Synthesis of quinazoline compound

Abstract

Provided herein are methods of synthesizing quinazoline compounds comprising at least one tumeroisomeric center. # imgabs0 #

Description

[0001] This case is a divisional application of a patent application with an application date of August 10, 2021, application number 202180056371X, and invention name “Synthesis of Quinazoline Compounds”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 064,746, filed on August 12, 2020, which is incorporated herein by reference in its entirety and for all purposes. Technical Field

[0004] Provided herein are methods for synthesizing atropisomers of quinazolinyl compounds via atropisomer-selective synthetic methods / techniques. Background Art

[0005] The configuration at the biaryl axis often plays an important role in the pharmacological properties of biologically active compounds and is a fundamental basis for useful reagents and catalysts in asymmetric synthesis. Highly atropselective cross-coupling, especially of heterocycles for the synthesis of biheteroaromatics, remains a challenging and unsolved problem. The present disclosure provides an improved method for the atropselective synthesis of aminopyridyl-quinazolinyl compounds via Negishi coupling using chiral ligands such as chiraphites or walphos. Summary of the invention

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

[0007] Disclosed herein are compounds as described herein and methods of preparing compounds of formula (I).

[0008] In one aspect, provided herein is a method for synthesizing a compound of formula (I) as described herein, the method comprising (a) contacting a compound of formula (II) as described herein with an organic magnesium compound and a zinc complex, and (b) contacting the mixture of step (a) with a compound of formula (III) as described herein, a transition metal (e.g., Pd or Ni) catalyst precursor, and a chiral ligand, thereby synthesizing a compound of formula (I).

[0009] In one aspect, provided herein are compounds of formula (I) as described herein, or solvates, tautomers, stereoisomers, atropisomers or salts thereof. In one aspect provided herein, compounds of formula (I) have formula Ia, Ib, Ib1, Ib2, Ib3, Ic1, Ic2, Id, Ia, Ib, Ic or 1 as described herein.

[0010] In another aspect, provided herein is a method for preparing a compound of formula (I), comprising: (a) contacting a compound of formula (II) as described herein or a tautomer, stereoisomer or salt thereof with an organic magnesium compound and a zinc complex; (b) contacting the mixture of step (a) with a compound of formula (III) as described herein or a stereoisomer or salt thereof, a transition metal (e.g., Pd or Ni) catalyst precursor and a chiral ligand, thereby synthesizing a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof.

[0011] Further provided herein is a process (P2) as described herein for preparing a compound of formula (II) as described herein, or a tautomer, stereoisomer or salt thereof.

[0012] In another aspect, provided herein is a process (P3) as described herein for preparing a compound of formula (III) as described herein or a salt thereof.

[0013] In another aspect, provided herein is a process (P4) as described herein for preparing a compound of formula (III) as described herein or a salt thereof.

[0014] In another aspect, provided herein is a process (P5) as described herein for preparing a compound of formula (III) as described herein or a salt thereof.

[0015] In another aspect, provided herein is a process (P6) as described herein for preparing a compound of formula (G) as described herein, or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof.

[0016] In another aspect, provided herein is a process (P7) as described herein for preparing a compound of formula (H) as described herein, or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof.

[0017] In another aspect, provided herein is a process as described herein for preparing a compound of formula (F) as described herein, or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof (P8).

[0018] In another aspect, provided herein is a process as described herein for preparing a compound of formula (F) as described herein, or a pharmaceutically acceptable salt thereof (P8). BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The single crystal structure of the cyclohexane crystalline solvate of Compound 1 is shown.

[0020] Figure 2 The single crystal structure of the methylcyclohexane crystalline solvate of Compound 1 is shown.

[0021] Figure 3The single crystal structure of the chlorobenzene crystalline solvate of Compound 1 is shown.

[0022] Figure 4 The single crystal structure of the ethylbenzene crystalline solvate of Compound 1 is shown.

[0023] Figure 5 The single crystal structure of the m-toluene crystalline solvate of Compound 1 is shown.

[0024] Figure 6 The single crystal structure of the toluene crystalline solvate of Compound 1 is shown. DETAILED DESCRIPTION

[0025] definition

[0026] The terms "halogen" and "halo" are used interchangeably herein to refer to F, Cl, Br or I.

[0027] The term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon radical. In one example, an alkyl group is one to eighteen carbon atoms (C 1-18 In other examples, the alkyl group is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 or C 1-3Examples of alkyl groups include methyl (Me, –CH3), ethyl (Et, –CH2CH3), 1-propyl (n-Pr, n-propyl, –CH2CH2CH3), 2-propyl (i-Pr, isopropyl, –CH(CH3)2), 1-butyl (n-Bu, n-butyl, –CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, –CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, –CH(CH3)CH 2CH3), 2-methyl-2-propyl (t-Bu, tert-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 (–CH2 CH2CH(CH3)2), 2-methyl-1-butyl (–CH2CH(CH3)CH2CH3), 1-hexyl (–CH2CH2CH2CH2CH2CH3), 2-hexyl (–CH(CH3)CH2CH2CH2CH3), 3-hexyl (–CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (–C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (–CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (–CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (–C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (–CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (–C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (–CH(CH3)C(CH3)3, 1-heptyl, and 1-octyl.

[0028] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens are replaced by halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl and fluoromethyl. "Fluoroalkyl" refers to an alkyl chain in which one or more hydrogens are replaced by F.

[0029] The term "hydroxy" refers to -NH2.

[0030] The term "oxo" refers to =0.

[0031] The term "carboxy" refers to -C(=O)OH.

[0032] The term "alkoxy" refers to an -O-alkyl group.

[0033] The terms "cyano" and "nitrile" are used interchangeably herein and refer to -C≡N or -CN.

[0034] The term "cyanoalkyl" refers to an alkyl group substituted with a cyano substituent.

[0035] The term "haloalkoxy" refers to an -O-haloalkyl group.

[0036] The term "hydroxyl" refers to -OH.

[0037] The term "hydroxyalkyl" refers to an alkyl group substituted with one hydroxy substituent.

[0038] The term "aryl" refers to a carbocyclic aromatic group, whether or not fused to one or more groups, having a specified number of carbon atoms, or if no number is specified, up to 14 carbon atoms. One example includes an aryl group having 6 to 14 carbon atoms. Another example includes an aryl group having 6 to 10 carbon atoms. Another example includes an aryl group having 5 to 7 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like (see, e.g., Lang's Handbook of Chemistry (Dean, JA, ed.) 13 th ed.Table 7-2

[1985] ). The specific aryl group is phenyl.

[0039] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyl includes monocyclic, bicyclic, tricyclic, spirocyclic and bridged saturated ring systems. In one example, a cycloalkyl is 3 to 12 carbon atoms (C 3-12 In another example, the cycloalkyl group as a bicyclic ring is C 3-7 , C 3-8 , C 3-10 or C 5-10 In other examples, the cycloalkyl group as a monocyclic ring is C 3-8 , C 3-6 or C 5-6 In another example, the cycloalkyl group as a bicyclic ring is C7-C 12 In another example, the cycloalkyl group as the spiro ring system is C 5-12. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Examples of spirocycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.

[0040] The terms "heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl" or "heterocycle" are used interchangeably and refer to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system having 3 to 20 ring atoms, wherein the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of the ring system is a heteroatom, the system is a heterocycle, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, the heterocyclyl includes 3 to 11 ring atoms ("members") and includes monocyclic, bicyclic, tricyclic, spiro and bridged ring systems, wherein the ring atoms are carbon, wherein at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In other examples, the heterocyclyl includes 4 to 10 or 5 to 10 ring atoms. In one example, the heterocyclyl includes 1 to 4 heteroatoms. In one example, the heterocyclyl includes 1 to 3 heteroatoms. In another example, the heterocyclic group includes a 3- to 7-membered monocyclic ring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, the heterocyclic group includes a 4- to 6-membered monocyclic ring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, the heterocyclic group includes a 3-membered monocyclic ring. In another example, the heterocyclic group includes a 4-membered monocyclic ring. In another example, the heterocyclic group includes a 5- to 6-membered monocyclic ring. In some embodiments, the heterocycloalkyl group includes at least one nitrogen. In one example, the heterocyclic group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR4] + Cl - 、[NR4] + OH -). Examples of heterocycles are oxirane, azetidinyl, thiopyranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolyl, tetrahydroisoquinolyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thiooxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine 1,4-diazepanyl, ... Thiazepine 1,1-dihydro-1,2 ... , thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolyl, pyrazolidinyl, dithienyl, dithiolanyl, pyrimidinone, pyrimidinedione, pyrimidine-2,4-diacyl, piperazinone, piperazine diacyl, pyrazolyl imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[3.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 2-azabicyclo[3.2.1]octyl, 2-azabicyclo[3.2.1]octyl, 2-azabicyclo[3.2.1]octyl, 2-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.1]oct ... bis[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptyl, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]dec-2-yl, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindolyl, 1,1-dioxohexahydrothiopyranyl.

[0041] The term "heteroaryl" refers to any monocyclic, bicyclic or tricyclic aromatic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and in an exemplary embodiment, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, JA, ed.) 13 th ed.Table 7-2

[1985] . Included in the definition are any bicyclic groups in which any of the above heteroaryl rings are fused to an aryl ring, wherein either the aryl ring or the heteroaryl ring is joined to the rest of the molecule. In one embodiment, the heteroaryl group includes a 5-6 membered monocyclic aromatic group in which one or more of the ring atoms is nitrogen, sulfur, or oxygen. Exemplary heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, and purinyl, as well as benzo-fused derivatives such as benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl.

[0042] In certain embodiments, the heterocyclyl or heteroaryl group is attached to a carbon atom of the heterocyclyl or heteroaryl group. For example, carbon-bonded heterocyclyl groups include the following bonding arrangements: at position 2, 3, 4, 5, or 6 of a pyridine ring; position 3, 4, 5, or 6 of a pyridazine ring; position 2, 4, 5, or 6 of a pyrimidine ring; position 2, 3, 5, or 6 of a pyrazine ring; position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring; position 2, 4, or 5 of an oxazole, imidazole, or thiazole ring; position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring; position 2 or 3 of an aziridine ring; position 2, 3, or 4 of an azetidine ring; position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring; or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

[0043] In certain embodiments, the heterocyclyl or heteroaryl is N-linked. For example, nitrogen-bonded heterocyclyl or heteroaryl groups include the following bonding arrangements: at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidinyl, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole; at position 2 of isoindole or isoindoleline; at position 4 of morpholine; and at position 9 of carbazole or β-carboline.

[0044] "Fused" refers to any ring structure described herein that shares one or more atoms (eg, carbon or nitrogen atoms) with an existing ring structure in the compounds of the invention.

[0045] The term "acyl" refers to a carbonyl group containing a substituent represented by the formula -C(=O)-R, wherein R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein alkyl, cycloalkyl, aryl and heterocyclyl are as defined herein. Acyl includes alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl) and heteroaroyl (e.g., pyridinoyl).

[0046] As used herein, "halogenating agent" refers to any reagent that adds one or more halogens to a compound described herein. As used herein, "chlorinating agent" refers to any reagent that adds one or more chlorine (Cl) atoms to a compound 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 a compound described herein.

[0047] As used herein, "haloalkylating agent" refers to any reagent that adds one or more haloalkyl groups (eg, CF3) to a compound described herein. "Fluoroalkylating agent" refers to a reagent that adds one or more fluoroalkyl groups to a compound described herein.

[0048] An "organomagnesium compound" is an organometallic compound in which the metal is magnesium.

[0049] "LDA" refers to lithium diisopropylamide.

[0050] "LiTMP" or "LTMP" refers to lithium tetramethylpiperidinium.

[0051] "NCS" refers to N-chlorosuccinimide. "NBS" refers to N-bromosuccinimide. "NIS" refers to N-iodosuccinimide.

[0052] As used herein, "chiral ligand" refers to one or more compounds and / or catalysts that result in the synthesis of a chiral compound (eg, an atropisomer).

[0053] As used herein, a wavy line intersecting a bond in a chemical structure Indicates the point of attachment of an atom in a chemical structure to the rest of a molecule or molecular fragment by a wavy bond.

[0054] In certain embodiments, a divalent group is generally described without a specific bonding configuration. Unless otherwise specified, it should be understood that the general description is meant to include both bonding configurations. For example, unless otherwise specified, in the group R 1 –R 2 –R 3 If the group R 2 If described as -CH2C(O)-, it is understood that this group can be R 1 –CH2C(O)–R3 And R 1 –C(O)CH2–R 3 Bonding.

[0055] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals such as, for example, humans (where appropriate).

[0056] The compounds of the present invention may be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base and are biologically or otherwise desirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids, the organic acid can be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic acid and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, fruit 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, embolic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0057] The term "pharmaceutical base addition salt" includes base addition salts derived from inorganic bases, such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts and the like. Specific base addition salts are ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines) cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, salts of polyamine resins, etc. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and caffeine.

[0058] In some embodiments, the salt is selected from hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, disulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), naphthalene disulfonate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethane disulfonate ( The salts of the compounds include benzoate, adipate, ethanesulfonate, malonate, trimethylbenzenesulfonate (2-mesitylenesulfonate), naphthoate (2-naphthalenesulfonate), camphorate (camphor-10-sulfonate, such as (1S)-(+)-10-camphorsulfonate), glutamate, glutarate, hippurate (2-(benzamido)acetate), orotate, ditoluenesulfonate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthomethane-3,3'-dicarboxylate).

[0059] Compounds of the present invention may include one or more chiral carbon atoms. Therefore, the compound may exist as diastereomers, enantiomers or mixtures thereof. The synthesis of these compounds may use racemates, diastereomers or enantiomers as starting materials or as intermediates. The mixture of specific diastereoisomers may be separated or enriched in the form of one or more specific diastereomers by chromatography or crystallization methods. Similarly, enantiomeric mixtures may be separated or enantiomeric enriched using the same techniques or other techniques known in the art. Each asymmetric carbon or nitrogen atom may be in the form of R or S configuration and both configurations are within the scope of the present invention.

[0060] In the structures shown herein, where the stereochemistry of any particular pair of chiral atoms is not specified, all stereoisomers are contemplated and included as compounds of the present invention. Where stereochemistry is designated by a solid wedge or dashed line representing a particular configuration, that stereoisomer is designated and defined in that manner. Unless otherwise specified, relative stereochemistry is intended when a solid wedge or dashed line is used.

[0061] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformational isomers, and the like.

[0062] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image partner, whereas the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0063] The term "diastereomer" refers to stereoisomers with two or more chiral centers and molecules that are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography (such as HPLC).

[0064] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0065] "Atropisomers" are stereoisomers that arise due to hindered rotation about a single bond or axis where energy differences due to steric strain or other factors create a sufficiently high barrier to rotation to allow separation of the individual conformers.

[0066] Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In 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 specify the sign of rotation of plane-polarized light around the compound, where (-) or l indicates that the compound is left-handed. Compounds with the (+) or d prefix are right-handed. For a given chemical structure, these stereoisomers are identical, but they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of these isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers refers to a racemic mixture or racemate, which may occur in a chemical reaction or process where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which is not optically active.

[0067] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions that occur by reorganization of some of the bonding electrons.

[0068] As used herein, the term "amino protecting group" refers to a derivative of a group that is generally used to block or protect an amino group, and reacts on other functional groups of a compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups and imines and many N-heteroatom derivatives, which can be removed to regenerate the desired amino group. Specific amino protecting groups are PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl), Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or triphenylmethyl), benzylidene, p-toluenesulfonyl or DMB (dimethoxybenzyl). In certain embodiments, an amino protecting group may be a group for blocking or protecting an amino group, which is produced by cyclization of a group connected to an amino group but can be removed or replaced subsequently. Such examples include 1,3,5-dioxazinane, 2,4-dimethyl-1,3,5-dioxazinane, 2,2,5,5-tetramethyl-1,2,5-azadisilamine and isoindoline-1,3-dione. Further exemplary amino protecting groups can be found in TW Greene and P.G.M. Wuts, "Protecting Groups in Organic Synthesis, 3 rd ed., John Wiley & Sons, Inc., 1999. The term "protected amino" refers to an amino group substituted with one of the above-mentioned amino protecting groups.

[0069] The term "leaving group" refers to a portion of the first reactant in a chemical reaction that moves away from the first reactant in the chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy groups, and sulfonyloxy groups. Exemplary sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (e.g., methylsulfonyloxy (mesylate) and trifluoromethylsulfonyloxy (trifluoromethanesulfonate)) and arylsulfonyloxy groups (e.g., p-toluenesulfonyloxy (toluenesulfonate) and p-nitrosulfonyloxy (nitrobenzenesulfonate)).

[0070] The terms "inhibit" and "reduce" or any variation of these terms include any measurable reduction or complete inhibition of the desired result. For example, the reduction in activity compared to normal activity can be a reduction of 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 derivable therein.

[0071] 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 action of the target protein. Although the preferred antagonists herein specifically interact with the target (e.g., bind to the target), compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway are also explicitly included in the definition, and the target protein is a member of the signal transduction pathway. The preferred biological activity inhibited by the antagonist is related to the generation, growth or spread of a tumor.

[0072] As used herein, the term "agonist" refers to a compound that has the ability to induce or enhance the biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Therefore, the term "agonist" is defined in the context of the biological effect of the target polypeptide. Although the preferred agonists herein specifically interact with the target (e.g., bind to the target), compounds that induce or enhance the biological activity of the target polypeptide by interacting with other components of the signal transduction pathway are also explicitly included in the definition, and the target polypeptide is a member of the signal transduction pathway.

[0073] The terms "cancer" and "cancerous," "neoplasm," and "tumor," and related terms refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include malignancies, blastomas, sarcomas, seminomas, glioblastomas, melanomas, leukemias, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas) and lung cancers, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinomas, and lung squamous cell carcinomas. Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cancer, pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, stomach cancer, stomach tumors, gastrointestinal cancer, small intestine cancer, large intestine cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, urinary system tumors, bile duct cancer, thyroid cancer, papillary cancer, liver tumors, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penis cancer, bone cancer, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system tumors, brain cancer, head and neck cancer, Hodgkin's disease and related metastases. Examples of neoplastic disorders include myeloproliferative diseases such as polycythemia vera, essential thrombocythemia, myelofibrosis (such as primary myelofibrosis), and chronic myeloid leukemia (CML).

[0074] A "chemotherapeutic agent" is an agent suitable for treating a given condition, such as cancer or an inflammatory condition. Examples of chemotherapeutic agents are well known in the art and include, for example, those disclosed in U.S. Published Application No. 2010 / 0048557, which is incorporated herein by reference. In addition, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any chemotherapeutic agent and combinations of two or more thereof.

[0075] Unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 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. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled compounds) are useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes may be useful due to their ease of preparation and detectability. Further, deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds of the invention, one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon replacement. Positron-emitting isotopes (e.g. 15 O. 13 N. 11 C and 18 ) is suitable for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0076] It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. In addition, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention.

[0077] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0078] Compound

[0079] Provided herein are compounds of formula (I):

[0080]

[0081] or a solvate, tautomer, stereoisomer, atropisomer or salt thereof

[0082] in,

[0083] X 0 For 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

[0084] or R 5 -substituted or unsubstituted C 5-7 heteroaryl;

[0085] X 1 is hydrogen or halogen;

[0086] 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 -Pick

[0087] substituted or unsubstituted cyclopropyl;

[0088] R 1 Hydrogen or PG 1 ;

[0089] Each R 2are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 Haloalkyl;

[0090] 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;

[0091] R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 Haloalkyl;

[0092] R 4 For R 4A -substituted or unsubstituted C 1-3 Haloalkyl;

[0093] R 4A For unsubstituted C 1-3 alkyl;

[0094] R 5 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 -substituted or unsubstituted 3-6 membered heterocyclic ring, R 5A -substituted or unsubstituted phenyl or R 5A - substituted or unsubstituted 6-membered heteroaryl;

[0095] R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C 1-6 Alkyl, R 5C -substituted or unsubstituted C 1-6 Haloalkyl, R 5C -substituted or unsubstituted C 3-7 Cycloalkyl; R5C -substituted or unsubstituted 3-7 membered heterocyclic ring; R 5C -substituted or unsubstituted C 5-7 Aryl or R 5C -substituted or unsubstituted C 5-7 heteroaryl;

[0096] R 5C are independently hydrogen, 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 Heterocyclic ring; R 5D -substituted or unsubstituted C 5-7 Aryl or R 5D -substituted or unsubstituted C 5-7 heteroaryl;

[0097] R 5D are independently hydrogen, halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl, unsubstituted C 3-7 Cycloalkyl; unsubstituted C 3-7 Heterocyclic; Unsubstituted C 5-7 Aryl or unsubstituted C 5-7 heteroaryl;

[0098] R 6 is hydrogen, halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 Cycloalkyl;

[0099] n is 1 or 2;

[0100] Each PG is independently an amino protecting group, or two PGs together form a C 3-8 a nitrogen heterocycle; and

[0101] PG 1 It is an amino protecting group.

[0102] In one embodiment of the compound of formula (I) described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, X 0 For halogen, OR 5A , SR5B , 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 In one embodiment of the compound of formula (I) described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, X 0 is hydrogen, halogen or OR 5A In another embodiment of the compound of formula (I) described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, X 0 For 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 In another embodiment of the compound of formula (I) described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, X 0 is hydrogen, halogen, CF3, CHF2 or CH2F. In a preferred embodiment, X 0 In one such embodiment of the compounds of Formula (I) described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, X 0 For F.

[0103] In another embodiment of the compounds of Formula (I) described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, X 0 is hydrogen, halogen, CF3, CHF2, CH2F or a moiety having the following structure:

[0104]

[0105]

[0106] or a stereoisomer thereof.

[0107] In one embodiment of the compound of formula (I) described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, R5 is halogen, cyano, OH or NO2. In one embodiment of the compound of formula (I) described herein or its solvate, tautomer, stereoisomer, atropisomer or salt, R 5 For R 5A -substituted or unsubstituted C 1-6 Alkyl, R 5A -substituted or unsubstituted C 1-6 Haloalkyl or R 5A -substituted or unsubstituted C 1-6 In one embodiment of the compound of formula (I) described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, R 5 For R 5A -substituted or unsubstituted C 3-6 Cycloalkyl, R 5A -substituted or unsubstituted 3-6 membered heterocyclic ring, R 5A -substituted or unsubstituted phenyl or R 5A -substituted or unsubstituted 6-membered heteroaryl.

[0108] In one embodiment, R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C 1-6 Alkyl or R 5C -substituted or unsubstituted C 1-6 In another embodiment, R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C 3-7 Cycloalkyl; R 5C -substituted or unsubstituted 3-7 membered heterocyclic ring, R 5C -substituted or unsubstituted C 5-7 Aryl or R 5C -substituted or unsubstituted C 5-7 In a preferred embodiment, R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C 1-6 alkyl.

[0109] In one embodiment, R 5C are independently halogen, OH, CN or NO2. In one embodiment, R 5C Independently for R 5D -substituted or unsubstituted C 1-6 Alkyl or R 5D -substituted or unsubstituted C1-6 In one embodiment, R 5C Independently for R 5D -substituted or unsubstituted C 3-7 Cycloalkyl or R 5D -substituted or unsubstituted C 3-7 In one embodiment, R 5C Independently for R 5D -substituted or unsubstituted C 5-7 Aryl or R 5D -substituted or unsubstituted C 5-7 In another embodiment, R 5C Independently for R 5D -substituted or unsubstituted C 3-7 Heterocyclic or R 5D -substituted or unsubstituted C 5-7 In another embodiment, R 5C For R 5D -substituted or unsubstituted pyrrolidinyl.

[0110] In one embodiment, R 5D are independently halogen, OH or CN. In another embodiment, R 5D For unsubstituted C 1-6 In another embodiment, R 5D For unsubstituted C 1-6 In another embodiment, R 5D For unsubstituted C 3-7 Cycloalkyl, unsubstituted C 3-7 Heterocyclic, unsubstituted C 5-7 Aryl or unsubstituted C 5-7 In one embodiment, R 5D It is methyl, ethyl or propyl.

[0111] In one embodiment, R 5A and R 5B Each independently

[0112]

[0113]

[0114] In one embodiment, R 5A and R 5B Each independently

[0115]

[0116]

[0117] In other aspects, provided herein is a compound of formula (Ia):

[0118]

[0119] or a solvate, tautomer, stereoisomer or salt thereof

[0120] in,

[0121] X 0 is hydrogen, halogen or OR 5A ;

[0122] X 1 and X 3 are independently halogen or methyl;

[0123] R 1 Hydrogen or PG 1 ;

[0124] Each R 2 are independently halogen, cyano, methyl, ethyl, propyl, -CH2CN,

[0125] (CH2)2CN, CF3, CHF2 or CH2F;

[0126] R 3 is hydrogen or methyl;

[0127] R 5A for

[0128]

[0129]

[0130] n is 0, 1 or 2;

[0131] Each PG is independently an amino protecting group, or two PGs together form a C 3-8 a nitrogen heterocycle; and

[0132] PG 1 It is an amino protecting group.

[0133] Further provided herein are compounds of formula (Ib):

[0134]

[0135] or a solvate, tautomer, stereoisomer, atropisomer or salt thereof

[0136] in,

[0137] X 1 is hydrogen or halogen;

[0138] 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 -Pick

[0139] substituted or unsubstituted cyclopropyl;

[0140] R 1 Hydrogen or PG 1 ;

[0141] Each R 2 are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 Haloalkyl;

[0142] 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;

[0143] R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 halogen

[0144] Alkyl groups;

[0145] R 4 For R 4A -substituted or unsubstituted C 1-3 Haloalkyl;

[0146] R 4A For unsubstituted C 1-3 alkyl;

[0147] R 6 is hydrogen, halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted

[0148] Generation C 1-6 Haloalkyl or unsubstituted C 3-7 Cycloalkyl;

[0149] n is 0, 1 or 2;

[0150] Each PG is independently an amino protecting group, or two PGs together form a C 3-8 a nitrogen heterocycle; and

[0151] PG 1 It is an amino protecting group.

[0152] In one embodiment, X 1 In one embodiment, X 1 In one embodiment, X 1 In another embodiment, when X 1 When X is a halogen, 3 In another embodiment, when X 1 When F, X 3 In another embodiment, when X 1 When F, X 3 For Cl.

