Synthesis of quinazoline compounds

Abstract

To provide methods of synthesizing quinazoline compounds comprising at least one atropisomeric center.SOLUTION: A method comprises (a) contacting a compound with an organomagnesium compound and a zinc complex, and (b) contacting the mixture from the step (a) with a transition metal (e.g., Pd or Ni) catalyst precursor and a chiral ligand, thereby synthesizing a compound of formula (I).SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0002] Provided herein are methods for synthesizing atropisomers of quinazolinyl compounds via atropselective synthetic methods / techniques. [Background technology]

[0003] The configuration of the biaryl axis often plays an important role in the pharmacological properties of biologically active compounds and is the fundamental basis for useful reagents and catalysts in asymmetric synthesis. Highly atroposelective cross-coupling, especially cross-coupling of heterocycles for the synthesis of biheteroaryls, remains a challenging and unsolved problem. The present disclosure provides an improved method for the atroposelective synthesis of aminopyridinyl-quinazolinyl compounds by Negishi coupling utilizing chiral ligands such as chiraphite or valphos. Summary of the Invention

[0004] Solutions to the above problems, as well as other problems in the art, are provided herein.

[0005] Disclosed herein are compounds and methods for producing the compounds of formula (I) described herein.

[0006] In one aspect, provided herein is a method for the synthesis of a compound of formula (I) as described herein, comprising: (a) contacting a compound of formula (II) as described herein with an organomagnesium 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).

[0007] In one aspect, provided herein is a compound of formula (I) as described herein, or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof. In one aspect provided herein, the compound of formula (I) has formula Ia, Ib, Ib1, Ib2, Ib3, Ic1, Ic2, Id, 1a, 1b, 1c, or 1 as described herein.

[0008] In another aspect, provided herein is a process for the preparation of 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 organomagnesium compound and a zinc complex; and (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.

[0009] Further provided herein is a process (P2) as described herein for the preparation of a compound of formula (II) as described herein, or a tautomer, stereoisomer or salt thereof.

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

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

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

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

[0014] In another aspect, provided herein is a method (P7) described herein for the preparation of a compound of formula (H) as described herein, or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof.

[0015] In another aspect, provided herein is a method (P8) described herein for the preparation of a compound of formula (F) as described herein, or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof.

[0016] In another aspect, there is provided herein a process (P8) described herein for the preparation of a compound of formula (F) as described herein, or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0017] [Figure 1] 1 shows the single crystal structure of the cyclohexane crystalline solvate of Compound 1.

[0018] [Diagram 2] 1 shows the single crystal structure of the methylcyclohexane crystalline solvate of compound 1.

[0019] [Diagram 3] 1 shows the single crystal structure of the chlorobenzene crystalline solvate of compound 1.

[0020] [Figure 4] 1 shows the single crystal structure of the ethylbenzene crystalline solvate of compound 1.

[0021] [Diagram 5] 1 shows the single crystal structure of the m-xylene crystalline solvate of compound 1.

[0022] [Figure 6] 1 shows the single crystal structure of the toluene crystalline solvate of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0024] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. In one example, an alkyl group has 1 to 18 carbon atoms (C 1-18 In another example, 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 are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(C H3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)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.

[0025] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Examples of haloalkyl include trifluoromethyl, difluoromethyl, and fluoromethyl. "Fluoroalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by F.

[0026] The term "amino" refers to --NH.sub.2.

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

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

[0029] The term "alkoxy" refers to --O-alkyl.

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

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

[0032] The term "haloalkoxy" refers to -O-haloalkyl.

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

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

[0035] The term "aryl" refers to a carbocyclic aromatic group having the specified number of carbon atoms, or up to 14 carbon atoms if no number is specified, whether or not fused to one or more groups. An example is an aryl group having 6 to 14 carbon atoms. Another example is an aryl group having 6 to 10 carbon atoms. Another example is an aryl group having 5 to 7 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like (see, e.g., Lang's Handbook of Chemistry (Dean, JA, ed.) 13). thed. Table 7-2

[1985] ). An exemplary aryl is phenyl.

[0036] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyl includes mono-, bi-, tricyclic, spiro, and bridged saturated ring systems. In one example, a cycloalkyl group contains 3 to 12 carbon atoms (C 3-12 In another embodiment, the cycloalkyl is C 3-7 , C 3-8 , C 3-10 , or C 5-10 In another embodiment, the cycloalkyl group as a single ring is 3-8 , C 3-6 , or C 5-6 In another embodiment, the cycloalkyl group for the bicycle is 7-C 12 In another example, the cycloalkyl group for the spiro system is C 5-12 Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary configurations of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Examples of spirocycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.

[0037] The terms "heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", or "heterocyclo" are used interchangeably and refer to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated, or unsaturated non-aromatic ring system having 3-20 ring atoms, where the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the ring system is a heteroatom, the system is a heterocyclic ring, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl contains 3-11 ring atoms ("members") and includes mono-, bi-, tricyclic, spiro, and bridged ring systems where the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclyl contains 4-10, or 5-10 ring atoms. In one example, a heterocyclyl contains 1-4 heteroatoms. In one example, a heterocyclyl includes 1-3 heteroatoms. In another example, a heterocyclyl includes a 3-7 membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl includes a 4-6 membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl includes a 3 membered monocyclic ring. In another example, a heterocyclyl includes a 4 membered monocyclic ring. In another example, a heterocyclyl includes a 5-6 membered monocyclic ring. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, a heterocyclyl group includes 0-3 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 -Exemplary heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothio ... sahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, ... Hydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, Pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl.

[0038] The term "heteroaryl" refers to any mono-, bi-, or tricyclic aromatic ring system containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur, and in exemplary embodiments, at least one heteroatom is nitrogen. See, e.g., Lang's Handbook of Chemistry (Dean, JA, ed.) 13 th ed. Table 7-2

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

[0039] In certain embodiments, the heterocyclyl or heteroaryl group is bonded at a carbon atom of the heterocyclyl or heteroaryl group. For example, carbon-bonded heterocyclyl groups include bonding arrangements at the 2-, 3-, 4-, 5-, or 6-position of the pyridine ring, the 3-, 4-, 5-, or 6-position of the pyridazine ring, the 2-, 4-, 5-, or 6-position of the pyrimidine ring, the 2-, 3-, 5-, or 6-position of the pyrazine ring, the 2-, 3-, 4-, or 5-position of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, the 2-, 4-, or 5-position of the oxazole, imidazole, or thiazole ring, the 3-, 4-, or 5-position of the isoxazole, pyrazole, or isothiazole ring, the 2-, or 3-position of the aziridine ring, the 2-, 3-, or 4-position of the azetidine ring, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of the quinoline ring, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of the isoquinoline ring.

[0040] In certain embodiments, the heterocyclyl or heteroaryl group is N-linked. For example, nitrogen-linked heterocyclyl or heteroaryl groups include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole at the 1-position, isoindole or isoindole at the 2-position, morpholine at the 4-position, and carbazole or β-carboline at the 9-position.

[0041] "Fused" means any cyclic structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with an existing cyclic structure in the compounds of the invention.

[0042] The term "acyl" refers to a carbonyl containing a substituent represented by -C(=O)-R, where R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, where alkyl, cycloalkyl, aryl, and heterocyclyl are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).

[0043] As used herein, a "halogenating agent" refers to any reagent that adds one or more halogens to a compound described herein. As used herein, a "chlorinating agent" refers to any reagent that adds one or more chlorine (Cl) atoms to a compound described herein. As used herein, a "brominating" or "iodinating" agent refers to any reagent that adds one or more bromine (Br) or iodine (I) atoms, respectively, to a compound described herein.

[0044] As used herein, "haloalkylating agent" refers to any reagent that adds one or more haloalkyl groups (e.g., CF) to a compound described herein. "Fluoroalkylating agent" refers to a reagent that adds one or more fluoroalkyl groups to a compound described herein.

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

[0046] "LDA" refers to lithium diisopropylamide.

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

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

[0049] As used herein, "chiral ligand" refers to one or more compounds and / or catalysts that synthesize one chiral compound, such as atropisomers, over another.

[0050] As used herein, a wavy line crossing a bond in a chemical structure JPEG2025032093000001.jpg9170 shows the attachment point of an atom in a chemical structure where a wavy bond attaches it to the rest of the molecule, or to the rest of a fragment of a molecule.

[0051] In certain embodiments, a divalent group is described generally without a specific bond structure. Unless otherwise specified, it is understood that the general description is meant to include both bond structures. For example, the group R 1 -R 2 -R 3 In the formula, the group R 2 When is depicted as -CHC(O)-, unless otherwise specified, this group represents R 1 -CH2C(O)-R 3 and R 1 -C(O)CH2-R 3 It is understood that both are combinable.

[0052] The term "pharmaceutical acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other side effects when properly administered to an animal, such as a human.

