted or unsubstituted C 1-3 alkyl or R 3A -substituted or unsubstituted C 1-3 haloalkyl. The method according to any one of Embodiments 1 to 27.

[0358] Embodiment 31. R 3 is R 3A -substituted or unsubstituted C 1-3 alkyl. The method according to any one of Embodiments 1 to 27.

[0359] Embodiment 32. R 3 is methyl. The method according to any one of Embodiments 1 to 27.

[0360] Embodiment 33.R 4 The method according to any one of Embodiments 1 to 32, wherein is CF3, CHF2, or CH2F.

[0361] Embodiment 34. The method according to any one of Embodiments 1 to 33, wherein each PG is independently a protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy).

[0362] Embodiment 35. The method according to any one of Embodiments 1 to 34, wherein each PG is p-methoxybenzyl.

[0363] Embodiment 36. A method according to any one of Embodiments 1 to 34, wherein two PGs are combined to form the following structure: A method for forming a portion having JPEG2026143404000233.jpg26170.

[0364] Embodiment 37.X 2 The method according to any one of embodiments 1 to 36, wherein is Br.

[0365] Embodiment 38. The method according to any one of Embodiments 1 to 37, wherein the organomagnesium compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate.

[0366] Embodiment 39. The method according to any one of Embodiments 1 to 38, wherein the zinc complex is selected from the group consisting of ZnCl2, ZnBr2, ZnI2, Zn(OAc)2, and Zn(OPiv)2.

[0367] Embodiment 40. The transition metal catalyst precursor is Pd or Ni, and the catalyst precursors are Pd(OAc)2, PdCl2, PdCl2(MeCN)2, and Pd(benzonitrile)2Cl 2、 The method according to any one of Embodiments 1 to 39, selected from the group consisting of Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(clotyl)]2, PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl2, NiBr2, Ni(OAc)2, and nickel(II) acetylacetonate.

[0368] Embodiment 41. A method according to any one of Embodiments 1 to 40, wherein the chiral ligand is The filename is JPEG2026143404000234.jpg80170. During the ceremony, Y is O or NR 7 and; Z is either O or N; R 7 and R 8 Independently, non-substituted C 1-6 It is alkyl; R 9 and R 10 R is independent of R 11 - Substitute or non-substitute C 5-6 Cycloalkyl or R 11 - Substituted or unsubstituted phenyl; Each R 11 These are, independently, hydrogen and C 1-6 Unsubstituted alkyl, or C 1-6 It is an unsubstituted haloalkyl; R 12 and R 13 Each of them is independent of R 14 - Substituted or unsubstituted C1-6 alkyl, R 14 - Substitute or non-substitute C 3-7 Cycloalkyl, R 14 - Substitutable or non-substitutable aryl, or R 14 - Substitute or non-substitute C 5-7 It is a heteroaryl; Each R 14 Independently, non-substituted C 1-4 A method that is alkyl.

[0369] Embodiment 42.R 7 and R 8 The method according to Embodiment 41, wherein the same applies.

[0370] Embodiment 43.R 7 and R 8 The method according to Embodiment 42, wherein each of these is methyl, ethyl, or phenyl.

[0371] Embodiment 44. The method according to Embodiment 2, wherein the base is LDA or LiTMP.

[0372] Embodiment 45. The method according to Embodiment 2, wherein the halogenating agent is NCS or 1,3-dichloro-5,5-dimethylhydantoin.

[0373] Embodiment 46. The method according to Embodiment 2, wherein the chlorinating agent is POCl3, PCl3, PCl5, or SOCl2.

[0374] Embodiment 47. The method according to Embodiment 4, wherein the halogenating agent is NIS or 1,3-diiodomo-5,5-dimethylhydantoin.

[0375] Embodiment 48. The method according to Embodiment 4, wherein the haloalkylating agent is a fluoroalkylating agent.

[0376] Embodiment 49. The method according to Embodiment 4, wherein the haloalkylating agent is methyl 2,2-difluoro-2-(fluorosulfonyl)acetate.

[0377] Embodiment 50. The method according to Embodiment 5 or 6, wherein the halogenating agent is SF4 in HF.

[0378] Embodiment 51. The method according to Embodiment 1, wherein the compound of formula (II) is: The file JPEG2026143404000235.jpg45170 is included. (In the formula, X 3 (is a halogen), method.

[0379] Embodiment 52. The method according to Embodiment 1, wherein the compound of formula (II) is: The file JPEG2026143404000236.jpg44170 is included. (In the formula, X 3 (is a halogen), method.

[0380] Embodiment 53. The method according to Embodiment 1, wherein the compound of formula (II) is: A method having JPEG2026143404000237.jpg46170.

[0381] Embodiment 54. The method according to Embodiment 1, wherein the compound of formula (III) is of formula: A method having JPEG2026143404000238.jpg27170.

[0382] Embodiment 55.R 3 is non-substituted C 1-3 The method according to embodiment 54, wherein the alkyl group is used.

[0383] Embodiment 56.R 4 is non-substituted C 1-3 The method according to embodiment 54 or 55, wherein the compound is a haloalkyl.

[0384] Embodiment 57. The method according to Embodiment 1, wherein the compound of formula (III) is: A method having JPEG2026143404000239.jpg27170.

[0385] Embodiment 58. The method according to Embodiment 1, wherein the compound of formula (I) is of formula: A method having JPEG2026143404000240.jpg51170.

[0386] Embodiment 59. The method according to Embodiment 1, wherein the compound of formula (I) is of formula: A method having JPEG2026143404000241.jpg52170.

[0387] Embodiment 60.R 3 is non-substituted C 1-3 The method according to embodiment 58 or 59, wherein the alkyl group is used.

[0388] Embodiment 61.R 4 is non-substituted C 1-3 The method according to any one of embodiments 58 to 60, wherein the material is a haloalkyl.

[0389] Embodiment 62. The method according to Embodiment 1, wherein the compound of formula (I) is: A method having JPEG2026143404000242.jpg49170.

[0390] Embodiment 63.R 2 However, non-substituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 The method according to any one of embodiments 58 to 62, wherein the material is a haloalkyl.

[0391] Embodiment 64.R 2 The method according to Embodiment 63, wherein is methyl, ethyl, CN, CH2CN, CF3, CHF2, or CH2F.

[0392] Embodiment 65.R 2The method according to Embodiment 63, wherein is methyl, ethyl, CN, or CH2CN.

[0393] Embodiment 66. The method according to Embodiment 1, wherein the compound of formula (I) is of formula: The file JPEG2026143404000243.jpg50170 is included. (In the formula, X 3 (is a halogen), method.

[0394] Embodiment 67. The method according to Embodiment 1, wherein the compound of formula (I) is of formula: A method having JPEG2026143404000244.jpg52170.

[0395] Embodiment 68. The method described in Embodiment 1, wherein X 0 The method involves a portion that is hydrogen, halogen, CF3, CHF2, CH2F, or has the following structure: JPEG2026143404000245.jpg249170JPEG2026143404000246.jpg32170

[0396] Embodiment 69. A compound having formula (Id); JPEG2026143404000247.jpg52170, X 3 It is a halogen, a compound.

[0397] Embodiment 70. Compound having formula (1): JPEG2026143404000248.jpg51170

[0398] Embodiment 71. The method according to Embodiment 2, wherein step (f) is A method further comprising step (g) fluorinating the compound of formula (IIa) to the compound of formula (IIa1). JPEG2026143404000249.jpg45170

[0399] Embodiment 72. The method according to Embodiment 2, wherein step (f) is A method further comprising step (h) alkoxylation of the compound of formula (IIa) to the compound of formula (IIa2). JPEG2026143404000250.jpg44170

[0400] Embodiment 73. The method according to Embodiment 2, wherein step (f) is A method further comprising step (j) thiolation of the compound of formula (IIa) to the compound of formula (IIe). JPEG2026143404000251.jpg45170

[0401] Embodiment 74. The method according to any one of Embodiments 1 to 6, wherein the compound of formula (I) is one of the compounds in Table 1.

[0402] Embodiment 75. Compound having the following formula: A method for the synthesis of JPEG2026143404000252.jpg57170 or a pharmaceutically acceptable salt thereof, (a) Formula (2) The compound of JPEG2026143404000253.jpg42170 or its salt is brought into contact with ZnCl2 and i-PrMgCl·LiCl, and formula (3) Contact the compound in JPEG2026143404000254.jpg24170, (b) The mixture from step (a) or a salt thereof is brought into contact with a transition metal (e.g., Pd or Ni) catalyst precursor and a chiral ligand, thereby forming the compound of formula (1). To synthesize JPEG2026143404000255.jpg52170 or its solvates or salts, (c) A compound of formula (1) or its solvate or salt, formula HO-X A (In the formula, X A is an expression Contact the compound (containing JPEG2026143404000256.jpg16170) with a base to obtain the compound of formula (1d); To synthesize JPEG2026143404000257.jpg47170 or its solvates or pharmaceutically acceptable salts; (d) Contact the compound of formula (1d) with MsOH in an acid to obtain the compound of formula (1e); Synthesizing JPEG2026143404000258.jpg43170 or its solvates or pharmaceutically acceptable salts; and (e) A compound of formula (1e) or its solvate or pharmaceutically acceptable salt, in the presence of a base and optionally an activator as described herein, A method comprising contacting JPEG2026143404000259.jpg23170 to produce a compound of formula (A) or a pharmaceutically acceptable salt thereof.

[0403] Embodiment 76. The method according to Embodiment 75, wherein the acid in step (d) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid, or trifluoromethanesulfonic acid.

[0404] Embodiment 77. Step (e) involves a compound of formula (1e) or its solvate or a pharmaceutically acceptable salt, The method according to embodiment 75, which includes contacting JPEG2026143404000260.jpg21170.

[0405] Embodiment 78. In one embodiment of the method described herein (P9), step (e) is to use a compound of formula (1e) or a solvate or pharmaceutically acceptable salt thereof. This includes contact with JPEG2026143404000261.jpg25170.

[0406] The following examples are presented as illustrations, not as limitations. [Examples]

[0407] Example 1

[0408] Synthesis of 2-amino-4-bromo-3-fluorobenzoic acid. Compound 4a JPEG2026143404000262.jpg21170

[0409] Step 1, Route 1: 4-bromo-2,3-difluorobenzoic acid

[0410] To a solution of dry THF (4 L) containing dry diisopropylamine (440 g, 4.352 mol), n-BuLi (1.6 L, 3.990 mol, 2.5 M in hexane) was added dropwise over 1 hour at -65°C to -50°C under N2. The mixture was stirred at -65°C for 1 hour. A solution of dry THF (1.2 L) containing 1-bromo-2,3-difluorobenzene (700 g, 3.627 mol) was added dropwise over 1 hour while maintaining the internal temperature at -65°C to -50°C. The mixture was stirred at -65°C for 1.5 hours. Solid dry ice (2.8 kg) was added to a dry basin, and the above reaction mixture was slowly poured into the basin over 10 minutes while stirring. The resulting mixture was then stirred for 30 minutes, slowly quenched with H2O (2 L), acidified with HCl (6 M, 1.6 L) aqueous solution to pH=3, and extracted with EA (3.5 L x 2). The combined organic layers were washed with brine (4 L), dried over Na2SO4 (500 g), filtered, and concentrated under reduced pressure to obtain 4-bromo-2,3-difluorobenzoic acid (790 g, 92%) as a grayish-white solid. HPLC: 90%, RT=4.507 min.

[0411] Step 2: 2-amino-4-bromo-3-fluorobenzoic acid

[0412] NH3 .A mixture of 4-bromo-2,3-difluorobenzoic acid (500 g, 2.11 mol) in H2O (1500 mL, 25% w / w) was heated to 150°C in a 5 L autoclave and stirred for 35 hours. The reaction mixture was cooled to 0°C and acidified in an ice bath with concentrated HCl until the pH was 3. The solid was collected by filtration, washed with water, and dried in air at 50°C to obtain the crude product. The crude solid was dissolved in EtOH (5 vol) at 75°C, and then water (5 vol) was added dropwise. The mixture was cooled to room temperature, the precipitate was filtered, and dried in air at 50°C overnight. The obtained solid was polished overnight at room temperature with DCM (5 vol), filtered, and dried in air at 50°C overnight to obtain 2-amino-4-bromo-3-fluorobenzoic acid (307 g, 61%) as a grayish-white solid. HPLC: 99%, RT=4.502 min; 1 H NMR(400MHz,DMSO-d6)δ13.09(brs,1H),7.50(dd,J=8.8Hz,1.6Hz,1H),6.80(brs,1H),6.78(dd,J=8.8Hz,6.4Hz,1H).

[0413] Example 2

[0414] tert-butyl(S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate compound 2: JPEG2026143404000263.jpg63170

[0415] Step 1: JPEG2026143404000264.jpg33170

[0416] Compound 4a (128.2 mol) was added to a 500 L reactor under an N2 atmosphere. EtOH was added to the 500 L reactor under an N2 atmosphere, and the mixture was heated to 55-60°C. NCS (154.3 mol) was added to the 500 L reactor in five portions over 3 hours at 55-60°C under an N2 atmosphere, and the mixture was stirred at 50-55°C for 0.5 hours.

[0417] 900g of water was added to another 1500L reactor and heated to 45-50°C. The reaction mixture was added to the hot water and slurred at 55-60°C for 1-2 hours. The reaction mixture was filtered to obtain approximately 50kg of moist 4b. The moist cake was slurred in hot water at 45-50°C for 0.5-1.0 hours, filtered, and washed with hot water. The cake was slurred in DCM at 15-30°C for 1-2 hours, filtered, and washed with DCM. The cake was dried under high vacuum at 30-40°C for 16 hours. 25.8kg of compound 4b (97.5A%) was isolated as a light brown solid in 80-81% yield.

[0418] Step 2: JPEG2026143404000265.jpg32170

[0419] 164 kg of water, 28.6 kg of compound 4b (106.5 mol), and 4.85 kg of NaOH (dissolved in 32.5 kg of water) were added to a 3000 L reactor. The reaction mixture was stirred at room temperature for 5 minutes. 188.9 mol of KOCN was dissolved in 392 kg of water and added to the 3000 L reactor, then stirred at room temperature for 5 minutes. The mixture was heated to 39-42°C, and the pH was adjusted to 6.3-6.7 with concentrated hydrochloric acid. The mixture was stirred at 39-42°C for 3 hours. 94.4 mol of KOCN was dissolved in 398 kg of water and added to the 3000 L reactor, then stirred at RT for 5 minutes. The mixture was heated to 39-42°C for 3 hours, and the pH was adjusted to 6.3-6.7 with concentrated hydrochloric acid. KOCN (94.4 mol) was dissolved in 398 kg of water and added to a 3000 L reactor. After stirring at room temperature for 5 minutes, the mixture was heated to 39-42°C for 2.5 hours, and the pH was adjusted to 6.3-6.7 with concentrated hydrochloric acid. The mixture was then stirred at 39-42°C for 1.0 hour, and the pH was adjusted to 5.3-5.7 with concentrated hydrochloric acid. NaOH (442 mol) was dissolved in 35.4 kg of water and added to a 3000 L reactor. The mixture was stirred at 45-50°C for 1 hour.