[0153] In one embodiment, X 3 is hydrogen, halogen, R 6 -substituted or unsubstituted C 1-3 Alkyl or R 6 -substituted or unsubstituted C 1-3 In another embodiment, X 3 For R 6 -substituted or unsubstituted C 1-3 Alkoxy or R 6 -substituted or unsubstituted cyclopropyl. In another embodiment, X 3 In another embodiment, X 3 is halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3 In another embodiment, X 3 is halogen or unsubstituted C 1-3 In another embodiment, X 3 For unsubstituted C 1-3 In a preferred embodiment, X 3 In one such embodiment, X 3 is Cl or F. In another embodiment, X 3 is Cl, F, CF3, CHF2 or CH2F. In another embodiment, X 3 It is CF3, CHF2 or CH2F.

[0154] In one embodiment, R 1In a preferred embodiment, R 1 For PG 1 In one such embodiment, PG 1 is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidene, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl). In another embodiment, PG 1 is Boc (tert-butyloxycarbonyl). In a preferred embodiment, R 1 It is Boc (tert-butoxycarbonyl).

[0155] In one embodiment, each R 2 are independently halogen or cyano. 2 are independently halogen or unsubstituted C 1-6 In another embodiment, each R 2 is independently unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 In one such embodiment, n is 1. In a preferred embodiment, each R 2 is independently unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 In one such 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, 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 is CH2CN and n is 1. In another embodiment, n is 0.

[0156] In one embodiment, R 3 is hydrogen or halogen. In one embodiment, R 3 In another embodiment, R 3 is hydrogen, R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3In another embodiment, R 3 For R 3A -substituted or unsubstituted C 1-3 Alkyl or R 3A -substituted or unsubstituted C 1-3 In another embodiment, R 3 is hydrogen or R 3A -substituted or unsubstituted C 1-3 In another embodiment, R 3 For R 3A -substituted or unsubstituted C 1-3 In one such embodiment, R 3 In another such embodiment, R 3 It is methyl.

[0157] In one embodiment, R 3 For R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 A haloalkyl group, wherein R 3A is halogen, OH, CN or unsubstituted C 1-3 In one such embodiment, R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 A haloalkyl group, wherein R 3A It is F, OH, CN, CF3, CHF2 or CH2F.

[0158] In a preferred embodiment, R 4 For unsubstituted C 1-3 In one such embodiment, R 4 is CF3, CHF2 or CH2F. In one such embodiment, R 4 It is CF3.

[0159] In one embodiment, R 6 In another embodiment, R 6 OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 Cycloalkyl.

[0160] In one embodiment, each PG is independently an amino protecting group. In one embodiment, each PG is the same. In one such embodiment, each PG is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidene, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl). In another embodiment, each PG is PMB, DMB or Boc. In a preferred embodiment, each PG is PMB.

[0161] In yet another embodiment, two PGs together form C3 -8 In one embodiment, two PGs together form a moiety having the following structure:

[0162]

[0163] In another aspect, provided herein is a compound of formula (Ib1):

[0164]

[0165] or a solvate, tautomer, stereoisomer, atropisomer or salt thereof

[0166] in,

[0167] X 1 and X 3 are independently halogen or methyl;

[0168] R 1 Hydrogen or PG 1 ;

[0169] Each R 2 are independently halogen, cyano, methyl, ethyl, propyl, -CH2CN,

[0170] (CH2)2CN, CF3, CHF2 or CH2F;

[0171] n is 1 or 2; and

[0172] PG 1 It is an amino protecting group.

[0173] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer, atropisomer or salt thereof comprises a compound of formula (Ib2):

[0174]

[0175] or a solvate, tautomer, stereoisomer, atropisomer or salt thereof.

[0176] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer, atropisomer or salt thereof comprises a compound of formula (Ib3):

[0177]

[0178] or a solvate, tautomer, stereoisomer or salt thereof.

[0179] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0180]

[0181] or a solvate, tautomer, stereoisomer or salt thereof.

[0182] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0183]

[0184] or a solvate, tautomer, stereoisomer or salt thereof.

[0185] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0186]

[0187] or a solvate, tautomer, stereoisomer or salt thereof.

[0188] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0189]

[0190] or a solvate, tautomer, stereoisomer or salt thereof.

[0191] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0192]

[0193] or a solvate, tautomer, stereoisomer or salt thereof.

[0194] In one embodiment, the compound of formula (I) described herein or its solvate, tautomer, stereoisomer or salt is a compound of formula 1:

[0195]

[0196] or a solvate, tautomer, stereoisomer or salt thereof.

[0197] Further provided herein are crystalline solvates of the compound of formula (I). In one embodiment, the compound of formula (I) is a cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene or toluene solvate.

[0198] In one embodiment, the compound of formula (I) is a crystalline solvate of a compound of formula 1:

[0199]

[0200] In one embodiment, the compound of formula (1) is a cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene or toluene solvate. In one embodiment, the compound of formula (1) is a crystalline cyclohexane solvate. In one such embodiment, the crystalline cyclohexane solvate of the compound of formula (1) is substantially as follows Figure 1 In another embodiment, the compound of formula (1) is a crystalline methylcyclohexane solvate. In one such embodiment, the crystalline methylcyclohexane solvate of the compound of formula (1) is substantially as Figure 2 In another embodiment, the compound of formula (1) is a crystalline chlorobenzene solvate. In one such embodiment, the crystalline chlorobenzene solvate of the compound of formula (1) is substantially as Figure 3 In another embodiment, the compound of formula (1) is a crystalline ethylbenzene solvate. In one such embodiment, the crystalline ethylbenzene solvate of the compound of formula (1) is substantially as follows Figure 4 In another embodiment, the compound of formula (1) is a crystalline meta-xylene solvate. In one such embodiment, the crystalline meta-xylene solvate of the compound of formula (1) is substantially as 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 follows Figure 6 shown.

[0201] In another aspect, provided herein is a crystalline solvate solid form of Compound (1).

[0202]

[0203] In certain embodiments, the crystalline solvate is a crystalline cyclohexane solvate of Compound 1. In one embodiment, the crystalline cyclohexane solvate of Compound 1 is obtained from cooling a hot cyclohexane solution to about room temperature. In one such embodiment, the solution is cooled for about 72 hours. In one embodiment, the crystalline cyclohexane solvate of Compound 1 is substantially as Figure 1 In another embodiment, the cyclohexane crystalline solvate of Compound 1 has a unit cell size as shown in Table 2.

[0204] In certain embodiments, the crystalline solvate is a crystalline methylcyclohexane solvate of Compound 1. In one embodiment, the crystalline methylcyclohexane solvate of Compound 1 is obtained from cooling a hot methylcyclohexane solution to about room temperature. In one such embodiment, the solution is cooled for about 48 hours. In one embodiment, the crystalline methylcyclohexane solvate of Compound 1 is substantially as Figure 2 In another embodiment, the methylcyclohexane crystalline solvate of Compound 1 has a unit cell size as shown in Table 3.

[0205] In certain embodiments, the crystalline solvate is a crystalline chlorobenzene solvate of Compound 1. In one embodiment, the crystalline chlorobenzene solvate of Compound 1 is obtained from a saturated chlorobenzene solution followed by slow vapor diffusion of heptane. In one embodiment, the crystalline chlorobenzene solvate of Compound 1 is substantially as Figure 3 In another embodiment, the chlorobenzene crystalline solvate of Compound 1 has a unit cell size as shown in Table 4.

[0206] In certain embodiments, the crystalline solvate is a crystalline ethylbenzene solvate of Compound 1. In one embodiment, the crystalline ethylbenzene solvate of Compound 1 is obtained from a saturated ethylbenzene solution followed by slow vapor diffusion of heptane. In one embodiment, the crystalline ethylbenzene solvate of Compound 1 is substantially as Figure 4 In another embodiment, the ethylbenzene crystalline solvate of Compound 1 has a unit cell size as shown in Table 5.

[0207] In certain embodiments, the crystalline solvate is a crystalline meta-xylene solvate of Compound 1. In one embodiment, the crystalline meta-toluene solvate of Compound 1 is obtained from a saturated meta-toluene solution followed by slow vapor diffusion of heptane. In one embodiment, the crystalline meta-toluene solvate of Compound 1 is substantially as Figure 5 In another embodiment, the meta-toluene crystalline solvate of Compound 1 has a unit cell size as listed in Table 6.

[0208] In certain embodiments, the crystalline solvate is a 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 Figure 6 In another embodiment, the toluene crystalline solvate of Compound 1 has a unit cell size as listed in Table 7.

[0209] In another embodiment, the compound of formula (I) described herein or its solvate, tautomer, stereoisomer, atropisomer or salt is a compound having the formula as shown in Table 1 or its solvate, tautomer, stereoisomer, atropisomer or salt.

[0210] Table 1:

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218] In one embodiment, the compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof comprises a 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 another embodiment, the compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof is a compound of formula 105, 106, 120, 126, 128, 129, 131, 137, 143 or 148. In 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, wherein R 1 For Boc.

[0219] In another embodiment, the compound of formula (I) is a crystalline solvate of a 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 a 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 a compound of formula 105, 126, 128, 129, 131 or 143, wherein R 1 In one embodiment, the compound of formula (I) is a crystalline solvate of the compound of formula 105, wherein R 1 For Boc.

[0220] Preparation method

[0221] Further provided herein are methods for preparing compounds of formula (I):

[0222]

[0223] or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, wherein 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 a cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene or toluene solvate.

[0224] In one aspect, provided herein is a method (P1) for preparing a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, the method comprising:

[0225] (a) making a compound of formula (II)

[0226]

[0227] or a tautomer, stereoisomer or salt thereof, wherein

[0228] X 0 , X 1 , X 3 , R 1 and R2 as described herein; and

[0229] X 2 Halogen or ZnY 1 , where Y 1 is halogen (e.g., Cl, Br or I), OAc, TFA, OTf or OPiv;

[0230] contacting with an organomagnesium compound and a zinc complex; and

[0231] (b) mixing the mixture of step (a) with a compound of formula (III),

[0232]

[0233] or a stereoisomer or salt thereof, wherein X 4 is a halogen;

[0234] A transition metal (eg, Pd or Ni) catalyst precursor and a chiral ligand are contacted to synthesize a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof.

[0235] In a preferred embodiment of the method (P1) described herein, X 0 In one such embodiment, X 0 In another embodiment, X 0 A portion selected from the group consisting of:

[0236]

[0237] In one embodiment of the method (P1) described herein, the organomagnesium compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, tri-n-butylmagnesium lithium, tri-isopropylmagnesium lithium, and (isopropyl)(di-n-butylbutyl)magnesium lithium. In one such 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°C to about -40°C. In one such embodiment, the temperature is about -80°C to about -60°C. In yet another embodiment, the temperature is about -70±5°C.

[0238] In one embodiment of the method (P1) described herein, 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 another embodiment, the zinc complex is Zn(OAc)2, Zn(TFA)2, Zn(OTf)2, or Zn(OPiv)2.

[0239] In one embodiment of the method (P1) described herein, the method is carried out in a polar aprotic solvent. In one such embodiment, the polar aprotic solvent is dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), ethyl acetate (EtOAc), acetonitrile (ACN or MeCN), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone or hexamethylphosphoric acid triamide (HMPA) or a combination thereof. In another embodiment, the method is carried out in THF. In another embodiment, the method is carried out in 2-MeTHF. In yet another embodiment, the method is carried out in THF and MeTHF.

[0240] In one embodiment of process (P1 ) described herein, the transition metal catalyst precursor is a Pd or Ni catalyst precursor. In one embodiment of the method (P1) described herein, the Pd or Ni catalyst precursor is selected from the group consisting of: Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl2, Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(lauroyl)Cl]2, [PdCl(crotyl)]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.

[0241] In one such embodiment of the method (P1) described herein, 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(lauroyl)Cl]2, [PdCl(crotyl)]2, PdCl(η5-cyclopentadienyl) or [(η3-allyl)(η5-cyclopentadienyl)palladium(II)]. In another embodiment of the method (P1) described herein, the Pd catalyst precursor is Pd(OAc)2 or PdCl2. In another embodiment of the method (P1) described herein, the Pd catalyst precursor is [PdCl(crotyl)]2, PdCl(η5-cyclopentadienyl), PdCl2(MeCN)2, Pd(dba)2, Pd2(dba)3, or Pd(TFA)2. In another embodiment of the method (P1) described herein, the Pd catalyst precursor is [Pd(allyl)Cl]2, [Pd(lauroyl)Cl]2, or (η3-allyl)(η5-cyclopentadienyl)palladium(II). In one embodiment, the Pd catalyst precursor is [Pd(allyl)Cl]2 or [Pd(lauroyl)Cl]2. In one embodiment, the Pd catalyst precursor is [Pd(lauroyl)Cl]2.

[0242] In another embodiment of the method (P1) described herein, 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 acetylacetonate nickel(II). 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 acetylacetonate nickel(II).

[0243] In one embodiment, step 1 of the P1 process is performed using a continuous flow mode including one or more continuous stirred reactors (CSTRs). In one embodiment, the Pd precursor described herein is contacted with a chiral ligand described herein to form a Pd-ligand complex in situ. In another embodiment, the Pd precursor described herein is treated with a chiral ligand described herein to form a Pd-ligand complex, which can be separated prior to use in the process described herein.

[0244] In one embodiment of the process (P1) described herein, the chiral ligand is:

[0245]

[0246] in

[0247] Y is O or NR 7 ;

[0248] Z is O or N;

[0249] R 7 and R 8 are each independently unsubstituted C 1-6 Alkyl or unsubstituted phenyl;

[0250] or where R 7 and R 8 Together they form unsubstituted C 5-6 Cycloalkyl or unsubstituted C 6-10 Aryl;

[0251] or where R 8 Together with the adjacent methylene group, it can form R 8A -substituted or unsubstituted C 5-8 Cycloalkyl or R containing at least one O atom 8A -substituted or unsubstituted 5 to 8 membered heterocyclic ring, wherein R 8A C 1-3 unsubstituted alkyl;

[0252] R 9 and R 10 Independently for R 10A -substituted or unsubstituted C 5-6 Cycloalkyl or R 10A - substituted or unsubstituted phenyl;

[0253] Each R 10A are independently hydrogen, C 1-6 Unsubstituted alkyl or C 1-6 Unsubstituted halogenated

[0254] alkyl;

[0255] R 11 C 1-4 unsubstituted alkyl;

[0256] R 12 and R 13 Each independently is R 14 -substituted or unsubstituted C 1-6 Alkyl, R 14 -substituted or unsubstituted C 3-7 Cycloalkyl, R 14 - substituted or unsubstituted aryl, or R 14 -substituted or unsubstituted C 5-7 heteroaryl; and

[0257] Each R 14 is independently unsubstituted C 1-4 alkyl.

[0258] In one embodiment of method (P1) described herein, the chiral ligand comprises a compound of the formula:

[0259]

[0260] Among them, Y, R 7 and R 8 As described in this article.

[0261] In one such embodiment, each Y is O. In one such embodiment, each Y is O and R 7 and R 8 is independently ethyl or phenyl. In one such embodiment, R 7 and R 8 In one such embodiment, each Y is NR 7 , where each R 7 In another embodiment, each Y is NR 7 , where each R 7 It is methyl.

[0262] In one such embodiment of the L1 compound, R 7 and R 8 In another such embodiment of compounds of L1, R 7 and R 8 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 Together with the adjacent methylene group it forms the tetrahydrofuran-dioxolyl moiety.

[0263] In one such embodiment of method (P1) described herein, the chiral ligand is:

[0264]

[0265]

[0266] In one such embodiment of method (P1) described herein, the chiral ligand is:

[0267]

[0268] In one such embodiment of method (P1) described herein, the chiral ligand is:

[0269]

[0270] In another embodiment of method (P1) described herein, the chiral ligand comprises a compound of the formula:

[0271]

[0272] Where R 12 and R 13 As described in this article.

[0273] In one such embodiment of the L2 compound, R 12 and R 13 Each independently is R 14 -substituted or unsubstituted C 1-6 In another embodiment of the L2 compound, R 12 and R 13 Each independently is R 14 -substituted or unsubstituted C 3-7 Cycloalkyl or R 14 -substituted or unsubstituted aryl. In one embodiment of L2 compound, R 12 and R 13 are each independently phenyl or unsubstituted C 3-7 In another embodiment of the L2 compound, each R 12 Phenyl, and each R 13 For unsubstituted C 3-7 In one embodiment of L2 compound, R 13 It is norbornyl.

[0274] In one such embodiment of method (P1) described herein, the chiral ligand is L2 having the following structure:

[0275]

[0276]

[0277]

[0278]

[0279] or a stereoisomer thereof.

[0280] In one embodiment of the method (P1) described herein, the chiral ligand is L2 having the following structure:

[0281]

[0282]

[0283] In another embodiment of the method (P1) described herein, the chiral ligand is L2 having the following structure:

[0284]

[0285] In one embodiment of the process (P1) described herein, the chiral ligand is:

[0286]

[0287] In one embodiment of the method (P1) described herein, the reaction with the chiral ligand is carried out at a temperature 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 a temperature of about 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C. In another embodiment, the reaction with the chiral ligand is carried out at a temperature of about 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C. In another embodiment, the reaction with the chiral ligand is carried out at a temperature of about 50°C, 52°C, 54°C, 56°C, 58°C, 60°C, 62°C, or 64°C.

[0288] In one embodiment of the method (P1) described herein, the reaction with the chiral ligand is carried out for: 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 is carried out for: about 1, 2, 3, 4, 5, 6, 8, 10, 12, 14 or 16 hours.

[0289] In one embodiment of method (P1) described herein, the compound of formula (II) or its tautomer, stereoisomer or salt and the compound of formula (III) or its stereoisomer or salt are present in about equal molar equivalents. In another embodiment of method (P1) described herein, the compound of formula (II) or its tautomer, stereoisomer or salt and the compound of formula (III) or its stereoisomer or salt are present in about 1:1, 1.1:1 or 1.2:1 equivalents.

[0290] In one embodiment of the method (P1) described herein, the method is performed using a Pd catalyst precursor described herein, and the mole % ratio of the Pd catalyst precursor to the chiral ligand is: 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. In one embodiment, the method is performed using a Pd catalyst precursor described herein, and the mole % ratio of the Pd catalyst precursor to the chiral ligand is about 0.5:1. In another embodiment, the method is performed using a Pd catalyst precursor described herein, and the mole % ratio of the Pd catalyst precursor to the chiral ligand is about 1:2. In another embodiment, the method is performed using a Pd catalyst precursor described herein, and the mole % ratio of the Pd catalyst precursor to the chiral ligand is about 1:1.1.

[0291] In one embodiment of the method (P1) described herein, the method is carried out using a Pd catalyst precursor described herein, wherein the catalyst loading (e.g., relative 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 catalyst loading is about 0.1 mol% to 10 mol%. In another embodiment, the catalyst loading is about 0.5 mol% to 2 mol%. In another embodiment, the catalyst loading is about 0.7 to 1.5 mol%.

[0292] In one embodiment, method (P1) further comprises adding a salt additive during step 2. In one embodiment, the additive is NaTFA, NaOAc or NaOTf.

[0293] In another embodiment of method (P1) described herein, the chiral ligand comprises a compound of the formula:

[0294]

[0295] Among them, R 9 , R 10 and R 11 As described in this article.

[0296] In one such embodiment of the L3 compound, R 9 and R 10 In one such embodiment of L3 compound, R9 and R 10 For R 10A -substituted or unsubstituted C 5-6 In one such embodiment of the L3 compound, R 9 and R 10 Each is an unsubstituted cyclohexyl group. In another embodiment of the compound L3, R 9 and R 10 For R 10A -substituted or unsubstituted phenyl. In one such embodiment of L3 compound, R 9 and R 10 In another such embodiment of the L3 compound, R 9 and R 10 For R 10A -substituted phenyl, wherein R 10A It is methyl, ethyl, tert-butyl or CF3.

[0297] In one embodiment of the L3 compound, Z is O and R 11 In another embodiment of the compound L3, Z is N and R 11 It is dimethyl, diethyl or di-tert-butyl.

[0298] In one embodiment, the chiral ligand is a compound of the formula:

[0299]

[0300] In another embodiment of the method (P1) described herein, the chiral ligand is a compound of the formula:

[0301]

[0302] In one embodiment, the compound of formula (II)

[0303]

[0304] or a tautomer, stereoisomer or salt thereof prepared according to process (P2), which comprises the steps of:

[0305] (a) making the compound of formula (IVa) or its stereoisomers or salts with the formula

[0306] contact with a halogenating agent, wherein X 3 is halogen, to prepare the compound of formula (IVb)

[0307] Compound or a stereoisomer or a salt thereof;

[0308] (c) cyclizing the compound of formula (IVb) to a compound of formula (V) or its stereo

[0309] isomers or salts;

[0310] (d) contacting the compound of formula (V) with a chlorinating agent to prepare a compound of formula (Va)

[0311] or a stereoisomer or a salt thereof;

[0312] (e) reacting a compound of formula (Va) with a piperazinyl moiety of formula (VI) Contact to prepare

[0313] Compound of formula (IIa) or a stereoisomer or a salt thereof; and

[0314] (f) reacting the compound of formula (IIa) with X 0 to form a compound of formula (II) or a tautomer, stereoisomer or salt thereof.

[0315] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0316]

[0317] or a tautomer, a stereoisomer or a salt thereof.

[0318] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0319]

[0320] or a tautomer, a stereoisomer or a salt thereof.

[0321] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0322]

[0323] or a tautomer, a stereoisomer or a salt thereof.

[0324] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0325]

[0326] or a tautomer, a stereoisomer or a salt thereof.

[0327] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0328]

[0329] or a tautomer, a stereoisomer or a salt thereof.

[0330] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0331]

[0332] or a tautomer, a stereoisomer or a salt thereof.

[0333] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0334]

[0335] or a tautomer, a stereoisomer or a salt thereof.

[0336] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0337]

[0338] or a tautomer, a stereoisomer or a salt thereof.

[0339] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0340]

[0341] or a tautomer, a stereoisomer or a salt thereof.

[0342] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0343]

[0344] or a tautomer, a stereoisomer or a salt thereof.

[0345] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0346]

[0347] or a tautomer, a stereoisomer or a salt thereof.

[0348] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0349]

[0350] or a tautomer, a stereoisomer or a salt thereof.

[0351] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0352]

[0353] or a tautomer, a stereoisomer or a salt thereof.

[0354] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0355]

[0356] or a tautomer, a stereoisomer or a salt thereof.

[0357] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0358]

[0359] or a tautomer, a stereoisomer or a salt thereof.

[0360] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0361]

[0362] or a tautomer, a stereoisomer or a salt thereof.

[0363] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0364]

[0365] or a tautomer, a stereoisomer or a salt thereof.

[0366] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer or salt thereof comprises a compound of the formula:

[0367]

[0368] or a salt thereof.

[0369] In one embodiment, the compound of formula (II) is contacted with an organomagnesium compound and a zinc complex as described herein (Method P1) to form a compound of formula (IIz):

[0370]

[0371] 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) to form a compound of the formula:

[0372]

[0373] where Y 1 is halogen (eg, Cl, Br or I), OAc, TFA, OTf or OPiv.

[0374] In one embodiment, Y 1 In one embodiment, the compound of step a as described herein in process P1 is carried into step b as 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.

[0375] In another embodiment, the compound of formula (2a) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1) to form a compound of the formula:

[0376]

[0377] In another embodiment, the compound of formula (2b) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1) to form a compound of the formula:

[0378]

[0379] In another embodiment, the compound of formula (2c) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1) to form a compound of the formula:

[0380]

[0381] In another embodiment, the compound of formula (2) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1) to form a compound of the formula:

[0382]

[0383] In such embodiments, Y 1 is halogen (e.g., Cl, Br, or I), OAc, TFA, OTf, or OPiv. In one such embodiment, Y 1 In one such embodiment, Y 1 For OPiv.

[0384] In one embodiment of the method (P2) described herein, the method further comprises:

[0385] (a0) making the compound of formula (IV) contacting with a base in the presence of CO2 gas and aminating the compound to form a compound of formula (IVa)

[0386] In one embodiment of process (P2) described herein, the base of step (a0) is n-butyllithium, LDA or LiTMP. In another embodiment, the base is LDA.

[0387] In one embodiment of process (P2) described herein, the halogenating agent of step (b) has the formula Where X 3 is Cl, Br or I. In one such embodiment, X 3 In another embodiment, X 3 In another embodiment, X 3 For I.

[0388] In one embodiment of process (P2) described herein, the halogenating agent of step (b) has the formula Where X 3 are the same and are Cl, Br or I. In one embodiment, each X 3 In another embodiment, each X 3 In yet another embodiment, each X 3 For I.

[0389] In one embodiment of the process (P2) described herein, the halogenating agent of step (b) is NCS or 1,3-dichloro-5,5-dimethylhydantoin. In another embodiment, the halogenating agent is NCS. In another embodiment, the halogenating agent is 1,3-dichloro-5,5-dimethylhydantoin.

[0390] In one embodiment of process (P2) described herein, step (c) of cyclizing the compound of formula (IVb) to the compound of formula (V) is carried out using KOCN in aqueous base (eg, NaOH or KOH) followed by contacting with an acid (eg, HCl).

[0391] In one embodiment of the method (P2) described herein, the chlorinating agent of step (d) is POCl3, PCl3, PCl5 or SOCl2. In another embodiment, the chlorinating agent is POCl3.

[0392] In one embodiment of method (P2) described herein, X of the compound of formula (II) 0 is F, and step (f) comprises contacting the compound of formula (IIa) with CsF to prepare a compound of formula (IIa1):

[0393]

[0394] or a tautomer, a stereoisomer or a salt thereof.

[0395] In one embodiment of method (P2) described herein, X of the compound of formula (II) or its tautomer, stereoisomer or salt is 0 is F, and step (f) comprises contacting the compound of formula (IIa) with CsF to prepare a compound of formula (IIa2):

[0396]

[0397] or a tautomer, a stereoisomer or a salt thereof.

[0398] In one embodiment of method (P2) described herein, X of the compound of formula (II) or its tautomer, stereoisomer or salt is 0 is F, and step (f) comprises contacting the compound of formula (IIa) with CsF to prepare a compound of formula (IIa3):

[0399]

[0400] or a tautomer, a stereoisomer or a salt thereof.

[0401] In one embodiment of method (P2) described herein, the compound of formula (IV) has the following formula:

[0402]

[0403] In one embodiment of method (P2) described herein, the compound of formula (IVa) has the following formula:

[0404]

[0405] or a salt thereof.

[0406] In one embodiment of method (P2) described herein, the compound of formula (IVa) has the following formula:

[0407]

[0408] or a salt thereof.

[0409] In one embodiment of method (P2) described herein, the compound of formula (IVb) has the following formula:

[0410]

[0411] or a salt thereof.