[0053] The compounds of the present invention can be in the form of salts, such as pharma- ceutically acceptable salts. "Pharmaceutically acceptable salts" includes both acid and base addition salts. By "pharmacologically acceptable acid addition salts" is meant salts which retain the biological effectiveness and properties of the free base and which are biologically or otherwise desirable, formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; the organic acids can be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0054] The term "pharmaceutically acceptable base addition salts" includes salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines including basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0055] In some embodiments, the salt is a hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate, or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonic acid), salt, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate), phthalenesulfonate), camsylate (camphor 10-sulfonate, e.g. (1S)-(+)-10-camphor-sulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0056] The compounds of the present invention may contain one or more chiral carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may use racemates, diastereomers, or enantiomers as starting materials or intermediates. A mixture of specific diastereomeric compounds may be separated or enriched into one or more specific diastereomers by chromatographic or crystallization techniques. Similarly, enantiomeric mixtures may be separated or enantiomerically enriched using the same techniques or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration, and both of these configurations are within the scope of the present invention.

[0057] In the structures depicted herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included as the compounds of the present invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, that stereoisomer is so specified and defined. Unless otherwise indicated, relative stereochemistry is intended when a solid wedge or dashed line is used.

[0058] 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, conformers, etc.

[0059] The term "chiral" refers to molecules that have the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0060] The term "diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0061] The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0062] "Atropisomers" are stereoisomers resulting from sterically hindered rotation about a single bond or axis, where the energy difference due to steric strain or other factors creates a barrier to rotation high enough to permit isolation of individual conformers.

[0063] Stereochemical definitions and conventions used herein are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0064] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0065] As used herein, the term "amino protecting group" refers to a derivative of a group commonly used to block or protect an amino group, while the reaction is carried out at another functional group of the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Particular amino protecting groups are PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), Cbz (carbobenzyloxy), Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, or DMB (dimethoxybenzyl). In some embodiments, the amino protecting group may be a group used to block or protect an amino group that results from cyclization of a group attached to the amino group, but that can be subsequently removed or replaced. Such examples include 1,3,5-dioxazinane, 2,4-dimethyl-1,3,5-dioxazinane, 2,2,5,5-tetramethyl-1,2,5-azadisilolidine, and isoindoline-1,3-dione. Further exemplary amino protecting groups are described in TW Greene and PG M Huts, "Protecting Groups in Organic Synthesis, 3 rd ed., John Wiley & Sons, Inc., 1999. The term "protected amino" means an amino group substituted with one of the amino-protecting groups described above.

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

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

[0068] The terms "antagonist" and "inhibitor" are used interchangeably to 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. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of a target protein by interacting with other elements of a signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with tumor progression, growth, or spread.

[0069] As used herein, the term "agonist" refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with the target (e.g., bind to the target), compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other elements of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0070] The terms "cancer" and "cancerous," "neoplasm," and "tumor," and related terms refer to or describe a physiological condition in mammals that is typically characterized by unregulated growth of cells. A "tumor" comprises one or more cancer cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinoma), and lung cancers (such as small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cavity cancer, pharyngeal (mouth) cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, small intestine cancer, large intestine cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, hepatic cancer, uterine cancer, uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B cell lymphoma, diffuse large B cell lymphoma (DLBCL), central nervous system, brain cancer, head and neck cancer, Hodgkin's disease, and associated metastases. Examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, myelofibrosis such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0071] A "chemotherapeutic agent" is an agent useful in the treatment of a given disorder, such as cancer or an inflammatory disorder. Examples of chemotherapeutic agents are known in the art and include examples such as those described in U.S. Patent Application Publication No. 2010 / 0048557, which is incorporated herein by reference. Additionally, chemotherapeutic agents include any pharma- ceutically acceptable salt, acid, or derivative of the chemotherapeutic agent, and combinations of two or more thereof.

[0072] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Isotopically labeled compounds (e.g., 3 H and 14 C-labeled compounds) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes can be useful because of their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2 Substitution with, for example, H, may result in greater metabolic stability and, as a result, certain therapeutic advantages (e.g., longer in vivo half-life or reduced dosage requirements). In some embodiments, one or more carbon atoms in the compounds of the invention are 13 C or 14It is replaced by C-enriched carbon. 15 O. 13 N, 11 C, and 18 Positron emitting isotopes such as F are useful for positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures similar to those described in the schemes or examples described herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0073] It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, 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.

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

[0075] Provided herein is a compound of formula (I): JPEG2025032093000002.jpg55170 or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof, During the ceremony, X 0 is hydrogen, halogen, OR 5A , S.R. 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 is heteroaryl; X 1 is hydrogen or halogen; X 3 is hydrogen, halogen, R 6 -Substituted or unsubstituted C 1-3 Alkyl, R 6 -Substituted or unsubstituted C 1-3 Haloalkyl, R 6 -Substituted or unsubstituted C 1-3 Alkoxy or R 6 - substituted or unsubstituted cyclopropyl; R 1 is hydrogen or PG 1 and; Each R 2 are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 is 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 is cycloalkyl; R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; R 4 is R 4A -substituted or unsubstituted C 1-3 is haloalkyl; R 4A is unsubstituted C 1-3 is alkyl; R 5 is halogen, cyano, OH, NO2, R 5A -Substituted or unsubstituted C 1-6 Alkyl, R 5A -Substituted or unsubstituted C 1-6 Haloalkyl, R 5A -Substituted or unsubstituted C 1-6 Cyanoalkyl, R 5A -Substituted or unsubstituted C 3-6 Cycloalkyl, R 5A-substituted or unsubstituted 3- to 6-membered heterocycle, R 5A -substituted or unsubstituted phenyl, or R 5A -substituted or unsubstituted 6-membered heteroaryl; R 5A and R 5B are each independently 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- to 7-membered heterocycle; R 5C -Substituted or unsubstituted C 5-7 Aryl or R 5C -Substituted or unsubstituted C 5-7 is heteroaryl; 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 Heterocycle; R 5D -Substituted or unsubstituted C 5-7 Aryl or R 5D -Substituted or unsubstituted C 5-7 is heteroaryl; 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 Heterocycle; Unsubstituted C 5-7 Aryl or unsubstituted C 5-7 is heteroaryl; R 6 is hydrogen, halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6Haloalkyl or unsubstituted C 3-7 is cycloalkyl; n is 1 or 2; Each PG is independently an amino protecting group, or two PGs together form C 3-8 forming a nitrogen heterocycle; and PG 1 is an amino protecting group.

[0076] In one embodiment of the compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers or salts thereof described herein, X 0 is halogen, OR 5A , S.R. 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 one embodiment of the compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers or salts thereof described herein, X is heteroaryl. 0 is hydrogen, halogen or OR 5A In another embodiment of the compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers or salts thereof described herein, X 0 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 compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers or salts thereof described herein, X is heteroaryl. 0is hydrogen, halogen, CF, CHF, or CHF. In a preferred embodiment, X 0 In one such embodiment of the compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers or salts thereof described herein, X 0 is F.

[0077] In yet another embodiment of the compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers or salts thereof described herein, X 0 is hydrogen, halogen, CF3, CHF2, CH2F, or the following structure: JPEG2025032093000003.jpg248170 or JPEG2025032093000004.jpg23170, or a stereoisomer thereof.

[0078] In one embodiment of the compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers or salts thereof described herein, R 5 is halogen, cyano, OH, or NO2. In one embodiment of the compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers, or salts thereof described herein, R 5 is 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 compounds of formula (I) or solvates, tautomers, stereoisomers, atropisomers, or salts thereof described herein, R 5 is R 5A -Substituted or unsubstituted C 3-6 Cycloalkyl, R 5A -substituted or unsubstituted 3- to 6-membered heterocycle, R 5A -substituted or unsubstituted phenyl, or R 5A -substituted or unsubstituted 6-membered heteroaryl.

[0079] In one embodiment, R 5A and R 5B are each independently 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 are each independently R 5C -Substituted or unsubstituted C 3-7 Cycloalkyl; R 5C -substituted or unsubstituted 3- to 7-membered heterocycle, R 5C -Substituted or unsubstituted C 5-7 Aryl or R 5C -Substituted or unsubstituted C 5-7 In a preferred embodiment, R 5A and R 5B are each independently R 5C -substituted or unsubstituted C 1-6 It is an alkyl.

[0080] In one embodiment, R 5C is independently halogen, OH, CN, or NO. In one embodiment, R 5C are independently 5D -Substituted or unsubstituted C 1-6 Alkyl or R 5D -Substituted or unsubstituted C 1-6 In one embodiment, R 5C are independently 5D -Substituted or unsubstituted C 3-7 Cycloalkyl or R 5D -Substituted or unsubstituted C 3-7 In one embodiment, R 5C are independently 5D -Substituted or unsubstituted C 5-7 Aryl or R 5D -Substituted or unsubstituted C 5-7 In another embodiment, R 5C are independently 5D -Substituted or unsubstituted C 3-7Heterocycle or R 5D -Substituted or unsubstituted C 5-7 In another embodiment, R 5C is R 5D -substituted pyrrolidinyl.