[0420] The mixture was cooled to 10-15°C and stirred at 10-15°C for 0.5 hours. The cake was filtered, washed with water (5 volumes), and then centrifuged. Acetone and water were added to a 2000 L reactor, heated to 25-30°C, the wet cake was added, and the mixture was stirred at 25-30°C for 1.5 hours. The pH was adjusted to 1.0 using concentrated hydrochloric acid, and the mixture was cooled to 5-10°C. The mixture was stirred at 5-10°C for 0.5 hours. The cake was filtered, washed with water (5 volumes x 2), centrifuged, and dried in a vacuum dryer at 55-60°C for 48 hours. 24 kg of compound 5 (98.4 A%) was isolated as a grayish-white solid in 72% yield (corrected).

[0421] Step 3: JPEG2026143404000266.jpg33170

[0422] POCl3 (264.8 mol) was added to a 100 L reactor under an N2 atmosphere, compound 5 (27.3 mol) was added, and the mixture was stirred at room temperature for 5 minutes. DIPEA (54.2 mol) was added dropwise using a riser over 5 to 10 minutes, the mixture was heated to 80 to 105°C, and the mixture was stirred for 40 minutes.

[0423] The mixture was cooled to 40-50°C and concentrated to approximately 10-15 L under vacuum. The mixture was diluted with ACN (14 kg), and the diluted portion was added to 105 kg of water at 15-30°C over 1-2 hours. The mixture was stirred at 25-30°C for 0.5 hours, filtered, and the cake was washed with water (2.5 vol x 3). The wet cake was dried in a vacuum dryer at 45-50°C for 12 hours. 8.5 kg of compound 5a (98.1 A%) was isolated as a yellow solid in 100% yield (corrected).

[0424] Step 4: JPEG2026143404000267.jpg47170

[0425] THF was added to a 500L reactor under an N2 atmosphere. After adding DIPEA (141.6 mol), compound 5a (5.7 mol) was added, and the mixture was stirred at room temperature for 5 minutes. The mixture was cooled to 5-10°C.

[0426] THF was added to a 100L reactor under an N2 atmosphere. tert-butyl(S)-3-methyl-1-piperazine carboxylate (83.4 mol) was added to the reactor and stirred at RT for 5 minutes, after which the THF solution in the 100L reactor was transferred to the riser tank of the 100L reactor. The THF solution of compound 5a was added dropwise to the 500L reactor via the riser tank over 60 minutes. The mixture was then stirred at 5-10°C for 30 minutes.

[0427] Approximately 500 kg of water was added to a 1000 L reactor and cooled to 0-10°C. The reaction mixture containing 5a was added to the water and stirred at 0-10°C for 1 hour. The cake was filtered, washed with water (4 vols x 2), then dissolved in DCM (10 vols) to separate the phases. The organic phase was washed with water (5 vols), and the water was extracted with DCM. The combined organic phase was added to a 500 L reactor and concentrated to approximately 20-25 L under vacuum at 45-50°C. Approximately 53 kg of N-heptane was added to the reactor, and the contents were concentrated to approximately 50-60 L under vacuum at 45-50°C, and this process was repeated. Another 53 kg of N-heptane was slowly added dropwise to the 500 L reactor at 20-30°C over 10 minutes. The mixture was stirred at 20-30°C for 0.5 hours. The mixture was cooled to 5-10°C and stirred at 5-10°C for 0.5 hours. The cake was filtered, washed with n-heptane (5 volumes), and then dried in a vacuum dryer at 45-50°C for 10 hours. 35.8 kg of compound 2d (98.0 A%) was isolated as a grayish-white solid in 94% yield (corrected).

[0428] Step 5: JPEG2026143404000268.jpg46170

[0429] 274 kg of DMF was added to a 500 L reactor under an N2 atmosphere, and the reactor was purged twice with N2. Compound 2d (70.8 mol) was added, followed by CsF (184.3 mol), and the reactor was purged three more times with N2, after which it was stirred at room temperature for 5 minutes. The mixture was heated to 51.5–52.5°C and stirred for 10 hours. A further amount of CsF (23.7 mol) was added, and the mixture was stirred under an N2 atmosphere at 51.5–52.5°C for 16 hours.

[0430] Approximately 870 kg of water was added to a 1500 L reactor and cooled to 5-10°C. The reaction mixture was added to the reactor at a temperature below 15°C and stirred at 5-10°C for 0.5 hours. After filtering the product, 1000 L reactors containing 320 L each of MeCN and water were added. The mixture was stirred at 20-25°C for 5 hours. The wet cake was dissolved in DCM and the phases were separated. The aqueous layer was extracted with DCM (100 L, 3 volumes), the organic layers were combined and concentrated to approximately 80 L under vacuum at 45-50°C. Approximately 59 kg of n-heptane was added to a 500 L reactor and the combined concentrated organic phase was added. The mixture was concentrated to approximately 80 L under vacuum at 45-50°C and stirred at 20-30°C for 0.5 hours. The mixture was then cooled to 10-15°C and stirred for 0.5 hours. The cake was filtered, washed with n-heptane (5 volumes), and then dried in a vacuum dryer at 45-50°C for 10 hours. 28.2 kg of compound 2 (97.2 A%) was isolated as a grayish-white solid in 82% yield (corrected).

[0431] Example 3

[0432] Compound 3 (6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine) JPEG2026143404000269.jpg73170

[0433] Step 1: 6-Chloro-N-(4-methoxybenzyl)-4-methylpyridine-2-amine (compound 7a) JPEG2026143404000270.jpg32170

[0434] PMBNH2 (175.0 L, 183.75 kg, 5V) was added to the reactor. 2,6-Dichloro-4-methylpyridine (compound 7, 35.0 kg, 1.0 equivalent) was added to the reactor and stirred below 30°C. The mixture was heated to 120±10°C and stirred at 120±10°C for 32 hours. After cooling the reaction mixture to a sample for LCMS, soft water / isopropanol = 2 / 1 (350.0 L, 10V) was added dropwise at 85-130°C. The reaction mixture was cooled to 85-95°C and stirred for 30-60 minutes. The mixture was cooled to 5±5°C (cooling 10±5°C every hour) and stirred at 5±5°C for at least 1 hour. The mixture was centrifuged and the cake was washed twice with water / isopropanol = 2 / 1 (3V). The cake was harvested and dried at 45±5℃ for at least 16 hours. Yield: 52.0 kg, 91.6%

[0435] Step 2: 6-Chloro-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (compound 7b) JPEG2026143404000271.jpg32170

[0436] THF (208.0 L, 4.0 V) was added to a reactor in N2. Compound 7a (52.0 kg, 1.0 equivalent) and PMBCl (37.4 kg, 1.2 equivalents) were added to the reactor in N2 and suspended by stirring at 0 ± 5°C. A solution of t-BuOK in THF (166.4 kg, 1.5 equivalents, 20 wt% of THF) was added dropwise at 0 ± 5°C and stirred for at least 6.0 hours at 0 ± 5°C. Water (780.0 L, 15.0 V) was added dropwise below 10°C and stirred for at least 2 hours at 5 ± 5°C. The mixture was centrifuged and the cake was washed with water. The cake was collected and slurryed with water / isopropanol = 2 / 1 (208.0 L, 5.0 V) for at least 6 hours at 25 ± 5°C. The cake was centrifuged again and washed twice with water / isopropanol = 2 / 1 (2V). The cake was collected, and the solid was dried at 45±5°C for at least 16 hours. Yield: 70.74 kg, 93.4%.

[0437] Step 3: 6-Chloro-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine JPEG2026143404000272.jpg41170

[0438] DMF (353.5 L, 5.0 V) and compound 7b (70.70 kg, 1.0 equivalent) were added to the reactor and clarified by stirring at 25 ± 5 °C. NIS (49.9 kg, 1.2 equivalents) solid was added to the reactor in 10 batches, with one batch added at least every 3 hours. The mixture was stirred at 25 ± 5 °C for at least 8 hours. After cooling to 0 ± 5 °C, a 5 wt% Na2SO3 aqueous solution (353.5 L, 5.0 V) was added dropwise at -5 to 25 °C. The mixture was stirred at 5 ± 5 °C for at least 30 minutes. The mixture was centrifuged and the cake was washed twice with soft water. The volume of elution was 2 V each time. The figure cake was collected and slurryed with soft water / isopropanol = 2 / 1 (373.5 L, 5.0 V) for at least 30 minutes at 70 ± 5 °C. The mixture was cooled to 20±5°C and stirred at 20±5°C for at least 1 hour. It was centrifuged again, and the cake was washed twice with water / isopropanol = 1 / 2. The volume of elution was 3V each time. The solid was collected and dried at 45±5°C for at least 16 hours. Yield: 86.56 kg, 92.1%.

[0439] Step 4: 6-(1,3-bis(4-methoxyphenyl)propan-2-yl)-2-chloro-4-methyl-3-(trifluoromethyl)pyridine (compound 7d) JPEG2026143404000273.jpg34170

[0440] DMF (432.5 L, 5.0 V) and HMPA (152.3 kg, 5.0 equivalents) were added to the reactor. Under a nitrogen atmosphere, compound 7c (86.5 kg, 1.0 equivalent) was added to the reactor. CuI (80.9 kg, 2.5 equivalents) was added to the reactor. N2 was blown in at 25±5°C for at least 40 minutes. The mixture was heated to 90±5°C, and methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (98.0 kg, 3.0 equivalents) was added dropwise to the reactor. The mixture was stirred at 90±5°C for at least 2 hours. After cooling, the mixture was filtered through diatomaceous earth. It was washed with RINKAN (865.0 L, 10.0 V). The mixture was evaporated to 4-8 V in a vacuum. After cooling to 5±5℃, soft water (865.0 L, 10.0 V) was added dropwise to the reactor at 0-25℃. The mixture was stirred at 20±5℃ for at least 30 minutes. The mixture was centrifuged, and the cake was washed twice with water. The volume of elution was 4 V each time. The cake was collected, and Depositphotos (865.0 L, 10.0 V) was added. The mixture was stirred at 25±5℃ for at least 30 minutes, filtered through diatomaceous earth, and then washed with Depositphotos (865.0 L, 10.0 V). The mixture was held, separated, and the organic phase was collected and concentrated to 2-4 V. Isopropanol (432.5 L, 5.0 V) was added to the reactor and concentrated to 2-4 V. The process of adding isopropanol (432.5 L, 5.0 V) and concentrating to 2-4 V was repeated until the area percentage of Depositphotos was 5.0% or less by GC. The mixture was heated to 60±5°C, water (4-6V) was added dropwise to the container, and the mixture was stirred at 60±5°C for at least 0.5 hours. The mixture was cooled to 20±5°C and stirred at 25±5°C for at least 1 hour. The mixture was centrifuged, and the cake was washed twice with water / isopropanol = 2 / 1 (3V). The solid was collected and dried at 50±5°C for at least 16 hours. Yield: 70.45 kg, 91.9%.

[0441] Step 5: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine JPEG2026143404000274.jpg32170

[0442] MeCN (176.0 L, 2.5V) and compound 7d (70.4 kg, 1.0 equivalent) were added to the reactor and stirred at 15±5°C to suspend. HBr (176.0 L, 2.5V, 48% in water) was added dropwise to the reactor at 10-40°C. The temperature was adjusted to 80±5°C and stirred for at least 2 hours. The mixture was cooled before adding IPAC (211.2 L, 3.0V). The mixture was cooled to 0±5°C and neutralized with 15 wt% NaOH aqueous solution at T≦25°C until the pH was 7-8. The aqueous layer was extracted three times with IPAC (211.2 L, 3.0V) to recover the organic layer, which was concentrated to 2-4V at T≦45°C. MeCN (352.0 L, 5.0 V) was added to the reactor and concentrated to 2-4 V at T ≤ 45°C to obtain a solution of 6-chloro-4-methyl-5-(trifluoromethyl)pyridine-2-amine in MeCN.

[0443] Step 6: N-(6-bromo-4-methyl-5-(trifluoromethyl)pyridine-2-yl)acetamide JPEG2026143404000275.jpg31170

[0444] AcBr (287.9 ​​kg, 15.0 equivalents) was added to the reactor at -10 to 40°C, adjusted to 70±5°C, and stirred for at least 10 hours. The mixture was cooled to 0±5°C and quenched with EtOH (176.0 L, 2.5 V) at T≦25°C. The mixture was cooled to 0±5°C and neutralized with 15 wt% NaOH aqueous solution at T≦25°C until the pH was 7-8. The organic layer was extracted three times with Depositphotos (281.6 L, 3.0 V), recovered, and concentrated to 2-4 V at T≦45°C. MeCN (352.0 L, 5.0 V) was added to the reactor and concentrated to 2-4 V at T≦45°C. AcBr (287.9 ​​kg, 15.0 equivalents) was added to the reactor at -10 to 40°C, adjusted to 70±5°C, and stirred for at least 10 hours. The mixture was cooled to 0±5°C and quenched with EtOH (176.0 L, 2.5V) at T≦25°C. The mixture was cooled to 0±5°C and neutralized with 15 wt% NaOH aqueous solution at T≦25°C until the pH was 7-8. The mixture was extracted three times with Depositphotos (281.6 L, 3V) to collect the organic layer, which was concentrated to 1-4V at T≦45°C. The mixture was cooled to 5-10°C and stirred for 1-2 hours at 5-10°C. The mixture was centrifuged, the cake was washed twice with Depositphotos (1V), and the cake was collected for the next step without further purification. Yield: Crude product 34.50 kg

[0445] Step 7: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine (compound 7e) JPEG2026143404000276.jpg30170

[0446] The starting compound, HBr (70.4 L, 1.0 V, 48 wt% in water), EtOH (35.2 L, 0.5 V), and MeCN (70.4 L, 1.0 V) were added to the reactor. The temperature was adjusted to 70 ± 5 °C and stirred for at least 8 hours. The temperature was adjusted to 70 ± 5 °C and stirred for at least 4 hours. The mixture was cooled to 0 ± 5 °C and neutralized with 15 wt% NaOH aqueous solution at T ≤ 25 °C until the pH was 7-8. The mixture was centrifuged and the cake was washed with soft water. The filtrate was extracted four times with MTBE. The volume of the extract was 3.0 V each time, and the organic layer was collected. The cake and the organic layer were added to the reactor. The temperature was adjusted to 45-50 °C and stirred for 1-2 hours. After cooling to 25-30 °C, the mixture was filtered through diatomaceous earth and washed with MTBE (353.0 L, 5.0 V). The filtrate was collected and concentrated to 2-4V. Isopropanol (353.0 L, 5.0V) was added and concentrated to 2-4V under vacuum. A second addition of isopropanol (353.0 L, 5.0V) was added and concentrated to 2-4V under vacuum. The temperature was adjusted to 50±5°C, water (3-5V) was added dropwise to the reactor, and the mixture was stirred at 50±5°C for at least 30 minutes. The mixture was cooled to 5±5°C and stirred at 5±5°C for at least 2 hours. The mixture was centrifuged, and the cake was washed twice with water / isopropanol = 2 / 1 (2V). The solid was collected and dried at 45±5°C for at least 16 hours. Yield: 25.50 kg, 64.0%.