[0412] In one embodiment of method (P2) described herein, the compound of formula (IVb) has the following formula:

[0413]

[0414] or a salt thereof.

[0415] In one embodiment of method (P2) described herein, the compound of formula (IVb) has the following formula:

[0416]

[0417] or a salt thereof.

[0418] In one embodiment of method (P2) described herein, the compound of formula (V) has the following formula:

[0419]

[0420] or a salt thereof.

[0421] In one embodiment of method (P2) described herein, the compound of formula (V) has the following formula:

[0422]

[0423] or a salt thereof.

[0424] In one embodiment of method (P2) described herein, the compound of formula (V) has the following formula:

[0425]

[0426] or a salt thereof.

[0427] In one embodiment, the compound of formula (III)

[0428]

[0429] The method described herein or a salt thereof is prepared according to method (P3), which comprises:

[0430] (a) making the compound of formula (VII) Where X 4 is a halogen, and has the formula

[0431] NH2(PG) is contacted to prepare a compound of formula (VIIa)

[0432] (b) reacting the compound of formula (VIIa) with a compound of formula X a PG contact compounds, wherein X a is halogen, to prepare a compound of formula (VIIb)

[0433] (c) reacting the compound of formula (VIIb) with a compound of formula Or contact with a halogenating agent, wherein X 5 is halogen, to prepare a compound of formula (VIIc)

[0434] (d) halogenating the compound of formula (VIIc) with a halogenating alkylating agent to prepare a compound of formula (VIId)

[0435] (e) brominating the compound of formula (VIId) to prepare a compound of formula (VIIe) as well as

[0436] (f) reacting the compound of formula (VIIe) with X a PG to prepare the compound of formula (III).

[0437] In one embodiment of the method (P3) described herein, 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 In another embodiment, X a For Cl.

[0438] In one embodiment of method (P3) described herein, the halogenating agent of step (c) is In one such embodiment, X 5 is Cl, Br or I. In another embodiment, X 5 In another embodiment, X 5 In another embodiment, X 5For Br.

[0439] In one embodiment of method (P3) described herein, the halogenating agent of step (c) is In one such embodiment, X 5 is Cl, Br or I. In another embodiment, X 5 In another embodiment, X 5 In another embodiment, X 5 For Br.

[0440] In another embodiment of the process (P3) described herein, the halogenating agent of step (c) is NIS or 1,3-dichloro-5,5-dimethylhydantoin. In one such embodiment, the halogenating agent is NIS. In another embodiment, the halogenating agent is 1,3-diiodo-5,5-dimethylhydantoin.

[0441] In one embodiment of process (P3) described herein, the haloalkylating agent of step (d) is a fluoroalkylating agent. In one such embodiment, the haloalkylating agent is methyl 2,2-difluoro-2-(fluorosulfonyl)acetate.

[0442] In one embodiment of process (P3) described herein, the bromination step (e) further comprises contacting the compound of formula (VIId) with HBr.

[0443] In one such embodiment of process (P3) described herein, the bromination step (e) further comprises contacting the compound of formula (VIId) with AcBr to produce the compound of formula (VIIe).

[0444] 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 For Cl.

[0445] In one embodiment, the compound of formula (VII) has the formula:

[0446]

[0447] In one embodiment, the compound of formula (VII) has the formula:

[0448]

[0449] In one embodiment, the compound of formula (VIIa) has the formula:

[0450]

[0451] or a salt thereof.

[0452] In one embodiment, the compound of formula (VIIa) has the formula:

[0453]

[0454] or a salt thereof.

[0455] In one embodiment, the compound of formula (VIIa) has the formula:

[0456]

[0457] or a salt thereof.

[0458] In one embodiment, the compound of formula (VIIb) has the following formula:

[0459]

[0460] or a salt thereof.

[0461] In one embodiment, the compound of formula (VIIb) has the following formula:

[0462]

[0463] or a salt thereof.

[0464] In one embodiment, the compound of formula (VIIb) has the following formula:

[0465]

[0466] or a salt thereof.

[0467] In one embodiment, the compound of formula (VIIc) has the formula:

[0468]

[0469] or a salt thereof.

[0470] In one embodiment, the compound of formula (VIIc) has the formula:

[0471]

[0472] or a salt thereof.

[0473] In one embodiment, the compound of formula (VIIc) has the formula:

[0474]

[0475] or a salt thereof.

[0476] In one embodiment, the compound of formula (VIIc) has the formula:

[0477]

[0478] or a salt thereof.

[0479] In one embodiment, the compound of formula (VIId) has the formula:

[0480]

[0481] or a salt thereof.

[0482] In one embodiment, the compound of formula (VIId) has the formula:

[0483]

[0484] or a salt thereof.

[0485] In one embodiment, the compound of formula (VIId) has the formula:

[0486]

[0487] or a salt thereof.

[0488] In one embodiment, the compound of formula (VIId) has the formula:

[0489]

[0490] or a salt thereof.

[0491] In one embodiment, the compound of formula (VIIe) has the formula:

[0492]

[0493] or a salt thereof.

[0494] In one embodiment, the compound of formula (VIIe) has the formula:

[0495]

[0496] or a salt thereof.

[0497] In another embodiment, the compound of formula (III)

[0498]

[0499] The method described herein or a salt thereof is prepared according to method (P4), which comprises:

[0500] (a) making a compound of formula (VIII) contact with a halogenating agent, wherein X 6 is Cl or I, to form a compound of formula (VIIIa)

[0501] (b) brominating the compound of formula (VIIIa) to form a compound of formula (VIIIb) as well as

[0502] (c) contacting the compound of formula (VIII) with a compound having the formula NH(PG)2, thereby preparing the compound of formula (III) or a salt thereof.

[0503] In one embodiment of the method (P4) described herein, each X 6 In one such embodiment, each X 6 In another embodiment, each X 6 For I.

[0504] In another embodiment, the compound of formula (III)

[0505]

[0506] The method described herein or a salt thereof is prepared according to method (P5), which comprises:

[0507] (a) making the compound of formula (VIIIc) Contacting with a brominating agent to form a compound of formula (VIIId)

[0508] (b) contacting the compound of formula (VIIId) with a halogenating agent to form a compound of formula (VIIIb)

[0509]

[0510] (c) contacting the compound of formula (VIIIb) with a compound having the formula NH(PG)2 to prepare a compound of formula (III).

[0511] In one embodiment of process (P4) or (P5) as described herein, the halogenating agent is SF4 in HF.

[0512] In one such embodiment, the compound of formula (VIII) has the formula:

[0513]

[0514] or a salt thereof.

[0515] In one such embodiment, the compound of formula (VIII) has the formula:

[0516]

[0517] or a salt thereof.

[0518] In one such embodiment, the compound of formula (VIIIa) has the formula:

[0519]

[0520] or a salt thereof.

[0521] In one such embodiment, the compound of formula (VIIIa) has the formula:

[0522]

[0523] or a salt thereof.

[0524] In one such embodiment, the compound of formula (VIIIa) has the formula:

[0525]

[0526] or a salt thereof.

[0527] In one such embodiment, the compound of formula (VIIIb) has the formula:

[0528]

[0529] or a salt thereof.

[0530] In one such embodiment, the compound of formula (VIIIb) has the formula:

[0531]

[0532] or a salt thereof.

[0533] In one such embodiment, the compound of formula (VIIIc) has the formula:

[0534]

[0535] or a salt thereof.

[0536] In one such embodiment, the compound of formula (VIIId) has the formula:

[0537]

[0538] or a salt thereof.

[0539] In one such embodiment, the compound of formula (III) has the formula:

[0540]

[0541] or a salt thereof.

[0542] In one such embodiment, the compound of formula (III) has the formula:

[0543]

[0544] or a salt thereof.

[0545] In one such embodiment, the compound of formula (III) has the formula:

[0546]

[0547] or a salt thereof.

[0548] In one such embodiment, the compound of formula (III) has the formula:

[0549]

[0550] or a salt thereof.

[0551] In one embodiment of the methods described herein, X 1 In one embodiment of the methods described herein, X 1 In one embodiment, X 1 is F or Cl. In another embodiment of the methods described herein, when X 1 When X is a halogen, 3 In another embodiment of the methods described herein, when X 1 When F, X 3 is not F. In another embodiment of the methods described herein, when X 1 When F, X 3 In another embodiment of the method described herein, when X 1 When H, X 3 For Cl.

[0552] In one embodiment of the methods described herein, X 2 is Br. In one embodiment of the methods 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.

[0553] In one embodiment of the methods described herein, X 3 is hydrogen, halogen, R 6 -substituted or unsubstituted C 1-3 Alkyl or R 6 -substituted or unsubstituted C 1-3 In another embodiment of the methods described herein, X 3 For R 6 -substituted or unsubstituted C 1-3 Alkoxy or R 6-substituted or unsubstituted cyclopropyl. In another embodiment of the methods described herein, X 3 In another embodiment of the methods described herein, X 3 is halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3 In another embodiment of the methods described herein, X 3 is halogen or unsubstituted C 1-3 In another embodiment of the methods described herein, X 3 For unsubstituted C 1-3 In a preferred embodiment of the method described herein, X 3 In one such embodiment of the methods described herein, X 3 is Cl or F. In another embodiment, X 3 is Cl, F, CF3, CHF2 or CH2F. In another embodiment of the method described herein, X 3 It is CF3, CHF2 or CH2F.

[0554] In one embodiment of the methods described herein, R 1 In a preferred embodiment of the method described herein, R 1 For PG 1 In one such embodiment of the methods described herein, PG 1 is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidene, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl). In another embodiment of the methods described herein, PG 1 In preferred embodiments of the methods described herein, R 1 It is Boc (tert-butoxycarbonyl).

[0555] In one embodiment of the methods described herein, each R 2 is independently halogen or cyano. In another embodiment of the methods described herein, each R 2 is independently unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 In another embodiment of the methods described herein, each R 2 is independently unsubstituted C 1-6 Alkyl or unsubstituted C 1-6In another such embodiment of the methods described herein, n is 1. In a preferred embodiment of the methods described herein, each R 2 is independently unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 In one such embodiment of the methods described herein, each R 2 is methyl or ethyl. In one such embodiment of the processes described herein, n is 1. In another such embodiment of the methods described herein, R 2 is methyl and n is 1. In another such embodiment of the methods described herein, R 2 is CF3, CHF2 or CH2F. In another such embodiment of the methods described herein, R 2 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 methods described herein, n is 1. In another such embodiment of the methods described herein, R 2 is CH2CN and n is 1. In yet another embodiment, n is 0.

[0556] In one embodiment of the methods described herein, R 3 is hydrogen or halogen. In one embodiment of the methods described herein, R 3 In another embodiment of the methods described herein, R 3 For R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 In another embodiment of the method described herein, R 3 For R 3A -substituted or unsubstituted C 1-3 Alkyl or R 3A -substituted or unsubstituted C 1-3 In another embodiment of the methods described herein, R 3 For R 3A -substituted or unsubstituted C 1-3 In one such embodiment of the methods described herein, R 3 is hydrogen or methyl. In another such embodiment of the methods described herein, R 3 It is methyl.

[0557] In one embodiment of the methods described herein, R 3 For R 3A-substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 A haloalkyl group, wherein R 3A is halogen, OH, CN or unsubstituted C 1-3 In one such embodiment of the methods described herein, R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 A haloalkyl group, wherein R 3A It is F, OH, CN, CF3, CHF2 or CH2F.

[0558] In preferred embodiments of the methods described herein, R 4 For unsubstituted C 1-3 In one such embodiment of the methods described herein, R 4 It is CF3, CHF2 or CH2F.

[0559] In one embodiment, R 5 is halogen, cyano or OH. In another embodiment, R 5 For R 5A -substituted or unsubstituted C 1-6 Alkyl, R 5A -substituted or unsubstituted C 1-6 Haloalkyl, or R 5A -substituted or unsubstituted C 1-6 In another embodiment, R 5 For R 5A -substituted or unsubstituted C 3-6 Cycloalkyl, R 5A -substituted or unsubstituted 3-6 membered heterocyclic ring, R 5A -substituted or unsubstituted phenyl, or R 5A -substituted or unsubstituted 6-membered heteroaryl.

[0560] In one embodiment of the methods described herein, R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C 1-6 Alkyl or R 5C -substituted or unsubstituted C 1-6 In another embodiment of the methods described herein, R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C3-7 Cycloalkyl; R 5C -substituted or unsubstituted 3-7 membered heterocyclic ring, R 5C -substituted or unsubstituted C 5-7 Aryl, or R 5C -substituted or unsubstituted C 5-7 In a preferred embodiment of the method described herein, R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C 1-6 alkyl.

[0561] In one embodiment of the methods described herein, R 5C are independently halogen, OH, CN or NO2. In one embodiment of the methods described herein, R 5C Independently for R 5D -substituted or unsubstituted C 1-6 Alkyl or R 5D -substituted or unsubstituted C 1-6 In one embodiment of the methods described herein, R 5C Independently for R 5D -substituted or unsubstituted C 3-7 Cycloalkyl or R 5D -substituted or unsubstituted C 3-7 In one embodiment, R 5C Independently for R 5D -substituted or unsubstituted C 5-7 Aryl or R 5D -substituted or unsubstituted C 5-7 In another embodiment of the methods described herein, R 5C Independently for R 5D -substituted or unsubstituted C 3-7 Heterocyclic or R 5D -substituted or unsubstituted C 5-7 In another embodiment of the methods described herein, R 5C For R 5D -substituted pyrrolidinyl.

[0562] In one embodiment of the methods described herein, R 5D are independently halogen, OH or CN. In another embodiment, R 5D For unsubstituted C 1-6 In another embodiment of the methods described herein, R 5D For unsubstituted C 1-6 In another embodiment of the methods described herein, R5D For unsubstituted C 3-7 Cycloalkyl, unsubstituted C 3-7 Heterocyclic, unsubstituted C 5-7 Aryl or unsubstituted C 5-7 In one embodiment of the methods described herein, R 5D It is methyl, ethyl or propyl.

[0563] In one embodiment of the methods described herein, R 5A and R 5B Each independently is:

[0564]

[0565] In one embodiment of the methods described herein, R 6 In another embodiment of the methods described herein, R 6 OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 Cycloalkyl.

[0566] In one embodiment of the methods described herein, each PG is independently an amino protecting group. In one embodiment, each PG is the same. In one such embodiment of the methods described herein, each PG is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidene, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl). In another embodiment, each PG is PMB, DMB or Boc. In a preferred embodiment of the methods described herein, each PG is PMB.

[0567] In yet another embodiment of the methods described herein, two PGs together form C 3-8 In one embodiment of the methods described herein, two PGs together form a moiety having the following structure:

[0568]

[0569] In one embodiment of the methods described herein, X 0 is hydrogen, halogen or OR 5A In another embodiment of the method described herein, X 0 For SR 5B , R 5 -substituted or unsubstituted C 1-6 Alkyl, R5 -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 In another embodiment of the methods described herein, X 0 is hydrogen, halogen, CF3, CHF2 or CH2. In a preferred embodiment of the method described herein, X 0 In one such embodiment of the methods described herein, X 0 is F. In yet another embodiment of the method described herein, X 0 is hydrogen, halogen, CF3, CHF2, CH2F or a moiety having the following structure:

[0570]

[0571] In one embodiment of method (P1) described herein, the compound of formula (III) has formula (III1), (III2), (III3) or (3) as described herein.

[0572] In one embodiment of the process (P2) described herein, the method comprises:

[0573]

[0574] Where X 1 , X 2 , X 3 , R 1 , R 2 and n are as described herein. In one such embodiment, R 1 For PG 1 And R 2 It is methyl.

[0575] In one embodiment of the process (P3) described herein, the method comprises:

[0576]

[0577] Where X 4 , X 5 , R 3 and PG as described herein.

[0578] In one embodiment of the process (P4) described herein, the method comprises:

[0579]

[0580] Where R 6 , R3 , R 4 and PG as described herein.

[0581] In one embodiment of the process (P5) described herein, the method comprises:

[0582]

[0583] Where R 3 , R 4 and PG as described herein.

[0584] The present invention further provides a method (P6) for synthesizing a compound of formula (G), the method comprising:

[0585]

[0586] or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof, wherein X 1 , X 3 , R 2 , R 3 , R 4 and n as described herein;

[0587] Ralk Alk is part of a group consisting of:

[0588]

[0589] and and

[0590] X A Freedom to choose

[0591]

[0592]

[0593] (a) contacting a compound of formula (II) or a tautomer, stereoisomer or salt thereof synthesized according to the method described herein with a compound of formula (III) or a salt thereof synthesized according to the method described herein to produce a compound of formula (I) or a solvate, tautomer or salt thereof as described herein;

[0594] isomer, stereoisomer, atropisomer or salt;

[0595] (b) reacting a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof with a A , thereby synthesizing the compound of formula (G1);

[0596]

[0597] or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, wherein PG and R 1 As stated in this article;

[0598] (c) removing the PG group from the compound of formula (G1); and

[0599] (d) Install R Alk group, thereby synthesizing the compound of formula (G) or its tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt.

[0600] In one such embodiment, the step (b) comprises X A The part is:

[0601]

[0602] 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.

[0603] In one embodiment of the method (P6) described herein, R Alk for In one embodiment of the method (P6) described herein, R Alk for In such embodiments, the method comprises a base and an activating agent as described herein.

[0604] In one embodiment of the method (P6) described herein, R 2 C 1-3 Alkyl or C 1-3 In one embodiment of the method (P6) described herein, each PG is PMB. In one embodiment of the method (P6) described herein, X 1 and X 3 are independently halogen.

[0605] Further provided herein is a method (P7) for synthesizing a compound of formula (H):

[0606]

[0607] or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof, wherein X 1 , X 3 , R 2 , R 3 , R 4 , PG and n are as described herein, the method comprising:

[0608] (a) contacting a compound of formula (II) or a tautomer, stereoisomer or salt thereof synthesized according to the method described herein with a compound of formula (III) or a salt thereof synthesized according to the method described herein to produce a compound of formula (I) or a solvate, tautomer or salt thereof as described herein;

[0609] isomer, stereoisomer, atropisomer or salt;

[0610] (b) in the presence of a base, reacting a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof with a A A compound, wherein the compound is selected from

[0611] The group consisting of:

[0612]

[0613] Thus preparing the compound of formula (G1);

[0614]

[0615] or a solvate, tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof,

[0616] Among them, PG and R 1 As described herein; and

[0617] (c) removing the PG group from the compound of formula (G1);

[0618] (d) reacting the compound of step (c) with

[0619] The contacting is carried out in the presence of a base and optionally an activating agent, thereby preparing a compound of formula (H) or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof.

[0620] In one embodiment of the method (P7) described herein, wherein R 1 For PG 1 The method further comprises step (b1): before carrying out step (d), removing PG from compound G1 1 .

[0621] In one embodiment of method (P7) described herein, the compound of step (d) is

[0622] In one embodiment of method (P7) described herein, the compound of step (d) is And step (d) is carried out in the presence of a base as described herein and an activator as described herein. In one such embodiment, the activator is EDCI.

[0623] In one embodiment of method (P7) described herein, the compound of step (d) is And step (d) is carried out in the presence of only the base described herein.

[0624] In one embodiment of method (P7) described herein, the compound of step (d) is And step (d) is carried out in the presence of only the base described herein.

[0625] In one embodiment of method (P7) described herein, the compound of step (d) is And step (d) is carried out in the presence of a base as described herein and an activator as described herein. In one such embodiment, the activator is EDCI.

[0626] In one embodiment of the method (P7) described herein, the base of 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 (P7) described herein, the base of step (d) is diisopropylethylamine (DIPEA). In one embodiment of the method (P7) described herein, R 2 C 1-3 Alkyl or C 1-3 cyanoalkyl and n is 1. In one embodiment of method (P7) described herein, each PG is PMB. In one embodiment, R 1 For PG 1 , where PG 1 is Boc. In one embodiment of the method (P7) described herein, X 1 and X 3 are independently halogen.

[0627] In one embodiment of method (P7) described herein, the activator is a carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI). In one embodiment of method (P7) described herein, the activator is a benzotriazole hexafluorophosphate compound (e.g., (benzotriazol-1-yloxy)tris(dimethylamino)hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidine hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidine hexafluorophosphate (PyAOP), bromotripyrrolidine hexafluorophosphate (PyBrOP), or BOP-Cl.

[0628] In one embodiment of method (P7) described herein, the activator is a urea compound (e.g., 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU), 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium 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 (TBTU), O-[ (ethoxycarbonyl) cyanomethyleneamino]-N,N,N'N'-tetramethyluronium tetrafluoroborate (TOTU). In yet another embodiment, the activating agent is O-(N-succinimidyl)-1,1,3,3-tetramethyl-uronium-tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximido)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU) and O-(1,2-dihydro-2-oxo-1-pyridinyl-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).

[0629] In one embodiment of the method (P7) described herein, the activator is EDCI, isobutyl chloroformate, ethyl chloroformate, or propylphosphonic anhydride. In one such embodiment, the activator is EDCI. In another such embodiment, the activator is isobutyl chloroformate or ethyl chloroformate. In another such embodiment, the activator is propylphosphonic anhydride.

[0630] In one embodiment of the method (P7) described herein, comprising X A The part is

[0631]

[0632] In one embodiment of the method (P7) described herein, comprising X A The part is

[0633]

[0634] In one embodiment of the method (P7) described herein, comprising X A The part is

[0635]

[0636] In one embodiment of the method (P7) described herein, comprising XA The part is

[0637]

[0638] In one embodiment of method (P6) or (P7) described herein, the compound of formula (G1) or its solvate, atropisomer, tautomer, stereoisomer or salt is a compound of Table 1. In one embodiment of method (P6) or (P7) described herein, the compound of formula (G1) or its solvate, atropisomer, tautomer, stereoisomer or salt is a compound of formula 5, 33, 35, 37, 40, 44, 46 or 69 of Table 1. In a preferred embodiment of method (P6) or (P7) described herein, the compound of formula (G1) or its solvate, atropisomer, tautomer, stereoisomer or salt is a compound of formula 5 of Table 1.

[0639] In another aspect, provided herein is a method (P8) for synthesizing a compound of formula (F) or a tautomer, stereoisomer, atropisomer or pharmaceutically acceptable salt thereof,

[0640]

[0641] Where R 2 and n as described herein, the method comprising;

[0642] (a) Executive Compound or its salt and formula

[0643] Compound or its tautomer, stereoisomer or salt is contacted to synthesize the compound of formula (1a)

[0644]

[0645] or a solvate, tautomer, stereoisomer, atropisomer or salt thereof,

[0646] (b) reacting a compound of formula (1a) or a solvate, tautomer, stereoisomer, or atropisomer thereof with a compound of formula HO-X A Compound contact, where X A With formula

[0647] Thus synthesizing the compound of formula (F1);

[0648]

[0649] or a solvate, tautomer stereoisomer or salt thereof;

[0650] (c) making the compound of formula (F1) or its solvate, tautomer, stereoisomer or salt

[0651] Contacting with methanesulfonic acid (MsOH) in acid to synthesize the compound of formula (F2);

[0652]

[0653] or a solvate, tautomer, stereoisomer or salt thereof; and

[0654] (d) reacting a compound of formula (F2) or a solvate, tautomer, stereoisomer or salt thereof with a compound of formula contacting, thereby preparing the compound of formula (F) or its tautomer, stereoisomer or pharmaceutically acceptable salt.

[0655] In one embodiment of process (P8) described herein, the acid of step (c) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid, or trifluoromethanesulfonic acid. In one such embodiment, the acid of step (c) is AcOH, trifluoroacetic acid, or chlorosulfonic acid. In another such embodiment, the acid of step (c) is AcOH.

[0656] In one embodiment of the method (P8) described herein, X A for In one embodiment of the methods described herein, X A for

[0657] In one embodiment of method (P8), step (d) further comprises a base and optionally an activator. In one such embodiment, step (d) of method (P8) further comprises only a base as described herein. In another such embodiment, step (d) of method (P8) further comprises a base and an activator as described herein.

[0658] In one embodiment of method (P8) described herein, the compound of step (d) is and alkali.

[0659] In one embodiment of method (P8) described herein, the compound of step (d) is and alkali.

[0660] In one embodiment of method (P8) described herein, the compound of step (d) is and a base and an activator as described herein.

[0661] In one embodiment of the method (P8) described herein, each R 2 is independently halogen or cyano. In one embodiment of method (P8) described herein, each R 2are independently halogen or unsubstituted C 1-6 In one embodiment of method (P8) described herein, each R 2 is independently unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 In one embodiment of method (P8) described herein, n is 1. In one embodiment of method (P8) described herein, each R 2 is independently unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 In one embodiment of method (P8) described herein, each R 2 is methyl or ethyl. In one such embodiment, n is 1. In one embodiment of method (P8) described herein, R 2 is methyl and n is 1. In one embodiment of method (P8) described herein, R 2 is CF3, CHF2 or CH2F. In one embodiment of method (P8) described herein, 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 method (P8) described herein, n is 1. In one embodiment of method (P8) described herein, R 2 is CH2CN and n is 1. In one embodiment of method (P8) described herein, n is 0.

[0662] In one embodiment, the compound of formula (F) has formula (F4):

[0663]

[0664] or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof.

[0665] In one embodiment, the compound of formula (F) has the formula (F5)

[0666]

[0667] or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof.

[0668] In one embodiment of method (P8) described herein, compound (F1) or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof is a compound of Table 1. In one embodiment of method (P8) described herein, the compound of formula (F1) or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof is a compound of formula 105, 133, 135, 137, 140, 144, 146 or 169 of Table 1. In a preferred embodiment of method (P8) described herein, the compound of formula (F1) or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof is a compound of formula 105 of Table 1.

[0669] Further provided herein are methods for preparing compounds of formula (A)

[0670]

[0671] or a pharmaceutically acceptable salt thereof (P9), the method comprising

[0672] (a) making a compound of formula (2) or its salt is contacted with i-PrMgCl·LiCl and ZnCl2, and then with NaTFA and a compound of formula (3) touch,

[0673] (b) contacting the mixture of step (a) or a salt thereof with the Pd or Ni catalyst precursor described herein and the chiral ligand described herein, thereby synthesizing a compound of formula (1)

[0674]

[0675] or a solvate or salt thereof;

[0676] (c) reacting the compound of formula (1) or its solvate or salt with a compound of formula HO-X A The compound is contacted with a base, wherein X A With formula Thus, the compound of formula (1d) is synthesized

[0677]

[0678] or a solvate or a pharmaceutically acceptable salt thereof;

[0679] (d) contacting the compound of formula (1d) with MsOH in an acid to synthesize the compound of formula (1e)

[0680] thing

[0681]

[0682] or a solvate or a pharmaceutically acceptable salt thereof; and

[0683] (e) reacting a compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with

[0684] contacting, followed by contacting with a base and optionally an activating agent, each as described herein, thereby preparing a compound of formula (A) or a pharmaceutically acceptable salt thereof.