[0081] In one embodiment, R 5D is independently halogen, OH, or CN. In another embodiment, R 5D is unsubstituted C 1-6 In another embodiment, R 5D is unsubstituted C 1-6 In yet another embodiment, R 5D is unsubstituted C 3-7 Cycloalkyl, unsubstituted C 3-7 Heterocyclic, unsubstituted C 5-7 Aryl or unsubstituted C 5-7 In one embodiment, R 5D is methyl, ethyl or propyl.

[0082] In one embodiment, R 5A and R 5B are each independently The image is JPEG2025032093000005.jpg227170.

[0083] In one embodiment, R 5A and R 5B are each independently The image is JPEG2025032093000006.jpg228170.

[0084] In another embodiment, the compound of formula (Ia): Provided herein is JPEG2025032093000007.jpg53170, or a solvate, tautomer, stereoisomer, or salt thereof, During the ceremony, X 0 is hydrogen, halogen or OR 5A and; X 1 and X 3 is independently halogen or methyl; R 1 is hydrogen or PG 1 and; Each R 2 are independently halogen, cyano, methyl, ethyl, propyl, -CHCN, (CH)CN, CF, CHF, or CHF; R 3 is hydrogen or methyl; R 5A teeth, JPEG2025032093000008.jpg227170; n is 0, 1 or 2; Each PG is independently an amino protecting group, or two PGs together form C 3-8 forming a nitrogen heterocycle; and PG 1 is an amino protecting group.

[0085] Further provided herein is a compound of formula (Ib): JPEG2025032093000009.jpg55170 or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof, During the ceremony, X 1 is hydrogen or halogen; X 3 is hydrogen, halogen, R 6 -Substituted or unsubstituted C 1-3 Alkyl, R 6 -Substituted or unsubstituted C 1-3 Haloalkyl, R 6 -Substituted or unsubstituted C 1-3 Alkoxy or R 6 - substituted or unsubstituted cyclopropyl; R 1 is hydrogen or PG 1 and; Each R 2 are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 is haloalkyl; R3 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 is cycloalkyl; R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; R 4 is R 4A -substituted or unsubstituted C 1-3 is haloalkyl; R 4A is unsubstituted C 1-3 is alkyl; R 6 is hydrogen, halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 is cycloalkyl; n is 0, 1 or 2; Each PG is independently an amino protecting group, or two PGs together form C 3-8 forming a nitrogen heterocycle; and PG 1 is an amino protecting group.

[0086] In one embodiment, X 1 is hydrogen. In one embodiment, X 1 is a halogen. In one embodiment, X 1 is F or Cl. In another embodiment, X 1 If is a halogen, X 3 is a halogen. In another embodiment, X 1 If F, then X 3 is not F. In another embodiment, X 1 If F, then X 3 is Cl.

[0087] In one embodiment, X 3is hydrogen, halogen, R 6 -Substituted or unsubstituted C 1-3 Alkyl or R 6 -Substituted or unsubstituted C 1-3 In another embodiment, X is haloalkyl. 3 is R 6 -Substituted or unsubstituted C 1-3 Alkoxy or R 6 -substituted or unsubstituted cyclopropyl. In another embodiment, X 3 is hydrogen or halogen. In another embodiment, X 3 is halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3 In yet another embodiment, X is haloalkyl. 3 is halogen or unsubstituted C 1-3 In yet another embodiment, X is haloalkyl. 3 is unsubstituted C 1-3 In a preferred embodiment, X is alkoxy or unsubstituted cyclopropyl. 3 is a halogen. In one such embodiment, X 3 is Cl or F. In another embodiment, X 3 is Cl, F, CF, CHF, or CHF. In yet another embodiment, X 3 is CF3, CHF2 or CH2F.

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

[0089] In one embodiment, each R 2 is independently halogen or cyano. In one embodiment, each R 2 are independently halogen or unsubstituted C 1-6 In another embodiment, each R 2 are 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 are 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, each R 2 is CF, CHF, or CHF. In another such embodiment, R 2 is methyl, ethyl, CN, CHCN, CF, CHF, or CHF. In another embodiment, R 2 is methyl, ethyl, CN, or CHCN. In such embodiments, n is 1. In other such embodiments, R 2 is CHCN and n is 1. In another embodiment, n is 0.

[0090] In one embodiment, R 3 is hydrogen or halogen. In one embodiment, R 3 is hydrogen. In another embodiment, R 3 is hydrogen, R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 haloalkyl, cyclopropyl. In another embodiment, R 3 is 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 yet another embodiment, R 3 is R 3A -Substituted or unsubstituted C 1-3 In one such embodiment, R 3 is hydrogen or methyl. In another such embodiment, R 3 is methyl.

[0091] In one embodiment, R 3 is R 3A -Substituted or unsubstituted C 1-3 Alkyl, R 3A -Substituted or unsubstituted C 1-3 haloalkyl, where 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 haloalkyl, where R 3A is F, OH, CN, CF3, CHF2 or CH2F.

[0092] In a preferred embodiment, R 4 is unsubstituted C 1-3 In one such embodiment, R 4 is CF, CHF, or CHF. In one such embodiment, R 4 is CF3.

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

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

[0095] In yet another embodiment, two PGs taken together form C 3-8 In one embodiment, two PGs taken together form a nitrogen heterocycle: Form a portion having JPEG2025032093000010.jpg25170.

[0096] In another embodiment, the compound of formula (Ib1): JPEG2025032093000011.jpg54170 or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof, During the ceremony, X 1 and X 3 is independently halogen or methyl; R 1 is hydrogen or PG 1 and; Each R 2 are independently halogen, cyano, methyl, ethyl, propyl, -CHCN, (CH)CN, CF, CHF, or CHF; n is 1 or 2; and PG 1 is an amino protecting group.

[0097] In one embodiment, the compounds of formula (I) described herein or solvates, tautomers, stereoisomers, atropisomers or salts thereof are represented by the formula (Ib2): JPEG2025032093000012.jpg51170 or a solvate, tautomer, stereoisomer, atropisomer or salt thereof.

[0098] In one embodiment, the compounds of formula (I) described herein or solvates, tautomers, stereoisomers, atropisomers or salts thereof are represented by the formula (Ib3): JPEG2025032093000013.jpg53170 or a solvate, tautomer, stereoisomer, or salt thereof.

[0099] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000014.jpg52170 or a solvate, tautomer, stereoisomer, or salt thereof.

[0100] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000015.jpg50170 or a solvate, tautomer, stereoisomer, or salt thereof.

[0101] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000016.jpg51170 or a solvate, tautomer, stereoisomer, or salt thereof.

[0102] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000017.jpg52170 or a solvate, tautomer, stereoisomer, or salt thereof.

[0103] In one embodiment, the compound of formula (I) described herein or a solvate, tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000018.jpg50170 or a solvate, tautomer, stereoisomer, or salt thereof.

[0104] In one embodiment, the compounds of formula (I) described herein or solvates, tautomers, stereoisomers, or salts thereof are provided by the method of the present invention, comprising administering to one or more of the compounds of formula 1: JPEG2025032093000019.jpg51170 or a solvate, tautomer, stereoisomer, or salt thereof.

[0105] Further provided herein is a crystalline solvate 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.

[0106] In one embodiment, the compound of formula (I) is a compound of formula 1: It is a crystalline solvate of JPEG2025032093000020.jpg51170.

[0107] 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 shown in FIG. 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 shown in FIG. 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 shown in FIG. 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 shown in FIG. 4. In another embodiment, the compound of formula (1) is a crystalline m-xylene solvate. In one such embodiment, the crystalline m-xylene solvate of the compound of formula (1) is substantially as shown in Figure 5. In another embodiment, the compound of formula (1) is a crystalline toluene solvate. In one such embodiment, the crystalline toluene solvate of the compound of formula (1) is substantially as shown in Figure 6.

[0108] In another aspect, provided herein is a crystalline solvate solid form of Compound (1). JPEG2025032093000021.jpg51170

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

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

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

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

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

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

[0115] In another embodiment, the compound of Formula (I) described herein or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof is a compound having the formula shown in Table 1, or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof.

[0116] [Table 1] JPEG2025032093000023.jpg211170JPEG2025032093000024.jpg201170JPEG2025032093000025.jpg23417 0JPEG2025032093000026.jpg220170JPEG2025032093000027.jpg238170JPEG2025032093000028.jpg62170

[0117] 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 yet another embodiment, the compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof 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 in Table 1, where R 1 is Boc.