[0447] Step 8: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Compound 3) JPEG2026143404000277.jpg30170

[0448] NMP (255.0 L, 10.0 V), PMBCl (47.0 kg, 3.0 equivalents), and compound 7e (25.5 kg, 1.0 equivalent) were added to a reactor in N2. The mixture was cooled to 0 ± 5 °C. Solid CH3ONa (16.2 kg, 3.0 equivalents) was added in 5 batches at 0 ± 5 °C. One batch was added at least every 0.5 hours. The mixture was stirred at 0 ± 5 °C for at least 4 hours. Water (20.0 V) was added dropwise at -10 to 10 °C, and the mixture was stirred at 5 ± 5 °C for at least 30 minutes. The mixture was filtered, and the filtered cake was washed twice with water (3 V). The filtered cake was collected and slurryed with water / isopropanol = 1 / 1 (127.5 L, 5.0 V) at 60 ± 5 °C for at least 2 hours. The mixture was cooled to 20±5°C (cooling by 10±5°C every hour) and stirred at 20±5°C for at least 1 hour. The mixture was centrifuged and the cake was washed twice with water / isopropanol = 1 / 1 (3V). The cake was collected and DCM (255.0 L, 10.0V) was added to the reactor. The temperature was adjusted to 25±10°C and stirred for at least 0.5 hours. The mixture was filtered through a filter and activated carbon, and washed with DCM (51.0 L, 2.0V). The filtrate was collected and concentrated to 2-4V at T≦45°C. n-heptane (255.0 L, 10.0V) was added to the reactor and concentrated to 2-4V at T≦45°C. n-heptane (255.0 L, 10.0V) was added to the reactor and adjusted to 70±5°C. The mixture was stirred at 70±5°C for at least 10 minutes. It was cooled to 20±5°C (cooling by 10±5°C every hour) and stirred at 20±5°C for at least 1 hour. The mixture was centrifuged and the cake was washed twice with n-heptane (3V). The mixture was centrifuged and the cake was washed with n-heptane / dimethyl = 10 / 1 (51.0 L, 2V). The solid was collected and dried at 45±5°C for at least 16 hours. Yield: 31.20 kg, 63.0%.

[0449] Step 8: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Compound 3) JPEG2026143404000278.jpg29170

[0450] Compound 7e (29 kg, 113 mol, 1 equivalent) and 213 kg of PMBCl (40.5 kg, 258 mol, 2.4 equivalents) were dissolved in THF (213 kg, 240 L, 8.2 v). t BuOK solution (132 kg, 148 L, 5.1 v THF, 31.5 kg, 280 mol, 2.5 equivalents) was added to the solution over 9 hours at 15-25°C, and the mixture was stirred at 10-25°C for 18 hours.

[0451] The mixture was filtered and treated in a CUNO cartridge for 8 hours. After concentrating to 120 L at below 40°C, EtOH (109 kg, 140 L, 4.8 v) and water (250 kg, 250 L, 8.6 v) were added to the residue at 15-25°C. The mixture was cooled to 5-15°C and stirred for 2-4 hours. The solid was filtered and washed twice with water (120 kg, 120 L, 4.1 v). The wet cake was re-slurried with 135 kg of EtOH (135 kg, 173 L, 6.0 v) at 15-25°C for 6 hours. The solid was filtered and washed twice with EtOH (15 kg, 19 L, 0.7 v). The wet cake was again slurryed using n-heptane (269 kg, 396 L, 13.7 v) and THF (11 kg, 12 L, 0.4 v) at 15-25°C for 4 hours. The solid was filtered and washed twice with n-heptane (30 kg, 44 L, 1.5 v). The wet cake was dried under vacuum at 45-55°C for 44 hours to obtain compound 3 (39.4 kg, purity 96.9 A%, assay 101 wt%, yield 70%).

[0452] Example 4

[0453] Compound 3 (6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine) JPEG2026143404000279.jpg87170

[0454] Step 1: 6-Chloro-N-(4-methoxybenzyl)-4-methylpyridine-2-amine (compound 7a) JPEG2026143404000280.jpg31170

[0455] Compound 7 (103 kg, 0.51 X, 0.51 equivalents) and 4-methoxybenzylamine (964 kg, 4.68 X, 5.64 equivalents) were added to a 5000 L-SS lining reactor R1. R1 was adjusted to 20-30°C and the reaction mixture was stirred for 1 hour. Then R1 was heated to 80-90°C over 3 hours. The reaction mixture was stirred for 1 hour. Then R1 was heated to 110-130°C over 5 hours and stirred for 24 hours. R1 was cooled to 35-45°C. The second portion of Compound 7 (99 kg, 0.49 X, 0.49 equivalents) and 4-methoxybenzylamine (43.0 kg, 0.21 X, 0.25 equivalents) were added to R1. R1 was heated to 110-130°C over 6 hours and stirred for 24 hours. R1 was cooled to 85-95°C. R1 was heated to 110-130°C and stirred for a further 10 hours. R1 was cooled to 85-95°C. 28 wt% IPA / aqueous solution (approximately 2224 kg) was added to R1 at 85-95°C, and the mixture was stirred at 85-95°C for 3 hours. Then, R1 was cooled to 0-10°C over 7 hours and stirred for 3 hours. The wet cake was filtered, and each load (6 loads in total) was washed twice with 28 wt% IPA / aqueous solution (approximately 485 kg) to obtain 337.55 kg of wet cake (purity of wet cake A: 99.6%, spec: ≥95.0%). The wet cake was dried in two stages. After drying at 40-50°C for 24 hours, 158.55 kg of compound 7a was obtained with a assay yield of 97.0% by weight and a purity of 99.3A%, and 149.40 kg of compound 7a was obtained with a assay yield of 97.6% by weight and a purity of 99.3A%.

[0456] Step 2: 6-Chloro-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (compound 7b) JPEG2026143404000281.jpg32170

[0457] Compound 7a (13.8 kg assay-corrected, 0.99X, 1.00 equivalent), t-BuOK (9.0 kg, 0.65X, 1.53 equivalents), and THF (approximately 139 kg) were added to R1, and 4-methoxybenzyl chloride (10.1 kg, 0.73X, 1.23 equivalents) was added dropwise to R1 at 15-25°C. The solution was stirred at 15-25°C for 18 hours. The solution was concentrated 4-5 times under vacuum at less than 40°C. The concentrated solution was cooled to -5-5°C, and water (approximately 112 kg) was slowly added. The mixture was stirred at -5-5°C for 4 hours. The IPC of residual B in the supernatant was 0.0%. The wet cake was filtered and washed with water (approximately 54 kg) to obtain 21.80 kg of wet cake. The wet cake was placed in a 28 wt% i-PrOH aqueous solution (approximately 82 kg), and the mixture was then stirred at 20-30°C for 8 hours. The wet cake was filtered and washed with a 28 wt% i-PrOH aqueous solution (approximately 50 kg) to obtain 20.60 kg of wet cake. After drying at 40-50°C for 21 hours, 17.90 kg of compound 7b was obtained with a purity of 98.9A% using a 98.4 wt% assay and an 88% corrected yield.

[0458] Step 3: 6-Chloro-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine JPEG2026143404000282.jpg40170

[0459] To a solution of compound 7b (assay-corrected 150 kg, 1.00 X, 1.00 equivalent) in DMF (802 kg, 5.3 ×), NIS (108 kg, 0.72 X, 1.23 equivalents) was added. The solution was stirred at 15-25°C for 24 hours. NIS (3 kg, 0.02 X, 0.03 equivalents) was added to the reactant. The solution was stirred at 15-25°C for 20 hours. The solution was stirred at 15-25°C for a further 4.5 hours. The reactant was cooled to 0-10°C, and 5 wt% a2SO3 aqueous solution (approximately 845 kg) was added. The mixture was stirred at 0-10°C for 2 hours. The wet cake was filtered and washed with water (approximately 466 kg) to obtain 224.85 kg of wet cake. The wet cake was added to EtOH (approximately 768 kg) and stirred at 45-55°C for 2 hours. The mixture was cooled to 15-25°C for 3 hours, stirred for 3 hours, then filtered and washed with EtOH (approximately 460 kg) to obtain 208.25 kg of wet cake. After drying at 45-55°C for 18.5 hours, 198.15 kg of compound 7c was obtained with a purity of 99.4 A% in assays with a 98.3 wt% yield and a 98% corrected yield.

[0460] Step 4: 6-(1,3-bis(4-methoxyphenyl)propan-2-yl)-2-chloro-4-methyl-3-(trifluoromethyl)pyridine (compound 7d) JPEG2026143404000283.jpg34170

[0461] To a solution of compound 7c (assay-corrected 103 kg, 1.00 equivalent, 1.00X) in DMF (approximately 364 kg, 3.5X), CuI (98 kg, 2.5 equivalents, 0.95×), methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (113 kg, 2.9 eq, 1.1×), and HMPA (180 kg, 5.0 equivalents, 1.75X) were added, and 30 kg of DMF was rinsed after each material was added. After adding DMF (approximately 352 kg, 3.48X) to the reactants, the mixture was heated to 75-85°C for 3 hours and stirred for 8 hours. R1 was cooled to 20-30°C. The mixture was heated to 75-85°C for 3 hours and stirred for 4.5 hours. R1 was cooled to 20-30°C. The reaction mixture was filtered. A 25 wt% aqueous solution of NH3 (approximately 411 kg, 4.0X) was added dropwise to the filtrate over 2 hours at 30-40°C. The mixture was stirred at 30-40°C for 5 hours. Then, water (approximately 702 kg, 6.8X) was added over 1 hour at 30-40°C. The mixture was stirred at 30-40°C for 6 hours. The mixture was heated to IT = 30-40°C, and the pH of the mixture was adjusted to 11-12 by adding aqueous solution of NH3 (approximately 142 kg). The mixture was stirred at 30-40°C for 10 hours. The mixture was cooled to 10-25°C. The residual Mel in the mother liquor was 168 ppm. The solid was filtered and washed twice with water (total: approximately 1004 kg) to obtain 112.05 kg of wet cake (purity 92.4A%). After drying at 45-55°C for approximately 45 hours, 100.00 kg of compound 7d was obtained with a purity of 91.1 A% using an assay yield of 83.7 wt% and a corrected yield of 92%.

[0462] Step 5A: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine JPEG2026143404000284.jpg35170

[0463] HOAc (approximately 190 kg) and compound 7d (97 kg, 1.00X) were added to R1. After adjusting R1 to 20-30°C, a 40 wt% HBr aqueous solution (approximately 180 kg, 1.86×) and water (approximately 12 kg) were added. The reaction solution was adjusted to 45-55°C over 2 hours, and then heated to 80-90°C over 2 hours. The reactants were stirred at 80-90°C for 6.5 hours. R1 was cooled to 60-70°C. ELISA (approximately 370 kg) was added to the mixture, and then cooled to 30-40°C. A 30 wt% NaOH solution (approximately 489 kg) was added below 45°C to adjust the pH to 7-8. Water (13 kg) was rinsed into the mixture. R1 was cooled to 20-30°C, the aqueous layer was separated, and extracted twice with phenylethylamine (approximately 388 kg, 384 kg). The combined organic layers were washed with a 2.2 wt% Na2SO4 aqueous solution (water: approximately 369 kg + 6 kg for rinsing; Na2SO4: approximately 8.7 kg). For emulsification, the mixture was heated to 30-40°C and left for 8 hours. The organic layers were separated and azeotropically distilled twice with phenylethylamine to 3-4X (approximately 470 kg, approximately 484 kg) to remove water (KF = 0.4%). phenylethylamine (approximately 366 kg) and TsOH·H2O (approximately 68 kg, 0.70X) were added to the mixture. R1 was adjusted to 20-25°C and stirred for 2 hours. The mixture was then cooled to 0-5°C and stirred for approximately 3 hours. The wet cake was filtered to obtain 70.90 kg of wet cake. The wet cake was slurryed using IgG (approximately 472 kg) at 20°C to 25°C for 3 hours. The wet cake was filtered and rinsed with IgG (total: approximately 120 kg) to obtain 69.45 kg of wet cake. This wet cake was used directly in the next step.

[0464] Steps 5B and 5C: N-(6-bromo-4-methyl-5-(trifluoromethyl)pyridine-2-yl)acetamide JPEG2026143404000285.jpg28170