[0685] In one embodiment, step (b) of process (P9) further comprises crystallization. In one such embodiment, the crystallization is carried out in toluene / n-heptane.

[0686] In one embodiment, step (c) of method (P9) further comprises washing with potassium carbonate and filtering (e.g., polishing filtration). In one such embodiment, step (c) of method (P9) further comprises solvent exchange to 1-PrOH. In one such embodiment, crystallization is performed from 1-PrOH / water after solvent exchange. In another embodiment, crystallization is performed from isopropanol / water, acetonitrile, acetonitrile / water, or acetone / water.

[0687] In one embodiment of the methods described herein, the base of step (c) is selected from LiOt-Am, NaOt-Am, KOt-Am, KDMO (potassium 3,7-dimethyl-3-octanol), LiOt-Bu, NaOt-Bu or KOt. In one such embodiment, the base is a base in the following table:

[0688]

[0689] The byproduct is -OH at the C2 position

[0690] In one such embodiment, the base is NaOt-Am or NaOt-Bu. In such embodiments, the base can be present in an amount of about 1.1 to about 1.35 equivalents relative to compound 1.

[0691] In one embodiment of method (P9) described herein, the acid of 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 of step (d) is AcOH, trifluoroacetic acid, or chlorosulfonic acid. In one such embodiment, the acid of step (d) is AcOH, formic acid, trifluoroacetic acid, or chlorosulfonic acid. In another such embodiment, the acid of step (d) is AcOH.

[0692] In one embodiment of the method (P9) described herein, the activator is EDCI, isobutyl chloroformate, ethyl chloroformate, or propylphosphonic anhydride. In one such embodiment, the activator is EDCI. In another such embodiment, the activator is isobutyl chloroformate or ethyl chloroformate. In another such embodiment, the activator is propylphosphonic anhydride.

[0693] In one embodiment, step (d) of method (P9) further comprises quenching with a base (e.g., a hydroxide base such as NaOH) and washing with the same base (e.g., NaOH). In another such embodiment, step (d) of the method of (P9) further comprises polishing filtration. In yet another embodiment, step (d) of the method of (P9) further comprises a crystallization step (e.g., with toluene / n-heptane).

[0694] In one embodiment of method (P9) described herein, the MsOH of step (d) may be present in an amount of about 10 to 30 equivalents, 15 to 30 equivalents, 15 to 27 equivalents, 15 to 25 equivalents, 15 to 23 equivalents, or about 20 to 30 equivalents relative to the compound of formula (1d). In one such embodiment, MsOH is present in an amount of about 15 to 27 equivalents relative to the compound of formula (1d). In another embodiment of method (P9) described herein, AcOH is present in an amount of about 1 to 4 volumes, 1.5 to 3.5 volumes, 1.6 to 3.4 volumes, or 1.8 to 3.3 volumes. In one embodiment of method (P9) described herein, step d further comprises toluene as a co-solvent. In one such embodiment, the volume of toluene is 0 to 7 volumes.

[0695] In one embodiment of method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with and contacting with a base as described herein and optionally an activating agent.

[0696] In one embodiment of the method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with touch.

[0697] In one embodiment of the method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with touch.

[0698] In one embodiment of method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with a base and an activating agent as described herein. touch.

[0699] In one embodiment of method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with a base and an activating agent as described herein. 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 comprises pivaloyl chloride (PivCl).

[0700] In one embodiment of the methods described herein, the base of step (e) is NaOH, KOH, LiOH, triethylamine or pyridine. In one such embodiment, the base is NaOH.

[0701] In one embodiment of method (P9) described herein, the compound of formula (1) is a cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene or toluene solvate. In one embodiment of method (P9) described herein, the compound of formula (1) is a crystalline cyclohexane solvate. In one such embodiment of method (P9) described herein, the crystalline cyclohexane solvate of the compound of formula (1) is substantially as Figure 1 In another embodiment of method (P9) described herein, the compound of formula (1) is a crystalline methylcyclohexane solvate. In one such embodiment of method (P9) described herein, the crystalline methylcyclohexane solvate of the compound of formula (1) is substantially as Figure 2 In another embodiment of method (P9) described herein, the compound of formula (1) is a crystalline chlorobenzene solvate. In one such embodiment of method (P9) described herein, the crystalline chlorobenzene solvate of the compound of formula (1) is substantially as Figure 3 In another embodiment of method (P9) described herein, the compound of formula (1) is a crystalline ethylbenzene solvate. In one such embodiment of method (P9) described herein, the crystalline ethylbenzene solvate of the compound of formula (1) is substantially as Figure 4 In another embodiment of the method (P9) described herein, the compound of formula (1) is a crystalline meta-xylene solvate. In one such embodiment of the method (P9) described herein, the crystalline meta-xylene solvate of the compound of formula (1) is substantially as Figure 5 In another embodiment of method (P9) described herein, the compound of formula (1) is a crystalline toluene solvate. In one such embodiment of method (P9) described herein, the crystalline toluene solvate of the compound of formula (1) is substantially as Figure 6 shown.

[0702] In one embodiment of the methods 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 another embodiment, step (f) comprises Scheme 3. In one embodiment, Scheme 3 further comprises n-heptane.

[0703] Scenario 1:

[0704]

[0705] Scenario 2:

[0706]

[0707] Scenario 3:

[0708]

[0709] Treatment

[0710] The methods described herein can be used to prepare compounds that can be used to treat cancer. In one embodiment, there is provided a method for treating KRas by administering an effective amount of a compound (A) synthesized according to any of the methods described herein or a pharmaceutically acceptable salt thereof. G12C In one embodiment, the present invention provides a method for treating a cancer mediated by KRas mutation by administering an effective amount of a compound (B) synthesized according to any method described herein. G12C Methods for treating cancer mediated by mutations. In a preferred embodiment of the methods described herein, compound (A) or a pharmaceutically acceptable salt thereof is synthesized according to method P9 described herein. In a preferred embodiment of the methods described herein, compound (B) or a pharmaceutically acceptable salt thereof is synthesized according to method P9 described herein.

[0711] Determining whether a tumor or cancer contains KRas G12C Mutation can be performed 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 putative K-Ras mutant protein. The sequence of wild-type human K-Ras (e.g., Accession No. NP203524) is known in the art.

[0712] In certain specific embodiments, the method comprises treating lung cancer. In one embodiment, a method for treating a patient with a KRas G12CA method for treating lung cancer in patients with lung cancer containing KRas mutations, the method comprising administering to the patient a therapeutically effective amount of compound (A) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof. In one embodiment, a method for treating lung cancer in patients with lung cancer containing KRas mutations is provided. G12C A method for treating lung cancer in patients with lung cancer that has a mutation in such lung cancer comprises administering to the patient a therapeutically effective amount of compound (B) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof.

[0713] In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the lung cancer is small cell lung cancer. NSCLC can be, for example, adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0714] In one embodiment of such methods, the patient is diagnosed with a cancer as described herein. In another embodiment of such methods, the sample is a tumor sample collected from a subject. In one such embodiment, the sample is collected before any treatment is administered. In another such embodiment, the sample is collected before administering a compound as described herein, or a pharmaceutically acceptable salt thereof, and after administering another chemotherapeutic agent. In another embodiment of such methods, a compound as described herein, or a pharmaceutically acceptable salt thereof, is administered (e.g., orally) as provided herein.

[0715] Further provided herein are methods for treating a patient with a KRas-containing G12C A method for treating pancreatic cancer in patients with pancreatic cancer containing a KRas mutation, the method comprising administering to the patient a therapeutically effective amount of a compound (A) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof. Further provided herein is a method for treating patients with pancreatic cancer containing a KRas mutation. G12C A method for treating pancreatic cancer in patients with pancreatic cancer having a pancreatic cancer mutation, the method comprising administering to the patient a therapeutically effective amount of compound (B) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof.

[0716] In one embodiment, the patient has previously been treated with radiation therapy and one or more chemotherapy drugs. 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.

[0717] The present invention further provides a method for treating a patient with KRas G12CA method for treating colon cancer in patients with KRas mutations, the method comprising administering to the patient a therapeutically effective amount of compound (A) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof. G12C A method for treating colon cancer in patients with colon cancer having a mutation in such cancer, the method comprising administering to the patient a therapeutically effective amount of compound (B) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof.

[0718] In one embodiment, the colon cancer is stage I or stage II. In another embodiment, the colon cancer is stage III or stage IV.

[0719] Further provided herein are methods for treating KRas G12C Mutations in blood cancers may include KRas G12C A method for treating a mutated MYH-associated polyposis cancer, the method comprising administering to a patient suffering from such a disease a therapeutically effective amount of a compound (A) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof. Further provided herein is a method for treating a KRas-containing G12C Mutations in blood cancers may include KRas G12C A method for treating a mutant MYH-associated polyposis cancer, the method comprising administering to a patient suffering from such a disease a therapeutically effective amount of a compound (B) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof.

[0720] Further provided herein are methods for treating KRas G12C A method for a tumor agnostic cancer of a mutation. In one embodiment of such a method, the method comprises:

[0721] (a) Determine the presence of KRas in samples collected from patients with suspected cancer G12C sudden

[0722] change; and

[0723] (b) administering a therapeutically effective amount of compound (A) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof to a patient suffering from such a disease.

[0724] Further provided herein are methods for treating KRas G12C A method for a tumor agnostic cancer of a mutation. In one embodiment of such a method, the method comprises:

[0725] (a) Determine the presence of KRas in samples collected from patients with suspected cancer G12C sudden

[0726] change; and

[0727] (b) administering a therapeutically effective amount of compound (B) synthesized according to method P9 described herein or a pharmaceutically acceptable salt thereof to a patient suffering from such a disease.

[0728] The patients described herein may be human. In some embodiments, the compounds described herein are administered via an oral route in the methods provided herein. In some embodiments, the compounds are administered via injection. The methods provided herein include administering the compounds as IL therapy.

[0729] Example

[0730] The following are exemplary embodiments.

[0731] Example 1. A method for preparing a compound of formula (I), comprising:

[0732]

[0733] in,

[0734] X 0 For 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;

[0735] X 1 is hydrogen or halogen;

[0736] 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;

[0737] R 1 Hydrogen or PG 1 ;

[0738] Each R 2 are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C1-6 Haloalkyl;

[0739] 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;

[0740] R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 Haloalkyl;

[0741] R 4 For R 4A -substituted or unsubstituted C 1-3 Haloalkyl;

[0742] R 4A For unsubstituted C 1-3 alkyl;

[0743] R 5 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 -substituted or unsubstituted 3-6 membered heterocyclic ring, R 5A -substituted or unsubstituted phenyl or R 5A - Replaced or not

[0744] Substituted 6-membered heteroaryl;

[0745] R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C 1-6 Alkyl, R 5C -substituted or unsubstituted C 1-6 Haloalkyl, R 5C -substituted or unsubstituted C 3-7 Cycloalkyl; R 5C -substituted or unsubstituted 3-7 membered heterocyclic ring; R 5C-substituted or unsubstituted C 5-7 Aryl or R 5C -substituted or unsubstituted C 5-7 heteroaryl;

[0746] R 5C are 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 Heterocyclic ring; R 5D -substituted or unsubstituted C 5-7 Aryl, or R 5D -substituted or unsubstituted C 5-7 heteroaryl;

[0747] R 5D are independently halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl, unsubstituted C 3-7 Cycloalkyl; unsubstituted C 3-7 miscellaneous

[0748] Ring; unsubstituted C 5-7 Aryl or unsubstituted C 5-7 heteroaryl;

[0749] R 6 Halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 Cycloalkyl;

[0750] n is 0, 1 or 2;

[0751] Each PG is independently an amino protecting group, or two PGs together form a C 3-7 a nitrogen heterocycle; and

[0752] PG 1 is an amino protecting group;

[0753] (a) making the compound of formula (II)

[0754]

[0755] Where X 2 is a halogen;

[0756] contacting with an organomagnesium compound and a zinc complex; and

[0757] (b) mixing the mixture of step (a) with a compound of formula (III),

[0758]

[0759] Where X 4 is a halogen;

[0760] A transition metal (eg, Pd or Ni) catalyst precursor and a chiral ligand are contacted to synthesize the compound of formula (I).

[0761] Embodiment 2. The method according to embodiment 1, wherein the compound of formula (II) is prepared according to the following method:

[0762] (a) making the compound of formula (Iva) (IVa) and having the formula Mode

[0763] contact with a halogenating agent, wherein X 3 is halogen, to prepare a compound of formula (IVb)

[0764]

[0765] (d) cyclizing the compound of formula (IVb) to a compound of formula (V)

[0766] (d) contacting the compound of formula (V) with a chlorinating agent to prepare a compound of formula (Va)

[0767] (Va);

[0768] (e) mixing a compound of formula (Va) with a compound of formula (VI) is contacted with the piperazinyl portion to prepare

[0769] Preparation of the compound of formula (IIa) (IIa); and

[0770] (f) reacting the compound of formula (IIa) with a 0 to form a compound of formula (II).

[0771] Embodiment 3. The method according to embodiment 2 further comprises the steps of:

[0772] (a0) making the compound of formula (IV) contacting with a base in the presence of CO2 gas and aminating the compound to form a compound of formula (IVa)

[0773] Embodiment 4. The method according to any one of embodiments 1 to 3, wherein the compound of formula (III) is prepared according to the following method:

[0774] (a) making the compound of formula (VII) (VII) with a compound having the formula NH2(PG)

[0775] To prepare the compound of formula (VIIa): (VIIa);

[0776] (b) reacting a compound of formula (VIIa) with a compound of formula X a PG contact compounds, wherein X a For halogen,

[0777] To prepare the compound of formula (VIIb) (VIIb);

[0778] (c) reacting a compound of formula (VIIb) with a compound of formula contact with a halogenating agent, wherein X 5 is halogen, to prepare a compound of formula (VIIc) (VIIc);

[0779] (d) halogenating the compound of formula (VIIc) with a halogenating alkylating agent to prepare a compound of formula (VIId)

[0780] Compound

[0781]

[0782] (e) Brominating the compound of formula (VIId) to prepare the compound of formula (VIIe) (VIIe); and

[0783] (f) reacting the compound of formula (VIIe) with X a PG to prepare the compound of formula (III).

[0784] Embodiment 5. The method according to embodiment 1, wherein the compound of formula (III) is prepared according to the following method:

[0785] (a) making a compound of formula (VIII) contact with a halogenating agent, wherein X 6 is Cl or I, to form a compound of formula (VIIIa)

[0786] (b) brominating the compound of formula (VIIIa) to form a compound of formula (VIIIb) as well as

[0787] (c) contacting a compound of formula (VIIIb) with a compound having the formula NH(PG)2 to prepare a compound of formula (III).

[0788] Embodiment 6. The method according to embodiment 1, wherein the compound of formula (III) is prepared according to the following method:

[0789] (a) making the compound of formula (VIIIc) contacted with a brominating agent to form a compound of formula (VIIId)

[0790] Compound

[0791] (b) contacting the compound of formula (VIIId) with a halogenating agent to form a compound of formula (VIIIb)

[0792]

[0793] (c) contacting a compound of formula (VIIIb) with a compound having the formula NH(PG)2 to prepare a compound of formula (III).

[0794] Embodiment 7. The method according to any one of embodiments 1 to 6, wherein X 1 It is a halogen.

[0795] Embodiment 8. The method according to any one of embodiments 1 to 7, wherein X 1 is F or Cl.

[0796] Embodiment 9. The method according to any one of embodiments 1 to 6, wherein X 1 is hydrogen or halogen.

[0797] Embodiment 10. The method according to any one of embodiments 1 to 8, wherein X 3 is halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3 Halogenated alkyl.

[0798] Embodiment 11. The method according to any one of embodiments 1 to 8, wherein X 3 is halogen or unsubstituted C 1-3 Halogenated alkyl.

[0799] Embodiment 12. The method according to any one of embodiments 1 to 8, wherein X 3 For unsubstituted C 1-3 alkoxy or unsubstituted cyclopropyl.

[0800] Embodiment 13. The method according to any one of embodiments 1 to 8, wherein X 3 It is a halogen.

[0801] Embodiment 14. The method according to any one of embodiments 1 to 8, wherein X 3 It is Cl or F.

[0802] Embodiment 15. The method according to any one of embodiments 1 to 8, wherein X 3 It is Cl, F, CF3, CHF2 or CH2F.

[0803] Embodiment 16. The method according to any one of embodiments 1 to 8, wherein X 3 It is CF3, CHF2 or CH2F.

[0804] Embodiment 17. The method according to any one of embodiments 1 to 16, wherein X 1 For PG 1 .

[0805] Embodiment 18. The method according to embodiment 17, wherein PG 1 It is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidene, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl).

[0806] Embodiment 19. The method according to any one of embodiments 1 to 16, wherein R 1 It is Boc (tert-butoxycarbonyl).

[0807] Embodiment 20. The method according to any one of embodiments 1 to 19, wherein R 2 is halogen or cyano.

[0808] Embodiment 21. The method according to any one of embodiments 1 to 19, wherein R 2 For unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 Halogenated alkyl.

[0809] Embodiment 22. The method according to any one of embodiments 1 to 19, wherein R 2 For unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 Cyanoalkyl.

[0810] Embodiment 23. The method according to any one of embodiments 1 to 19, wherein R 2 For unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 Halogenated alkyl.

[0811] Embodiment 24. The method according to any one of embodiments 1 to 19, wherein R 2 It is methyl or ethyl.

[0812] Embodiment 25. The method according to any one of embodiments 1 to 19, wherein R 2 It is methyl.

[0813] Embodiment 26. The method according to any one of embodiments 1 to 19, wherein R 2 It is CF3, CHF2 or CH2F.

[0814] Embodiment 27. The method according to any one of embodiments 1 to 19, wherein R 2 is CH2CN.

[0815] Embodiment 28. The method according to any one of embodiments 1 to 27, wherein R 3 is hydrogen or R 3A -substituted or unsubstituted C 1-3 alkyl.

[0816] Embodiment 29. The method according to any one of embodiments 1 to 27, wherein R 3 For R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 haloalkyl or cyclopropyl.

[0817] Embodiment 30. The method according to any one of embodiments 1 to 27, wherein R 3 For R 3A -substituted or unsubstituted C 1-3 Alkyl or R 3A -substituted or unsubstituted C 1-3 Halogenated alkyl.

[0818] Embodiment 31. The method according to any one of embodiments 1 to 27, wherein R 3 For R 3A -substituted or unsubstituted C 1-3 alkyl.

[0819] Embodiment 32. The method according to any one of embodiments 1 to 27, wherein R 3 It is methyl.

[0820] Embodiment 33. The method according to any one of embodiments 1 to 32, wherein R 4 It is CF3, CHF2 or CH2F.

[0821] 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), benzylene, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz (carbonylbenzyloxy).

[0822] Embodiment 35. The method of any one of embodiments 1 to 34, wherein each PG is p-methoxybenzyl.

[0823] Embodiment 36. The method according to any one of embodiments 1 to 34, wherein the two PGs together form a moiety having the following structure:

[0824]

[0825] Embodiment 37. The method according to any one of embodiments 1 to 36, wherein X 2 For Br.

[0826] Embodiment 38. A 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, tri-n-butylmagnesium lithium, tri-isopropylmagnesium lithium and (isopropyl)(di-n-butyl)magnesium lithium.

[0827] Embodiment 39. The method of 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.

[0828] Embodiment 40. The method of any one of embodiments 1 to 39, wherein the transition metal catalyst precursor is a Pd or Ni catalyst precursor selected from the group consisting of Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl2, Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TF A)2, [Pd(allyl)Cl]2, [Pd(cinnamoyl)Cl]2, [PdCl(crotyl)]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.

[0829] Embodiment 41. The method according to any one of embodiments 1 to 40, wherein the chiral ligand is

[0830]

[0831] in

[0832] Y is O or NR 7 ;

[0833] Z is O or N;

[0834] R 7 and R 8 is independently unsubstituted C 1-6 alkyl;

[0835] R 9 and R 10 Independently for R 11 -substituted or unsubstituted C 5-6 Cycloalkyl or R 11 - substituted or unsubstituted phenyl;

[0836] Each R 11 are independently hydrogen, C 1-6 Unsubstituted alkyl or C 1-6 unsubstituted haloalkyl;

[0837] R 12 and R 13 Each independently is R 14 -substituted or unsubstituted C1-6 alkyl, R 14 -substituted or unsubstituted C 3-7 Cycloalkyl, R 14 -substituted or unsubstituted aryl or R 14 -substituted or unsubstituted C5-7 heteroaryl;

[0838] Each R 14 is independently unsubstituted C 1-4 alkyl.

[0839] Embodiment 42. The method according to embodiment 41, wherein R 7 With R 8 same.

[0840] Embodiment 43. The method according to embodiment 42, wherein R 7 and R 8 Each is methyl, ethyl or phenyl.

[0841] Embodiment 44. The method of Embodiment 2, wherein the base is LDA or LiTMP.

[0842] Embodiment 45. The method of embodiment 2, wherein the halogenating agent is NCS or 1,3-dichloro-5,5-dimethylhydantoin.

[0843] Embodiment 46. The method of embodiment 2, wherein the chlorinating agent is POCl3, PCl3, PCl5 or SOCl2.

[0844] Embodiment 47. The method of embodiment 4, wherein the halogenating agent is NIS or 1,3-diiodo-5,5-dimethylhydantoin.

[0845] Embodiment 48. The method of Embodiment 4, wherein the haloalkylating agent is a fluoroalkylating agent.

[0846] Embodiment 49. The method of Embodiment 4, wherein the haloalkylating agent is methyl 2,2-difluoro-2-(fluorosulfonyl)acetate.

[0847] Embodiment 50. The method of Embodiment 5 or 6, wherein the halogenating agent is SF4 in HF.

[0848] Embodiment 51. The method according to embodiment 1, wherein the compound of formula (II) has the formula:

[0849]

[0850] Where X 3 It is a halogen.

[0851] Embodiment 52. The method according to embodiment 1, wherein the compound of formula (II) has the formula:

[0852]

[0853] Where X 3It is a halogen.

[0854] Embodiment 53. The method according to embodiment 1, wherein the compound of formula (II) has the formula:

[0855]

[0856] Embodiment 54. The method according to embodiment 1, wherein the compound of formula (III) has the formula:

[0857]

[0858] Embodiment 55. The method according to embodiment 54, wherein R 3 For unsubstituted C 1-3 alkyl.

[0859] Embodiment 56. The method according to embodiment 54 or 55, wherein R 4 For unsubstituted C 1-3 Halogenated alkyl.

[0860] Embodiment 57. The method according to embodiment 1, wherein the compound of formula (III) has the formula:

[0861]

[0862] Embodiment 58. The method according to embodiment 1, wherein the compound of formula (I) has the formula:

[0863]

[0864] Embodiment 59. The method according to embodiment 1, wherein the compound of formula (I) has the formula:

[0865]

[0866] Embodiment 60. The method according to embodiment 58 or 59, wherein R 3 For unsubstituted C 1-3 alkyl.

[0867] Embodiment 61. The method according to any one of embodiments 58 to 60, wherein R 4 For unsubstituted C 1-3 Halogenated alkyl.

[0868] Embodiment 62. The method according to embodiment 1, wherein the compound of formula (I) has the formula:

[0869]

[0870] Embodiment 63. The method according to any one of embodiments 58 to 62, wherein R2 For unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 Halogenated alkyl.

[0871] Embodiment 64. The method according to embodiment 63, wherein R 2 It is methyl, ethyl, CH2CN, CF3, CHF2 or CH2F.

[0872] Embodiment 65. The method according to embodiment 63, wherein R 2 It is methyl, ethyl, CN or CH2CN.

[0873] Embodiment 66. The method according to embodiment 1, wherein the compound of formula (I) has the formula:

[0874]

[0875] Where X 3 It is a halogen.

[0876] Embodiment 67. The method according to embodiment 1, wherein the compound of formula (I) has the formula:

[0877]

[0878] Embodiment 68. The method according to embodiment 1, wherein X 0 is hydrogen, halogen, CF3, CHF2, CH2F or a moiety having the following structure:

[0879]

[0880]

[0881] Example 69. A compound having formula (Id):

[0882]

[0883] Where X 3 It is a halogen.

[0884] Example 70. A compound having formula (1):

[0885]

[0886] Embodiment 71. The method of embodiment 2, wherein step (f) further comprises:

[0887] Step (g) fluorinating the compound of formula (IIa) to obtain the compound of formula (IIa1)

[0888]

[0889] Embodiment 72. The method of embodiment 2, wherein step (f) further comprises:

[0890] Step (h) alkoxylating the compound of formula (IIa) to a compound of formula (IIa2)

[0891]

[0892] Embodiment 73. The method of embodiment 2, wherein step (f) further comprises:

[0893] Step (j) thiolation of the compound of formula (IIa) to a compound of formula (IIe):

[0894]

[0895] Embodiment 74. The method according to any one of embodiments 1 to 6, wherein the compound of formula (I) is a compound of Table 1.

[0896] Example 75. A method for synthesizing a compound having the formula

[0897]

[0898] or a pharmaceutically acceptable salt thereof, the method comprising

[0899] (a) making a compound of formula (2) or its salt is contacted with ZnCl2 and i-PrMgCl·LiCl, and the compound of formula (3) touch,

[0900] (b) contacting the mixture of step (a) or its salt with a transition metal (e.g., Pd or Ni) catalyst precursor and a chiral ligand to synthesize a compound of formula (1)

[0901]

[0902] or a solvate or salt thereof;

[0903] (c) reacting a compound of formula (1) or a solvate or salt thereof with a compound of formula HO-X A The compound is contacted with a base, wherein X A With formula Thus, the compound of formula (1d) is synthesized

[0904]

[0905] or a solvate or a pharmaceutically acceptable salt thereof;

[0906] (d) contacting the compound of formula (1d) with MsOH in an acid to synthesize the compound of formula (1e)

[0907]

[0908] or a solvate or a pharmaceutically acceptable salt thereof; and

[0909] (e) reacting the compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with a base as described herein and optionally an activating agent

[0910] contacting, thereby preparing the compound of formula (A) or a pharmaceutically acceptable salt thereof.

[0911] Embodiment 76. The method of embodiment 75, wherein the acid of step (d) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid or trifluoromethanesulfonic acid.