[0118] 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 an embodiment, the solvate is a cyclohexane, methylcyclohexane, chlorobenzene, ethylbenzene, m-xylene, or toluene solvate of a 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 is Boc. In one embodiment, the compound of formula (I) is a crystalline solvate of a compound of formula 105, wherein R 1 is Boc. Preparation method

[0119] In addition, the compound of formula (I): Further provided herein is a method for the preparation of JPEG2025032093000029.jpg57170 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 methods 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.

[0120] In one embodiment, there is provided a process (P1) for preparing a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, comprising (a) A compound of formula (II) JPEG2025032093000030.jpg45170 or a tautomer, stereoisomer, or salt thereof, X 0 , X 1 , X 3 , R 1 , and R 2 is as described herein; and X 2 is halogen or ZnY 1 where Y 1 is a halogen (e.g., Cl, Br, or I), OAc, TFA, OTf, or OPiv); contacting the organomagnesium compound and the zinc complex; and (b) reacting the mixture of step (a) with a compound of formula (III), JPEG2025032093000031.jpg28170 or a stereoisomer or salt thereof (wherein, X 4 is a halogen); Provided herein is a process comprising contacting 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.

[0121] In one preferred embodiment of the method (P1) described herein, X 0 is a halogen. In one such embodiment, X 0 is F. In another embodiment, X 0 is a moiety selected from the group consisting of: JPEG2025032093000032.jpg227170JPEG2025032093000033.jpg26170

[0122] 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, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate). 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 to about -40°C. In one such embodiment, the temperature is about -80 to about 60°C. In yet another embodiment, the temperature is about -70±5°C.

[0123] In one embodiment of the method (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.

[0124] 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), dimethylsulfoxide (DMSO), acetone, or hexamethylphosphoric 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.

[0125] In one embodiment of the method (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 Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl 2、is selected from the group consisting of Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(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.

[0126] 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(cinnamyl)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(cinnamyl)Cl]2, or (η3-allyl)(η5-cyclopentadienyl)palladium(II). In one embodiment, the Pd catalyst precursor is [Pd(allyl)Cl]2 or [Pd(cinnamyl)Cl]2. In one embodiment, the Pd catalyst precursor is [Pd(cinnamyl)Cl]2.

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

[0128] In one embodiment, step 1 of the process of P1 is carried out using a continuous flow mode including one or more continuously stirred reactors (CSTRs). In one embodiment, a Pd precursor as described herein and a chiral ligand as described herein are contacted to form a Pd-ligand complex in situ. In another embodiment, a Pd precursor as described herein is treated with a chiral ligand as described herein to form a Pd-ligand complex, which can be isolated prior to use in the methods described herein.

[0129] In one embodiment of the method (P1) described herein, the chiral ligand is JPEG2025032093000034.jpg81170, During the ceremony, Y is O or NR 7 and; Z is O or N; Each R 7 and R 8 are independently unsubstituted C 1-6 alkyl or unsubstituted phenyl; Or, in the formula, R 7 and R 8 together, the unsubstituted C 5-6 Cycloalkyl or unsubstituted C 6-10 Forming aryl; Or, in the formula, R 8 Together with the adjacent methylene, R 8A -Substituted or unsubstituted C 5-8Cycloalkyl or R containing at least one O atom 8A - can form a substituted or unsubstituted 5-8 membered heterocyclic ring, wherein R 8A is C 1-3 is an unsubstituted alkyl; R 9 and R 10 are independently 10A -Substituted or unsubstituted C 5-6 Cycloalkyl or R 10A - substituted or unsubstituted phenyl; Each R 10A are independently hydrogen, C 1-6 Unsubstituted alkyl, or C 1-6 unsubstituted haloalkyl; R 11 is C 1-4 is an unsubstituted alkyl; R 12 and R 13 are each independently 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 is heteroaryl; and Each R 14 are independently unsubstituted C 1-4 It is an alkyl.

[0130] In one embodiment of the method (P1) described herein, the chiral ligand comprises a compound of the formula: JPEG2025032093000035.jpg51170In formula, Y, R 7 and R 8 is as described herein.

[0131] 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 R8 In one such embodiment, each Y is NR 7 And each R 7 is independently methyl, ethyl, or propyl. In another embodiment, each Y is NR 7 And each R 7 is methyl.

[0132] In one such embodiment of the compound of L1, R 7 and R 8 In another such embodiment of the compound of L1, R 7 and R 8 Each is methyl, ethyl, or propyl. In another such embodiment, R 7 and R 8 taken together form an unsubstituted cyclopentyl, cyclohexyl, or indenyl moiety. In another such embodiment, R 8 taken together with the adjacent methylene forms a tetrahydrofurodioxolyl moiety.

[0133] In one such embodiment of the method (P1) described herein, the chiral ligand is JPEG2025032093000036.jpg255170JPEG2025032093000037.jpg108170.

[0134] In one such embodiment of the method (P1) described herein, the chiral ligand is The image is JPEG2025032093000038.jpg130170.

[0135] In one such embodiment of the method (P1) described herein, the chiral ligand is The image is JPEG2025032093000039.jpg47170.

[0136] In another embodiment of the method (P1) described herein, the chiral ligand comprises a compound of the formula: JPEG2025032093000040.jpg28170In formula, R 12 and R 13 is as described herein.

[0137] In one such embodiment of the compound of L2, R 12 and R 13 are each independently R 14 -substituted or unsubstituted C 1-6 In another embodiment of the compound of L2, R 12 and R 13 are each independently R 14 -Substituted or unsubstituted C 3-7 Cycloalkyl or R 14 -substituted or unsubstituted aryl. In one embodiment of the compound L2, R 12 and R 13 each independently represents phenyl or unsubstituted C 3-7 In another embodiment of the compound of L2, each R 12 Phenyl and each R 13 is unsubstituted C 3-7 In one embodiment of the compound of L2, R 13 is norbornanyl.

[0138] In one such embodiment of the method (P1) described herein, the chiral ligand is L2 having the following structure: JPEG2025032093000041.jpg237170JPEG2025032093000042.jpg249170JPEG2025032093000043.jpg231170or JPEG2025032093000044.jpg38170 or a stereoisomer thereof.

[0139] In one embodiment of the method (P1) described herein, the chiral ligand is L2 having the following structure: JPEG2025032093000045.jpg163170JPEG2025032093000046.jpg196170

[0140] In another embodiment of the method (P1) described herein, the chiral ligand is L2 having the following structure: JPEG2025032093000047.jpg87170

[0141] In one embodiment of the method (P1) described herein, the chiral ligand is The image is JPEG2025032093000048.jpg38170.

[0142] 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, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50° C. In another embodiment, the reaction with the chiral ligand is carried out at a temperature of about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50° C. In another embodiment, the reaction with the chiral ligand is carried out at a temperature of about 50, 52, 54, 56, 58, 60, 62, or 64° C.

[0143] In one embodiment of the method (P1) described herein, the reaction with the chiral ligand 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.

[0144] In one embodiment of the method (P1) described herein, the compound of formula (II) or a tautomer, stereoisomer or salt thereof and the compound of formula (III) or a stereoisomer or salt thereof are present in about equal molar equivalents. In another embodiment of the method (P1) described herein, the compound of formula (II) or a tautomer, stereoisomer or salt thereof and the compound of formula (III) or a stereoisomer or salt thereof are present in about 1:1, 1.1:1, or 1.2:1 equivalents.

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

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

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

[0148] In another embodiment of the method (P1) described herein, the chiral ligand comprises a compound of the formula: JPEG2025032093000049.jpg33170In formula, R 9 , R 10 and R 11 is as described herein.

[0149] In one embodiment of the compound of L3, R 9 and R 10 are the same. In one such embodiment of the compound of L3, R 9 and R 10 is R 10A -substituted or unsubstituted C 5-6 In one such embodiment of the compound of L3, R 9 and R 10 Each is unsubstituted cyclohexyl. In another embodiment of the compound of L3, R 9 and R 10 is R 10A -substituted or unsubstituted phenyl. In one such embodiment of the compound of L3, R 9 and R 10 is unsubstituted phenyl. In another such embodiment of the compound of L3, R 9 and R 10 is R 10A -substituted phenyl, wherein R 10A is methyl, ethyl, tert-butyl or CF3

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

[0151] In one embodiment, the chiral ligand is a compound of the formula: JPEG2025032093000050.jpg123170

[0152] In another embodiment of the method (P1) described herein, the chiral ligand is a compound of the formula: JPEG2025032093000051.jpg73170

[0153] In one embodiment, the compound of formula (II) JPEG2025032093000052.jpg45170 or a tautomer, stereoisomer or salt thereof is prepared according to a method (P2) comprising the steps of: (a) Formula (IVa) JPEG2025032093000053.jpg28170 or a stereoisomer or salt thereof, JPEG2025032093000054.jpg27170(in the formula, 3 is a halogen) to form a compound having the formula (IVb): Producing a compound of formula JPEG2025032093000055.jpg27170 or a stereoisomer or salt thereof; (c) reacting a compound of formula (IVb) with a compound of formula (V) cyclizing the compound of formula JPEG2025032093000056.jpg27170 or a stereoisomer or salt thereof; (d) contacting the compound of formula (V) with a chlorinating agent to obtain a compound of formula (Va) Producing a compound of formula JPEG2025032093000057.jpg27170 or a stereoisomer or salt thereof; (e) reacting a compound of formula (Va) with JPEG2025032093000058.jpg28170, by contacting with a piperazinyl moiety having the formula (IIa) Producing a compound of formula (I) or a stereoisomer or salt thereof; and (f) reacting a compound of formula (IIa) with X0 to form a compound of formula (II) or a tautomer, stereoisomer or salt thereof.