[0465] Approximately 341 kg of toluene, compound 7e-TsOH wet cake, and water (approximately 337 kg) were added to R1. R1 was adjusted to 15-25°C. The pH of the aqueous layer was then adjusted to 7-8 by adding approximately 30 kg of 30% by weight NaOH aqueous solution at a temperature below 45°C. Water (approximately 10 kg) was rinsed into R1. R1 was adjusted to 15-25°C and stirred for 3 hours. The organic layer was separated and washed with water (approximately 298 kg). The organic layer was concentrated 1-3 times under vacuum at a temperature below 45°C. After adding approximately 578 kg of toluene, the organic layer was concentrated 1-3 times under vacuum at a temperature below 45°C. R1 was adjusted to 20-30°C, and approximately 411 kg of AcBr and approximately 14 kg of toluene were added to R1 at a temperature below 40°C. R1 was heated to IT=45-55°C over 2 hours, then heated to 65-75°C over 2 hours, and stirred at 65-75°C for 16 hours. R1 was cooled to 30-40°C. After heating R1 to 65-75°C, the mixture was distilled to 1.0-3.0× at below 75°C. R1 was cooled to 20-30°C. AcBr (approx. 224 kg) and pharmaceutically acceptable phosphate (approx. 24 kg) were added to R1 at below 40°C. pharmaceutically acceptable phosphate (approx. 42 kg) was rinsed into R1. R1 was heated to 45-55°C over 2 hours, then heated to 65-75°C over 2 hours. R1 was stirred at 65-75°C for 9.5 hours, then cooled to 30-40°C. R1 was heated to 65-75°C, and the mixture was distilled 1-3 times at below 75°C. R1 was adjusted to 60-75°C. AcBr (approx. 108.4 kg) and pharmaceutically acceptable phosphate (approx. 10 kg) were added to R1 at a temperature below 75°C. pharmaceutically acceptable phosphate (approx. 16 kg) was rinsed into R1. R1 was heated to 70-75°C for 2 hours. The mixture was distilled 1-3 times at a temperature below 75°C and stirred at 65-75°C for 3 hours. The mixture was cooled to 0-10°C. EtOH (approx. 248 kg) and water (approx. 98 kg) were added gradually at a temperature below 45°C. R1 was adjusted to 40-45°C for 3 hours and stirred for 8 hours. Then R1 was cooled to 30-40°C. R1 was adjusted to IT = 40-55°C and stirred for 8 hours. R1 was cooled to 30-40°C. R1 was adjusted to 40-55°C and stirred for 10 hours. A 40% by weight HBr aqueous solution (approximately 46 kg) was added to R1 at a temperature below 40°C. ELISA (approximately 100 kg) was then added to R1. R1 was adjusted to 40-55°C and stirred for 5 hours.R1 was cooled to 30-40°C, EtOH (approx. 196 kg) was added, and the mixture was stirred for about 2.5 hours. R1 was adjusted to 40-55°C. The material was circulated through a diatomaceous earth filter for about 8 hours. The filtrate was distilled to 1.0-2.0 times its original volume at a temperature below 45°C. Water (approx. 572 kg) was added. After cooling R1 to 0-10°C, 30 wt% NaOH aqueous solution (approx. 238 kg) was added at a temperature below 45°C to adjust the pH to 7-8. Water (6 kg) was rinsed into R1. R1 was cooled to 0-10°C, and the mixture was stirred for 3 hours. The wet cake was filtered and washed with water (total: approx. 200 kg) to obtain 40.80 kg of wet cake (93.7 A%). The wet cake was added to ELISA (approx. 320 kg). The mixture was adjusted to 20-30°C and stirred for 30 minutes. The mixture was concentrated 2.5 to 5 times at a temperature below 45°C, and then phenylalanine (approximately 32 kg) was added. After cooling R1 to 0 to 10°C, AcBr (approximately 200 kg) was added to R1 under vacuum. phenylalanine (approximately 28 kg) was added to R1. R1 was adjusted to 45 to 55°C for 2 hours, then heated to 65 to 75°C for 1.5 hours and stirred for 11 hours. R1 was cooled to 30 to 40°C, then heated to 65 to 75°C, and the mixture was distilled to 2.5 to 5.0 × at a temperature below 75°C. R1 was cooled to 0 to 10°C. EtOH (approximately 276 kg) and water (approximately 104 kg) were added little by little at a temperature below 45°C. R1 was adjusted to 40 to 45°C for 3 hours and stirred for 12 hours. R1 was cooled to 30 to 40°C. R1 was cooled to 0-10°C, and a 30% NaOH solution (approximately 213 kg) was added at a temperature below 45°C to adjust the pH to 7-8. R1 was distilled under vacuum at a temperature below 45°C until no distillate remained. Water (approximately 449 kg) was added, the mixture was cooled to 0-10°C, and stirred for approximately 2 hours. The wet cake was filtered and washed with water (total: approximately 80 kg) to obtain 41.50 kg of wet cake. The wet cake was dried at 20-30°C for 4 hours, and then dried at 45-55°C for 44 hours. 35.85 kg of compound 7e1 was obtained with a purity of 97.4 A% in assay yield of 95.1 wt% and a corrected yield of 53%.

[0466] Step 6: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Compound 3) JPEG2026143404000286.jpg32170

[0467] THF (approx. 292 kg), compound 7e (33.8 kg, assay corrected, 0.97 X), and 4-methoxybenzyl chloride (51.0 kg, 1.5 X) were added to R1, and the mixture was stirred at 15-25°C for 1 hour. t-BuOK (36.0 kg, 1.03 X) was added in three portions. The reaction solution was then stirred at 15-25°C for approximately 21 hours. Water (approx. 200 kg) and Na2SO4 (approx. 6.8 kg) were added. The solution was adjusted to 20-25°C and stirred for 2 hours. After filtration through a diatomaceous earth filter, the filtrate was allowed to stand and separated. The aqueous phase was extracted twice with THF (total: approx. 193 kg). The combined organic layers were filtered through a diatomaceous earth filter and a cartridge filter. The filtrate was circulated for 20 hours through a CUNO (3M-R55SP) and a cartridge filter. 29 kg of THF was rinsed into R1. The solution was adjusted to 30-40°C and distilled to 2-5 volumes under vacuum below 40°C. R1 was cooled to 15-25°C and EtOH (approx. 175 kg) was added dropwise to R1 over 4.5 hours. The mixture was stirred at 15-25°C for 3 hours. Water (approx. 152 kg) was added. R1 was cooled to 5-15°C and the mixture was stirred for 3 hours. After filtration, the wet cake was slurryed with EtOH (approx. 102 kg) at 15-25°C for 8 hours. After filtration, the purity of the wet cake was 95.6A%. The wet cake, n-heptane (approx. 82 kg) and THF (approx. 2 kg) were added to R1. The mixture was adjusted to 40-50°C and stirred for 8 hours. R1 was cooled to 0-10°C over 3 hours and the mixture was stirred for approximately 1.5 hours. The wet cake was filtered and washed with n-heptane (approximately 65 kg). After drying at 55-65°C for 26.5 hours, the dried cake was sieved (20 mesh). 51.65 kg of compound 3 was obtained with a purity of 97.0 A% at a 97.2 wt% assay and a 76% corrected yield.

[0468] Example 5

[0469] 2,6-Dibromo-4-methyl-3-(trifluoromethyl)pyridine (compound 8b) JPEG2026143404000287.jpg32170

[0470] Step 1: 2,6-dichloro-4-methylnicotinic acid (compound 8, 100 g, 2.06 mol, 100 mol%) and acetic acid containing HBr (33 wt%, 1.00 L, 10 v) were added to a Hastelloy autoclave reactor at 20°C. The reaction mixture was gradually heated and stirred for 32 hours. The mixture was quenched with water (1.00 L, 10 v), and the organic layer was extracted three times with methyl tert-butyl ether (300 mL, 3 v). The organic layers were then combined and concentrated under reduced pressure. The resulting residue was then slurryed with heptane (500 mL, 5 v), followed by filtration and drying to obtain 2,6-dibromo-4-methylnicotinic acid (compound 8d, 133 g, yield 92.9%) as a gray solid. 1 H NMR(400MHz,DMSO-d6)δ14.16(s,1H),7.74(d,1H),2.31-2.51(m,3H). 13 C NMR(101MHz,DMSO-d6)δ166.7,149.5,139.5,135.6,133.8,128.7,18.6.MS([M+H] + Calculated value C7H5Br2NO2 293.8757, measured value 293.876.

[0471] Step 2: Compound 8d (130 g, 2.27 mol, 100 mol%) was added to a Hastelloy autoclave reactor at 20°C. The reaction mixture was cooled to -20°C and anhydrous hydrogen fluoride was added (178 g, 8.90 mol, 392 mol%). The reaction mixture was further cooled to -78°C and sulfur tetrafluoride was added (761 g, 7.04 mol, 310 mol%). The stirred reaction mixture was heated to 20°C under ambient conditions, then heated further and stirred for 24 hours. The mixture was then cooled to 0°C, diluted with dichloromethane, and neutralized to pH 10-12 with aqueous potassium carbonate. The resulting mixture was then filtered through Celite, and the aqueous layer was extracted three times with dichloromethane (390 mL, 3V). The organic layers were then combined and concentrated under reduced pressure to obtain compound 8b (135 g, yield 96.0%) as a black solid.

[0472] Example 6

[0473] Step 1: 2,6-Dichloro-4-methyl-3-(trifluoromethyl)pyridine (Compound 8a) JPEG2026143404000288.jpg30170

[0474] 2,6-Dichloro-4-methylnicotinic acid (compound 8, 1.0 equivalent) was added to an autoclave at ambient temperature (20-30°C), followed by anhydrous HF (1.37 rels by weight) at -20°C, and then SF4 (2.5 equivalents) at -78°C. The reaction mixture was heated to ambient temperature, then heated at 70-80°C for 17-24 hours. After cooling the reaction mixture to ambient temperature (25-30°C), it was purged with KOH (alkaline scrubber). The solvent was replaced with MTBE, the reaction mixture was cooled to 0-10°C, and K2CO3 (4 rels by weight) in DM water (1 rel) and DM water (8 relative volumes) was added.

[0475] After setting the reaction temperature to approximately 20-30°C, the mixture was filtered and washed with 2.5 volumes of MTBE. The layers were separated, and the aqueous layer was washed with 2.5 volumes of MTBE. The layers were separated, the organic layers were combined, and washed twice with 2.5 volumes of water at ambient temperature (20-30°C). The organic layers were distilled to obtain a slurry, which was then washed with methanol (1 rel. vol). The mixture was distilled, dissolved in methanol (4 rel. vol), and added to activated carbon (Norit CG1 10% w / w). The mixture was stirred for at least 60 minutes, then filtered through Celite or a cellulose pad. The filtrate was added to a new reactor containing water (1.3 rel. vol) and stirred at 20-25°C for 10-15 minutes. Compound 8a seed crystals (1% w / w) were added, and the contents were stirred for 10-15 minutes, after which 1.7 vol. DM water was added. The contents were cooled to 0-5°C and stirred for at least 60 minutes before filtering. The filtrate was washed with 1 volume of water, and the wet cake was dried under pressure to obtain compound 8a (94.88 kg, yield 86.3%).

[0476] 2,6-Dichloro-4-methyl-3-(trifluoromethyl)pyridine (Compound 8a) JPEG2026143404000289.jpg30170

[0477] Nicotinic acid substrate (compound 8, 1.0 equivalent) was placed in an autoclave at ambient temperature, followed by anhydrous HF (1.37 rel. wt) at -20°C, and then SF4 (3.5 equivalents) at -78°C. The reaction mixture was warmed to ambient temperature, and then heated at 90-100°C for 24 hours. Conversion was confirmed by HPLC analysis. After completion, DCM was added to the reactants, the mixture was unloaded with ice, neutralized with K2CO3, filtered through Celite, and extracted with DCM (3 × 3V). The combined organic layer was concentrated to obtain a black semi-solid.

[0478] Charcoal treatment: The crude product mixture was dissolved in MeOH (5V), treated with charcoal (10% w / w), and stirred at 50°C for 1 hour. The resulting slurry was passed through a Celite bed, filtered, washed with MeOH (2V), and concentrated under reduced pressure to obtain compound 8a as a brown solid (96.97% A% by HPLC after charcoal treatment; 91.2% yield on a 500g scale).

[0479] 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (Compound 3) JPEG2026143404000290.jpg28170

[0480] Step 1: Compound 8b JPEG2026143404000291.jpg27170

[0481] Compound 8a (977 g, 1 equivalent) and 33 wt% HBr / AcOH (600 g, 0.5 v) were added to the reactor. The mixture was heated to 115°C. 33 wt% HBr / AcOH (9700 g) was added dropwise to the mixture over 24 hours at 115°C. After the addition was complete, the reaction solution was cooled to 40°C and then bubbling with N2 for 2 hours. The mixture was heated to 115°C, and 33 wt% HBr / AcOH (1300 g) was added dropwise to the mixture over 2.5 hours at 115°C. 33 wt% HBr / AcOH (1200 g) was added dropwise to the mixture over 2.5 hours at 115°C. 33 wt% HBr / AcOH (1246 g) was added dropwise to the mixture over 2.5 hours at 115°C. The complete reaction solution was cooled to 20°C, and water (8000 mL, 8v) was added at below 30°C. The mixed solution was extracted twice with MTBE (8 L / 3 L, 8v / 3v). The organic phases were combined and the pH was adjusted to 7-8 with a 15 wt% NaOH aqueous solution at below 30°C. The organic phases were then washed with water (2 L, 2v) and dried over anhydrous Na2SO4 (500 g, 0.5X). After filtration, the filtrate was concentrated to dryness under reduced pressure (0.06-0.1 MPa) at 40-45°C to obtain the product as a brown oily substance (HPLC purity: 97.6%, assay: 94.3%, yield: 93.3%). 1 H NMR(400MHz,CHLOROFORM-d)δ2.42-2.61(m,3H),7.31-7.48(s,1H).

[0482] Step 2: JPEG2026143404000292.jpg26170

[0483] Compound 8b (877 g, 1 equivalent) was added to a mixed solution of triethylamine (TEA) (414 g, 1.5 equivalents), N-butylpyrrolidinone (NBP) (4650 mL, 5 v), (PMB) 2NH (1080 g, 1.5 equivalents). The mixed solution was heated to 70°C and stirred at that temperature for 24 hours. The complete reaction solution was cooled to 50°C, and 20 wt% aqueous citric acid solution (10 L, 10 v) was added dropwise at 50°C over 1 hour. The mixed solution was then cooled to 20°C over 1 hour. The suspension was filtered and subsequently washed with water (2 L, 2 v) and MeOH (2 L, 2 v). The filtered cake was dried under reduced pressure at 25°C for 20 hours to obtain the crude product (1115 g, assay: 88.2%, residual MeOH: 0.01%).

[0484] Recrystallization: Crude product (1115g) and THF (4.46L, 4L) were added to the reactor, and the mixed solution was stirred until clear. Then, it was decolorized with activated carbon (110g, 10% by weight). The decolorized solution was concentrated under reduced pressure to 1.2v at less than 40°C, and then methanol (2.23L, 1.2v) was added. The mixed solution was heated to 50°C and stirred for 0.5 hours to obtain a clear solution. MeOH (4.65L, 4.2v) was added to the solution, and then crystal seed crystals (1% by weight) were added. The mixed solution was stirred at 50°C for 1 hour. MeOH (2.23L, 1.2v) was added to the suspension at 50°C and stirred at that temperature for 0.5 hours. Then, the suspension was cooled to 0°C over 1 hour and stirred at that temperature for 16 hours. The suspension was filtered and washed with MeOH (2.23L, 1.2v). The filtered cake was dried under reduced pressure at 45°C for 20 hours to obtain the product as a grayish-white solid (931.6 g, HPLC purity: 99.7 A%, assay: 102.3 wt%, yield: 68.4%). 1 H NMR(400MHz,CHLOROFORM-d)δ2.24-2.45(m,3H),3.73-3.90(s,6H),4.57-4.85(s ,4H),6.11-6.22(s,1H),6.80-6.93(m,4H),7.10-7.23(m,4H),7.24-7.34(s,1H)

[0485] Example 7

[0486] Compound 1: tert-butyl(S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3-methylpiperazine-1-carboxylate JPEG2026143404000293.jpg41170

[0487] Compound 2 (50.0 g, 104.7 mmol, 1.1 equivalents) and THF (350 mL, 7 v, 100-200 ppm H2O) were added to a dry flask (1 L). i-PrMgCl·LiCl (1.3 M in THF, 93.0 mL, 1.265 equivalents) was added dropwise under argon at -78 to -70°C for 30 minutes. The reaction mixture was stirred at -78°C for 10 minutes. ZnCl2 (1.9 M in Me-THF, 72 mL, 1.43 equivalents, approximately 230 ppm H2O) was added dropwise at -78 to -70°C for 20 minutes, and then the mixture was gradually heated to 10°C over 2 hours. The mixture was stirred at 10°C for approximately 0.5 hours. After the addition of ZnCl2, the reaction mixture was stirred at -70 to -30°C for at least 1 hour. Compound 3 (47.1 g, 95.2 mmol, 1.0 equivalent) and 1,4-dioxane (8v) were added to a separate dry flask (1 L). The Zn reagent was added under an argon atmosphere. Argon was blown into the reaction mixture at a rate of 0.3 L / min for 2 hours. A solution of [PdCinnamylCl]2 (0.5 mol%) and (R,R)-quiraffite ligand (1.0 mol%) in 1,4-dioxane (approximately 14 mL, approximately 0.27 v) was added under an argon atmosphere. The mixture was stirred at approximately 48°C for 21 hours.