[0912] Embodiment 77. The method according to embodiment 75, wherein step (e) comprises reacting a compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with touch.

[0913] Embodiment 78. In the method (P9) of one embodiment described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or a pharmaceutically acceptable salt thereof with touch.

[0914] The following examples are presented by way of illustration and not limitation.

[0915] Examples

[0916] Example 1

[0917] Synthesis of 2-amino-4-bromo-3-fluorobenzoic acid. Compound 4a

[0918]

[0919] Step 1, Route 1: 4-Bromo-2,3-difluorobenzoic acid

[0920] Under N2, between -65 ℃ and -50 ℃, n-BuLi (1.6 L, 3.990 mol, 2.5 M in hexane) was added dropwise to a solution of anhydrous diisopropylamine (440 g, 4.352 mol) in anhydrous THF (4 L) over 1 hour. The mixture was stirred at -65 ℃ for 1 hour. A solution of 1-bromo-2,3-difluorobenzene (700 g, 3.627 mol) in anhydrous THF (1.2 L) was added dropwise over 1 hour while maintaining the internal temperature between -65 ℃ and -50 ℃. The mixture was stirred at -65 ℃ 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 and stirred over 10 minutes. After the resulting mixture was stirred for 30 minutes, it was slowly quenched with H2O (2L), then acidified to pH=3 with aqueous HCl (6M, 1.6L) and extracted with EA (3.5L×2). The combined organic layers were washed with brine (4L), dried over Na2SO4 (500g), filtered and concentrated in vacuo to give 4-bromo-2,3-difluorobenzoic acid (790g, 92%) as an off-white solid. HPLC: 90%, RT=4.507min.

[0921] Step 2: 2-Amino-4-bromo-3-fluorobenzoic acid

[0922] A mixture of 4-bromo-2,3-difluorobenzoic acid (500 g, 2.11 mol) in NH3.H2 (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 to pH=3 with concentrated HCl in an ice bath. The solid was collected by filtration, washed with water and dried in air at 50°C to give the crude product. The crude solid was dissolved in EtOH (5 volumes) at 75°C and then added dropwise to water (5 volumes). The mixture was cooled to room temperature, the precipitate was filtered and dried in air at 50°C overnight. The resulting solid was triturated with DCM (5 volumes) at room temperature overnight, filtered and dried in air at 50°C overnight to give 2-amino-4-bromo-3-fluorobenzoic acid (307 g, 61%) as an off-white solid. HPLC: 99%, RT=4.502 min; 1 H NMR (400MHz, DMSO-d6) δ 13.09 (brs, 1H), 7.50 (dd, J = 8.8Hz, 1.6Hz, 1H), 6.80 (brs, 1H), 6.78 (dd, J = 8.8Hz, 6.4Hz, 1H).

[0923] Example 2

[0924] (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester Compound 2:

[0925]

[0926] Step 1:

[0927]

[0928] Under N2 atmosphere, compound 4a (128.2 mol) was added to a 500 L reactor. Under N2 atmosphere, EtOH was added to a 500 L reactor, and the mixture was heated to 55° C. to 60° C. Under N2 atmosphere, NCS (154.3 mol) was added to a 500 L reactor in five portions over 3 hours at 55° C. to 60° C., and the mixture was stirred at 50° C. to 55° C. for 0.5 hours.

[0929] 900 kg of water was added to a separate 1500 L reactor, and the water was heated to 45° C. to 50° C. The reaction mixture was added to hot water and slurried at 55° C. to 60° C. for 1 to 2 hours. The reaction was filtered and about 50 kg of wet 4b was obtained. The wet cake was slurried with hot water at 45° C. to 50° C. for 0.5 to 1.0 hours and filtered, and washed with hot water. The filter cake was slurried with DCM at 15° C. to 30° C. for 1 to 2 hours, filtered and washed with DCM. The filter cake was dried at 30° C. to 40° C. under high vacuum for 16 hours. 25.8 kg of compound 4b (97.5A%) was isolated as a light brown solid with a yield of 80% to 81%.

[0930] Step 2:

[0931]

[0932] 164 kg water, 28.6 kg compound 4b (106.5 mol) and 4.85 kg NaOH (dissolved in 32.5 kg water) were added to a 3000 L reactor. The reaction was stirred at room temperature for 5 minutes. KOCN (188.9 mol) was dissolved in 392 kg water and added to the 3000 L reactor, and then stirred at room temperature for 5 minutes. The mixture was heated to 39° C. to 42° C., and the pH was adjusted to 6.3 to 6.7 with concentrated hydrochloric acid. The mixture was stirred at 39° C. to 42° C. for 3 hours. KOCN (94.4 mol) was dissolved in 398 kg water and added to the 3000 L reactor, and stirred at room temperature for 5 minutes. The mixture was heated to 39° C. to 42° C. for 3 hours, and the pH was adjusted to 6.3 to 6.7 with concentrated hydrochloric acid. KOCN (94.4 mol) was dissolved in 398 kg water and added to the 3000 L reactor and stirred at room temperature for 5 minutes, then heated to 39 to 42 ° C for 2.5 hours, and the pH was adjusted to 6.3 to 6.7 with concentrated hydrochloric acid. The mixture was then stirred at 39 to 42 ° C for 1.0 hour, and the pH was adjusted to 5.3 to 5.7 with concentrated hydrochloric acid. NaOH (442 mol) was dissolved in 35.4 kg water and added to the 3000 L reactor and stirred at 45 to 50 ° C for 1 hour.

[0933] The mixture was cooled to 10°C to 15°C and stirred at 10°C to 15°C for 0.5 hours. The filter cake was filtered and washed with water (5 volumes) and then centrifuged. Acetone and water were added to a 2000L reactor and heated to 25°C to 30°C, and a wet filter cake was added and stirred at 25°C to 30°C for 1.5 hours. The pH was adjusted to 1.0 with concentrated hydrochloric acid, and the mixture was cooled to 5°C to 10°C. The mixture was stirred at 5°C to 10°C for 0.5 hours. The filter cake was filtered and washed with water (5 volumes × 2), centrifuged, and dried at 55°C to 60°C in a vacuum dryer for 48 hours. 24kg of compound 5 (98.4A%) was isolated as an off-white solid with a yield of 72% (corrected).

[0934] Step 3:

[0935]

[0936] Under N2 atmosphere, POCl3 (264.8 mol) was added to a 100 L reactor, and compound 5 (27.3 mol) was added and stirred at room temperature for 5 minutes. DIPEA (54.2 mol) was added dropwise through a high level tank within 5 to 10 minutes, and the mixture was heated to 80 to 105°C, and the mixture was stirred for 40 minutes.

[0937] The mixture was cooled to 40°C to 50°C and concentrated to about 10L to 15L under vacuum. The mixture was diluted with ACN (14kg) and the diluted portion was added to 105kg water at 15°C to 30°C over 1 to 2 hours. The mixture was stirred at 25°C to 30°C for 0.5 hours, filtered and the filter cake was washed with water (2.5 volumes x 3). The wet filter cake was dried in a vacuum dryer at 45°C to 50°C for 12 hours. 8.5kg of compound 5a (98.1A%) was isolated as a yellow solid with a yield of 100% (corrected).

[0938] Step 4:

[0939]

[0940] Under N2 atmosphere, THF was added to a 500 L reactor. DIPEA (141.6 mol) was added, followed by compound 5a (5.7 mol), and the mixture was stirred at room temperature for 5 minutes. The mixture was cooled to 5°C to 10°C.

[0941] Under N2, THF was added to a 100L reactor. (S)-3-methyl-1-piperazinecarboxylic acid tert-butyl ester (83.4 mol) was added to the reactor and stirred at room temperature for 5 minutes, and then the THF solution in the 100L reactor was transferred to the header tank of the 100L reactor. The THF solution of compound 5a was added dropwise to a 500L reactor through the header tank within 60 minutes. The mixture was then stirred at 5°C to 10°C for 30 minutes.

[0942] About 500 kg of water was added to a 1000 L reactor and cooled to 0 to 10 ° C. The reaction containing 5a was added to water and stirred at 0 to 10 ° C for 1 hour. The filter cake was filtered and washed with water (4 volumes × 2), then dissolved in DCM (10 volumes) and the phases were separated. The organic phase was washed with water (5 volumes) and the aqueous solution was extracted with DCM. The combined organic phase was added to a 500 L reactor and concentrated to about 20 L to 25 L at 45 to 50 ° C under vacuum. About 53 kg of n-heptane was added to the reactor, and the contents were concentrated to about 50 L to 60 L at 45 to 50 ° C under vacuum and separated. At 20 to 30 ° C, another 53 kg of n-heptane was slowly added dropwise to the 500 L reactor over 10 minutes. The mixture was stirred at 20 to 30 ° C for 0.5 hours. The mixture was brought to 5 to 10 ° C and stirred at 5 to 10 ° C for 0.5 hours. The filter cake was filtered and washed with n-heptane (5 vol) and then dried in a vacuum desiccator at 45-50°C for 10 hours. 35.8 kg of compound 2d (98.0 A%) were isolated as an off-white solid with a yield of 94% (corrected).

[0943] Step 5:

[0944]

[0945] Under N2, 274 kg DMF was added to a 500 L reactor and 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, then stirred at room temperature for 5 minutes. The mixture was heated to 51.5 to 52.5 °C and stirred for 10 hours. Additional CsF (23.7 mol) was added, and the mixture was stirred at 51.5 to 52.5 °C for 16 hours under N2 atmosphere.

[0946] About 870kg of water was added to a 1500L reactor and cooled to 5°C to 10°C. The reaction mixture was added to the reactor below 15°C and stirred for 0.5 hours at 5°C to 10°C. The yield was filtered and then added to a 1000L reactor containing 320L of MeCN and water. The mixture was stirred for 5 hours at 20°C to 25°C. The wet cake was dissolved in DCM and each phase was separated. The aqueous layer was extracted with DCM (100L, 3 volumes), the organic layers were combined and concentrated to about 80L at 45°C to 50°C in a vacuum. About 59kg of n-heptane was added to a 500L reactor and the combined concentrated organic phase was added. The mixture was concentrated to about 80L at 45°C to 50°C under vacuum and stirred for 0.5 hours at 20°C to 30°C. The mixture was then cooled to 10°C to 15°C and stirred for 0.5 hours. The filter cake was filtered and washed with n-heptane (5 vol) and then dried in a vacuum desiccator at 45-50°C for 10 hours. 28.2 kg of compound 2 (97.2A%) were isolated as an off-white solid with a yield of 82% (corrected).

[0947] Example 3

[0948] Compound 3 (6-bromo-N,N-bis(4-p-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine)

[0949]

[0950] Step 1: 6-Chloro-N-(4-p-methoxybenzyl)-4-methylpyridin-2-amine (Compound 7a)

[0951]

[0952] PMBNH2 (175.0L, 183.75kg, 5V) was added to the reactor. 2,6-dichloro-4-methylpyridine (Compound 7, 35.0kg, 1.0eq.) was added to the reactor and stirred at less than 30°C. Heat to 120°C ± 10°C and stir at 120°C ± 10°C for 32 hours. The reaction was cooled to sample for LCMS analysis, and then soft water / isopropanol = 2 / 1 (350.0L, 10V) was added dropwise at 85°C to 130°C. The reaction was cooled to 85°C to 95°C and stirred for 30 to 60 minutes. Cool to 5°C ± 5°C (10°C ± 5°C per hour), and stirred at 5°C ± 5°C for at least 1 hour. Centrifuge and wash the filter cake twice with water / isopropanol = 2 / 1 (3V). Collect the filter cake and dry it at 45°C ± 5°C for at least 16 hours. Yield: 52.0kg, 91.6%

[0953] Step 2: 6-Chloro-N,N-bis(4-p-methoxybenzyl)-4-methylpyridin-2-amine (Compound 7b)

[0954]

[0955] Under N2, THF (208.0L, 4.0V) was added to the reactor. Under N2, compound 7a (52.0kg, 1.0eq.), PMBCl (37.4kg, 1.2eq.) were added to the reactor and stirred into a suspension at 0°C±5°C. A solution of t-BuOK in THF (166.4kg, 1.5eq, 20% by weight in THF) was added dropwise at 0°C±5°C and stirred at 0°C±5°C for at least 6.0 hours. Water (780.0L, 15.0V) below 10°C was added dropwise and stirred at 5°C±5°C for at least 2 hours. Centrifuge and wash the filter cake with water. Collect the filter cake and slurry it with water / isopropanol=2 / 1 (208.0L, 5.0V) at 25°C±5°C for at least 6 hours. Centrifuge again and wash the filter cake twice with water / isopropanol=2 / 1 (2V). The filter cake was collected and the solid was dried at 45°C ± 5°C for at least 16 hours. Yield: 70.74 kg, 93.4%.

[0956] Step 3: 6-Chloro-5-iodo-N,N-bis(4-p-methoxybenzyl)-4-methylpyridin-2-amine

[0957]

[0958] DMF (353.5 L, 5.0 V), compound 7b (70.70 kg, 1.0 eq.) were added to the reactor and stirred at 25°C ± 5°C until clear. NIS (49.9 kg, 1.2 eq.) solid was added to the reactor in 10 batches, at least one batch every three hours. Stir at 25°C ± 5°C for at least 8 hours. Cool to 0°C ± 5°C, then add 5 wt% Na2SO3 aqueous solution (353.5 L, 5.0 V) dropwise at -5°C to 25°C. Stir at 5°C ± 5°C for at least 30 minutes. Centrifuge and wash the filter cake twice with soft water, each elution volume is 2 V. Collect the shaped filter cake and slurry with soft water / isopropanol = 2 / 1 (373.5 L, 5.0 V) at 70°C ± 5°C for at least 30 minutes. Cool to 20°C ± 5°C, stir at 20°C ± 5°C for at least 1 hour. Centrifuge again and wash the filter cake twice with water / isopropanol=2 / 1, each elution volume is 3 V. Collect the solid and dry at 45°C±5°C for at least 16 hours. Yield: 86.56 kg, 92.1%.

[0959] Step 4: 6-(1,3-bis(4-methoxyphenyl)propan-2-yl)-2-chloro-4-methyl-3-(trifluoromethyl)pyridine (Compound 7d)

[0960]

[0961] DMF (432.5L, 5.0V) and HMPA (152.3kg, 5.0eq.) were added to the reactor. Under a nitrogen atmosphere, compound 7c (86.5kg, 1.0eq.) was added to the reactor. CuI (80.9kg, 2.5eq.) was added to the reactor. Bubble with N2 at 25°C ± 5°C for at least 40 minutes. Heat to 90°C ± 5°C, and 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (98.0kg, 3.0eq.) was added dropwise to the reactor. Stir at 90°C ± 5°C for at least 2 hours. Cool and filter through diatomaceous earth. Wash with EtOAc (865.0L, 10.0V). Evaporation in vacuum is 4V to 8V. Cool to 5°C ± 5°C, then soft water (865.0L, 10.0V) is added dropwise to the reactor at 0°C to 25°C. Stir at least 30 minutes at 20°C ± 5°C. Centrifuge and wash the filter cake twice with water, each elution volume is 4V. Collect the filter cake and add EtOAc (865.0L, 10.0V). Stir at least 30 minutes at 25°C ± 5°C, filter through diatomaceous earth, and then wash with EtOAc (865.0L, 10.0V). Keep, separate, collect the organic phase, and concentrate it to 2 to 4V. Isopropanol (432.5L, 5.0V) is added to the reactor and concentrated to 2 to 4V. Repeat adding isopropanol (432.5L, 5.0V), and concentrate to 2 to 4V until the peak area % of EtOAc is determined by GC≤5.0%. Heat to 60°C ± 5°C and add water (4 to 6V) dropwise to the tube, and stir at 60°C ± 5°C for at least 0.5 hours. Cool to 20°C ± 5°C and stir at 25°C ± 5°C for at least 1 hour. Centrifuge and wash the filter cake twice with water / isopropanol = 2 / 1 (3V). Collect the solid and dry at 50°C ± 5°C for at least 16 hours. Yield: 70.45 kg, 91.9%.

[0962] Step 5: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0963]

[0964] MeCN (176.0 L, 2.5 V), compound 7d (70.4 kg, 1.0 eq.) were added to the reactor and stirred into a suspension at 15°C ± 5°C. HBr (176.0 L, 2.5 V, 48% in water) was added dropwise to the reactor at 10°C to 40°C. Adjust to 80°C ± 5°C and stir for at least 2 hours. Cool, then add IPAC (211.2 L, 3.0 V). Cool to 0°C ± 5°C, and neutralize to pH = 7 to 8 with a 15 wt% NaOH aqueous solution at T≤25°C. The aqueous layer was extracted three times with IPAC (211.2 L, 3.0 V), the organic layer was collected and concentrated to 2 to 4 V at T≤45°C. MeCN (352.0 L, 5.0 V) was added to the reactor and concentrated to 2 to 4 V at T≤45°C to obtain a solution of 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine in MeCN.

[0965] Step 6: N-(6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide

[0966]

[0967] AcBr (287.9 ​​kg, 15.0 eq.) was added to the reactor at -10°C to 40°C and adjusted to 70°C ± 5°C, then stirred for at least 10 hours. Cooled to 0°C ± 5°C and quenched by EtOH (176.0 L, 2.5 V) at T≤25°C. Cooled to 0°C ± 5°C and neutralized to pH = 7 to 8 with a 15 wt% NaOH aqueous solution at T≤25°C. Extracted three times with EtOAc (281.6 L, 3.0 V), the organic layer was collected and concentrated to 2 to 4 V at T≤45°C. MeCN (352.0 L, 5.0 V) was added to the reactor and concentrated to 2 to 4 V at T≤45°C. AcBr (287.9 ​​kg, 15.0 eq.) was added to the reactor at -10°C to 40°C and adjusted to 70°C ± 5°C, then stirred for at least 10 hours. Cool to 0°C ± 5°C and quench by EtOH (176.0L, 2.5V) at T≤25°C. Cool to 0°C ± 5°C and neutralize to pH=7 to 8 with a 15 wt% NaOH aqueous solution at T≤25°C. Extract three times with EtOAc (281.6L, 3V), collect the organic layer and concentrate to 1 to 4V at T≤45°C. Cool to 5°C to 10°C and stir at 5°C to 10°C for 1 to 2 hours. Centrifuge and wash the filter cake twice with EtOAc (1V), and collect the filter cake for the next step without further purification. Yield: 34.50kg crude product

[0968] Step 7: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Compound 7e)

[0969]

[0970] 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. Adjust to 70°C ± 5°C and stir for at least 8 hours. Adjust to 70°C ± 5°C and stir for at least 4 hours. Cool to 0°C ± 5°C and neutralize to pH = 7 to 8 with a 15 wt % NaOH aqueous solution at T≤25°C. Centrifuge and wash the filter cake with soft water. The filtrate was extracted four times with MTBE, each time with a volume of 3.0 V, and the organic layer was collected. The filter cake and the organic layer were added to the reactor. Adjust to 45°C to 50°C and stir for 1 to 2 hours. Cool to 25°C to 30°C, then filter through diatomaceous earth and wash with MTBE (353.0 L, 5.0 V). The filtrate was collected and concentrated to 2 to 4 V. Isopropanol (353.0 L, 5.0 V) was added and concentrated to 2 to 4 V under vacuum. A second portion of isopropanol (353.0 L, 5.0 V) was added and concentrated to 2 to 4 V under vacuum. Adjust to 50°C ± 5°C and water (3 to 5 V) was added dropwise to the reactor, then stirred at 50°C ± 5°C for at least 30 minutes. Cool to 5°C ± 5°C and stir at 5°C ± 5°C for at least 2 hours. Centrifuge and wash the filter cake twice with water / isopropanol = 2 / 1 (2 V). Collect the solid and dry at 45°C ± 5°C for at least 16 hours. Yield: 25.50 kg, 64.0%.

[0971] Step 8: 6-Bromo-N,N-bis(4-p-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Compound 3)

[0972]

[0973] Under N2, NMP (255.0L, 10.0V), PMBCl (47.0kg, 3.0eq.) and compound 7e (25.5kg, 1.0eq.) were added to the reactor. Cooled to 0°C ± 5°C. Solid CH3ONa (16.2kg, 3.0eq.) was added in 5 batches at 0°C ± 5°C. One batch was added at least every 0.5 hours. Stirred at 0°C ± 5°C for at least 4 hours. Water (20.0V) was added dropwise at -10°C to 10°C and stirred at 5°C ± 5°C for at least 30 minutes. Filtered and the filter cake was washed twice with water (3V). The filter cake was collected and slurried at 60°C ± 5°C with water / isopropanol = 1 / 1 (127.5L, 5.0V) for at least 2 hours. Cooled to 20°C ± 5°C (10°C ± 5°C dropped per hour) and stirred at 20°C ± 5°C for at least 1 hour. Centrifuge and wash the filter cake twice with water / isopropanol=1 / 1 (3V). Collect the filter cake and add it to the reactor with DCM (255.0L, 10.0V). Adjust to 25℃±10℃ and stir for at least 0.5 hours. Filter through a filter with activated carbon and wash with DCM (51.0L, 2.0V). Collect the filtrate and concentrate to 2 to 4V at T≤45℃. Add n-heptane (255.0L, 10.0V) to the reactor and concentrate to 2 to 4V at T≤45℃. Add n-heptane (255.0L, 10.0V) to the reactor and adjust to 70℃±5℃. Stir at 70℃±5℃ for at least 10 minutes. Cool to 20℃±5℃ (drop 10℃±5℃ per hour) and stir at 20℃±5℃ for at least 1 hour. Centrifuge and wash the filter cake twice with n-heptane (3V). Centrifuge and wash the filter cake with n-heptane / EtOAc=10 / 1 (51.0 L, 2V). Collect the solid and dry at 45°C±5°C for at least 16 hours. Yield: 31.20 kg, 63.0%.

[0974] Step 8: 6-Bromo-N,N-bis(4-p-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Compound 3)

[0975]

[0976] Compound 7e (29 kg, 113 mol, 1 eq) and PMBCl (40.5 kg, 258 mol, 2.4 eq) were dissolved in 213 kg THF (213 kg, 240 L, 8.2 v). t BuOK solution (31.5 kg, 280 mol, 2.5 eq in 132 kg THF (148 L, 5.1 v)) was added to the solution at 15 to 25°C over 9 hours, and the mixture was stirred at 10 to 25°C for 18 hours.

[0977] The mixture was filtered and treated with CUNO column for 8 hours. After being concentrated to 120L at less than 40°C, EtOH (109kg, 140L, 4.8v) and water (250kg, 250L, 8.6v) were added to the residue at 15°C to 25°C. The mixture was cooled to 5°C to 15°C and stirred for 2 to 4 hours. The solid was filtered and washed twice with water (120kg, 120L, 4.1v). The wet cake was re-slurried for 6 hours at 15°C to 25°C with 135kg EtOH (135kg, 173L, 6.0v). The solid was filtered and washed twice with EtOH (15kg, 19L, 0.7v). The wet cake was re-slurried for 4 hours at 15°C to 25°C with n-heptane (269kg, 396L, 13.7v) and THF (11kg, 12L, 0.4v). The solid was filtered and washed twice with n-heptane (30 kg, 44 L, 1.5 v). The wet cake was dried at 45° C. to 55° C. under vacuum for 44 hours to obtain compound 3 (39.4 kg, purity 96.9A%, content 101 wt%, yield 70%).

[0978] Example 4

[0979] Compound 3 (6-bromo-N,N-bis(4-p-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine)

[0980]

[0981] Step 1: 6-Chloro-N-(4-p-methoxybenzyl)-4-methylpyridin-2-amine (Compound 7a)

[0982]

[0983] Compound 7 (103 kg, 0.51X, 0.51 equivalent) and 4-p-methoxybenzylamine (964 kg, 4.68X, 5.64 equivalent) were added to a 5000 L SS lined reactor R1. R1 was adjusted to 20°C to 30°C and the reaction was stirred for 1 hour. R1 was then heated to 80°C to 90°C over 3 hours. The reaction was stirred for 1 hour. R1 was then heated to 110°C to 130°C over 5 hours and stirred for 24 hours. R1 was cooled to 35°C to 45°C. A second portion of compound 7 (99 kg, 0.49X, 0.49 equivalent) and 4-p-methoxybenzylamine (43.0 kg, 0.21X, 0.25 equivalent) were added to R1. R1 was heated to 110°C to 130°C over 6 hours and stirred for 24 hours. R1 was cooled to 85°C to 95°C. R1 was heated to 110°C to 130°C and stirred for another 10 hours. R1 was cooled to 85°C to 95°C. A 28 wt% IPA / water solution (about 2224 kg) was added to R1 at 85-95°C and the mixture was stirred at 85°C to 95°C for 3 hours. R1 was then cooled to 0°C to 10°C within 7 hours and stirred for 3 hours. The wet cake was filtered and washed twice with 28 wt% IPA / water solution (about 485 kg) for each load (a total of 6 loads) to obtain 337.55 kg of wet cake (purity of A wet cake: 99.6%, specification: ≥95.0%). The wet cake was dried in two portions. After drying at 40 to 50° C. for 24 hours, 158.55 kg of compound 7a with a content of 97.0 wt % and a purity of 99.3A% and 149.40 kg of compound 7a with a content of 97.6 wt % and a purity of 99.3A% were obtained, respectively.

[0984] Step 2: 6-Chloro-N,N-bis(4-p-methoxybenzyl)-4-methylpyridin-2-amine (Compound 7b)

[0985]

[0986] Compound 7a (13.8 kg (content corrected), 0.99X, 1.00 equiv) and t-BuOK (9.0 kg, 0.65X, 1.53 equiv) and THF (about 139 kg) were added to R1, and 4-p-methoxybenzyl chloride (10.1 kg, 0.73X, 1.23 equiv) was added dropwise to R1 at 15°C to 25°C. The solution was stirred at 15°C to 25°C for 18 hours. The solution was concentrated to 4 to 5X under vacuum at less than 40°C. The concentrated solution was cooled to -5°C to 5°C, and water (about 112 kg) was slowly added. The mixture was stirred at -5°C to 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 (about 54 kg) to obtain 21.80 kg of wet cake. The wet cake was added to a 28 wt % i-PrOH aqueous solution (about 82 kg), and the mixture was stirred at 20° C. to 30° C. for 8 hours. The wet cake was filtered and washed with a 28 wt % i-PrOH aqueous solution (about 50 kg) to obtain 20.60 kg of wet cake. After drying at 40° C. to 50° C. for 21 hours, 17.90 kg of compound 7b was obtained, with a content of 98.4 wt %, a purity of 98.9A, and a corrected yield of 88%.