[0154] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000060.jpg47170 or a tautomer, stereoisomer, or salt thereof.

[0155] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000061.jpg46170 or a tautomer, stereoisomer, or salt thereof.

[0156] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000062.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0157] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000063.jpg46170 or a tautomer, stereoisomer, or salt thereof.

[0158] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000064.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0159] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000065.jpg46170 or a tautomer, stereoisomer, or salt thereof.

[0160] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000066.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0161] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000067.jpg47170 or a tautomer, stereoisomer, or salt thereof.

[0162] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000068.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0163] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000069.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0164] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000070.jpg46170 or a tautomer, stereoisomer, or salt thereof.

[0165] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000071.jpg46170 or a tautomer, stereoisomer, or salt thereof.

[0166] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000072.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0167] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000073.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0168] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000074.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0169] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000075.jpg46170 or a tautomer, stereoisomer, or salt thereof.

[0170] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000076.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0171] In one embodiment, the compound of formula (II) or a tautomer, stereoisomer, or salt thereof is a compound of the following formula: JPEG2025032093000077.jpg45170 or a salt thereof.

[0172] In one embodiment, a compound of formula (II) is contacted with an organomagnesium compound and a zinc complex as described herein (Method P1), thereby producing a compound of formula (IIz): Form JPEG2025032093000078.jpg46170.

[0173] In one embodiment, a compound of formula (IIb), (IIb1), (IIb2), (IIb3), (IIc), (IIc1), (IIc2), (IIc3), (IId), (IId1), (IId2), (IId3), (IIa1), (IIa2), or (IIa3) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby forming a compound of formula: JPEG2025032093000079.jpg125170In formula, Y 1 is halogen (e.g., Cl, Br, or I), OAc, TFA, OTf, or OPiv.

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

[0175] In another embodiment, a compound of formula (2a) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby producing a compound of formula: Form JPEG2025032093000080.jpg46170.

[0176] In another embodiment, a compound of formula (2b) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby producing a compound of formula: Form JPEG2025032093000081.jpg45170.

[0177] In another embodiment, a compound of formula (2c) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby producing a compound of formula: Form JPEG2025032093000082.jpg47170.

[0178] In another embodiment, a compound of formula (2) is contacted with a zinc complex and an organomagnesium compound as described herein (Method P1), thereby producing a compound of formula: Form JPEG2025032093000083.jpg44170.

[0179] In such an embodiment, 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 is OPiv.

[0180] In one embodiment of the method (P2) described herein, the method comprises: (a0) In the presence of CO2 gas, the reaction product of formula (IV) contacting the compound of formula (IVa) with a base to aminated the compound JPEG2025032093000085.jpg28170 further comprising forming a compound.

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

[0182] In one embodiment of the method (P2) described herein, the halogenating agent in step (b) is of the formula JPEG2025032093000086.jpg21170, where X 3 is Cl, Br, or I. In one such embodiment, X 3is Cl. In another embodiment, X 3 In yet another embodiment, X is Br. 3 is I.

[0183] In one embodiment of the method (P2) described herein, the halogenating agent in step (b) is of the formula JPEG2025032093000087.jpg25170, where each X 3 are the same and are Cl, Br, or I. In one embodiment, each X 3 is Cl. In another embodiment, each X 3 In yet another embodiment, each X 3 is I.

[0184] In one embodiment of the method (P2) described herein, the halogenating agent in 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.

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

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

[0187] In one embodiment of the method (P2) described herein, X of a compound of formula (II) 0 is F, and step (f) is contacting the compound of formula (IIa) with CsF to produce a compound of formula (IIa1): This includes producing JPEG2025032093000088.jpg44170 or a tautomer, stereoisomer, or salt thereof.

[0188] In one embodiment of the method (P2) described herein, X of a compound of formula (II) or a tautomer, stereoisomer or salt thereof is 0 is F, and step (f) is contacting the compound of formula (IIa) with CsF to produce a compound of formula (IIa2): This includes producing JPEG2025032093000089.jpg45170 or a tautomer, stereoisomer, or salt thereof.

[0189] In one embodiment of the method (P2) described herein, X of a compound of formula (II) or a tautomer, stereoisomer or salt thereof is 0 is F, and step (f) is contacting the compound of formula (IIa) with CsF to produce a compound of formula (IIa3): This includes producing JPEG2025032093000090.jpg44170 or a tautomer, stereoisomer, or salt thereof.

[0190] In one embodiment of the method (P2) described herein, the compound of formula (IV) has the formula: JPEG2025032093000091.jpg21170

[0191] In one embodiment of the method (P2) described herein, the compound of formula (IVa) has the formula: JPEG2025032093000092.jpg27170 or its salt.

[0192] In one embodiment of the method (P2) described herein, the compound of formula (IVa) has the formula: JPEG2025032093000093.jpg27170 or its salt.

[0193] In one embodiment of the method (P2) described herein, the compound of formula (IVb) has the formula: JPEG2025032093000094.jpg28170 or its salt.

[0194] In one embodiment of the method (P2) described herein, the compound of formula (IVb) has the formula: JPEG2025032093000095.jpg28170 or its salt.

[0195] In one embodiment of the method (P2) described herein, the compound of formula (IVb) has the formula: JPEG2025032093000096.jpg27170 or its salt.

[0196] In one embodiment of the method (P2) described herein, the compound of formula (V) has the formula: JPEG2025032093000097.jpg27170 or its salt.

[0197] In one embodiment of the method (P2) described herein, the compound of formula (V) has the formula: JPEG2025032093000098.jpg28170 or its salt.

[0198] In one embodiment of the method (P2) described herein, the compound of formula (V) has the formula: JPEG2025032093000099.jpg28170 or its salt.

[0199] In one embodiment, the compound of formula (III) JPEG2025032093000100.jpg29170 or a salt thereof of the methods described herein may be prepared according to method (P3), which comprises: (a) Formula (VII) The compound of formula 21170 (wherein X 4 is a halogen) with a compound having the formula NH2(PG), thereby producing a compound of formula (VIIa) To generate compound JPEG2025032093000102.jpg26170; (b) reacting a compound of formula (VIIa) with a compound of formula X a PG (wherein X ais a halogen, to form a compound having the formula (VIIb) JPEG2025032093000103.jpg27170 compounds to be produced; (c) reacting a compound of formula (VIIb) with JPEG2025032093000104.jpg27170(in the formula, 5 is a halogen) to form a compound having the formula (VIIc) To generate compound JPEG2025032093000105.jpg27170; (d) haloalkylating the compound of formula (VIIc) with a haloalkylating agent to obtain a compound of formula (VIId) JPEG2025032093000106.jpg27170 compound (e) brominating a compound of formula (VIId) to give a compound of formula (VIIe) producing a compound of formula JPEG2025032093000107.jpg21170; and (f) reacting a compound of formula (VIIe) with X a with PG to produce a compound of formula (III) or a salt thereof.

[0200] 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 is Cl or Br. In another embodiment, X a is Cl.

[0201] In one embodiment of the method (P3) described herein, the halogenating agent in step (c) is JPEG2025032093000108.jpg21170. In one such embodiment, X 5 is Cl, Br or I. In another embodiment, X 5 is I. In another embodiment, X 5 In yet another embodiment, X 5 is Br.

[0202] In one embodiment of the method (P3) described herein, the halogenating agent in step (c) is JPEG2025032093000109.jpg25170. In one such embodiment, X 5 is Cl, Br or I. In another embodiment, X 5 is I. In another embodiment, X 5 In yet another embodiment, X 5 is Br.

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

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

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

[0206] 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 a compound of Formula (VIIe).

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

[0208] In one embodiment, the compound of formula (VII) has the formula: JPEG2025032093000110.jpg24170

[0209] In one embodiment, the compound of formula (VII) has the formula: JPEG2025032093000111.jpg21170

[0210] In one embodiment, the compound of formula (VIIa) has the formula: JPEG2025032093000112.jpg28170 or its salt.