[0488] The reaction mixture was cooled to 10-20°C. The reaction mixture was added dropwise to a saturated NH4 aqueous solution. Cl (approximately 471 mL, 10V) was added below 20°C, and the resulting mixture was stirred for 30 minutes. The mixture was filtered through diatomaceous earth (approximately 1 wt), and the cake was washed with toluene (236 mL, 5V). The two phases (filtrate) were separated, and the aqueous phase was extracted with toluene (236 mL, 5V). The combined organic phase was washed with brine (236 mL, 5V). The toluene was then concentrated to 4 volumes (approximately 200 mL) under vacuum at 40-50°C. Toluene (200 mL, 4V) was added, and the solution was then concentrated to approximately 200 mL (4V). Toluene (200 mL, 4V) was added, and the solution was then concentrated to approximately 200 mL (279 g, 4V). The solution was cooled to 15-20°C. N-heptane (6v, 637mL) was added dropwise over 50 minutes at 15-20°C. The mixture was stirred at room temperature (15-20°C) for approximately 1 hour. The mixture was filtered, and the cake was washed with toluene / n-heptane (approximately 2.5v x 2, n-heptane / toluene = 2 / 6). The solid was dried. Yield: 60.7g of crude product = 98.6 / 1.4, pale yellow solid (approximately 69% corrected yield).

[0489] Example 8 JPEG2026143404000294.jpg39170

[0490] To a solution of compound 2 (42.0 g, 88 mmol, 1.1 equivalent) in THF (200 mL), i-PrMgCl·LiCl (1.14 M in THF, 77.78 g, 92 mmol, 1.15 equivalents) was added at -70±5°C, and the corresponding mixture was stirred for 30 minutes. Then, a ZnCl2 solution (50.0 g, 94 mmol, 1.18 equivalents) was added at -70±5°C. After the addition was complete, the reaction mixture was heated to -10°C, and then NaTFA (32.6 g, 240 mmol, 3.0 equivalents) was added little by little. Next, the mixture was heated to 50°C, and then a solution of bromopyridine compound 3 (39.6 g, 80 mmol, 1.0 equivalent) in THF (80 mL) was added. After stirring the mixture for approximately 15 minutes, a solution of palladium (π-cinnamyl) chloride dimer (0.201 g, 0.4 mmol, 0.005 equivalents) and (R,R)-quillafite (0.77 g, 0.88 mmol, 0.011 equivalents) in THF (16 mL) was added, and the reaction mixture was stirred until complete conversion was achieved. The reaction mixture was cooled to 20°C and quenched by adding it to an aqueous solution of trisodium citrate (300 g, 20% w / w) and toluene (200 mL). The reactor was rinsed with THF (20 mL), and the two-phase mixture was stirred for 15 minutes. After phase separation, an aqueous solution of trisodium citrate (300 g, 20% w / w) was added, and the two-phase mixture was stirred for 15 minutes. After phase separation, water (100 mL) was added, and the two-phase mixture was stirred for 15 minutes. After phase separation, water, THF, and 2-Me-THF were replaced with toluene (200 mL) by a constant volume under vacuum. The solution was then filtered through a charcoal filter at 50 ± 2°C, and the reactor and filter were rinsed with toluene (42 g) to reduce the reaction volume to approximately 130-150 mL under vacuum. The reactor was cooled to 20°C, and n-heptane (27.1 g) and 0.04 g of seed crystal were added. The resulting dilute suspension was aged for 1 hour. Then, n-heptane (301 g) was added over 2 hours, and the resulting suspension was stirred for at least 12 hours. The crystals were filtered off and washed three times with 100 mL of toluene / n-heptane (1:1) to obtain the crude title compound as yellowish crystals. The crude title compound can be recrystallized from toluene / n-heptane according to the crystallization procedure described above to obtain the title compound as grayish-white crystals in a yield of 70-75%.

[0491] [Table 3] JPEG2026143404000296.jpg210170JPEG2026143404000297.jpg65170

[0492] Example 9 JPEG2026143404000298.jpg43170

[0493] Compound 2 (53g, 111 mmol, 1.10 equivalents) was dissolved in THF (223g, 250mL, 5V), and then cooled to -78 to -70°C under N2 protection. i-PrMgCl.LiCl (98g, 122 mmol, 1.21 equivalents, 97mL, 1.9V, 1.26M (in THF)) was added dropwise to the solution under N2 protection at -78 to -70°C for 1 hour, and the mixture was stirred for 1 hour. ZnCl2 (70g, 126 mmol, 1.25 equivalents, 63mL, 1.3V, 2.0M (in 2-MeTHF)) was added dropwise to the solution under N2 protection at 78 to -70°C for 1 hour, and the mixture was stirred for 1 hour. The solution was gradually adjusted to 0 to 10°C over 2 to 3 hours under N2 protection. NaTFA (41 g, 301 mmol, 3.0 equivalents) was added to the solution under N2 protection. The suspension was stirred at 15-25°C for 30 minutes, then heated to 50-55°C. After stirring at 50-55°C for 1 hour, this suspension was used directly for the Negishi coupling (Step 2). Compound 3 (50 g, 101 mmol, 1.0 equivalent) was dissolved in THF (142 g, 160 mL, 3.2 V), and then N2 was injected into the solution at 15-25°C for 2 hours. (PdCinCl)2 (390 mg, 0.765 mmol, 0.75 mol%) and (R,R)-Chirafite (1.4 g, 1.60 mmol, 1.5 mol%) were added to the solution under N2 protection. N2 was injected into the solution for another hour. The solution was added dropwise to the solution of compound 2 under N2 protection at 50-55°C. The reaction mixture was stirred at 50-55°C for 11 hours.

[0494] The reaction mixture was cooled to 15-25°C, and 300 mL of 20 wt% NH4Cl aqueous solution (6v) was added and stirred for 1 hour. The organic layer was separated, and the aqueous layer was extracted with toluene (250 mL, 5v). The organic phase was changed to one containing 5 wt% Na2SO4 (250 mL, 5v), the mixture was filtered through diatomaceous earth, and washed with THF (250 mL, 5v). The crude THF / toluene solution was passed through charcoal (CUNO) at 15-25°C for 5 hours (flow rate 80 mL / min), and the CUNO channel was filtered with THF. The solution was washed with 50 mL (1 v). The THF / toluene solution was passed through a continuous diatomaceous earth pad and charcoal pad (CUNO) again at 15-25°C for 16 hours (flow rate 80 mL / min). The solution was concentrated to 2 v and toluene (200 mL, 4 v) was added. The solution was passed through a continuous diatomaceous earth pad and charcoal (CUNO) again at 15-25°C for 16 hours (flow rate 80 mL / min). The CUNO channel was washed with toluene (50 mL, 1 v) and concentrated to (4 v) under vacuum at 40-50°C. Toluene (200 mL, 4 v) was added to the residue and the solution was concentrated again to 4 v under vacuum at 40-50°C.

[0495] The residue was cooled to 15-25°C, and then n-heptane (50 mL, 1 v) was added to the crude solution. 150 mg of seed crystals were added to the mixture. The mixture was stirred at 15-25°C for 1 hour, and then n-heptane (11 v) was added dropwise to the crude solution over 2 hours. The wet cake was filtered and washed with toluene / n-heptane 2 × 125 mL (2 × 2.5 v, toluene / n-heptane = 1:3). 90.8 g of crude wet product 1 was obtained by 85.4 wt% assay.

[0496] The wet cake was added to toluene (131 g, 150 mL, 3 v), and then heptane (408 g, 600 mL, 12 v) was added dropwise to the suspension. The suspension was stirred at 15-25°C for 19 hours. The wet cake was filtered and rinsed with n-heptane (34 g, 50 mL, 1 v). 81.8 g of wet cake was obtained and dried in a vacuum below 45°C for 16 hours. Finally, 65.2 g of product toluene solvate was obtained with an assay yield of 68.9 wt% and a purity of 98.5 A%. Purity: 98.5 A%; Assay: 86.8 wt%; Toluene: 11.0 wt%; Chiral purity: 99.1 A%.

[0497] Example 10

[0498] Compound 1: tert-butyl(S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3-methylpiperazine-1-carboxylate JPEG2026143404000299.jpg65170

[0499] Ultra-dried THF (53 L, 8.4 v) and compound 2 (8.5 kg, 17.79 mol, 1.4 equivalents) were added to the reactor under an argon atmosphere. The mixture was degassed by three cycles of vacuum / argon and cooled to -78°C in a liquid N2 bath. i-PrMgCl·LiCl solution (1.3 M in THF, 15.74 L, 20.46 mol, 1.61 equivalents) was added dropwise over 15 minutes at -78 to -70°C under argon. The reaction mixture was stirred at -78°C for 15 minutes. ZnCl2 (1.9 M in Me-THF, 12.2 L, 23.18 mmol, 1.82 equivalents, approximately 1300 ppm) was added dropwise over 15 minutes at -78 to -70°C, and then gradually heated to -10°C over 3.0 hours. After adding ZnCl2, the reaction mixture was stirred at -70 to -30°C for at least 1 hour.

[0500] In a separate reactor, ultra-dried THF (44.4 L, 7.0 v) and compound 3 (6.3 kg, 12.71 mol, 1.0 equivalent) were added under an argon atmosphere. The mixture from the first reactor was added to the second reactor under argon pressure, and the resulting mixture was bubbling with argon for 2 hours. A solution of PdCinCl (65.9 g, 0.13 mol, 1.0 mol% Pd) and Walphos ligand (88.3 g, 0.13 mol, 1.0 mol%) in degassed THF (1.7 L, 0.27 v) was added via a PFA tube under argon pressure, and the mixture was bubbling with argon for 2 hours. The mixture was heated to 40-45°C and stirred under argon for 3 hours.

[0501] The mixture was cooled to 20°C and then added to a saturated NH4Cl (64 L, 10V) solution at <20°C. The mixture was filtered through 3.2 kg of diatomaceous earth to separate the two phases (filtrate). The aqueous phase was extracted twice with RINKAN (32 L, 5 volumes). The combined organic phase was washed with brine (32 L, 5V), then concentrated to approximately 2V (approximately 17 L) at 40°C, and then solvent-exchanged with RINKAN (approximately 30 L x 3) to obtain a RINKAN solution (approximately 17 L). The above solution was concentrated under high vacuum at approximately 40°C to remove most of the RINKAN, and then solvent-exchanged with DCM (approximately 30 L x 3) to obtain a DCM solution (approximately 17 L, DCM / RINKAN = 5-6 / 1).

[0502] Approximately 14 kg of silica (60-100 M, approximately 2.2x) was added to the above solution, and the resulting mixture was stirred at approximately 15°C for approximately 1 hour. The resulting mixture was added to a column packed with approximately 74 kg of silica (wet-packed column, 200-300 M, approximately 11x), and then eluted with approximately 200 L of n-heptane, followed by a total of approximately 2000 L of n-heptane / siRNA = 4 / 1. The desired fraction was concentrated to approximately 2-3 v (17-25 L) under vacuum at approximately 40°C.

[0503] Approximately 60 L of toluene was added, and the resulting mixture was heated to approximately 40°C until it was in solution (toluene / n-heptane = approximately 1 / 2) after about 1 hour. The solution was then allowed to cool naturally to approximately 15°C. Approximately 680 g of C941 (8% by weight relative to the amount of compound) was added, and the resulting mixture was stirred at approximately 15°C for about 1 hour. The mixture was filtered, the cake was washed with toluene (2.5 L x 2), and the filtrate and washings were concentrated to 2-3 L (17-25 L). The mixture was then further dried in a rotary evaporator at 40°C to obtain the final compound 1. 1 H NMR(600MHz,DMSO-d6)δppm 7.97(s,1H),7.15(d,J=8.7Hz,4H),6.87(br d,J=8.2Hz,4H),6.84(s,1H),4.71-4.88(m,3H),4.56(br d,J=15.7Hz,2H),4.19-4.25(m,1H),3.86-4.02(m,1H),3.79-3.86(m,1H),3.74(br d,J=5.8Hz,1H),3.72(s,6H),2.94-3.30(m,2H),2.40(d,J=1.7Hz,3H),1.43(s,8H),1.33-1.36(m,3H).HR-MS(ESI): Calculated value C 41 H 42 ClF5N6m / z([M+H] + )813.2965; Measured value 813.2963.

[0504] Example 11 JPEG2026143404000300.jpg44170

[0505] A solution of 2-Me-THF (320 g) containing tert-butyl(3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2,8-difluoroquinazolin-4-yl]-3-methylpiperazine-1-carboxylate (50.0 g, 53.7 mmol, 1.00 equivalent, 87.3% assay) and [(2S)-1-methylpyrrolidine-2-yl]methanol (7.44 g, 64.6 mmol, 1.20 equivalent) was concentrated to 250 mL under reduced pressure (235 mbar). The solution was cooled to -10°C. Next, sodium tert-pentoxide (27.5 g, 64.6 mmol, 1.20 equivalents, 25% w / w) was added as a solution in toluene over 10-20 minutes. The reaction mixture was stirred at 0°C until complete conversion was achieved (typically 1 hour). The reaction mixture was then diluted with 2-Me-THF (214 g), heated to 15-25°C, and quenched by adding aqueous potassium carbonate solution (200 g, 10% w / w solution). The two-phase mixture was stirred for 1 hour, and the layers were separated. The organic layer was further washed with aqueous potassium carbonate solution (200 g, 10% w / w). The two-phase mixture was stirred for 15 minutes, and the layers were separated. The organic layer was concentrated to 250 mL under reduced pressure (235 mbar), cooled to 20-25°C, and filtered by polishing. The filtrate was further concentrated to 175 mL under reduced pressure (235 mbar). 100 g of 1-PrOH was added, and 2-Me-THF was continuously exchanged for 1-PrOH under reduced pressure (150 to 60 mbar). Then, 100 g of water was added at 50°C, and the solution was seeded at this temperature. The resulting mixture was further stirred at this temperature for 2 hours, and 100 g of water was added over at least 2 hours. The crystalline slurry was cooled to 20°C over at least 3 hours, and further stirred at this temperature for at least 5 hours. The crystals were filtered off, washed with a 1-PrOH / water solution, and dried under reduced pressure until a constant weight was obtained. The title compound was isolated as grayish-white crystals in 96% yield (47.5 g). 1H NMR(600MHz,DMSO-d6)δ ppm 7.82(s,1H),7.16(d,J=8.7Hz,4H),6.87(br d,J=8.3Hz,4H),6.82(s,1H),4.62-4.89(m,3H),4.56(br d,J=15.6Hz,2H),4.39(dd,J=10.7,4.7Hz,1H),4.12-4.25(m,1H),4.05(br d,J=13.4Hz,1H), 3.89-4.00(m,1H), 3.76-3.84(m,1H), 3.51-3.67(m,1H), 2.88-3.18(m,2H), 2.55-2.84(m,1H), 2.27-2.43(m,5H), 2.07-2.31(m,1H), 1.85-2.00(m,1H), 1.68(br dd,J=13.3,7.9Hz,3H), 1.42(s,9H), 1.28(br d,J=6.6Hz,3H)ppm.HR-MS(ESI): Calculated value C47H54ClF4N7O5 907.3811; Measured value: 907.3808.