[0987] Step 3: 6-Chloro-5-iodo-N,N-bis(4-p-methoxybenzyl)-4-methylpyridin-2-amine

[0988]

[0989] To a solution of compound 7b (150 kg (content corrected), 1.00X, 1.00 equiv) in DMF (802 kg 5.3X) was added NIS (108 kg, 0.72X, 1.23 equiv). The solution was stirred at 15°C to 25°C for 24 hours. NIS (3 kg, 0.02X, 0.03 equiv) was added to the reaction. The solution was stirred at 15°C to 25°C for 20 hours. The solution was stirred at 15°C to 25°C for another 4.5 hours. The reaction was cooled to 0°C to 10°C, and a 5 wt% Na2SO3 aqueous solution (about 845 kg) was added. The mixture was stirred at 0°C to 10°C for 2 hours. The wet cake was filtered and washed with water (about 466 kg) to obtain 224.85 kg of wet cake. The wet cake was added to EtOH (about 768 kg) and stirred at 45°C to 55°C for 2 hours. After the mixture was cooled to 15°C to 25°C for 3 hours and stirred for 3 hours, the wet cake was filtered and washed with EtOH (about 460 kg) to obtain 208.25 kg of wet cake. After drying at 45°C to 55°C for 18.5 hours, 198.15 kg of compound 7c was obtained, with a content of 98.3% by weight, a purity of 99.4A, and a corrected yield of 98%.

[0990] Step 4: 6-(1,3-bis(4-methoxyphenyl)propan-2-yl)-2-chloro-4-methyl-3-(trifluoromethyl)pyridine (Compound 7d)

[0991]

[0992] To a solution of compound 7c (103 kg (content corrected), 1.00 eq., 1.00X) in DMF (about 364 kg, 3.5X) was added CuI (98 kg, 2.5 eq., 0.95X), 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (113 kg, 2.9 eq., 1.1X), HMPA (180 kg, 5.0 eq., 1.75X) and 30 kg DMF, purging after each addition. After adding DMF (about 352 kg, 3.48X) to the reaction, the mixture was heated to 75°C to 85°C within 3 hours and stirred for 8 hours. R1 was cooled to 20°C to 30°C. The mixture was heated to 75°C to 85°C within 3 hours and stirred for 4.5 hours. R1 was cooled to 20°C to 30°C. The reaction mixture was filtered. At 30°C to 40°C, 25 wt% NH3 aqueous solution (about 411 kg, 4.0X) was added dropwise to the filtrate within 2 hours. The mixture was stirred at 30°C to 40°C for 5 hours. Then water (about 702 kg, 6.8X) was added at 30°C to 40°C within 1 hour. The mixture was stirred at 30°C to 40°C for 6 hours. The mixture was heated to IT=30°C to 40°C, and the pH of the mixture was adjusted to 11 to 12 by adding NH3 aqueous solution (about 142 kg). The mixture was stirred at 30°C to 40°C for 10 hours. The mixture was cooled to 10°C to 25°C. The MeI residual in the mother liquor was 168 ppm. The solid was filtered and washed twice with water (total: about 1004 kg) to obtain 112.05 kg wet cake (purity 92.4A%). After drying at 45°C to 55°C for about 45 hours, 100.00 kg of compound 7d was obtained with a content of 83.7% by weight, a purity of 91.1A, and a corrected yield of 92%.

[0993] Step 5A: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0994]

[0995] HOAc (about 190 kg) and compound 7d (97 kg, 1.00X) were added to R1. After R1 was adjusted to 20°C to 30°C, 40 wt% HBr aqueous solution (about 180 kg, 1.86X) and water (about 12 kg) were added. The reaction solution was adjusted to 45°C to 55°C within 2 hours, and then heated to 80°C to 90°C within 2 hours. The reaction was stirred at 80°C to 90°C for 6.5 hours. R1 was cooled to 60°C to 70°C. EtOAc (about 370 kg) was added to the mixture, which was then cooled to 30°C to 40°C. A 30 wt% NaOH solution (about 489 kg) was added below 45°C to adjust the pH to 7 to 8. The mixture was rinsed with water (13 kg). R1 ​​was cooled to 20°C to 30°C, and the aqueous layer was separated and extracted twice with EtOAc (about 388 kg, 384 kg). The combined organic layers were combined and washed with 2.2 wt% Na2SO4 aqueous solution (water: about 369kg+6kg for rinsing, Na2SO4: about 8.7kg). Due to emulsification, the mixture was heated to 30°C to 40°C and allowed to stand for 8 hours. The organic layer was separated and azeotropically distilled twice with EtOAc (about 470kg, about 484kg) to 3 to 4X to remove water (KF=0.4%). EtOAc (about 366kg) and TsOH·H2O (about 68kg, 0.70X) were added to the mixture. R1 was adjusted to 20°C to 25°C and stirred for 2 hours. The mixture was then cooled to 0°C to 5°C and stirred for about 3 hours. The wet cake was filtered to obtain 70.90kg of wet cake. The wet cake was slurried with EtOAc (about 472kg) at 20°C to 25°C for 3 hours. The wet cake was filtered and rinsed with EtOAc (total: about 120 kg) to obtain 69.45 kg of wet cake. The wet cake was used directly in the next step.

[0996] Steps 5B and 5C: N-(6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide

[0997]

[0998] EtOAc (about 341 kg), compound 7e-TsOH wet cake and water (about 337 kg) are added to R1. R1 is adjusted to 15°C to 25°C. Then the pH of the water layer is adjusted to 7 to 8 by adding a 30 wt% NaOH aqueous solution (about 30 kg) at less than 45°C. Water (about 10 kg) is rinsed into R1. R1 is adjusted to 15°C to 25°C and stirred for 3 hours. The organic layer is separated and washed with water (about 298 kg). The organic layer is concentrated to 1 to 3X under vacuum at less than 45°C. After adding EtOAc (about 578 kg), the organic layer is concentrated to 1 to 3X under vacuum at less than 45°C. R1 is adjusted to 20°C to 30°C, and AcBr (about 411 kg) and EtOAc (about 14 kg) are added to R1 at less than 40°C. R1 was heated to IT = 45°C to 55°C in 2 hours, then heated to 65°C to 75°C in 2 hours, and stirred at 65°C to 75°C for 16 hours. R1 was cooled to 30°C to 40°C. After R1 was heated to 65°C to 75°C, the mixture was distilled to 1.0 to 3.0X below 75°C. R1 was cooled to 20°C to 30°C. AcBr (about 224 kg) and EtOAc (about 24 kg) were added to R1 below 40°C. EtOAc (about 42 kg) was flushed into R1. R1 was heated to 45°C to 55°C in 2 hours, then heated to 65°C to 75°C in 2 hours. R1 was stirred at 65°C to 75°C for 9.5 hours, then cooled to 30°C to 40°C. R1 was heated to 65°C to 75°C, and the mixture was distilled to 1 to 3X below 75°C. R1 is adjusted to 60°C to 75°C. AcBr (about 108.4kg) and EtOAc (about 10kg) are added to R1 below 75°C. EtOAc (about 16kg) is rinsed into R1. R1 is heated to 70°C to 75°C in 2 hours. The mixture is distilled to 1 to 3X below 75°C and stirred at 65°C to 75°C for 3 hours. The mixture is cooled to 0°C to 10°C. EtOH (about 248kg) and water (about 98kg) are added in batches below 45°C. R1 is adjusted to 40°C to 45°C for 3 hours and stirred for 8 hours. Then R1 is cooled to 30°C to 40°C. R1 is adjusted to IT=40°C to 55°C and stirred for 8 hours. R1 is cooled to 30°C to 40°C. R1 is adjusted to 40°C to 55°C and stirred for 10 hours. 40 wt % HBr aqueous solution (about 46 kg) was added to R1 at less than 40°C. EtOAc (about 100 kg) was added to R1. R1 was adjusted to 40°C to 55°C and stirred for 5 hours. R1 was cooled to 30°C to 40°C and EtOH (about 196 kg) was added, and the mixture was stirred for about 2.5 hours. R1 was adjusted to 40°C to 55°C. The material was circulated through a diatomaceous earth filter for about 8 hours.The filtrate was distilled to 1.0 to 2.0X at 45°C. Water (about 572kg) was added. After R1 was cooled to 0°C to 10°C, a 30 wt% NaOH aqueous solution (about 238kg) was added below 45°C to adjust the pH to 7 to 8. Water (6kg) was rinsed into R1. R1 was cooled to 0°C to 10°C, and the mixture was stirred for 3 hours. The wet cake was filtered and washed with water (total: about 200kg) to obtain 40.80kg wet cake (93.7A%). The wet cake was added to EtOAc (about 320kg). The mixture was adjusted to 20°C to 30°C and stirred for 30 minutes. The mixture was concentrated to 2.5 to 5X below 45°C, and then EtOAc (about 32kg) was added. After R1 was cooled to 0°C to 10°C, AcBr (about 200kg) was added to R1 by vacuum. EtOAc (about 28kg) is added to R1. R1 is adjusted to 45°C to 55°C for 2 hours, then heated to 65°C to 75°C and stirred for 11 hours in 1.5 hours. R1 is cooled to 30°C to 40°C, then R1 is heated to 65°C to 75°C, and the mixture is distilled to 2.5 to 5.0X below 75°C. R1 is cooled to 0°C to 10°C. EtOH (about 276kg) and water (about 104kg) are added in batches below 45°C. R1 is adjusted to 40°C to 45°C in 3 hours, and stirred for 12 hours. R1 is cooled to 30°C to 40°C. R1 is cooled to 0°C to 10°C, and 30% NaOH solution (about 213kg) is added below 45°C to adjust the pH to 7 to 8. R1 is distilled under vacuum below 45°C until there is no distillate. Water (about 449 kg) was added, and the mixture was cooled to 0° C. to 10° C. and stirred for about 2 hours. The wet cake was filtered and washed with water (total: about 80 kg) to obtain 41.50 kg of wet cake. The wet cake was dried at 20° C. to 30° C. for 4 hours, and then dried at 45° C. to 55° C. for 44 hours. 35.85 kg of compound 7e1 was obtained, with a content of 95.1% by weight, a purity of 97.4A, and a corrected yield of 53%.

[0999] Step 6: 6-Bromo-N,N-bis(4-p-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Compound 3)

[1000]

[1001] THF (about 292 kg), compound 7e (33.8 kg (content corrected), 0.97X) and 4-p-methoxybenzyl chloride (51.0 kg, 1.5X) were added to R1, and the mixture was stirred at 15°C to 25°C for 1 hour. t-BuOK (36.0 kg, 1.03X) was added in three batches. The reaction solution was then stirred at 15°C to 25°C for about 21 hours. Water (about 200 kg) and Na2SO4 (about 6.8 kg) were added. The solution was adjusted to 20°C to 25°C and stirred for 2 hours. After filtering through a diatomaceous earth filter, the filtrate was allowed to stand for separation. The aqueous phase was extracted twice with THF (total: about 193 kg). The combined organic layer was filtered through a diatomaceous earth filter and a cartridge filter. The filtrate was circulated through CUNO (3M-R55SP) and a cartridge filter for 20 hours. 29 kg of THF was rinsed into R1. The solution is adjusted to 30°C to 40°C and distilled to 2 to 5 volumes below 40°C under vacuum. R1 is cooled to 15°C to 25°C, and EtOH (about 175kg) is added dropwise to R1 in 4.5 hours. The mixture is stirred at 15°C to 25°C for 3 hours. Water (about 152kg) is added. R1 is cooled to 5°C to 15°C, and the mixture is stirred for 3 hours. After filtration, the wet cake is slurried with EtOH (about 102kg) at 15°C to 25°C for 8 hours. After filtration, the purity of the wet cake is 95.6A%. The wet cake, n-heptane (about 82kg) and THF (about 2kg) are added to R1. The mixture is adjusted to 40°C to 50°C and stirred for 8 hours. R1 is cooled to 0°C to 10°C in 3 hours, and the mixture is stirred for about 1.5 hours. The wet cake is filtered and washed with n-heptane (about 65kg). After drying at 55° C. to 65° C. for 26.5 hours, the dry cake was sieved (20 mesh) to obtain 51.65 kg of compound 3 with a content of 97.2% by weight, a purity of 97.0A%, and a corrected yield of 76%.

[1002] Example 5

[1003] 2,6-Dibromo-4-methyl-3-(trifluoromethyl)pyridine (Compound 8b)

[1004]

[1005] Step 1: 2,6-dichloro-4-methylnicotinic acid (Compound 8, 100g, 2.06mol, 100% by mole) and acetic acid containing HBr (33% by weight, 1.00L, 10v) 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 (1.00L, 10v), and the organic layer was extracted three times with methyl tert-butyl ether (300mL, 3v). The organic layers were then combined and concentrated under reduced pressure. The resulting residue was then slurried with heptane (500mL, 5v), then filtered and dried to obtain 2,6-dibromo-4-methylnicotinic acid (Compound 8d, 133g, 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] + ): The calculated value for C7H5Br2NO2 is 293.8757, and the measured value is 293.876.

[1006] 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 (178 g, 8.90 mol, 392 mol%) was added. The reaction mixture was further cooled to -78 ° C, and sulfur tetrafluoride (761 g, 7.04 mol, 310 mol%) was added. The reaction mixture was stirred under ambient conditions, warmed to 20 ° C, and then further heated and stirred for 24 hours. The mixture was then cooled to 0 ° C, diluted with dichloromethane, and neutralized to pH 10 to 12 with aqueous potassium carbonate. The resulting mixture was then filtered through diatomaceous earth, and the water layer was extracted three times with dichloromethane (390 mL, 3 v). The organic layers were then combined and concentrated under reduced pressure to obtain compound 8b (135 g, yield 96.0%) as a black solid.

[1007] Example 6

[1008] Step 1: 2,6-Dichloro-4-methyl-3-(trifluoromethyl)pyridine (Compound 8a)

[1009]

[1010] 2,6-dichloro-4-methylnicotinic acid (Compound 8, 1.0 eq) was added to an autoclave at ambient temperature (20°C to 30°C), followed by anhydrous HF (1.37 rel wt) at -20°C and SF4 (2.5 eq) at -78°C. The reaction mixture was warmed to ambient temperature and then heated at 70°C to 80°C for 17 to 24 hours. The reaction was cooled to ambient temperature (25°C to 30°C) and then rinsed into KOH (alkaline detergent). The solvent was exchanged to MTBE and the reaction was cooled to 0°C to 10°C, and DM water (1 rel vol) and DM water (8 rel vol) containing K2CO3 (4 rel wt) were added.

[1011] The reaction temperature is set to about 20°C to 30°C, then filtered and washed with 2.5 volumes of MTBE. Separate the layers and wash the water layer with 2.5 volumes of MTBE. Separate the layers, and combine the organic layers, then wash twice with 2.5 volumes of water at ambient temperature (20°C to 30°C). The organic layer is distilled to obtain a slurry, then washed with methanol (1 relative volume). The mixture is distilled and dissolved in methanol (4 relative volumes), then activated carbon (Norit CG110% w / w) is added. The mixture is stirred for at least 60 minutes, then filtered with diatomaceous earth or cellulose pad. The filtrate is added to a new reactor containing water (1.3 relative volumes), and stirred at 20°C to 25°C for 10 minutes to 15 minutes. Add compound 8a seeds (1% w / w), and stir the contents for 10 minutes to 15 minutes, then add 1.7 volumes of DM water. The contents are cooled to 0°C to 5°C and stirred for at least 60 minutes, then filtered. 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%).

[1012] 2,6-Dichloro-4-methyl-3-(trifluoromethyl)pyridine (Compound 8a)

[1013]

[1014] Nicotinic acid substrate (compound 8, 1.0 equivalent) was added to an autoclave at ambient temperature, followed by the addition of anhydrous HF (1.37 relative weight) at -20°C and SF4 (3.5 equivalent) at -78°C. The reaction mixture was warmed to ambient temperature and then heated at 90°C to 100°C for 24 hours. The conversion was checked by HPLC analysis. After completion, DCM was added to the reaction, and the mixture was then unloaded onto ice, neutralized with K2CO3, filtered through diatomaceous earth, and extracted with DCM (3×3V). The combined organic layers were concentrated to give a black semi-solid.

[1015] Charcoal treatment: The crude product mixture was dissolved in MeOH (5 V), treated with charcoal (10% w / w) and stirred at 50° C. for 1 h. The resulting slurry was filtered through a celite bed, washed with MeOH (2 V) and concentrated under reduced pressure to afford compound 8a as a brown solid (96.97A% purity by HPLC after charcoal treatment, 91.2% yield at 500 g scale).

[1016] 6-Bromo-N,N-bis(4-p-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Compound 3)

[1017]

[1018] Step 1: Compound 8b

[1019]

[1020] Compound 8a (977 g, 1 eq.) and 33 wt % HBr / AcOH (600 g, 0.5 v) were added to the reactor. The mixture solution was heated to 115° C. At 115° C., 33 wt % HBr / AcOH (9700 g) was added dropwise to the mixture solution over 24 hours. After the addition was completed, the reaction solution was cooled to 40° C. and then bubbled 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 solution at 115° C. over 2.5 hours. At 115° C., 33 wt % HBr / AcOH (1200 g) was added dropwise to the mixture solution over 2.5 hours. At 115° C., 33 wt % HBr / AcOH (1246 g) was added dropwise to the mixture solution over 2.5 hours. The reaction solution was completely cooled to 20°C, and water (8000mL, 8v) was added at less than 30°C. The mixture solution was extracted twice with MTBE (8L / 3L, 8v / 3v). The organic phases were combined and adjusted to pH 7 to 8 with a 15 wt% NaOH aqueous solution at less than 30°C. The organic phase was then washed with water (2L, 2v) and dried with anhydrous Na2SO4 (500g, 0.5X). After filtration, the filtrate was concentrated to dryness at 40°C to 45°C under reduced pressure (0.06 to 0.1MPa) to obtain a product as a brown oil (HPLC purity: 97.6%, content: 94.3%, yield: 93.3%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 2.42-2.61 (m, 3H), 7.31-7.48 (s, 1H).

[1021] Step 2:

[1022]

[1023] To a mixture solution of compound 8b (877 g, 1 eq.) and triethylamine (TEA) (414 g, 1.5 eq.) in N-butylpyrrolidone (NBP) (4650 mL, 5 v) was added (PMB) 2NH (1080 g, 1.5 eq.). The mixture solution was heated to 70 ° C and stirred at this temperature for 24 hours. The completed reaction solution was cooled to 50 ° C, and 20 wt % citric acid aqueous solution (10 L, 10 v) was added dropwise at 50 ° C within 1 hour. The mixture solution was then cooled to 20 ° C within 1 hour. The suspension was filtered and then washed with water (2 L, 2 v) and MeOH (2 L, 2 v). The filter cake was dried at 25 ° C under reduced pressure for 20 hours to obtain a crude product (1115 g, content: 88.2%, residual MeOH: 0.01%).

[1024] Recrystallization: The crude product (1115 g) and THF (4.46 L, 4 L) were added to the reactor, and the mixture solution was stirred until clear and then decolorized by activated carbon (110 g, 10 wt %). The decolorized solution was concentrated to 1.2 v under reduced pressure at less than 40 ° C, and then methanol (2.23 L, 1.2 v) was added. The mixture solution was heated to 50 ° C, and stirred for 0.5 hours at this time to obtain a clear solution. MeOH (4.65 L, 4.2 v) was added to the solution, and then seed crystals (1 wt %) were added. The mixture solution was stirred at 50 ° C for 1 hour. MeOH (2.23 L, 1.2 v) was added to the suspension at 50 ° C, and stirred at this temperature for 0.5 hours. The suspension was then cooled to 0 ° C within 1 hour and stirred at this temperature for 16 hours. The suspension was filtered and washed with MeOH (2.23 L, 1.2 v). The filter cake was dried at 45° C. under reduced pressure for 20 hours to obtain an off-white solid product (931.6 g, HPLC purity: 99.7A%, content: 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)

[1025] Example 7

[1026] Compound 1: (S)-4-((R)-7-(6-(bis(4-p-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[1027]

[1028] Compound 2 (50.0 g, 104.7 mmol, 1.1 eq) and THF (350 mL, 7 v, 100 ppm to 200 ppm H2O) were added to a dry flask (1 L). i-PrMgCl·LiCl (1.3 M in THF, 93.0 mL, 1.265 eq) was added dropwise at -78°C to -70°C over 30 minutes under argon. The reaction mixture was stirred at -78°C for 10 minutes. ZnCl2 (1.9 M in Me-THF, 72 mL, 1.43 eq, about 230 ppm H2O) was added dropwise at -78°C to -70°C over 20 minutes, and then gradually warmed to 10°C over 2 hours. The mixture was stirred at 10°C for about 0.5 hours. After the addition of ZnCl2, the reaction mixture was stirred at -70°C to -30°C for at least 1 hour. Compound 3 (47.1 g, 95.2 mmol, 1.0 equiv) and 1,4-dioxane (8 v) were added to another dry flask (1 L). The Zn reagent was added under an argon atmosphere. The reaction mixture was bubbled with argon at 0.3 L / min for 2 hours. Under an argon atmosphere, a solution of [PdCinnamylCl]2 (0.5 mol%), (R,R)-chiraphite ligand (1.0 mol%) in 1,4-dioxane (about 14 mL, about 0.27 v) was added. The mixture was stirred at about 48 ° C for 21 hours.

[1029] The reaction mixture was cooled to 10°C to 20°C. The reaction mixture was added dropwise to a saturated NH4Cl aqueous solution (about 471mL, 10v) below 20°C, and the resulting mixture was stirred for 30 minutes. Filtered through diatomaceous earth (about 1 weight), and the filter cake was washed with toluene (236mL, 5v). The two phases (filtrate) were separated, and the aqueous phase was extracted with toluene (236mL, 5v). The combined organic phase was washed with brine (236mL, 5v). Toluene was concentrated to 4 volumes (about 200mL) at 40°C to 50°C under vacuum. Toluene (200mL, 4v) was added, and then concentrated to about 200mL (4v). Toluene (200ml, 4v) was added, and then concentrated to about 200mL (279g, 4v). The solution was cooled to 15°C to 20°C. At 15°C to 20°C, n-heptane (6v, 637mL) was added dropwise over 50 minutes. Stir at room temperature (15°C to 20°C) for about 1 hour. Filter, and wash the filter cake with toluene / n-heptane (about 2.5v×2, n-heptane / toluene=2 / 6). Dry the solid. Yield: 60.7g crude product=98.6 / 1.4, light yellow solid, corrected yield is about 69%.

[1030] Example 8

[1031]

[1032] i-PrMgCl LiCl (1.14M, 77.78g, 92mmoL, 1.15 eq.) was added to a solution of compound 2 (42.0g, 88mmoL, 1.1 eq.) in THF (200mL) at -70°C ± 5°C, and the corresponding mixture was stirred for 30 minutes. Then, a solution of ZnCl2 (50.0g, 94mmoL, 1.18 eq.) was added at -70°C ± 5°C. After the addition was completed, the reaction mixture was heated to -10°C, and NaTFA (32.6g, 240mmoL, 3.0eq.) was then added in batches. The mixture was then heated to 50°C, and a solution of bromopyridine compound 3 (39.6g, 80mmoL, 1.0 eq.) in THF (80mL) was then added. The mixture was stirred for about 15 minutes, then a solution of palladium (π-cinnamoyl) chloride dimer (0.201 g, 0.4 mmoL, 0.005 eq.) and (R,R)-Chiraphite (0.77 g, 0.88 mmoL, 0.011 eq.) 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 after the addition of trisodium citrate (300 g, 20% w / w) aqueous solution and toluene (200 mL). The reactor was rinsed with THF (20 mL) and the biphasic mixture was stirred for 15 minutes. After phase separation, trisodium citrate (300 g, 20% w / w) aqueous solution was added, and the biphasic mixture was stirred for 15 minutes. After phase separation, water (100 mL) was added and the biphasic mixture was stirred for 15 minutes. After phase separation, water, THF and 2-Me-THF are replaced with an equal volume of toluene (200 mL) under vacuum. The solution is then filtered with a charcoal filter at 50 ± 2 ° C, the reactor and filter are rinsed with toluene (42 g), and the reaction volume is reduced to 130 mL to 150 mL under vacuum. The reactor is cooled to 20 ° C, n-heptane (27.1 g) and 0.04 g of seed are added, and the resulting thin suspension is aged for 1 hour. Then n-heptane (301 g) is added within 2 hours, and the resulting suspension is stirred for at least 12 hours. The crystals are filtered out and washed three times with 100 mL of toluene / n-heptane (1: 1) to obtain a crude title compound in the form of pale yellow crystals. The crude title compound can be recrystallized from toluene / n-heptane, and then the above-mentioned crystallization procedure is performed to obtain the title compound in the form of off-white crystals (yield 70% to 75%).

[1033] Exemplary chiral ligand conversions and selectivities

[1034]

[1035]

[1036] Example 9

[1037]

[1038] Compound 2 (53g, 111mmoL, 1.10eq) was dissolved in THF (223g, 250mL, 5v), then cooled to -78°C to -70°C under N2 protection. Under N2 protection, i-PrMgCl.LiCl (98g, 122mmoL, 1.21eq, 97mL, 1.9v, 1.26M in THF) was added dropwise to the solution at -78°C to -70°C in 1 hour and stirred for 1 hour. Under N2 protection, ZnCl2 (70g, 126mmoL, 1.25eq, 63mL, 1.3v, 2.0M in 2-MeTHF) was added dropwise to the solution at -78°C to -70°C in 1 hour and stirred for 1 hour. Under N2 protection, the solution was gradually adjusted to 0°C to 10°C in 2 to 3 hours. Under N2 protection, NaTFA (41g, 301mmoL, 3.0eq) was added to the solution. The suspension was stirred at 15°C to 25°C for 30 minutes and then heated to 50°C to 55°C. After stirring at 50°C to 55°C for 1 hour, the suspension was directly used for Negishi coupling (step-2). Compound 3 (50g, 101mmoL, 1.0eq) was dissolved in THF (142g, 160mL, 3.2v), and then N2 was sprayed into the solution at 15°C to 25°C for 2 hours. Under N2 protection, (PdCinCl) 2 (390mg, 0.765mmoL, 0.75 mol%) and (R,R)-Chiraphite (1.4g, 1.60mmoL, 1.5 mol%) were added to the solution. N2 was sprayed into the solution for another 1 hour. Under the protection of N2, the solution was added dropwise to the solution of Compound 2 at 50 to 55°C. The reaction mixture was stirred at 50 to 55°C for 11 hours.