[0211] In one embodiment, the compound of formula (VIIa) has the formula: JPEG2025032093000113.jpg28170 or its salt.

[0212] In one embodiment, the compound of formula (VIIa) has the formula: JPEG2025032093000114.jpg27170 or its salt.

[0213] In one embodiment, the compound of formula (VIIb) has the formula: JPEG2025032093000115.jpg28170 or its salt.

[0214] In one embodiment, the compound of formula (VIIb) has the formula: JPEG2025032093000116.jpg28170 or its salt.

[0215] In one embodiment, the compound of formula (VIIb) has the formula: JPEG2025032093000117.jpg27170 or its salt.

[0216] In one embodiment, the compound of formula (VIIc) has the formula: JPEG2025032093000118.jpg28170 or its salt.

[0217] In one embodiment, the compound of formula (VIIc) has the formula: JPEG2025032093000119.jpg28170 or its salt.

[0218] In one embodiment, the compound of formula (VIIc) has the formula: JPEG2025032093000120.jpg28170 or its salt.

[0219] In one embodiment, the compound of formula (VIIc) has the formula: JPEG2025032093000121.jpg27170 or its salt.

[0220] In one embodiment, the compound of formula (VIId) has the formula: JPEG2025032093000122.jpg29170 or its salt.

[0221] In one embodiment, the compound of formula (VIId) has the formula: JPEG2025032093000123.jpg30170 or its salt.

[0222] In one embodiment, the compound of formula (VIId) has the formula: JPEG2025032093000124.jpg29170 or its salt.

[0223] In one embodiment, the compound of formula (VIId) has the formula: JPEG2025032093000125.jpg27170 or its salt.

[0224] In one embodiment, the compound of formula (VIIe) has the formula: JPEG2025032093000126.jpg22170 or its salt.

[0225] In one embodiment, the compound of formula (VIIe) has the formula: JPEG2025032093000127.jpg22170 or its salt.

[0226] In another embodiment, the compound of formula (III) JPEG2025032093000128.jpg29170 or a salt thereof of the methods described herein may be prepared according to method (P4), which comprises: (a) Formula (VIII) JPEG2025032093000129.jpg23170 compound (wherein X 6 is Cl or I) with a halogenating agent to obtain a compound of formula (VIIIa) forming a compound of JPEG2025032093000130.jpg22170; (b) brominating a compound of formula (VIIIa) to obtain a compound of formula (VIIIb) forming a compound of formula JPEG2025032093000131.jpg21170; and (c) contacting the compound of formula (VIII) with a compound having the formula NH(PG)2, thereby producing a compound of formula (III) or a salt thereof.

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

[0228] In yet another embodiment, the compound of formula (III) JPEG2025032093000132.jpg29170 or a salt thereof of the methods described herein may be prepared according to method (P5), which method comprises: (a) Formula (VIIIc) JPEG2025032093000133.jpg22170 is contacted with a brominating agent to obtain a compound of formula (VIIId) forming a compound of JPEG2025032093000134.jpg22170; (b) contacting a compound of formula (VIIId) with a halogenating agent to obtain a compound of formula (VIIIb) forming a compound of JPEG2025032093000135.jpg21170; (c) contacting the compound of formula (VIIIb) with a compound having the formula NH(PG)2, thereby producing a compound of formula (III).

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

[0230] In one such embodiment, the compound of formula (VIII) has the formula: JPEG2025032093000136.jpg23170 or its salt.

[0231] In one such embodiment, the compound of formula (VIII) has the formula: JPEG2025032093000137.jpg24170 or its salt.

[0232] In one such embodiment, the compound of formula (VIIIa) has the formula: JPEG2025032093000138.jpg24170 or its salt.

[0233] In one such embodiment, the compound of formula (VIIIa) has the formula: JPEG2025032093000139.jpg24170 or its salt.

[0234] In one such embodiment, the compound of formula (VIIIa) has the formula: JPEG2025032093000140.jpg22170 or its salt.

[0235] In one such embodiment, the compound of formula (VIIIb) has the formula: JPEG2025032093000141.jpg24170 or its salt.

[0236] In one such embodiment, the compound of formula (VIIIb) has the formula: JPEG2025032093000142.jpg21170 or its salt.

[0237] In one such embodiment, the compound of formula (VIIIc) has the formula: JPEG2025032093000143.jpg23170 or its salt.

[0238] In one such embodiment, the compound of formula (VIIId) has the formula: JPEG2025032093000144.jpg23170 or its salt.

[0239] In one such embodiment, the compound of formula (III) has the formula: JPEG2025032093000145.jpg29170 or its salt.

[0240] In one such embodiment, the compound of formula (III) has the formula: JPEG2025032093000146.jpg30170 or a salt thereof.

[0241] In one such embodiment, the compound of formula (III) has the formula: JPEG2025032093000147.jpg29170 or its salt.

[0242] In one such embodiment, the compound of formula (III) has the formula: JPEG2025032093000148.jpg26170 or its salt.

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

[0244] 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 is ZnCl.

[0245] 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 is a haloalkyl. 3 is 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 is hydrogen or halogen. In another embodiment of the methods described herein, X 3 is halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3In yet another embodiment of the methods described herein, X is haloalkyl. 3 is halogen or unsubstituted C 1-3 In yet another embodiment of the methods described herein, X is haloalkyl. 3 is unsubstituted C 1-3 In one preferred embodiment of the method described herein, X is alkoxy or unsubstituted cyclopropyl. 3 is a halogen. In one such embodiment of the methods described herein, X 3 is Cl or F. In another embodiment, X 3 is Cl, F, CF, CHF, or CHF. In yet another embodiment of the method described herein, X 3 is CF3, CHF2 or CH2F.

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

[0247] 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 are independently unsubstituted C 1-6 Alkyl, unsubstituted C 1-6Cyanoalkyl or unsubstituted C 1-6 In another embodiment of the methods described herein, each R 2 are independently unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 In one such embodiment of the methods described herein, n is 1. In one preferred embodiment of the methods described herein, each R 2 are 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 methods 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, each R 2 is CF, CHF, or CHF. In another such embodiment of the methods described herein, R 2 is methyl, ethyl, CN, CHCN, CF, CHF, or CHF. In another embodiment of the methods described herein, R 2 is methyl, ethyl, CN, or CHCN. In such embodiments of the methods described herein, n is 1. In another such embodiment of the methods described herein, R 2 is CHCN and n is 1. In yet another embodiment, n is 0.

[0248] In one embodiment of the methods described herein, R 3 is hydrogen or halogen. In one embodiment of the methods described herein, R 3 is hydrogen. In another embodiment of the methods described herein, R 3 is R 3A -substituted or unsubstituted C 1-3 Alkyl, R 3A -substituted or unsubstituted C 1-3 In another embodiment of the methods described herein, R 3 is R3A -substituted or unsubstituted C 1-3 Alkyl or R 3A -substituted or unsubstituted C 1-3 In yet another embodiment of the methods described herein, R 3 is 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 is methyl.

[0249] In one embodiment of the methods described herein, R 3 is R 3A -Substituted or unsubstituted C 1-3 Alkyl, R 3A -Substituted or unsubstituted C 1-3 haloalkyl, where 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 haloalkyl, where R 3A is F, OH, CN, CF3, CHF2 or CH2F.

[0250] In a preferred embodiment of the method described herein, R 4 is unsubstituted C 1-3 In one such embodiment of the methods described herein, R 4 is CF3, CHF2, or CH2F.

[0251] In one embodiment, R 5 is halogen, cyano, or OH. In another embodiment, R 5 is R 5A -Substituted or unsubstituted C 1-6 Alkyl, R 5A -Substituted or unsubstituted C1-6 Haloalkyl, or R 5A -Substituted or unsubstituted C 1-6 In another embodiment, R 5 is R 5A -Substituted or unsubstituted C 3-6 Cycloalkyl, R 5A -substituted or unsubstituted 3- to 6-membered heterocycle, R 5A -substituted or unsubstituted phenyl, or R 5A -substituted or unsubstituted 6-membered heteroaryl.

[0252] In one embodiment of the methods described herein, R 5A and R 5B are each independently 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 are each independently R 5C -Substituted or unsubstituted C 3-7 Cycloalkyl; R 5C -substituted or unsubstituted 3- to 7-membered heterocycle, R 5C -Substituted or unsubstituted C 5-7 Aryl or R 5C -Substituted or unsubstituted C 5-7 In a preferred embodiment of the method described herein, R 5A and R 5B are each independently R 5C -substituted or unsubstituted C 1-6 It is an alkyl.