[0506] Example 12 JPEG2026143404000301.jpg46170

[0507] A mixture of acetic acid (46.2 g), methanesulfonic acid (52.9 g), and toluene (34.7 g) was to be added at 40°C over a period of at least 15 minutes, using a solution of tert-butyl(3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (20.0 g, 22.0 mmol) in toluene (86.7 g). The reaction mixture was then heated to 52°C until complete conversion was achieved (typically 2 hours). The reaction mixture was then cooled to 25°C, and the layers were separated. The acidic layer was slowly quenched (typically over 1 hour) at 40°C with a mixture of aqueous sodium hydroxide (211.5 g, 28% w / w), water (80.0 g), and toluene (121.4 g). After quenching was complete, the line was rinsed with acetic acid (10.0 g). The two-phase mixture was heated to 50°C and the layers were separated. The organic layer was washed twice with aqueous sodium hydroxide (2 × 90.0 g, 0.1 N solution). The toluene layer was then distilled under reduced pressure at a constant volume (90 mbar; typically, 69 g of toluene was replaced). After polishing and filtration, the obtained toluene solution was concentrated to 94 mL under reduced pressure (90 mbar) and then heated to 60°C. Then, n-heptane (34.6 g) was added over at least 30 minutes, and the solution was seeded at this temperature. The resulting mixture was stirred further at this temperature for at least 1 hour, the crystalline slurry was cooled to 0°C over at least 4 hours, and then stirred further at this temperature for at least 1 hour. The crystals were filtered off, washed with toluene / n-heptane solution (1:1 v / v), and dried under reduced pressure until a constant weight was obtained. The title compound was isolated as grayish-white crystals in 89% yield (11.7 g). 1H NMR(600MHz,DMSO-d6)δ ppm 7.74(d,J=0.9Hz,1H),6.84(s,2H),6.49(s,1H),4.54-4.65(m,1H),4.38(dd,J=10.8,4.6Hz,1H),4.14(dd,J=10.7,6.5Hz,1H),3.96(br d,J=13.1Hz,1H), 3.47-3.57(m,1H), 2.89-3.00(m,3H), 2.73-2.82(m,2H), 2.55-2.60(m,1H), 2.32-2.40(m,7H), 2.12-2.20(m,1H), 1.94(dd,J=11.9,7.6Hz,1H), 1.67(br d,J=8.3Hz,3H), 1.40(d,J=6.9Hz,3H)ppm.HR-MS(ESI): Calculated value C26H30ClF4N7O 567.2136; Measured value: 567.2141.

[0508] Example 13 JPEG2026143404000302.jpg47170

[0509] Compound 1e (8.00 g, 14.1 mmol, 1.0 equivalent), 3-(phenylsulfonyl)propanoic acid (3.66 g, 16.9 mmol, 1.20 equivalents), and acetonitrile (48 mL, 6 v) were added to a 250 mL round-bottom flask equipped with overhead stirring and a nitrogen line. After stirring the mixture for 5 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI·HCl) (3.11 g, 16.2 mmol, 1.15 equivalents) was added, and the mixture was rinsed forward with acetonitrile (16 mL, 2 v). The reaction mixture was stirred at 20°C for at least 3 hours. Once the reaction was complete and a sulfone intermediate had formed, water (32 mL, 4 v) and sodium hydroxide pellet (1.60 g, 39.9 mmol, 2.85 equivalents) were added to adjust the pH to 13.0-13.5. The reaction mixture was stirred for at least 2 hours to obtain compound A, which was isolated by first adding water (24 mL, 3v) and a seed crystal (0.5 wt%). Then, further water (24 mL, 3v) was slowly added over 2 hours, followed by aging at 20°C for 2 hours, and then water (64 mL, 8v) was slowly added over 5 hours to complete precipitation. The resulting slurry was held at 20°C for 2 hours, filtered, and washed with 1:1 acetonitrile / water (64 mL, 8v), followed by water (64 mL, 8v). Upon drying, compound A (7.42 g) was obtained as a grayish-white solid in 89.6% yield (corrected for purity).

[0510] Example 14 JPEG2026143404000303.jpg86170

[0511] Compound 1e (10.0 g, 17.6 mmol, 1.00 equivalent), followed by 2-MeTHF (50.0 mL, 5 mL / g), was added to a 400 mL reactor, and the materials were stirred at room temperature until complete dissolution was observed. Next, a 10% aqueous solution of Na2CO3 (50.0 mL, 5 mL / g) was added, the reactor was cooled to 0°C (internal temperature control), and the overhead stirrer was set to 350 RPM. Once the internal temperature of the reactor reached 0°C, a solution of 3-chloropropionyl chloride (4.47 g, 35.2 mmol, 2.00 equivalent) dissolved in MeTHF (50.0 mL, 5 mL / g) was added dropwise to the two-phase solution over 30 minutes while maintaining the internal temperature at 0°C. The mixture was then stirred at 0°C for 1 hour (97.8% conversion).

[0512] Next, a 10% NaOH aqueous solution (50.0 mL / 5 mL / g) was added, the reactor was set to 40°C (internal temperature control), and stirred for 16 hours. Then, the reactor was cooled to 25°C, the mixture was transferred to a 500 mL separatory funnel, and the lower (aqueous) layer was removed. The upper (organic) layer was returned to the 400 mL reactor, a 10% NaOH aqueous solution (50.0 mL / 5 mL / g) was added, the reactor was set to 40°C (internal temperature control), and stirred for 4 hours (350 RPM). Then, the reactor was cooled to 25°C, the mixture was transferred to a 500 mL separatory funnel, and the lower (aqueous) layer was removed. Next, the organic layer was transferred to a 250 mL round-bottom flask, concentrated to approximately 20 mL, and 60 mL of MeCN was added. This method was repeated 6 times, and the solvent composition was confirmed by headspace GC (0.03% MeTHF after solvent exchange). Next, the mixture in the round-bottom flask was placed in a refrigerator at 5°C for two days, filtered, and washed twice with 20 mL of MeCN (pre-cooled to -10°C).

[0513] Next, the wet cake was dried under vacuum with nitrogen sweeping at ambient temperature for 24 hours. Compound A was isolated as a grayish-white solid in 69% yield (7.52 g, 12.1 mmol).

[0514] Example 15 JPEG2026143404000304.jpg46170

[0515] In a 250 mL round-bottom flask equipped with overhead stirring and a nitrogen line, 3-(phenylsulfonyl)propanoic acid (3.66 g, 16.9 mmol, 1.20 equivalents), acetonitrile (32 mL, 4 v), N-methylmorpholine (2.33 mL, 21.1 mmol, 1.50 equivalents), and forward acetonitrile rinse solution (8 mL, 1 v) were added. After cooling the mixture to -10°C, pivaloyl chloride (1.90 mL, 15.5 mmol, 1.10 equivalents) was added over 5 minutes, and the mixture was rinsed forward with acetonitrile (8 mL, 1 v). After stirring the mixture at -10°C for at least 1 hour, compound 1e (8.00 g, 14.1 mmol, 1.0 equivalent) was added, and the mixture was rinsed forward with acetonitrile (8 mL, 1 v). The reaction mixture was stirred at -10°C for at least 30 minutes. After the reaction was complete and the sulfone intermediate was formed, the mixture was heated to 20°C. Water (32 mL, 4v) and sodium hydroxide pellet (2.11 g, 52.8 mmol, 3.75 equivalents) were added to adjust the pH to 13.0-13.5. The reaction mixture was stirred for at least 2 hours to obtain compound A, which was isolated by first adding water (24 mL, 3v) and a seed crystal (0.5 wt%). Then, further water (24 mL, 3v) was slowly added over 2 hours, followed by aging at 20°C for 2 hours, and then water (48 mL, 6v) was slowly added over 4 hours to complete precipitation. The resulting slurry was kept at 20°C for 2 hours, filtered, and washed with 1:1 acetonitrile / water (64 mL, 8v), followed by water (64 mL, 8v). After drying, compound A (7.10 g) was obtained as a grayish-white solid in 87.4% yield (corrected for purity).

[0516] Example 16 JPEG2026143404000305.jpg104170

[0517] A solution of 3-(phenylsulfonyl)propionic acid (24.1 g, 112 mmol, 1.40 equivalents) and N-methylmorpholine (13.4 g, 133 mmol, 1.65 equivalents) in acetonitrile (180.7 g) was cooled to -10°C. Pivaloyl chloride (11.8 g, 97.9 mmol, 1.22 equivalents) was administered over 30 minutes. The reaction mixture was further stirred at this temperature for 1 hour. Next, a solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazine-1-yl]-2-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine (50.0 g, 80.4 mmol, 1.00 equivalent) in acetonitrile (176.9 g) was added to the cold reaction mixture over 1 hour, and the mixture was further stirred at -10°C until complete conversion to the sulfone intermediate was achieved (typically 1 hour). The reaction mixture was heated to 20°C and quenched by adding water (62.5 g) and aqueous sodium hydroxide solution (51.7 g, 362 mmol, 4.5 equivalents, 28% w / w solution). Stirring was continued until complete conversion was achieved (typically 8 hours), the mixture was seeded, and then water (865 g) was added over at least 2 hours. The crystalline slurry was stirred further at this temperature for at least 4 hours, the crystals were filtered, washed with acetonitrile / water (3:7 v / v) solution, washed with water, and then dried under reduced pressure until a constant weight was obtained. The title compound was isolated as grayish-white crystals in 91% yield (45.6 g). 1H NMR(600MHz,DMSO-d6)δ7.82(s,1H),6.73-6.98(m,3H),6.50(s,1H),6.10-6 .28(m,1H),5.68-5.81(m,1H),4.66-4.85(m,1H),4.32-4.46(m,1H),4.25(br d,J=13.5Hz,1H),4.06-4.21(m,2H),3.98(br d,J=13.4Hz,1H),3.38-3.76(m,2H),2.91-3.27(m,2H),2.53-2.68(m,1H),2.37(br d,J=1.4Hz,6H),2.11-2.26(m,1H),1.87-2.00(m,1H),1.56-1.79(m,3H),1.27(br dd,J=11.7,6.7Hz,3H)ppm.HR-MS(ESI): Calculated value C29H32ClF4N7O2 621.2242;Actual value:621.2257.

[0518] Example 17 JPEG2026143404000306.jpg47170

[0519] To a solution of compound 1e (3.02 kg, 5.32 mol, 1.0 equivalent) in DCM (in a 100 L reactor), DIPEA (2.05 kg, 15.86 mol, 2.98 equivalents) was added. The mixture was cooled to -25°C, and a solution of acrylic anhydride (0.87 kg, 6.90 mol, 1.30 equivalents) in DCM (28.30 kg, 7V) was slowly added over 140 minutes while maintaining the temperature below -20°C. The reaction mixture was stirred for at least 10 minutes, warmed to 5°C, and quenched with 10 wt% potassium bicarbonate aqueous solution (12.1 kg, 4V).

[0520] The organic layer was washed with a 20 wt% ammonium chloride aqueous solution (12.2 kg, 4V), then washed with a 10 wt% monobasic potassium phosphate aqueous solution, and dried with magnesium sulfate (1.50 kg, 50 wt%). The slurry was filtered, rinsed with DCM (8.05 kg, 2V), and then passed through a CUNO filter housing containing E-Pak Graver C-941 (850 g). The filtrate was then concentrated to 19 L (6V) and diluted with acetonitrile (9.60 kg, 4V). The solution was transferred to a 25 L reactor through an in-line polishing filter. Distillation was continued to remove DCM while replacing it with acetonitrile (8.80 kg, 4V) until a final volume of 18 L was reached, and the concentrated slurry was cooled to 0°C. After being held at 0°C for a minimum of 3 hours, the slurry was filtered, pre-cooled (temperature = 0°C), rinsed with acetonitrile (4.65 kg, 2V), and dried at 20°C to obtain compound A (2.32 kg) in a yield of 69.7%. 1 H NMR(400MHz,DMSO-d6)δ 7.84(d,J=1.6Hz,1H),6.87(s,2H),6.83(m,1H),6.52(m,1H),6.20(dd,J=16.8,6.8Hz,1H),5 .75(dd,J=10.4,2.4Hz,1H),4.76(m,1H),4.41(dd,J=10.8,4.7Hz,1H),4.24(m,1H),4.18(dd, J=10.8,6.5Hz,1H),4.13(m,2H),3.67(m,1H),3.47(m,1H),3.25(m,1H),2.95(m,1H),2.58(m ,1H),2.39(m,3H),2.37(s,3H),2.17(m,1H),1.94(m,1H),1.68(m,3H),1.29(t,J=6.6Hz,3H); 13C NMR(101MHz,DMSO-d6):δ 165.4,164.8,164.7,162.2,161.3,154.4,151.8,148.7,148.7,147.6,143.0,142.8,131.1,130. 9,129.6,128.4,128.4,128.3,128.2,128.1,126.9,125.2,125.2,124.2,121.5,120.9,120.9,11 4.6,114.6,112.5,112.2,111.9,111.7,110.5,69.8,63.8,57.4,52.4,52.3,49.3,45.8,45.1,44.8,44.2,42.0,41.6,40.6,40.4,40.2,40.0,39.8,39.6,39.4,29.0,23.1,20.3,20.2,15.8,15.2; 19 F NMR (376MHz, DMSO-d6): δ-53.7,-125.9.