[1039] The reaction mixture is cooled to 15°C to 25°C, and 20% by weight NH4Cl aqueous solution (300mL, 6v) is added, and stirred for 1 hour. The organic layer is separated, and the aqueous layer is extracted with toluene (250mL, 5v). 5% by weight Na2SO4 (250mL, 5v) is changed into the organic phase merged, and the mixture is filtered with diatomaceous earth and washed with THF (250mL, 5v). At 15°C to 25°C, the crude THF / toluene solution is passed through charcoal (CUNO) for 5 hours (flow rate 80mL / min), and the CUNO channel is washed with THF 50mL (1v). At 15°C to 25°C, the THF / toluene solution is passed through a continuous diatomaceous earth pad and a charcoal pad (CUNO) for 16 hours (flow rate 80mL / min). The solution is concentrated to 2v and toluene (200mL, 4v) is added. The solution was passed through a continuous diatomaceous earth pad and charcoal (CUNO) again at 15° C. to 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° C. to 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° C. to 50° C.

[1040] The residue was cooled to 15°C to 25°C, and n-heptane (50mL, 1v) was then added to the crude solution. 150mg of seed crystals were added to the mixture. The mixture was stirred at 15°C to 25°C for 1 hour, and then n-heptane (11v) was added dropwise to the crude solution within 2 hours. The wet cake was filtered and washed with toluene / n-heptane 2×125mL (2×2.5v, toluene / n-heptane=1:3). 90.8g of wet crude product 1 was obtained, and its content was 85.4% by weight.

[1041] 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° C. to 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 at less than 45° C. for 16 hours. Finally, 65.2 g of product toluene solvate was obtained with a purity of 98.5A% and a content of 68.9 wt%. Purity: 98.5A%; Content: 86.8 wt%; Toluene: 11.0 wt%; Chiral purity: 99.1A%.

[1042] Example 10

[1043] Compound 1: (S)-4-((R)-7-(6-(bis(4-p-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[1044]

[1045] Under argon atmosphere, ultra dry THF (53L, 8.4v) and compound 2 (8.5kg, 17.79mol, 1.4 equivalents) were added to the reactor. The mixture was degassed by 3 vacuum / argon cycles and cooled to -78°C by a liquid N2 bath. Under argon, i-PrMgCl LiCl (1.3M in THF, 15.74L, 20.46moL, 1.61 equivalents) solution was added at -78°C to -70°C in 15 minutes. The reaction mixture was stirred at -78°C for 15 minutes. ZnCl2 (1.9M in Me-THF, 12.2L, 23.18mmoL, 1.82 equivalents, about 1300ppm) was added dropwise at -78°C to -70°C in 15 minutes, and then gradually warmed to -10°C in 3.0 hours. After the addition of ZnCl2, the reaction mixture was stirred at -70°C to -30°C for at least 1 hour.

[1046] Under argon atmosphere, ultra dry THF (44.4L, 7.0v) and compound 3 (6.3kg, 12.71mol, 1.0 equivalent) were added to another reactor. Under argon pressure, the mixture in the first reactor was added to the second reactor, and the resulting mixture was bubbled with argon for 2 hours. Under argon pressure, a solution of PdCinCl (65.9g, 0.13mol, 1.0 mol% Pd) and Walphos ligand (88.3g, 0.13mol, 1.0 mol%) in degassed THF (1.7L, 0.27v) was added via a PFA tube, and the mixture was bubbled with argon for 2 hours. Heat to 40°C to 45°C under argon and stir for 3 hours.

[1047] Cool to 20 ° C, then add saturated NH4Cl (64L, 10v) solution at <20 ° C. Filter through 3.2kg diatomaceous earth and separate the two phases (filtrate). The aqueous phase is extracted twice with EtOAc (32L, 5 volumes). The combined organic phase is washed with brine (32L, 5v), then concentrated to about 2v (about 17L) at 40 ° C, and then exchanged with EtOAc (about 30L×3) solvent to obtain EtOAc solution (about 17L). The above solution is concentrated at about 40 ° C in a high vacuum to remove most of EtOAc, and then exchanged with DCM (about 30L×3) solvent to obtain DCM solution (about 17L, DCM / EtOAc=5-6 / 1).

[1048] About 14 kg of silica (60 M to 100 M, about 2.2x) was added to the above solution, and the resulting mixture was stirred at about 15 ° C for about 1 hour. The resulting mixture was added to a column filled with about 74 kg of silica (wet packed column, 200 M to 300 M, about 11x), then eluted with about 200 L of n-heptane, and then eluted with a total of about 2000 L of n-heptane / EtOAc=4 / 1. The desired fraction was concentrated to about 2 to 3 v (17 L to 25 L) at about 40 ° C under vacuum.

[1049] About 60L EtOAc was added, and the resulting mixture was warmed to about 40°C, becoming a solution after about 1 hour (EtOAc / n-heptane was about 2 / 1). The solution was then cooled to about 15°C naturally. About 680g C941 (8w%, relative to the amount of the compound) was added, and the resulting mixture was stirred at about 15°C for about 1 hour. Filtered, and the filter cake was washed with EtOAc (2.5L×2), and the filtrate and washings were concentrated to 2 to 3v (17L to 25L), and then further dried at 40°C in a rotary evaporator to obtain final compound 1. 1 H NMR (600MHz, DMSO-d6) δppm7.97(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):C 41 H 42 ClF5N6 m / z([M+H] + )The calculated value is 813.2965; the measured value is 813.2963.

[1050] Example 11

[1051]

[1052] A solution of (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridinyl]-6-chloro-2,8-difluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (50.0 g, 53.7 mmol, 1.00 eq, 87.3% content) and [(2S)-1-methylpyrrolidin-2-yl]methanol (7.44 g, 64.6 mmol, 1.20 eq) in 2-Me-THF (320 g) was concentrated to 250 mL of solution under reduced pressure (235 mbar). The solution was cooled to -10°C. A solution of sodium tert-amyl alcohol in toluene (27.5 g, 64.6 mmol, 1.20 eq, 25% w / w) was then added over 10 to 20 minutes. The reaction mixture was stirred at 0 ° C until complete conversion was achieved (usually 1 hour). Then, the reaction mixture was diluted with 2-Me-THF (214g), warmed to 15 ° C to 25 ° C, and quenched by adding potassium carbonate (200g, 10% w / w solution) aqueous solution. The biphasic mixture was stirred for 1 hour and the layers were separated. The organic layer was further washed with potassium carbonate (200g, 10% w / w) aqueous solution. The biphasic mixture was stirred for 15 minutes and the layers were separated. The organic layer was concentrated to 250mL solution under reduced pressure (235mbar), cooled to 20 ° C to 25 ° C and finely treated and filtered. The filtrate was further concentrated to 175mL solution under reduced pressure (235mbar). 1-PrOH (100g) was added and 2-Me-THF was continuously exchanged for 1-PrOH under reduced pressure (150 to 60mbar). Then, water (100g) was added at 50 ° C and the solution was crystallized at this temperature. The resulting mixture temperature was further stirred for 2 hours, and water (100 g) was added over at least 2 hours. The crystal 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 1-PrOH / water solution, and dried under reduced pressure until constant weight was reached. The title compound was isolated as off-white crystals with a yield of 96% (47.5 g). 1H NMR (600MHz, DMSO-d6) δppm 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 = 13.4 Hz, 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, 7.9 Hz, 3H), 1.42 (s, 9H), 1.28 (br d, J = 6.6 Hz, 3H) ppm. HR-MS (ESI): calculated for C47H54ClF4N7O5 is 907.3811; found: 907.3808.

[1053] Example 12

[1054]

[1055] To a mixture of acetic acid (46.2 g), methanesulfonic acid (52.9 g) and toluene (34.7 g) at 40° C. was added a solution of (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridinyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (20.0 g, 22.0 mmol) in toluene (86.7 g) over at least 15 minutes. 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 separated. The acidic layer was slowly quenched with a mixture of aqueous sodium hydroxide solution (211.5 g, 28% w / w), water (80.0 g) and toluene (121.4 g) at 40°C (usually over 1 hour). After the quenching was complete, acetic acid (10.0 g) was added to flush the line. The biphasic mixture was warmed to 50°C and the layers were separated. The organic layer was washed twice with aqueous sodium hydroxide solution (2×90.0 g, 0.1 N solution). Then, a constant volume of the toluene layer was distilled under reduced pressure (90 mbar; usually 69 g toluene was exchanged). After polishing filtration, the resulting toluene solution was concentrated under reduced pressure (90 mbar) to 94 mL of solution, which was then warmed 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 further stirred at this temperature for at least 1 hour, and the crystal slurry was cooled to 0°C over at least 4 hours, and further stirred at this temperature for at least 1 hour. The crystals were filtered off, washed with a toluene / n-heptane (1:1 v / v) solution, and dried under reduced pressure until a constant weight was reached. The title compound was isolated as off-white crystals with a yield of 89% (11.7 g). 1H NMR(600MHz,DMSO-d6)δppm 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 = 13.1 Hz, 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, 7.6 Hz, 1H), 1.67 (br d, J = 8.3 Hz, 3H), 1.40 (d, J = 6.9 Hz, 3H) ppm. HR-MS (ESI): calculated for C26H30ClF4N7O: 567.2136; found: 567.2141.

[1056] Example 13

[1057]

[1058] Compound 1e (8.00 g, 14.1 mmoL, 1.0 equiv.), 3-(phenylsulfonyl) propionic acid (3.66 g, 16.9 mmoL, 1.20 equiv.) and acetonitrile (48 mL, 6 v) were added to a 250 mL round-bottom flask equipped with overhead stirring and a nitrogen line. The mixture was stirred for 5 minutes, then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI HCl) (3.11 g, 16.2 mmoL, 1.15 equiv.) was added and flushed forward with acetonitrile (16 mL, 2 v). The reaction was stirred at 20 ° C for at least three hours. After the reaction was completed to form the sulfone intermediate, water (32 mL, 4 v) and sodium hydroxide pellets (1.60 g, 39.9 mmoL, 2.85 equiv.) were added to adjust the pH to 13.0 to 13.5. The reaction mixture was stirred for at least two hours to obtain compound A, which was separated by first adding water (24 mL, 3 v) and crystallizing (0.5 wt %). Then, by slowly adding more water (24 mL, 3 v) within 2 hours, aging for 2 hours at 20 ° C, and then slowly adding water (64 mL, 8 v) within 5 hours to complete precipitation. The resulting slurry was kept at 20 ° C for 2 hours, filtered, washed with 1: 1 acetonitrile / water (64 mL, 8 v), and then washed with water (64 mL, 8 v). After drying, compound A (7.42 g) was obtained as an off-white solid with a yield of 89.6% yield (purity corrected).

[1059] Example 14

[1060]

[1061] Compound 1e (10.0 g, 17.6 mmoL, 1.00 equiv) was added to a 400 mL reactor, followed by 2-MeTHF (50.0 mL, 5 mL / g), and the material was stirred at room temperature until complete dissolution was observed. Next, 10% Na2CO3 aqueous solution (50.0 mL, 5 mL / g) was added, and 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 equiv) dissolved in MeTHF (50.0 mL, 5 mL / g) was added dropwise to the biphasic solution over 30 minutes, while maintaining the internal temperature at 0°C. The mixture was then stirred at 0°C for 1 hour (conversion rate was 97.8%).

[1062] Next, add the 10%NaOH aqueous solution (50.0mL / 5mL / g), and reactor is set to 40 ℃ (internal temperature control), and stir for 16 hours.Then, reactor is cooled to 25 ℃, and mixture is transferred to 500mL separatory funnel, and remove bottom layer (water layer). Upper strata (organic layer) is transferred back to 400mL reactor, and the 10%NaOH aqueous solution (50.0mL / 5mL / g) is added, and reactor is set to 40 ℃ (internal temperature control) and stir for 4 hours (350RPM).Then, reactor is cooled to 25 ℃, and mixture is transferred to 500mL separatory funnel, and remove bottom layer (water layer).Next, organic layer is transferred in 250mL round-bottom flask and is concentrated to about 20mL, and re-adds 60mL MeCN, the method is repeated 6 times, and solvent composition is checked by headspace gas chromatography (headspace GC) (0.03%MeTHF after solvent exchange). The mixture in the round bottom flask was then placed in a 5°C refrigerator for two days, filtered and washed with two 20 mL portions of MeCN (pre-cooled to -10°C).

[1063] The wet cake was then dried under vacuum with a nitrogen purge at ambient temperature for 24 hours.Compound A was isolated as an off-white solid in 69% yield (7.52 g, 12.1 mmol).

[1064] Example 15

[1065]

[1066] To a 250 mL round bottom flask equipped with overhead stirring and a nitrogen line was added 3-(phenylsulfonyl)propionic acid (3.66 g, 16.9 mmoL, 1.20 equiv), acetonitrile (32 mL, 4 v), N-methylmorpholine (2.33 mL, 21.1 mmoL, 1.50 equiv), and rinsed with acetonitrile (8 mL, 1 v). The mixture was cooled to -10 ° C, then pivaloyl chloride (1.90 mL, 15.5 mmoL, 1.10 equiv) was added over 5 minutes, and forward rinsed with acetonitrile (8 mL, 1 v). The mixture was stirred at -10 ° C for at least 1 hour, then compound 1e (8.00 g, 14.1 mmoL, 1.0 equiv) was added, and forward rinsed with acetonitrile (8 mL, 1 v). The reaction was stirred at -10 ° C for at least 30 minutes. After the reaction was completed to form the sulfone intermediate, the mixture was warmed to 20 ° C. Water (32mL, 4v) and sodium hydroxide particles (2.11g, 52.8mmoL, 3.75 equivalents) were added to adjust the pH to 13.0 to 13.5. The reaction mixture was stirred for at least 2 hours to obtain compound A, by first adding water (24mL, 3v) and crystallization (0.5 wt %) to separate it. Then by slowly adding more water (24mL, 3v) within 2 hours, aging for 2 hours at 20°C, then slowly adding water (48mL, 6v) within 4 hours to complete precipitation. The resulting slurry was kept at 20°C for 2 hours, filtered, washed with 1:1 acetonitrile / water (64mL, 8v), and then washed with water (64mL, 8v). After drying, compound A (7.10g) was obtained as an off-white solid, with a yield of 87.4% yield (purity corrected).

[1067] Example 16

[1068]

[1069] A solution of 3-(phenylsulfonyl)propionic acid (24.1 g, 112 mmol, 1.40 eq), N-methylmorpholine (13.4 g, 133 mmol, 1.65 eq) in acetonitrile (180.7 g) was cooled to -10°C. Pivaloyl chloride (11.8 g, 97.9 mmol, 1.22 eq) was added over 30 minutes. The reaction mixture was further stirred at this temperature for 1 hour. Then, a solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (50.0 g, 80.4 mmol, 1.00 equiv) in acetonitrile (176.9 g) was added to the cold reaction mixture over 1 hour and further stirred at -10°C until complete conversion to the sulfone intermediate (typically 1 hour). The reaction mixture was warmed to 20°C and quenched by addition of water (62.5 g) and aqueous sodium hydroxide solution (51.7 g, 362 mmol, 4.5 equiv, 28% w / w solution). Stirring was continued until complete conversion was obtained (typically 8 hours) and the mixture was seeded and then water (865 g) was added over at least 2 hours. The crystal slurry was further stirred at this temperature for at least 4 hours, and the crystals were filtered off, washed with acetonitrile / water (3:7 v / v) solution, washed with water, and then dried under reduced pressure until constant weight was reached. The title compound was isolated as off-white crystals with a yield of 91% (45.6 g). 1 H 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 = 1.4 Hz, 6H), 2.11-2.26 (m, 1H), 1.87-2.00 (m, 1H), 1.56-1.79 (m, 3H), 1.27 (brdd, J = 11.7, 6.7 Hz, 3H) ppm. HR-MS (ESI): calculated for C29H32ClF4N7O2: 621.2242; found: 621.2257.

[1070] Example 17

[1071]

[1072] To a solution of compound 1e (3.02 kg, 5.32 mol, 1.0 equiv) in DCM (in a 100 L reactor) was added DIPEA (2.05 kg, 15.86 mol, 2.98 equiv). The mixture was cooled to -25 °C, and a solution of acrylic anhydride (0.87 kg, 6.90 mol, 1.30 equiv) in DCM (28.30 kg, 7 V) 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 % aqueous potassium bicarbonate solution (12.1 kg, 4 V).

[1073] The organic layer is washed with 20 wt % aqueous ammonium chloride solution (12.2 kg, 4 V), then washed with 10 wt % monobasic potassium dihydrogen phosphate solution, and dried with magnesium sulfate (1.50 kg, 50 wt %). The slurry is filtered and rinsed with DCM (8.05 kg, 2 V), then passed through a CUNO filter housing containing E-PakGraver C-941 (850 g). The filtrate is then concentrated to 19 L (6 V) and diluted with acetonitrile (9.60 kg, 4 V). The solution is transferred to a 25 L reactor via an online polishing filter. Continuous distillation is performed to remove DCM, while replacing with ether (8.80 kg, 4 V) to reach a final volume of 18 L, and then the concentrated slurry is cooled to 0 ° C. After keeping at 0°C for at least 3 hours, the slurry was filtered, rinsed with pre-cooled (temperature = 0°C) acetonitrile (4.65 kg, 2V) and dried at 20°C to give Compound A (2.32 kg) with a yield of 69.7%. 1 H NMR (400MHz, DMSO-d6) δ7.84(d,J=1.6Hz,1H),6.87(s,2H),6.83(m,1H),6.52(m,1H),6.20(dd,J=1 6.8,6.8Hz,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): δ165.4,164.8,164.7,162.2,161.3,154.4,151.8,148.7,148.7,147.6,143.0, 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. 9,120.9,114.6,114.6,112.5,112.2,111.9,111.7,110.5,69.8,63.8,57.4,52.4,52.3,49.3,45.8,45.1,44.8,44.2,42.0,41.6,40.6,40.4,40.2,40.0,39.8,39.6,39.4,29.0,23.1,20.3,20.2,15.8,15.2; 19 F NMR (376MHz, DMSO-d6): δ-53.7,-125.9.

[1074] Example 18

[1075]

[1076] In a 25L reactor equipped with an active nitrogen line, hanging stirring and a temperature probe, compound A (2.32kg, 3.53mol) and 2-butanone (17.42L, 7.5L / kg) after finishing and filtering were combined. In a separate 5L glass bottle, adipic acid (0.46kg, 3.17mol, 0.9 equivalent) and 2-butanone (1.16L, 0.5L / kg) after finishing and filtering were added. The reactor was then heated to 50°C ± 10°C, and after reaching the desired internal temperature target of> 45°C, the adipic acid slurry in 2-butanone was added to the reactor by vacuuming. Compound B seed (0.02kg, 1 wt%) was added to a 5L glass bottle, followed by the addition of butanone (2.32L, 1.0L / kg) after finishing and filtering. The slurry was added to the reactor by vacuuming again. Finally, the 5L glass bottle was rinsed with 2-butanone (1.16L, 0.5L / kg) after fine treatment filtration and then added to the reactor by vacuuming. The reactor contents were aged for at least 1 hour, cooled to 0°C in at least 2 hours, and then aged overnight (15 hours) at 0°C. The contents were transferred to a pre-cooled filter dryer at 0°C. At the same time, 2-butanone (9.29L, 4.0L / kg) after fine treatment filtration was added to the reactor at 0°C and then stirred for 30 minutes. The material in the filter dryer was then filtered, and the resulting filter cake was washed with cooled 2-butanone. After drying for at least 8 hours with vacuum suction and nitrogen purge, the filter dryer contents were discharged to obtain compound B (2.137kg, 77%) as an off-white solid. 1 H NMR (600MHz, DMSO-d6) δ7.77(s,1H),6.81(s,2H),6.76(dd,J=16.8,10.6Hz,1H),6.45(s,1H),6.18–6.10(m,1H),5.70(dd,J=10.4 ,2.3Hz,1H),4.75–4.66(m,1H),4.38–4.30(m,2H),4.25–3.89(m,4H),3.61(dq,J=21.3,12.4,10.9Hz,2H),3.20(dd,J=13.4,3.8H z,1H),3.00(td,J=12.6,3.7Hz,1H),2.91(ddd,J=9.0,6.0,2.8Hz,1H),2.59–2.51(m,1H),2.32(d,J=6.2Hz,6H),2.15(td,J=8.6, 7.7,4.7Hz,5H),1.94–1.85(m,1H),1.61(dddd,J=20.8,12.3,8.0,4.1Hz,3H),1.45(h,J=3.4Hz,4H),1.22(dd,J=12.4,6.6Hz,3H);13 C{ 1 H, 19 F}NMR(151MHz,DMSO-d6)δ174.9,165.5,164.8,162.2,161.4,153.2,148.8,147.7,143.0,131.1,128.5,128.4,128.3,128.2,125.6,125.3,121 .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 (565MHz, DMSO-d6) δ-53.5,-125.9.

[1077] Example 19

[1078]

[1079] Compound A (1 molar equivalent) and adipic acid (1 molar equivalent) are suspended in 2-butanol and 2-methyltetrahydrofuran and dissolved after heating to about 70°C. The finely treated filtered solution is cooled to about 25°C. The jet-milled compound B material is used for seeding. The seeding material compound B material is suspended in 2-butanol / n-heptane. The suspension is used to seed the solution at about 25°C. The seeding equipment is rinsed with n-heptane and then added to the seeded suspension. At about 25°C, n-heptane is added within 15 minutes to 30 minutes. The suspension is stirred at about 25°C for about 3 hours. The suspension is cooled to about 0°C and stirred for at least 5 hours. The solid is separated by a solid / liquid separation method and rinsed with 2-butanol / n-heptane and n-heptane in turn. The solid is dried at about 40°C under reduced pressure to obtain a white to off-white powder with a yield of 88% to 95%.

[1080] In another procedure, compound A (1 molar equivalent) and adipic acid (1 molar equivalent or excess) are suspended in 2-butanol and 2-methyltetrahydrofuran and dissolved after heating to about 70°C. The fine filtered solution is cooled to the seeding temperature (about 25°C). For seeding compound B, it can be used without pretreatment or after impact grinding, jet grinding or wet grinding. The seeding material compound B is suspended in a solvent (n-heptane, or a 2-butanol / n-heptane mixture, or 2-butanol). The suspension is used for seeding at the seeding temperature. The seeding equipment is rinsed with a solvent (n-heptane, or a 2-butanol / n-heptane mixture, or 2-butanol, respectively), and then added to the seeding suspension. N-heptane is added at the seeding temperature or at a lower temperature (generally about 25°C) for 15 minutes to 30 minutes. The suspension is stirred for at least 3 hours at the temperature of adding n-heptane. The suspension is cooled to about 0°C and stirred for at least 5 hours. The solid was isolated by solid / liquid separation and washed sequentially with 2-butanol / n-heptane and n-heptane.The solid was dried at about 40°C under reduced pressure to give a white to off-white powder with a yield of 88% to 95%.

[1081] Example 20: Cyclohexane crystallization solvate compound 1

[1082] X-ray quality crystals were grown from hot cyclohexane solutions which were slowly cooled to room temperature and left to stand for 72 hours to deposit diffracting crystals. A colorless prism of dimensions 0.110×0.090×0.050 mm was mounted on a Cryoloop containing Paratone oil. Data were collected in a nitrogen flow at 90(2)K using φ and ω scans. The crystal to detector distance was 40 mm, the exposure time was 0.15 seconds per frame, and the scan width was 0.5°. Data collection from θ to 67.000° was 100% complete. A total of 112434 reflections were collected with coverage indices of -11<=h<=11, -16<=k<=17, -40<=l<=41. 8888 reflections were found to be symmetry independent with an R of 0.0352 int . Indexing and unit cell refinement indicated the original orthorhombic lattice. The space group was found to be P 21 21 21 (No.19). The data were integrated and scaled using CrysAlisPro 1.171.41.72a. An iterative solution (SHELXT-2014) produced a complete heavy atom phased model. Anisotropic refinement was performed on all non-hydrogen atoms by full-matrix least-squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions relative to their parent atoms were constrained using the appropriate HFIX commands in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[1083] Table 2: Crystallographic data and structure refinements of the cyclohexane solvate.

[1084]

[1085]

[1086] Example 21: Methylcyclohexane crystalline solvate compound 1

[1087] X-ray quality crystals were grown from hot cyclohexane solutions that were slowly cooled to room temperature and allowed to stand for 48 hours. A colorless prism measuring 0.206×0.097×0.068 mm was mounted on a Cryoloop containing Paratone oil. Data were collected in a nitrogen flow at 90(2)K using φ and ω scanning. The crystal to detector distance was 40 mm, the exposure time was 0.1 s per frame, and the scan width was 0.5°. Data collection from θ to 67.000° was 100% complete. A total of 128,902 reflections were collected with coverage indices of -17<=h<=17, -11<=k<=12, -41<=l<=40. 17,535 reflections were found to be symmetry independent with an R of 0.0912 int . Indexing and unit cell refinement indicated the original monoclinic lattice. The space group was found to be P 21 (No.4). The data were integrated and scaled using CrysAlisPro 1.171.41.72a. An iterative solution (SHELXT-2014) produced a complete heavy-atom phased model. Anisotropic refinement of all non-hydrogen atoms was performed by full-matrix least-squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions relative to their parent atoms were constrained using the appropriate HFIX commands in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[1088] Table 3: Crystallographic data and structure refinements of methylcyclohexane solvate.