[0253] In one embodiment of the methods described herein, R 5C is independently halogen, OH, CN, or NO. In one embodiment of the methods described herein, R 5C are independently 5D -Substituted or unsubstituted C 1-6 Alkyl or R 5D -Substituted or unsubstituted C 1-6In one embodiment of the methods described herein, R 5C are independently 5D -Substituted or unsubstituted C 3-7 Cycloalkyl or R 5D -Substituted or unsubstituted C 3-7 In one embodiment, R 5C are independently 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 are independently 5D -Substituted or unsubstituted C 3-7 Heterocycle or R 5D -Substituted or unsubstituted C 5-7 In another embodiment of the methods described herein, R 5C is R 5D -substituted pyrrolidinyl.

[0254] In one embodiment of the methods described herein, R 5D is independently halogen, OH, or CN. In another embodiment, R 5D is unsubstituted C 1-6 In another embodiment of the methods described herein, R 5D is unsubstituted C 1-6 In yet another embodiment of the methods described herein, R 5D is 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 is methyl, ethyl or propyl.

[0255] In one embodiment of the methods described herein, R 5A and R 5B are each independently: The image is JPEG2025032093000149.jpg231170.

[0256] In one embodiment of the methods described herein, R 6 is a halogen. 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 It is cycloalkyl.

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

[0258] In yet another embodiment of the methods described herein, two PGs are combined to form C 3-8 In one embodiment of the methods described herein, two PGs together form a nitrogen heterocycle: JPEG2025032093000150.jpg26170 is formed as a portion having the image.

[0259] In one embodiment of the methods described herein, X 0 is hydrogen, halogen or OR 5A In another embodiment of the methods described herein, X 0 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 methods described herein, X is heteroaryl. 0 is hydrogen, halogen, CF, CHF, or CHF. In one preferred embodiment of the method described herein, X 0 is a halogen. In one such embodiment of the methods described herein, X 0 is F. In yet another embodiment of the methods described herein, X 0 is hydrogen, halogen, CF3, CHF2, CH2F, or the following structure: This is the part that has JPEG2025032093000151.jpg228170 and JPEG2025032093000152.jpg54170.

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

[0261] In one embodiment of the method (P2) described herein, the method comprises: JPEG2025032093000153.jpg74170, X 1 , X 2 , X 3 , R 1 , R 2 and n is as described herein. In one such embodiment, R 1 is PG 1 and R 2 is methyl.

[0262] In one embodiment of the method (P3) described herein, the method comprises: JPEG2025032093000154.jpg55170, X 4 , X 5 , R 3and PG is as described herein.

[0263] In one embodiment of the method (P4) described herein, the method comprises: JPEG2025032093000155.jpg25170, X 6 , R 3 , R 4 and PG is as described herein.

[0264] In one embodiment of the method (P5) described herein, the method comprises: JPEG2025032093000156.jpg25170In formula, R 3 , R 4 and PG is as described herein.

[0265] Further provided herein is a process (P6) for the synthesis of a compound of formula (G), comprising: JPEG2025032093000157.jpg56170, or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof, 1 , X 3 , R 2 , R 3 , R 4 and n is as described herein; R Alk is the following: JPEG2025032093000158.jpg42170; and X A teeth, JPEG2025032093000159.jpg228170); (a) contacting a compound of formula (II) synthesized according to the methods described herein, or a tautomer, stereoisomer or salt thereof, with a compound of formula (III) synthesized according to the methods described herein, or a salt thereof, to produce a compound of formula (I) as described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof; (b) reacting a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof with X A with a moiety comprising the formula (G1); JPEG2025032093000160.jpg55170 or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof, 1 are as described herein); (c) removing the PG group from the compound of formula (G1); and (d)R Alk synthesizing a compound of formula (G) or a tautomer, stereoisomer, atropisomer or pharma- ceutically acceptable salt thereof by introducing a group.

[0266] In one such embodiment, X in step (b) A The part containing: The image is JPEG2025032093000161.jpg233170.

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

[0268] In one embodiment of the method (P6) described herein, R Alk teeth In one embodiment of the method (P6) described herein, R Alk teeth JPEG2025032093000163.jpg17170. In such embodiments, the method includes a base and an activator as described herein.

[0269] In one embodiment of the method (P6) described herein, R 2 is C 1-3 Alkyl or C 1-3cyanoalkyl, and n is 1. 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.

[0270] Further provided herein is a method (P7), comprising reacting a compound of formula (H): JPEG2025032093000164.jpg57170, or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof, 1 , X 3 , R 2 , R 3 , R 4 wherein n is as described herein, the method comprising: (a) contacting a compound of formula (II) synthesized according to the methods described herein, or a tautomer, stereoisomer or salt thereof, with a compound of formula (III) synthesized according to the methods described herein, or a salt thereof, to produce a compound of formula (I) as described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof; (b) reacting a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof with a compound of formula HO-X in the presence of a base. A wherein the compound is: JPEG2025032093000165.jpg232170, thereby providing a compound of formula (G1); synthesizing JPEG2025032093000166.jpg55170 or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof; (Wherein, PG and R 1 are as described herein); and (c) removing the PG group from the compound of formula (G1); (d) reacting the compound of step (c) in the presence of a base and, optionally, an activating agent, JPEG2025032093000167.jpg23170, thereby producing a compound of formula (H) or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof.

[0271] In one embodiment of the method (P7) described herein, R 1 PG 1 and the method further comprises the step (b1): converting compound G1 into PG before carrying out step (d). 1 further comprising removing

[0272] In one embodiment of the method (P7) described herein, the compound of step (d) is The image is JPEG2025032093000168.jpg17170.

[0273] In one embodiment of the method (P7) described herein, the compound in step (d) is JPEG2025032093000169.jpg15170, and step (d) is carried out in the presence of a base as described herein and an activating agent as described herein. In one such embodiment, the activating agent is EDCI.

[0274] In one embodiment of the method (P7) described herein, the compound in step (d) is JPEG2025032093000170.jpg15170, and step (d) is carried out in the presence of only a base as described herein.

[0275] In one embodiment of the method (P7) described herein, the compound in step (d) is JPEG2025032093000171.jpg14170, and step (d) is carried out in the presence of only a base as described herein.

[0276] In one embodiment of the method (P7) described herein, the compound in step (d) is JPEG2025032093000172.jpg22170, and step (d) is carried out in the presence of a base as described herein and an activating agent as described herein. In one such embodiment, the activating agent is EDCI.

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

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

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

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

[0281] In one embodiment of the method (P7) described herein, X A The part containing The image is JPEG2025032093000173.jpg157170.

[0282] In one embodiment of the method (P7) described herein, X A The part containing JPEG2025032093000174.jpg19170.

[0283] In one embodiment of the method (P7) described herein, X A The part containing JPEG2025032093000175.jpg103170.

[0284] In one embodiment of the method (P7) described herein, X A The part containing The image is JPEG2025032093000176.jpg24170.

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

[0286] In another aspect, there is provided herein a process (P8) for the synthesis of a compound of formula (F) or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof, JPEG2025032093000177.jpg56170In formula, R 2 and n is as described herein, and the method includes: Formula (a) JPEG2025032093000178.jpg25170 or a salt thereof or a tautomer, stereoisomer or salt thereof, thereby producing a compound of formula (1a) synthesizing JPEG2025032093000180.jpg53170 or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof; (b) reacting a compound of formula (1a) or a solvate, tautomer, stereoisomer, or atropisomer thereof with a compound of formula HO-X A (In the formula, X A is the formula JPEG2025032093000181.jpg25170), thereby producing a compound of formula (F1); synthesizing JPEG2025032093000182.jpg50170 or a solvate, tautomer, stereoisomer, or salt thereof; (c) contacting a compound of formula (F1) or a solvate, tautomer, stereoisomer, or salt thereof with methanesulfonic acid (MsOH) in acid, thereby producing a compound of formula (F2); synthesizing JPEG2025032093000183.jpg52170 or a solvate, tautomer, stereoisomer, or salt thereof; and (d) reacting a compound of formula (F2) or a solvate, tautomer, stereoisomer, or salt thereof with a compound of formula JPEG2025032093000184.jpg20170, thereby producing a compound of formula (F) or a tautomer, stereoisomer, or pharma- ceutically acceptable salt thereof.

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

[0288] In one embodiment of the method (P8) described herein, X A teeth In one embodiment of the method described herein, X A teeth The image is JPEG2025032093000186.jpg16170.

[0289] In one embodiment of method (P8), step (d) further comprises a base and optionally an activating agent. 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 activating agent as described herein.

[0290] In one embodiment of the method (P8) described herein, the compound of step (d) is JPEG2025032093000187.jpg15170 and base.

[0291] In one embodiment of the method (P8) described herein, the compound of step (d) is JPEG2025032093000188.jpg14170 and base.

[0292] In one embodiment of the method (P8) described herein, the compound of step (d) is JPEG2025032093000189.jpg21170 and the bases and activators described herein.