[0521] Example 18 JPEG2026143404000307.jpg51170

[0522] Compound A (2.32 kg, 3.53 mol) and polished and filtered 2-butanone (17.42 L, 7.5 L / kg) were combined in a 25 L reactor equipped with an activated nitrogen line, overhead stirring, and a temperature probe. In a separate 5 L glass bottle, adipic acid (0.46 kg, 3.17 mol, 0.9 equivalents) and polished and filtered 2-butanone (1.16 L, 0.5 L / kg) were added. The reactor was then heated to 50°C ± 10°C, and once the desired internal temperature target of >45°C was reached, the adipic acid slurry in 2-butanone was introduced into the reactor by vacuum. Seed crystals of compound B (0.02 kg, 1 wt%) were added to a 5 L glass bottle, followed by polished and filtered butanone (2.32 L, 1.0 L / kg). The slurry was again introduced into the reactor by vacuum. Finally, a 5L glass bottle was rinsed with polished and filtered 2-butanone (1.16L, 0.5L / kg) and then placed into the reactor under vacuum. The contents of the reactor were allowed to mature for at least 1 hour, cooled to 0°C over at least 2 hours, and then matured overnight (15 hours) at 0°C. The contents were transferred to a pre-cooled filtration dryer at 0°C. In parallel, polished and filtered 2-butanone (9.29L, 4.0L / kg) was added to the reactor at 0°C and stirred for 30 minutes. The material in the filtration dryer was then filtered, and the resulting cake was washed with cooled 2-butanone. After drying for at least 8 hours using vacuum and nitrogen sweeping, the contents of the filtration dryer were discharged to obtain compound B (2.137kg, 77%) as a grayish-white solid. 1H NMR (600 MHz, DMSO-d₆) δ 7.77 (s, 1H), 6.81 (s, 2H), 6.76 (dd, J=16.8, 10.6 Hz, 1H), 6.45 (s, 1H), 6.18-6.10 (m, 1H), 5.70 (dd, J=10.4, 2.3 Hz, 1H), 4.75-4.66 (m, 1H), 4.38-4.30 (m, 2H), 4.25-3.89 (m, 4H), 3.61 (dq, J=21.3, 12.4, 10.9 Hz, 2H), 3.20 (dd, J=13.4, 3.8 Hz, 1H), 3.00 (td, J=12.6, 3.7 Hz, 1H), 2.91 (ddd, J=9.0, 6.0, 2.8 Hz, 1H), 2.59-2.51 (m, 1H), 2.32 (d, J=6.2 Hz, 6H), 2.15 (td, J=8.6, 7.7, 4.7 Hz, 5H), 1.94-1.85 (m, 1H), 1.61 (dddd, J=20.8, 12.3, 8.0, 4.1 Hz, 3H), 1.45 (h, J=3.4 Hz, 4H), 1.22 (dd, J=12.4, 6.6 Hz, 3H); 13 C{ 1 H, 19 F} NMR (151 MHz, DMSO-d₆) δ 174.9, 165.5, 164.8, 162.2, 161.4, 153.2, 148.8, 147.7, 143.0, 131.1, 128.5, 128.4, 128.3, 128.2, 125.6, 125.3, 121.0, 114.7, 112.2, 110.5, 69.8, 63.9, 57.4, 52.5, 52.4, 49.4, 45.9, 45.2, 44.9, 44.3, 42.0, 41.7, 40.6, 34.0, 29.1, 24.6, 23.1, 20.3, 15.9, 15.3; 19 F NMR (565 MHz, DMSO-d₆) δ -53.5, -125.9.

[0523] Example 19 JPEG2026143404000308.jpg54170

[0524] Compound A (1 molar equivalent) and adipic acid (1 molar equivalent) were suspended in 2-butanol and 2-methyltetrahydrofuran and heated to approximately 70°C to dissolve. The polished and filtered solution was cooled to approximately 25°C. For sowing, the material of compound B, which had been jet-milled, was used. The sowing material compound B was suspended in 2-butanol / n-heptane. This suspension was used to sow the solution at approximately 25°C. The sowing apparatus was rinsed with n-heptane and then added to the sowing suspension. N-heptane was added at approximately 25°C within 15-30 minutes. The suspension was stirred at approximately 25°C for approximately 3 hours. The suspension was cooled to approximately 0°C and stirred for at least 5 hours. The solid was isolated by solid / liquid separation and rinsed with a mixture of 2-butanol / n-heptane, followed by n-heptane. The solid was dried under reduced pressure at approximately 40°C to obtain a white to grayish-white powder with a yield of 88-95%.

[0525] In a separate procedure, compound A (1 molar equivalent or excess) and adipic acid (1 molar equivalent) were suspended in 2-butanol and 2-methyltetrahydrofuran and heated to approximately 70°C to dissolve. The polished and filtered solution was cooled to the seeding temperature (approximately 25°C). For seeding, compound B was used either without pretreatment or after using an impact mill, jet mill, or wet mill. Seeding material compound B was suspended in a solvent (n-heptane, or a 2-butanol / n-heptane mixture, or 2-butanol). This suspension was used for seeding at the seeding temperature. The seeding apparatus was rinsed with the solvent (n-heptane, or a 2-butanol / n-heptane mixture, or 2-butanol) and then added to the seeding suspension. N-heptane was added at the seeding temperature or lower (typically at approximately 25°C) for approximately 15-30 minutes. The suspension was stirred at the n-heptane addition temperature for at least 3 hours. The suspension was cooled to approximately 0°C and stirred for at least 5 hours. The solid was isolated by solid / liquid separation and rinsed with a mixture of 2-butanol / n-heptane, followed by n-heptane. The solid was dried under reduced pressure at approximately 40°C to obtain a white to off-white powder in a yield of 88–95%.

[0526] Example 20: Cyclohexane crystalline solvate compound 1

[0527] X-ray quality crystals were grown from a high-temperature cyclohexane solution, slowly cooled to room temperature, and allowed to stand for 72 hours to deposit the diffracted crystals. A colorless rod measuring 0.110 x 0.090 x 0.050 mm was mounted on a Cryoloop using parathonine oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The distance from the crystal to the detector was 40 mm, and the exposure time was 0.15 seconds per frame using a scan width of 0.5°. Data acquisition was 100.0% complete up to 67.000°(θ). A total of 112,434 reflections were collected, covering the indices -11<=h<=11, -16<=k<=17, -40<=l<=41. 8,888 reflections had an R of 0.0352. int It was found to be symmetry-independent and possess the following properties. Indexing and unit cell refinement revealed a simple orthorhombic lattice. The space group was found to be P 21 21 21 (No. 19). Data were integrated and scaled using CrysAlisPro 1.171.41.72a. The iterative solution (SHELXT-2014) generated a complete heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by complete matrix least squares (SHELXL-2018). All hydrogen atoms were fixed using a riding model. Their positions were constrained to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was clearly determined to be S at all chiral centers.

[0528] [Table 4]

[0529] Example 21: Methylcyclohexane crystalline solvate compound 1

[0530] X-ray quality crystals were grown from a high-temperature methylcyclohexane solution and allowed to cool slowly to room temperature for 48 hours. A colorless prism measuring 0.206 x 0.097 x 0.068 mm was mounted on a Cryoloop using parathon oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The distance from the crystal to the detector was 40 mm, and the exposure time was 0.1 seconds per frame using a scan width of 0.5°. Data acquisition was 100.0% complete up to 67.000°(θ). A total of 128,902 reflections were collected, covering the exponents -17<=h<=17, -11<=k<=12, -41<=l<=40. 17,535 reflections had an R of 0.0912. int It was found to be symmetry-independent and possess the following properties. Indexing and unit cell refinement revealed a simple monoclinic lattice. The space group was found to be P 21 (No. 4). Data were integrated and scaled using CrysAlisPro 1.171.41.72a. The iterative solution (SHELXT-2014) generated a complete heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by complete matrix least squares (SHELXL-2018). All hydrogen atoms were fixed using a riding model. Their positions were constrained to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was clearly determined to be S at all chiral centers.

[0531] [Table 5]

[0532] Example 22: Chlorobenzene crystalline solvate compound 1

[0533] X-ray quality crystals were grown from a saturated chlorobenzene solution, followed by the slow vapor diffusion of heptane to deposit diffracted crystals. A colorless prism measuring 0.130 x 0.110 x 0.060 mm was mounted on a Cryoloop using parathon oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The distance from the crystal to the detector was 40 mm, and the exposure time was 0.05 seconds per frame using a scan width of 0.5°. Data acquisition was 100.0% complete up to 67.000°(θ). A total of 110,828 reflections were collected, covering the exponents -12<=h<=12, -16<=k<=16, and -41<=l<=41. 8,734 reflections had an R of 0.0384. int It was found to be symmetry-independent and possess the following properties. Indexing and unit cell refinement revealed a simple orthorhombic lattice. The space group was found to be P 21 21 21 (No. 19). Data were integrated and scaled using CrysAlisPro 1.171.41.71a. The iterative solution (SHELXT-2014) generated a complete heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by complete matrix least squares (SHELXL-2018). All hydrogen atoms were fixed using a riding model. Their positions were constrained to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was clearly determined to be S at all chiral centers.

[0534] [Table 6]

[0535] Example 23: Ethylbenzene crystalline solvate compound 1

[0536] X-ray quality crystals were grown from a saturated ethylbenzene solution, followed by the slow vapor diffusion of heptane to deposit diffracted crystals. A colorless prism measuring 0.162 x 0.103 x 0.067 mm was mounted on a Cryoloop using parathonine oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The distance from the crystal to the detector was 40 mm, and the exposure time was 0.25 seconds per frame using a scan width of 0.5°. Data acquisition was 100.0% complete up to 67.000°(θ). A total of 20385 reflections were collected, covering the exponents -16<=h<=16, -12<=k<=12, and -42<=l<=42. The 20385 reflections had an R of 0.1540. int It was found to be symmetry-independent and possess the following properties. Indexing and unit cell refinement revealed a simple monoclinic lattice. The space group was found to be P 21 (No. 4). Data were integrated and scaled using CrysAlisPro 1.171.41.71a. The iterative solution (SHELXT-2014) generated a complete heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by complete matrix least squares (SHELXL-2018). All hydrogen atoms were fixed using a riding model. Their positions were constrained to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was clearly determined to be S at all chiral centers.

[0537] [Table 7]

[0538] Example 24: m-xylene crystalline solvate compound 1

[0539] X-ray quality crystals were grown from a saturated m-xylene solution, followed by the slow vapor diffusion of heptane to deposit the diffracted crystals. A colorless prism measuring 0.190 x 0.170 x 0.130 mm was mounted on a Cryoloop using parathon oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The distance from the crystal to the detector was 40 mm, and the exposure time was 0.1 seconds per frame using a scan width of 0.5°. Data acquisition was 100.0% complete up to 67.000°(θ). A total of 115,184 reflections were collected, covering the exponents -11<=h<=12, -16<=k<=16, and -40<=l<=40. 8,996 reflections had an R of 0.0373. int It was found to be symmetry-independent and possess the following properties. Indexing and unit cell refinement revealed a simple orthorhombic lattice. The space group was found to be P 21 21 21 (No. 19). Data were integrated and scaled using CrysAlisPro 1.171.41.71a. The iterative solution (SHELXT-2014) generated a complete heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by complete matrix least squares (SHELXL-2018). All hydrogen atoms were fixed using a riding model. Their positions were constrained to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was determined to be S at C12.

[0540] [Table 8]

[0541] Example 25: Toluene crystalline solvate compound 1

[0542] X-ray quality crystals were grown from a saturated toluene solution, followed by the slow vapor diffusion of heptane to deposit the diffracted crystals. A colorless prism measuring 0.150 x 0.130 x 0.110 mm was mounted on a Cryoloop using parathonine oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The distance from the crystal to the detector was 40 mm, and the exposure time was 0.1 seconds per frame using a scan width of 0.5°. Data acquisition was 100.0% complete up to 67.000°(θ). A total of 329,491 reflections were collected, covering the exponents -12<=h<=12, -41<=k<=41, and -50<=l<=49. 26,769 reflections had an R of 0.0335. int It was found to be symmetry-independent and possess the following properties. Indexing and unit cell refinement revealed a simple orthorhombic lattice. The space group was found to be P 21 21 21 (No. 19). Data were integrated and scaled using CrysAlisPro 1.171.41.70a. The iterative solution (SHELXT-2014) generated a complete heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by complete matrix least squares (SHELXL-2018). All hydrogen atoms were fixed using a riding model. Their positions were constrained to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was clearly determined to be S at all chiral centers.

[0543] [Table 9]

[0544] All technical and scientific terms used herein have the same meaning. While efforts have been made to ensure accuracy regarding the numerical values ​​used (e.g., quantities, temperatures, etc.), some experimental error and deviation should be taken into consideration.

[0545] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense unless otherwise required by context. Embodiments described herein are understood to include embodiments that “consist of” and / or “essentially consist of.”

[0546] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, it should be understood that the upper and lower limits of the range and any other stated or intervening values ​​within that stated range, up to one-tenth of the lower limit unit, are included herein. The upper and lower limits of these smaller ranges, which can be independently included in smaller ranges, are also included herein, subject to the limits specifically excluded in the stated range. If a stated range includes one or both of the limits, the range excluding one or both of those included limits is also included herein.

[0547] Many modifications and other embodiments of the inventions described herein will be conceivable to those skilled in the art, benefiting from the teachings presented in the foregoing description and the accompanying drawings. Therefore, it should be understood that the invention is not to be limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Certain terms are used herein, but these are used in a general and descriptive sense only and are not intended to be limiting.

Claims

1. Equation (I) (In the formula, X ０ represents hydrogen, halogen, OR ５Ａ , SR ５Ｂ , R ５ -substituted or unsubstituted C １－６ alkyl, R ５ -substituted or unsubstituted C １－６ haloalkyl, R ５ -substituted or unsubstituted C ５－７ aryl, or R ５ -substituted or unsubstituted C ５－７ heteroaryl; X １ is hydrogen or halogen; X ３ is hydrogen, halogen, R ６ - Substituted or non-substituted C １－３ Alkyl, R ６ - Substituted or non-substituted C １－３ Haloalkyl, R ６ - Substituted or non-substituted C １－３ Alkoxy, or R ６ - Substituted or unsubstituted cyclopropyl; R １ is hydrogen or PG １ And; Each R ２ These are, independently, halogen, cyano, and unsubstituted C １－６ Alkyl, unsubstituted C １－６ Cyanoalkyl or unsubstituted C １－６ It is a haloalkyl; R ３ is hydrogen, halogen, R ３Ａ - Substituted or non-substituted C １－３ Alkyl, R ３Ａ - Substituted or non-substituted C １－３ Haloalkyl, or R ３Ａ - Substituted or non-substituted C ３－６ It is cycloalkyl; R ３Ａ These are halogens, OH, CN, and unsubstituted C. １－３ Alkyl or unsubstituted C １－３ It is a haloalkyl; R ４ R ４Ａ - Substitute or non-substitute C １－３ It is a haloalkyl; R ４Ａ is unsubstituted C １－３ It is alkyl; R ５ These are halogen, cyano, OH, NO ２ , R ５Ａ - Substituted or non-substituted C １－６ Alkyl, R ５Ａ - Substituted or non-substituted C １－６ Haloalkyl, R ５Ａ - Substituted or non-substituted C １－６ Cyanoalkyl, R ５Ａ - Substituted or non-substituted C ３－６ Cycloalkyl, R ５Ａ - Substitutive or unsubstituted 3- to 6-membered hetero rings, R ５Ａ - Substituted or unsubstituted phenyl, or R ５Ａ - It is a substituted or unsubstituted six-membered heteroaryl; R ５Ａ and R ５Ｂ Each of them is independent of R ５Ｃ - Substituted or non-substituted C １－６ Alkyl, R ５Ｃ - Substituted or non-substituted C １－６ Haloalkyl, R ５Ｃ - Substituted or non-substituted C ３－７ Cycloalkyl, R ５Ｃ - Substitutable or unsubstituted 3- to 7-membered hetero rings, R ５Ｃ - Substituted or non-substituted C ５－７ Aryl, or R ５Ｃ - Substituted or non-substituted C ５－７ It is a heteroaryl; R ５Ｃ These are, independently, halogen, OH, CN, NO ２ , R ５Ｄ - Substituted or non-substituted C １－６ Alkyl, R ５Ｄ - Substituted or non-substituted C １－６ Haloalkyl, R ５Ｄ - Substituted or non-substituted C ３－７ Cycloalkyl, R ５Ｄ - Substituted or non-substituted C ３－７ The complex algebra R ５Ｄ - Substituted or non-substituted C ５－７ Aryl, or R ５Ｄ - Substituted or non-substituted C ５－７ It is a heteroaryl; R ５Ｄ These are, independently, halogen, OH, CN, NO ２ , unsubstituted C １－６ Alkyl, unsubstituted C １－６ Haloalkyl, unsubstituted C ３－７ Cycloalkyl, unsubstituted C ３－７ Heterogeneous algebras, non-substituted C ５－７ Aryl or unsubstituted C ５－７ It is a heteroaryl; R ６ is halogen, OH, CN, NO ２ , unsubstituted C １－６ alkyl, unsubstituted C １－６ haloalkyl, or unsubstituted C ３－７ cycloalkyl; n is 0, 1, or 2; Each PG is either an amino protecting group independently, or two PGs together form a C ３－７ Forming a nitrogen heterocycle; and PG １ (This is an amino protecting group.) A method for preparing the compound, (a) Equation (II) (wherein X ２ is halogen) contacting the compound with an organomagnesium compound and a zinc complex; and (b) The mixture from step (a) is given formula (III) (In the formula, X ４ A method comprising contacting a compound (where is a halogen), a transition metal catalyst precursor, and a chiral ligand to synthesize a compound of formula (I).