[1089]

[1090]

[1091]

[1092] Example 22: Chlorobenzene Crystalline Solvate Compound 1

[1093] X-ray quality crystals were grown from saturated chlorobenzene solutions followed by slow vapor diffusion with heptane to deposit diffracting crystals. A colorless prism measuring 0.130 × 0.110 × 0.060 mm was mounted on a Cryoloop containing Paratone oil. Data were collected in a nitrogen flow at 90(2)K using φ and ω scans. The crystal to detector distance was 40 mm, the exposure time was 0.05 s per frame, and the scan width was 0.5°. Data collection from θ to 67.000° was 100% complete. A total of 110,828 reflections were collected with coverage indices of -12 <= h <= 12, -16 <= k <= 16, -41 <= l <= 41. 8734 reflections were found to be symmetry independent with an R of 0.0384 int . Indexing and unit cell refinement indicated a primitive orthorhombic lattice. The space group was found to be P 21 2121 (No.19). The data were integrated and scaled using CrysAlisPro 1.171.41.71a. An iterative solution (SHELXT-2014) produced a complete heavy-atom phased model. Anisotropic refinement of all non-hydrogen atoms was performed by full-matrix least-squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions relative to their parent atoms were constrained using the appropriate HFIX commands in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[1094] Table 4: Crystallographic data and structural refinement of chlorobenzene solvate

[1095]

[1096]

[1097]

[1098] Example 23: Ethylbenzene Crystalline Solvate Compound 1

[1099] X-ray quality crystals were grown from saturated ethylbenzene solutions followed by slow vapor diffusion with heptane to deposit diffracting crystals. A colorless prism measuring 0.162 × 0.103 × 0.067 mm was mounted on a Cryoloop containing Paratone oil. Data were collected in a nitrogen stream at 90(2)K using φ and ω scans. The crystal to detector distance was 40 mm, the exposure time was 0.25 s per frame, and the scan width was 0.5°. Data collection from θ to 67.000° was 100% complete. A total of 20385 reflections were collected with coverage indices of -16 <= h <= 16, -12 <= k <= 12, -42 <= l <= 42. The 20385 reflections were found to be symmetry independent with an R of 0.1540 int . Indexing and unit cell refinement indicated the original monoclinic lattice. The space group was found to be P 21 (No.4). The data were integrated and scaled using CrysAlisPro 1.171.41.71a. An iterative solution (SHELXT-2014) produced a complete heavy-atom phased model. Anisotropic refinement of all non-hydrogen atoms was performed by full-matrix least-squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions relative to their parent atoms were constrained using the appropriate HFIX commands in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[1100] Table 5: Crystallographic data and structure refinement of ethylbenzene solvate

[1101]

[1102]

[1103]

[1104] Example 24: Meta-xylene Crystallization Solvate Compound 1

[1105] X-ray quality crystals were grown from a saturated m-xylene solution followed by slow vapour diffusion with heptane to deposit the diffracting crystals. A colourless prism measuring 0.190 × 0.170 × 0.130 mm was mounted on a Cryoloop containing Paratone oil. Data were collected in a nitrogen stream at 90(2)K using φ and ω scans. The crystal to detector distance was 40 mm, the exposure time was 0.1 s per frame and the scan width was 0.5°. Data collection from θ to 67.000° was 100% complete. A total of 115184 reflections were collected with coverage indices of -11 <= h <= 12, -16 <= k <= 16, -40 <= l <= 40. 8996 reflections were found to be symmetry independent with an R of 0.0373 int . Indexing and unit cell refinement indicated the original orthorhombic lattice. The space group was found to be P 21 2121 (No.19). The data were integrated and scaled using CrysAlisPro1.171.41.71a. An iterative solution (SHELXT-2014) produced a complete heavy atom phased model. Anisotropic refinement of all non-hydrogen atoms was performed by full-matrix least-squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions relative to their parent atoms were constrained using the appropriate HFIX commands in SHELXL-2018. The absolute stereochemistry was determined to be S at C12.

[1106] Table 6: Crystallographic data and structure refinement of m-xylene solvate

[1107]

[1108]

[1109]

[1110] Example 25: Toluene Crystallization Solvate Compound 1

[1111] X-ray quality crystals were grown from saturated toluene solutions followed by slow vapour diffusion with heptane to deposit diffracting crystals. A colourless prism measuring 0.150 × 0.130 × 0.110 mm was mounted on a Cryoloop containing Paratone oil. Data were collected in a nitrogen stream at 90(2)K using φ and ω scans. The crystal to detector distance was 40 mm, the exposure time was 0.1 s per frame and the scan width was 0.5°. Data collection from θ to 67.000° was 100% complete. A total of 329,491 reflections were collected with coverage indices of -12 <= h <= 12, -41 <= k <= 41, -50 <= l <= 49. 26,769 reflections were found to be symmetry independent with an R of 0.0335 int . Indexing and unit cell refinement indicated the original orthorhombic lattice. The space group was found to be P 21 2121 (No.19). The data were integrated and scaled using CrysAlisPro1.171.41.70a. An iterative solution (SHELXT-2014) produced a complete heavy atom phased model. Anisotropic refinement of all non-hydrogen atoms was performed by full-matrix least-squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions relative to their parent atoms were constrained using the appropriate HFIX commands in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[1112] Table 7: Crystallographic data and structure refinement of toluene solvate

[1113]

[1114]

[1115] All technical and scientific terms used herein have the same meaning. Efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.

[1116] Throughout the specification and claims, the words "comprise" and "include" are used in a non-exclusive sense unless the context requires otherwise. It should be understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments.

[1117] Where a range of values ​​is provided, it is understood that each intervening value to the tenth of the unit of the lower limit within the upper and lower limits of that range and any other stated or intermediate ranges are encompassed herein unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in smaller ranges, which are also encompassed herein, subject to any specifically excluded limits in the stated ranges. Where the stated range includes one or both limits, ranges excluding one or both of the included limits are also encompassed herein.

[1118] Many modifications and other embodiments of the invention described herein will occur to those skilled in the art with the benefit of the teachings provided by the foregoing description and the associated drawings. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[1119] The present invention also includes the following embodiments:

[1120] Item 1: A method for preparing a compound of formula (I), comprising:

[1121]

[1122] in,

[1123] X 0 For 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;

[1124] X 1 is hydrogen or halogen;

[1125] 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;

[1126] R 1 Hydrogen or PG 1 ;

[1127] Each R 2 are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted

[1128] Generation C 1-6 Cyanoalkyl or unsubstituted C 1-6 Haloalkyl;

[1129] 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;

[1130] R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 Haloalkyl;

[1131] R 4 For R 4A -substituted or unsubstituted C 1-3 Haloalkyl;

[1132] R 4A For unsubstituted C 1-3 alkyl;

[1133] R 5 Halogen, cyano, OH, NO2, R 5A -substituted or unsubstituted C 1-6 alkyl

[1134] Base, 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 -substituted or unsubstituted 3-6 membered heterocyclic ring, R 5A -substituted or unsubstituted phenyl or R 5A - substituted or unsubstituted 6-membered heteroaryl;

[1136] R5A and R 5B Each independently is R 5C -substituted or unsubstituted C 1-6 Alkyl, R 5C -substituted or unsubstituted C 1-6 Haloalkyl, R 5C -substituted or unsubstituted C 3-7 Cycloalkyl; R 5C -substituted or unsubstituted 3-7 membered heterocyclic ring; R 5C -substituted or unsubstituted C 5-7 Aryl or R 5C - replaced or not

[1137] Substituted C 5-7 heteroaryl;

[1138] R 5C are 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 Heterocyclic ring; R 5D -substituted or unsubstituted C 5-7 Aryl or R 5D - Replaced or not replaced

[1139] Generation C 5-7 heteroaryl;

[1140] R 5D are independently halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl, unsubstituted C 3-7 Cycloalkyl; unsubstituted C 3-7 Heterocyclic; Unsubstituted C 5-7 Aryl or unsubstituted C 5-7 heteroaryl;

[1141] R 6 Halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 Cycloalkyl;

[1142] n is 0, 1 or 2;

[1143] Each PG is independently an amino protecting group, or two PGs together form a C 3-7 a nitrogen heterocycle; and

[1144] PG 1 is an amino protecting group;

[1145] (a) making a compound of formula (II)

[1146]

[1147] Where X 2 is a halogen;

[1148] contacting with an organomagnesium compound and a zinc complex; and

[1149] (b) mixing the mixture of step (a) with a compound of formula (III),

[1150]

[1151] Where X 4 is a halogen;

[1152] The transition metal catalyst precursor and the chiral ligand are contacted to synthesize the compound of formula (I). Item 2. The method according to Item 1, wherein the compound of formula (II) is prepared according to the following method

[1153] preparation:

[1154] (a) making the compound of formula (IVa) With the formula

[1155] contact with a halogenating agent, wherein X 3 is halogen, to prepare formula (IVb)

[1156] Compounds;

[1157] (d) cyclizing the compound of formula (IVb) to a compound of formula (V)

[1158]

[1159] (d) contacting the compound of formula (V) with a chlorinating agent to prepare a compound of formula (Va)

[1160] as well as

[1161] (e) mixing the compound of formula (Va) with a compound of formula to prepare a compound of formula (IIa) as well as

[1162] (f) making the compound of formula (IIa) and a 0 to form a compound of formula (II).

[1163] Item 3. The method according to Item 2 further comprises the steps of:

[1164] (a0) Formula (IV) The compound is contacted with a base in the presence of CO2 gas, and the compound is aminated to form a compound of formula (IVa) Item 4. A method according to any one of Items 1 to 3, wherein the compound of formula (III)

[1165] Prepare according to the following method:

[1166] (a) making the compound of formula (VII) Contacting with a compound having the formula NH2(PG) to prepare a compound of formula (VIIa)

[1167] (b) reacting the compound of formula (VIIa) with a compound of formula X a PG contact compounds, wherein X a is halogen, to prepare a compound of formula (VIIb)

[1168] (c) reacting the compound of formula (VIIb) with a compound of formula contact with a halogenating agent, wherein X 5 is halogen, to prepare a compound of formula (VIIc)

[1169]

[1170] (d) halogenating the compound of formula (VIIc) with a halogenating alkylating agent to prepare a compound of formula (VIId)

[1171]

[1172] (e) brominating the compound of formula (VIId) to prepare a compound of formula (VIIe)

[1173] as well as

[1174] (f) reacting the compound of formula (VIIe) with X a PG to prepare the compound of formula (III).

[1175] Item 5. The method according to Item 1, wherein the compound of formula (III) is prepared according to the following method

[1176] preparation:

[1177] (a) making a compound of formula (VIII) contact with a halogenating agent, wherein X 6 is Cl or I, to form formula (VIIIa) Compounds;

[1178] (b) brominating the compound of formula (VIIIa) to form the compound of formula (VIIIb) Compounds; and

[1179] (c) contacting the compound of formula (VIIIb) with a compound having the formula NH(PG)2 to prepare a compound of formula (III).

[1180] Item 6. The method according to Item 1, wherein the compound of formula (III) is prepared according to the following method

[1181] preparation:

[1182] (a) Formula (VIIIc) The compound is contacted with a brominating agent to form a compound of formula (VIIId) Compounds;

[1183] (b) contacting the compound of formula (VIIId) with a halogenating agent to form a compound of formula (VIIIb)

[1184] Compounds;

[1185] (c) contacting the compound of formula (VIIIb) with a compound having the formula NH(PG)2 to prepare a compound of formula (III).

[1186] Item 7. The method according to any one of Items 1 to 6, wherein X 1 It is a halogen.

[1187] Item 8. The method according to any one of Items 1 to 7, wherein X 1 is F or Cl. Item 9. The method according to any one of Items 1 to 6, wherein X 1 Item 10. The method according to any one of Items 1 to 8, wherein X 3 Halogen, untreated

[1188] Substituted C 1-4 Alkyl or unsubstituted C 1-3 Halogenated alkyl.

[1189] Item 11. The method according to any one of Items 1 to 8, wherein X 3 Halogen or untreated

[1190] Substituted C 1-3 Halogenated alkyl.

[1191] Item 12. The method according to any one of Items 1 to 8, wherein X 3 For unsubstituted C 1-3 alkoxy or unsubstituted cyclopropyl.

[1192] Item 13. The method according to any one of Items 1 to 8, wherein X 3 It is a halogen.

[1193] Item 14. The method according to any one of Items 1 to 8, wherein X 3 is Cl or F. Item 15. The method according to any one of Items 1 to 8, wherein X 3 It is Cl, F, CF3, CHF2 or CH2F.

[1194] Item 16. The method according to any one of Items 1 to 8, wherein X 3 It is CF3, CHF2 or CH2F.

[1195] Item 17. The method according to any one of Items 1 to 16, wherein R 1 For PG 1 .

[1196] Item 18. The method according to Item 17, wherein PG 1 Ac (acetyl), trifluoroacetyl

[1197] Acyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidene, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc

[1198] (9-fluorenylmethoxycarbonyl) or Cbz (benzyloxycarbonyl).

[1199] Item 19. The method according to any one of Items 1 to 16, wherein R 1 Boc (tert-butyl

[1200] oxycarbonyl).

[1201] Item 20. The method according to any one of Items 1 to 19, wherein R 2 is halogen or cyano.

[1203] Item 21. The method according to any one of Items 1 to 19, wherein R 2 For unsubstituted C 1-6 Alkyl, unsubstituted C 1-6Cyanoalkyl or unsubstituted C 1-6 Halogenated alkyl.

[1204] Item 22. The method according to any one of Items 1 to 19, wherein R 2 For unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 Cyanoalkyl.

[1205] Item 23. A method according to any one of Items 1 to 19, wherein R 2 For unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 Halogenated alkyl.

[1206] Item 24. The method according to any one of Items 1 to 19, wherein R 2 It is methyl or ethyl.

[1208] Item 25. The method according to any one of Items 1 to 19, wherein R 2 It is methyl.

[1209] Item 26. A method according to any one of Items 1 to 19, wherein R 2 It is CF3, CHF2 or CH2F.

[1210] Item 27. The method according to any one of Items 1 to 19, wherein R 2 Item 28. The method according to any one of Items 1 to 27, wherein R 3 is hydrogen or R 3A -Pick

[1211] Substituted or unsubstituted C 1-3 alkyl.

[1212] Item 29. The method according to any one of Items 1 to 27, wherein R 3 For R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 haloalkyl or cyclopropyl.

[1213] Item 30. The method according to any one of Items 1 to 27, wherein R 3 For R 3A -Replaced

[1214] or unsubstituted C 1-3 Alkyl or R 3A -substituted or unsubstituted C 1-3Item 31. The method according to any one of Items 1 to 27, wherein R 3 For R 3A -Replaced

[1215] or unsubstituted C 1-3 alkyl.

[1216] Item 32. A method according to any one of Items 1 to 27, wherein R 3 It is methyl.

[1217] Item 33. A method according to any one of Items 1 to 32, wherein R 4 It is CF3, CHF2 or CH2F.

[1218] Item 34. A method according to any one of Items 1 to 33, wherein each PG is independently

[1219] A protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidene, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl) or Cbz

[1220] (Benzyloxycarbonyl).

[1221] Item 35. A method according to any one of Items 1 to 34, wherein each PG is para-methoxy

[1222] Benzyl.

[1223] Item 36. A method according to any one of Items 1 to 34, wherein the two PGs are formed together

[1224] A section with the following structure:

[1225]

[1226] Item 37. The method according to any one of Items 1 to 36, wherein X 2 For Br.

[1227] Item 38. A method according to any one of Items 1 to 37, wherein the organomagnesium compound

[1228] The compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, tri-n-butylmagnesium lithium, tri-isopropylmagnesium lithium and (isopropyl)(di-n-butyl)magnesium lithium.

[1229] Item 39. A method according to any one of Items 1 to 38, wherein the zinc complex is selected from

[1230] The group consisting of ZnCl2, ZnBr2, ZnI2, Zn(OAc)2 and Zn(OPiv)2.

[1231] Item 40. A method according to any one of Items 1 to 39, wherein the transition metal catalyst

[1232] The catalyst precursor is a Pd or Ni catalyst precursor selected from the group consisting of:

[1233] Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl2, Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(lauroyl)Cl]2, [PdCl(crotyl)]2, PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadienyl)nickel(0)], NiCl2, NiBr2, Ni(OAc)2 and nickel(II) acetylacetonate.

[1234] Item 41. A method according to any one of Items 1 to 40, wherein the chiral ligand is

[1235]

[1236]

[1237] in

[1238] Y is O or NR 7 ;

[1239] Z is O or N;

[1240] R 7 and R 8 is independently unsubstituted C 1-6 alkyl;

[1241] R 9 and R 10 Independently for R 11 -substituted or unsubstituted C 5-6 Cycloalkyl or R 11 - substituted or unsubstituted phenyl;

[1242] Each R 11 are independently hydrogen, C 1-6Unsubstituted alkyl or C 1-6 unsubstituted haloalkyl;

[1243] R 12 and R 13 Each independently is R 14 -substituted or unsubstituted C1-6 alkyl, R 14 -substituted or unsubstituted C 3-7 Cycloalkyl, R 14 -substituted or unsubstituted aryl or R 14 -substituted or unsubstituted C 5-7 heteroaryl;

[1244] Each R 14 is independently unsubstituted C 1-4 alkyl.

[1245] Item 42. The method according to Item 41, wherein R 7 With R 8 same.

[1246] Item 43. The method according to Item 42, wherein R 7 and R 8 Each is methyl, ethyl or phenyl.

[1247] Item 44. The method according to Item 2, wherein the base is LDA or LiTMP.

[1248] Item 45. The method according to Item 2, wherein the halogenating agent is NCS or 1,3-dichloro-5,5-dimethylhydantoin.

[1249] Item 46. A method according to Item 2, wherein the chlorinating agent is POCl3, PCl3, PCl5 or SOCl2.

[1250] Item 47. The method according to Item 4, wherein the halogenating agent is NIS or 1,3-diiodo-5,5-dimethylhydantoin.

[1251] Item 48. The method according to Item 4, wherein the halogenated alkylating agent is a fluoroalkylating agent.

[1252] Item 49. The method according to Item 4, wherein the halogenated alkylating agent is methyl 2,2-difluoro-2-(fluorosulfonyl)acetate.

[1253] Item 50. The method according to Item 5 or 6, wherein the halogenating agent is SF4 in HF.

[1254] Item 51. The method according to Item 1, wherein the compound of formula (II) has the formula:

[1255]

[1256] Where X 3 It is a halogen.

[1257] Item 52. The method according to Item 1, wherein the compound of formula (II) has the formula:

[1258]

[1259] Where X 3 It is a halogen.

[1260] Item 53. The method according to Item 1, wherein the compound of formula (II) has the formula:

[1261]

[1262] Item 54. The method according to Item 1, wherein the compound of formula (III) has the formula:

[1263]

[1264] Item 55. The method according to Item 54, wherein R 3 For unsubstituted C 1-3 alkyl.

[1265] Item 56. The method according to Item 54 or 55, wherein R 4 For unsubstituted C 1-3 halogen

[1266] Alkyl group.

[1267] Item 57. The method according to Item 1, wherein the compound of formula (III) has the formula:

[1268]

[1269] Item 58. The method according to Item 1, wherein the compound of formula (I) has the formula:

[1270]

[1271] Item 59. The method according to Item 1, wherein the compound of formula (I) has the formula:

[1272]

[1273] Item 60. The method according to Item 58 or 59, wherein R 3 For unsubstituted C 1-3 alkyl.

[1275] Item 61. A method according to any one of Items 58 to 60, wherein R 4 For unreplaced

[1276] C 1-3 Halogenated alkyl.

[1277] Item 62. The method according to Item 1, wherein the compound of formula (I) has the formula:

[1278]

[1279] Item 63. A method according to any one of Items 58 to 62, wherein R 2 For unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 Halogenated alkyl.

[1280] Item 64. The method according to Item 63, wherein R 2 It is methyl, ethyl, CN, CH2CN, CF3, CHF2 or CH2F.

[1281] Item 65. The method according to Item 63, wherein R 2 It is methyl, ethyl, CN or CH2CN.

[1282] Item 66. The method according to Item 1, wherein the compound of formula (I) has the formula:

[1283]

[1284] Where X 3 It is a halogen.

[1285] Item 67. The method according to Item 1, wherein the compound of formula (I) has the formula:

[1286]

[1287] Item 68. The method according to Item 1, wherein X 0 is hydrogen, halogen, CF3, CHF2, CH2F or a moiety having the following structure:

[1288]

[1289]

[1290]

[1291] Item 69. A compound having formula (Id):

[1292]

[1293] Where X 3 It is a halogen.

[1294] Item 70. A compound having formula (1):

[1295]

[1296] Item 71. The method according to Item 2, wherein step (f) further comprises:

[1297] Step (g) fluorinating the compound of formula (IIa) to obtain a compound of formula (IIa1)

[1298]

[1299] Item 72. The method according to Item 2, wherein step (f) further comprises:

[1300] Step (h) alkoxylating the compound of formula (IIa) to a compound of formula (IId)

[1301]

[1302] Item 73. The method according to Item 2, wherein step (f) further comprises:

[1303] Step (j) thiolates the compound of formula (IIa) to form a compound of formula (IIe):

[1304]

[1305] Item 74. A method according to any one of Items 1 to 6, wherein the compound of formula (I)

[1306] The compounds in Table 1.

[1307] Project 75. A method for synthesizing a compound having the following formula

[1308]

[1309] or a pharmaceutically acceptable salt thereof, the method comprising

[1310] (a) Formula (2) The compound or its salt is contacted with i-PrMgCl·LiCl and ZnCl2, and then with NaTFA and formula (3) Compound exposure;

[1311] (b) contacting the mixture of step (a) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand to synthesize a compound of formula (1)

[1312]

[1313] or a solvate or salt thereof;

[1314] (c) reacting the compound of formula (1) or its solvate or salt with a compound of formula HO-X A The compound is contacted with a base, wherein X A With formula Thus, the compound of formula (1d) is synthesized

[1315]

[1316] or a solvate or a pharmaceutically acceptable salt thereof;

[1317] (d) contacting the compound of formula (1d) with MsOH in an acid to synthesize the compound of formula (1e)

[1318] Compound

[1319]

[1320] or a solvate or a pharmaceutically acceptable salt thereof; and

[1321] (e) reacting the compound of formula (1e) or its solvate or pharmaceutically acceptable salt in the presence of a base and optionally an activating agent

[1322] contacting, thereby preparing the compound of formula (A) or a pharmaceutically acceptable salt thereof.

[1323] Item 76. The method according to Item 75, wherein the acid in step (d) is AcOH, tris(III)

[1324] Fluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid or trifluoromethanesulfonic acid.

[1325] Item 77. The method according to Item 75, wherein step (e) comprises reacting the compound of formula (1e)

[1326] or its solvate or pharmaceutically acceptable salt and touch.

[1327] Item 78. The method according to Item 75, wherein step (e) comprises reacting the compound of formula (1e)

[1328] or its solvate or pharmaceutically acceptable salt and Item 79. The method according to Item 75, wherein step (e) comprises contacting in the presence of a base and an activating agent

[1329] The formula below of compounds.

[1330] Item 80. The method according to Item 75, wherein step (e) comprises the formula

[1331] of compounds and bases.

[1332] Item 81. The method according to any one of Items 75 to 80, further comprising the steps of:

[1333] (f) contacting the compound of formula (A) with adipic acid in a solvent according to Scheme 1, Scheme 2 or Scheme 3 described herein.

Claims

1. A method for preparing a compound of formula (I), comprising: in, X 0 For 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 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 Hydrogen or PG 1 ; Each R 2 are 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 For R 4A -substituted or unsubstituted C 1-3 Haloalkyl; R 4A For unsubstituted C 1-3 alkyl; R 5 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 -substituted or unsubstituted 3-6 membered heterocyclic ring, R 5A -substituted or unsubstituted phenyl or R 5A - substituted or unsubstituted 6-membered heteroaryl; R 5A and R 5B Each independently is R 5C -substituted or unsubstituted C 1-6 Alkyl, R 5C -substituted or unsubstituted C 1-6 Haloalkyl, R 5C -substituted or unsubstituted C 3-7 Cycloalkyl; R 5C -substituted or unsubstituted 3-7 membered heterocyclic ring; R 5C -substituted or unsubstituted C 5-7 Aryl or R 5C -substituted or unsubstituted C 5-7 heteroaryl; R 5C are 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 Heterocyclic ring; R 5D -substituted or unsubstituted C 5-7 Aryl or R 5D -substituted or unsubstituted C 5-7 heteroaryl; R 5D are independently halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl, unsubstituted C 3-7 Cycloalkyl; unsubstituted C 3-7 Heterocyclic; Unsubstituted C 5-7 Aryl or unsubstituted C 5-7 heteroaryl; R 6 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 a nitrogen heterocycle; and PG 1 is an amino protecting group; (a) making a compound of formula (II) Where X 2 is a halogen; contacting with an organomagnesium compound and a zinc complex; and (b) mixing the mixture of step (a) with a compound of formula (III), Where X 4 is a halogen; The transition metal catalyst precursor and the chiral ligand are contacted to synthesize the compound of formula (I).

2. The method according to claim 1, wherein the compound of formula (II) is prepared according to the following method: (a) making the compound of formula (IVa) With the formula or contact with a halogenating agent, wherein X 3 is halogen, to prepare formula (IVb) Compounds; (d) cyclizing the compound of formula (IVb) to a compound of formula (V) (d) contacting the compound of formula (V) with a chlorinating agent to prepare a compound of formula (Va) as well as (e) mixing the compound of formula (Va) with a compound of formula to prepare a compound of formula (IIa): as well as (f) making the compound of formula (IIa) and a 0 to form a compound of formula (II).

3. The method according to claim 2, further comprising the steps of: (a0) Formula (IV) The compound is contacted with a base in the presence of CO2 gas, and the compound is aminated to form a compound of formula (IVa) 4. The method according to any one of claims 1 to 3, wherein the compound of formula (III) is prepared according to the following method: (a) making the compound of formula (VII) Contacting with a compound having the formula NH2(PG) to prepare a compound of formula (VIIa) (b) reacting the compound of formula (VIIa) with a compound of formula X a PG compound contact, wherein X a is halogen, to prepare a compound of formula (VIIb) (c) reacting the compound of formula (VIIb) with a compound of formula contact with a halogenating agent, wherein X 5 is halogen, to prepare a compound of formula (VIIc) (d) halogenating the compound of formula (VIIc) with a halogenating alkylating agent to prepare a compound of formula (VIId) (e) brominating the compound of formula (VIId) to prepare a compound of formula (VIIe) as well as (f) reacting the compound of formula (VIIe) with X a PG to prepare the compound of formula (III).

5. The method according to claim 1, wherein the compound of formula (III) is prepared according to the following method: (a) making a compound of formula (VIII) contact with a halogenating agent, wherein X 6 is Cl or I, to form formula (VIIIa) Compounds; (b) brominating the compound of formula (VIIIa) to form the compound of formula (VIIIb) Compounds; and (c) contacting the compound of formula (VIIIb) with a compound having the formula NH(PG)2 to prepare a compound of formula (III).

6. The method according to claim 1, wherein the compound of formula (III) is prepared according to the following method: (a) Formula (VIIIc) The compound is contacted with a brominating agent to form a compound of formula (VIIId) Compounds; (b) contacting the compound of formula (VIIId) with a halogenating agent to form a compound of formula (VIIIb) Compounds; (c) contacting the compound of formula (VIIIb) with a compound having the formula NH(PG)2 to prepare a compound of formula (III).

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

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

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

10. The method according to any one of claims 1 to 8, wherein X 3 is halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3 Halogenated alkyl.

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