2. The compound of formula (II) is obtained by the following method: (a) Equation (IVa) The compound of formula (In the formula, X ３ When contacted with a halogenating agent having (which is a halogen), formula (IVb) To produce the compound; (d) The compound of formula (IVb) Cyclization of the compound; (d) The compound of formula (V) is brought into contact with a chlorinating agent to obtain formula (Va) To produce compounds of; and (e) The compound of formula (Va) By bringing it into contact with the piperazinyl moiety having formula (IIa) To produce compounds of; and (f) The compound of formula (IIa) is X ０ To bring into contact with the portion containing and form the compound of formula (II), The method according to claim 1, which is prepared by...

3. The following steps: (a0)CO ２ Equation (IV) in the presence of gas The compound is brought into contact with a base, and the compound is aminated to obtain formula (IVa). Forming the aforementioned compound The method according to claim 2, further comprising:

4. The compound of formula (III) is obtained by the following method: (a) Equation (VII) The compound of formula NH ２ By contacting a compound containing (PG), the compound of formula (VIIa) To produce the compound; (b) The compound of formula (VIIa) ａ PG (where X ａ When a compound having (which is a halogen) is brought into contact with the compound of formula (VIIb) To produce the compound; (c) The compound of formula (VIIb) (In the formula, X ５ When contacted with a halogenating agent having (which is a halogen), formula (VIIc) To produce the compound; (d) Haloalkylating the compound of formula (VIIc) with a haloalkylating agent to produce the compound of formula (VIId). (e) Brominate the compound of formula (VIId) to obtain formula (VIIe) To produce compounds of; and (f) The compound of formula (VIIe) is X ａ To produce the compound of formula (III) by contacting it with PG, The method according to any one of claims 1 to 3, prepared by...

5. The compound of formula (III) is obtained by the following method: (a) Formula (VIII) Compound of (wherein X in the formula) ６ (This is Cl or I) is brought into contact with a halogenating agent to form formula (VIIIa) Forming compounds of the same name; (b) Brominate the compound of formula (VIIIa) to obtain formula (VIIIb) To form compounds of; and (c) The compound of formula (VIIIb) of formula NH(PG) ２ Contacting a compound having the compound to produce a compound of formula (III), The method according to claim 1, which is prepared by...

6. The compound of formula (III) is obtained by the following method: (a) Formula (VIIIc) When the compound is brought into contact with a brominating agent, formula (VIIId) Forming compounds of the same name; (b) The compound of formula (VIIId) is brought into contact with a halogenating agent to obtain formula (VIIIb) Forming compounds of the same name; (c) The compound of formula (VIIIb) of formula NH(PG) ２ Contacting a compound having the compound to produce a compound of formula (III), The method according to claim 1, which is prepared by...

7. X １ The method according to any one of claims 1 to 6, wherein is a halogen.

8. X １ The method according to any one of claims 1 to 7, wherein the substance is F or Cl.

9. X １ The method according to any one of claims 1 to 6, wherein the substance is hydrogen or a halogen.

10. X ３ However, halogen, unsubstituted C １－４ Alkyl or unsubstituted C １－３ The method according to any one of claims 1 to 8, wherein the material is a haloalkyl.

11. X ３ However, halogen or unsubstituted C １－３ The method according to any one of claims 1 to 8, wherein the material is a haloalkyl.

12. X ３ However, non-substituted C １－３ The method according to any one of claims 1 to 8, wherein the hydroxyl group is an alkoxy group or an unsubstituted cyclopropyl group.

13. X ３ The method according to any one of claims 1 to 8, wherein is a halogen.

14. X ３ The method according to any one of claims 1 to 8, wherein the material is Cl or F.

15. X ３ However, Cl, F, CF ３ CHF ２ or CH ２ The method according to any one of claims 1 to 8, wherein F.

16. X ３ However, CF ３ CHF ２ or CH ２ The method according to any one of claims 1 to 8, wherein F.

17. R １ PG １ The method according to any one of claims 1 to 16.

18. PG １ The method according to claim 17, wherein the compound is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy).

19. R １ The method according to any one of claims 1 to 16, wherein is Boc(tert-butyloxycarbonyl).

20. R ２ The method according to any one of claims 1 to 19, wherein the element is a halogen or a cyanoacrylate.

21. R ２ However, non-substituted C １－６ Alkyl, unsubstituted C １－６ Cyanoalkyl or unsubstituted C １－６ The method according to any one of claims 1 to 19, wherein the material is a haloalkyl.

22. R ２ However, non-substituted C １－６ Alkyl or unsubstituted C １－６ The method according to any one of claims 1 to 19, wherein the material is a cyanoalkyl.

23. R ２ However, non-substituted C １－６ Alkyl or unsubstituted C １－６ The method according to any one of claims 1 to 19, wherein the material is a haloalkyl.

24. R ２ The method according to any one of claims 1 to 19, wherein the compound is methyl or ethyl.

25. R ２ The method according to any one of claims 1 to 19, wherein is methyl.

26. R ２ However, CF ３ CHF ２ or CH ２ The method according to any one of claims 1 to 19, wherein F.

27. R ２ ga CH ２ The method according to any one of claims 1 to 19, wherein the material is CN.

28. R ３ However, hydrogen or R ３Ａ - Substituted or non-substituted C １－３ The method according to any one of claims 1 to 27, wherein the alkyl group is alkyl.

29. R ３ However, R ３Ａ - Substituted or non-substituted C １－３ Alkyl, R ３Ａ - Substituted or non-substituted C １－３ The method according to any one of claims 1 to 27, wherein the member is a haloalkyl or cyclopropyl.

30. R ３ However, R ３Ａ - Substituted or non-substituted C １－３ Alkyl or R ３Ａ - Substituted or non-substituted C １－３ The method according to any one of claims 1 to 27, wherein the material is a haloalkyl.

31. R ３ However, R ３Ａ - Substituted or non-substituted C １－３ The method according to any one of claims 1 to 27, wherein the alkyl group is alkyl.

32. R ３ The method according to any one of claims 1 to 27, wherein is methyl.

33. R ４ However, CF ３ CHF ２ or CH ２ The method according to any one of claims 1 to 32, wherein F.

34. The method according to any one of claims 1 to 33, wherein each PG is independently a protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy).

35. The method according to any one of claims 1 to 34, wherein each PG is p-methoxybenzyl.

36. The two programmable components combine to form the following structure: The method according to any one of claims 1 to 34, which forms a portion having

37. X ２ The method according to any one of claims 1 to 36, wherein is Br.

38. The method according to any one of claims 1 to 37, wherein the organomagnesium compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate.

39. The aforementioned zinc complex is ZnCl ２ , ZnBr ２ ZnI ２ , Zn (OAc) ２ , and Zn (OPiv) ２ A method according to any one of claims 1 to 38, selected from the group consisting of the following.

40. The transition metal catalyst precursor is Pd or Ni catalyst precursor, and Pd(OAc) ２ , PdCl ２ , PdCl ２ (MeCN) ２ , Pd (benzonitrile) ２ Cl ２、 Pd(dba) ２ , Pd ２ (dba) ３ , Pd(PPh ３ ) ４ , Pd(PCy ３ ) ２ , Pd(PtBu ３ ) ２ , Pd(TFA) ２ [Pd(allyl)Cl] ２ [Pd (Cinnamyl) Cl] ２ [PdCl (clotyl)] ２ , PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl ２ NiBr ２ Ni(OAc) ２ The method according to any one of claims 1 to 39, selected from the group consisting of , and nickel(II) acetylacetonate.

41. The aforementioned chiral ligand, And, During the ceremony, Y is O or NR ７ And; Z is either O or N; R ７ and R ８ Independently, non-substituted C １－６ It is alkyl; R ９ and R １０ R is independent of R １１ - Substituted or non-substituted C ５－６ Cycloalkyl or R １１ - Substituted or unsubstituted phenyl; Each R １１ These are, independently, hydrogen and C １－６ Unsubstituted alkyl, or C １－６ It is an unsubstituted haloalkyl; R １２ and R １３ Each of them is independent of R １４ - Substituted or unsubstituted C1-6 alkyl, R １４ - Substituted or non-substituted C ３－７ Cycloalkyl, R １４ - Substituted or unsubstituted aryl, or R １４ - Substituted or non-substituted C ５－７ It is a heteroaryl; Each R １４ Independently, non-substituted C １－４ The method according to any one of claims 1 to 40, wherein the alkyl group is used.

42. R ７ and R ８ The method according to claim 41, wherein the same applies.

43. R ７ and R ８ The method according to claim 42, wherein each of the compounds is methyl, ethyl, or phenyl.

44. The method according to claim 2, wherein the base is LDA or LiTMP.

45. The method according to claim 2, wherein the halogenating agent is NCS or 1,3-dichloro-5,5-dimethylhydantoin.

46. The chlorinating agent is POCl ３ , PCL ３ , PCL ５ , or SOCl ２ The method according to claim 2.

47. The method according to claim 4, wherein the halogenating agent is NIS or 1,3-diiodomo-5,5-dimethylhydantoin.

48. The method according to claim 4, wherein the haloalkylating agent is a fluoroalkylating agent.

49. The method according to claim 4, wherein the haloalkylating agent is methyl 2,2-difluoro-2-(fluorosulfonyl)acetate.

50. The halogenating agent is SF in HF ４ The method according to claim 5 or 6.

51. The compound of formula (II) is: (In the formula, X ３ The method according to claim 1, wherein ( is a halogen).

52. The compound of formula (II) is: (In the formula, X ３ The method according to claim 1, wherein ( is a halogen).

53. The compound of formula (II) is: The method according to claim 1, comprising:

54. The compound of formula (III) is: The method according to claim 1, comprising:

55. R ３ is non-substituted C １－３ The method according to claim 54, wherein the alkyl group is alkyl.

56. R ４ is non-substituted C １－３ The method according to claim 54 or 55, wherein the material is a haloalkyl.

57. The compound of formula (III) is: The method according to claim 1, comprising:

58. The compound of formula (I) is: The method according to claim 1, comprising:

59. The compound of formula (I) is: The method according to claim 1, comprising:

60. R ３ is non-substituted C １－３ The method according to claim 58 or 59, wherein the alkyl group is used.

61. R ４ is non-substituted C １－３ The method according to any one of claims 58 to 60, wherein the material is a haloalkyl.

62. The compound of formula (I) is: The method according to claim 1, comprising:

63. R ２ However, non-substituted C １－６ Alkyl, unsubstituted C １－６ Cyanoalkyl or unsubstituted C １－６ The method according to any one of claims 58 to 62, wherein the material is a haloalkyl.

64. R ２ However, methyl, ethyl, CN, CH ２ CN, CF ３ CHF ２ or CH ２ The method according to claim 63, wherein F.

65. R ２ However, methyl, ethyl, CN or CH ２ The method according to claim 63, wherein the material is CN.

66. The compound of formula (I) is: (In the formula, X ３ The method according to claim 1, wherein ( is a halogen).

67. The compound of formula (I) is: The method according to claim 1, comprising:

68. X ０ However, hydrogen, halogen, CF ３ CHF ２ ,CH ２ F, or the following structure: The method according to claim 1, wherein the portion is a part having the following characteristics.

69. Formula (Id): (In the formula, X ３ A compound that contains (a halogen).

70. Formula (1): A compound having the following properties.

71. Process (f) is Step (g) The compound of formula (IIa) is used in formula (IIa1) The method according to claim 2, further comprising fluorinating the compound.

72. Process (f) is Step (h) The compound of formula (IIa) is used in formula (IId) The method according to claim 2, further comprising alkoxylation of the compound.

73. Process (f) is Step (j) The compound of formula (IIa) is used in step (IIe) The method according to claim 2, further comprising thiolation of the compound.

74. The method according to any one of claims 1 to 6, wherein the compound of formula (I) is one of the compounds in Table 1.

75. formula: A method for synthesizing a compound having or a pharmaceutically acceptable salt thereof, (a) Formula (2) The compound or salt thereof, i-PrMgCl・LiCl and ZnCl ２ It is brought into contact with NaTFA and formula (3) Contacting the compound, (b) The mixture or salt thereof from step (a) is brought into contact with a Pd or Ni catalyst precursor and a chiral ligand, thereby producing formula (1) To synthesize the compound or its solvate or salt, (c) The compound of formula (1) or its solvate or salt, of formula HO-X Ａ (In the formula, X Ａ is an expression The compound (containing) and the base are brought into contact, thereby producing formula (1d) To synthesize the compound or its solvate or pharmaceutically acceptable salt, (d) Contact the compound of formula (1d) with MsOH in an acid, thereby producing formula (1e) To synthesize compounds of the same, or solvates or pharmaceutically acceptable salts thereof; and (e) The compound of formula (1e) or its solvate or a pharmaceutically acceptable salt thereof, in the presence of a base and optionally an activator, A method comprising contacting with to produce a compound of formula (A) or a pharmaceutically acceptable salt thereof.

76. The method according to claim 75, wherein the acid in step (d) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid, or trifluoromethanesulfonic acid.

77. Step (e) involves the compound of formula (1e) or its solvate or pharmaceutically acceptable salt, The method according to claim 75, comprising bringing into contact with the following.

78. Step (e) involves the compound of formula (1e) or its solvate or pharmaceutically acceptable salt, The method according to claim 75, comprising bringing into contact with the following.

79. Step (e) is performed in the presence of a base and an activator, and the formula The method according to claim 75, comprising the compound.

80. Step (e) is, The method according to claim 75, comprising the compound and base.

81. Process: (f) The method according to any one of claims 75 to 80, further comprising contacting the compound of formula (A) with adipic acid in a solvent according to scheme 1, scheme 2, or scheme 3 described herein.

Images