[0293] In one embodiment of the method (P8) described herein, each R 2 is independently halogen or cyano. In one embodiment of the method (P8) described herein, each R 2 are independently halogen or unsubstituted C 1-6 In one embodiment of the method (P8) described herein, each R 2 are independently unsubstituted C 1-6Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 In one embodiment of the method (P8) described herein, n is 1. In one embodiment of the method (P8) described herein, each R 2 are independently unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 In one embodiment of the method (P8) described herein, each R 2 is methyl or ethyl. In one such embodiment, n is 1. In one embodiment of the method (P8) described herein, R 2 is methyl and n is 1. In one embodiment of the method (P8) described herein, each R 2 is CF, CHF, or CHF. In one embodiment of the method (P8) described herein, R 2 is methyl, ethyl, CN, CHCN, CF, CHF, or CHF. In another embodiment, R 2 is methyl, ethyl, CN, or CHCN. In one embodiment of method (P8) described herein, n is 1. In one embodiment of method (P8) described herein, R 2 is CHCN and n is 1. In one embodiment of the method (P8) described herein, n is 0.

[0294] In one embodiment, the compound of formula (F) has the formula (F4): JPEG2025032093000190.jpg55170 or a tautomer, stereoisomer, or pharma- ceutically acceptable salt thereof.

[0295] In one embodiment, the compound of formula (F) has the formula (F5) JPEG2025032093000191.jpg56170 or a tautomer, stereoisomer, or pharma- ceutically acceptable salt thereof.

[0296] In one embodiment of the method (P8) described herein, the compound (F1) or a tautomer, stereoisomer, or pharma- ceutically acceptable salt thereof is a compound of Table 1. In one embodiment of the method (P8) described herein, the compound of formula (F1) or a tautomer, stereoisomer, or pharma- ceutically acceptable salt thereof is a compound of formula 105, 133, 135, 137, 140, 144, 146, or 169 in Table 1. In a preferred embodiment of the method (P8) described herein, the compound of formula (F1) or a tautomer, stereoisomer, or pharma- ceutically acceptable salt thereof is a compound of formula 105 in Table 1.

[0297] Further provided herein is a method (P9), comprising reacting a compound of formula (A): 1. A process for the preparation of JPEG2025032093000192.jpg57170 or a pharma- ceutically acceptable salt thereof, comprising: (a) Equation (2) The compound of formula (3) or a salt thereof is contacted with i-PrMgCl·LiCl and ZnCl2, followed by contacting with NaTFA and a compound of formula (3) contacting a compound of formula (I) with the compound of formula (I); (b) contacting the mixture of step (a) or a salt thereof with a Pd or Ni catalyst precursor as described herein and a chiral ligand as described herein, thereby producing a compound of formula (1) synthesizing JPEG2025032093000195.jpg50170 or a solvate or salt thereof; (c) reacting a compound of formula (1) or a solvate or salt thereof with a compound of formula HO-X A (In the formula, X A is the formula JPEG2025032093000196.jpg16170) and a base, thereby producing a compound of formula (1d); synthesizing JPEG2025032093000197.jpg47170 or a solvate or pharma- ceutically acceptable salt thereof; (d) contacting a compound of formula (1d) with MsOH in an acid, thereby producing a compound of formula (1e); synthesizing JPEG2025032093000198.jpg42170 or a solvate or a pharma- ceutically acceptable salt thereof; and (e) a compound of formula (1e) or a solvate or a pharma- ceutically acceptable salt thereof, JPEG2025032093000199.jpg20170, and a base and optionally an activating agent, each as described herein, thereby producing a compound of formula (A) or a pharma- ceutically acceptable salt thereof.

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

[0299] In one embodiment, step (c) of method (P9) further comprises washing with potassium carbonate and filtering (e.g., polishing filtering). 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.

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

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

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

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

[0304] In one embodiment, step (d) of process (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 process (P9) further comprises an abrasive filtration. In yet another embodiment, step (d) of process (P9) further comprises a crystallization step (e.g., with toluene / n-heptane).

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

[0306] In one embodiment of the method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or pharma- ceutically acceptable salt thereof with JPEG2025032093000201.jpg21170 and contacting it with a base and optionally an activating agent as described herein.

[0307] In one embodiment of the method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or a pharma- ceutically acceptable salt thereof in the presence of a base. This includes contacting with JPEG2025032093000202.jpg14170.

[0308] In one embodiment of the method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or a pharma- ceutically acceptable salt thereof in the presence of a base. This includes contacting with JPEG2025032093000203.jpg15170.

[0309] In one embodiment of the method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or pharma- ceutically acceptable salt thereof in the presence of a base and an activating agent as described herein. This includes contacting with JPEG2025032093000204.jpg15170.

[0310] In one embodiment of the method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or pharma- ceutically acceptable salt thereof in the presence of a base and an activating agent as described herein. JPEG2025032093000205.jpg21170. In one such embodiment, the reaction is carried out in a solvent such as 2-Me-THF or toluene. In one embodiment, the activating agent is EDCI. In another embodiment, the activating agent comprises pivaloyl chloride (PivCl).

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

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

[0313] In one embodiment of the methods described herein, method (P9) further comprises step (f): contacting the 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. Scheme 1: JPEG2025032093000206.jpg57170 Scheme 2: JPEG2025032093000207.jpg57170 Scheme 3: JPEG2025032093000208.jpg57170 Treatment method

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

[0315] The tumor or cancer is KRas G12CDetermining whether or not a K-Ras protein contains a 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 properties of a predicted K-Ras mutant protein. The sequence of wild-type human K-Ras (e.g., Accession No. NP 203524) is known in the art.

[0316] In certain embodiments, the method comprises treating lung cancer. G12C A method of treating a lung cancer containing a mutation in a patient having such a lung cancer, comprising administering to the patient a therapeutically effective amount of compound (A) or a pharma- ceutical acceptable salt thereof, synthesized according to method P9 described herein. In one embodiment, G12C A method of treating a lung cancer comprising a mutation in a patient having such a lung cancer, the method comprising administering to the patient a therapeutically effective amount of compound (B) or a pharma- ceutically acceptable salt thereof, synthesized according to method P9 described herein.

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

[0318] In one embodiment of such a method, the patient is diagnosed with a cancer as described herein. In another embodiment of such a method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before administration of any therapy. In another such embodiment, the sample is taken before administration of a compound of a pharma- ceutically acceptable salt thereof as described herein and after administration of another chemotherapeutic agent. In another embodiment of such a method, the compound as described herein or a pharma- ceutically acceptable salt thereof is administered as provided herein (e.g., orally).

[0319] KRas G12C Further provided herein is a method of treating pancreatic cancer comprising a mutation in KRas in a patient having such pancreatic cancer, the method comprising administering to the patient a therapeutically effective amount of compound (A) or a pharma- ceutically acceptable salt thereof, synthesized according to method P9 described herein. G12C There is a method of treating a mutation-containing pancreatic cancer in a patient having such pancreatic cancer, comprising administering to the patient a therapeutically effective amount of compound (B) or a pharma- ceutically acceptable salt thereof, synthesized according to method P9 described herein.

[0320] In one embodiment, the patient has previously been treated with radiation and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is stage 0, stage I, or stage II. In another embodiment, the pancreatic cancer is stage III or stage IV.

[0321] KRas G12C Further provided herein is a method of treating colon cancer comprising a mutation in KRas in a patient having such colon cancer, the method comprising administering to the patient a therapeutically effective amount of compound (A) or a pharma- ceutically acceptable salt thereof, synthesized according to method P9 described herein. G12CFurther provided herein is a method of treating a mutation-containing colon cancer in a patient having such colon cancer, comprising administering to the patient a therapeutically effective amount of compound (B) or a pharma- ceutically acceptable salt thereof, synthesized according to method P9 described herein.

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

[0323] KRas G12C Hematological cancers including KRas mutations G12C Further provided herein is a method of treating MYH-associated polyposis cancer containing a mutation by administering to a subject having such disease a therapeutically effective amount of compound (A) or a pharma- ceutically acceptable salt thereof, synthesized according to method P9 described herein. G12C Hematological cancers including KRas mutations G12C Further provided herein is a method of treating a mutation-containing MYH-associated polyposis cancer by administering to a subject having such disease a therapeutically effective amount of a compound (B) synthesized according to method P9 described herein.

[0324] KRas G12C Further provided herein is a method for treating a tumor-independent cancer comprising a mutation. In one embodiment of such a method, the method comprises: (a) KRas expression in samples from patients diagnosed with suspected cancer. G12C Determining the presence or absence of mutations; and (b) administering to a subject having such a disease a therapeutically effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, synthesized according to method P9 as described herein.

[0325] KRas G12C Further provided herein is a method for treating a tumor-independent cancer comprising a mutation. In one embodiment of such a method, the method comprises: (a) KRas expression in samples from patients diagnosed with suspected cancer.G12C Determining the presence or absence of mutations; and (b) administering to a subject having such a disease a therapeutically effective amount of compound (B), synthesized according to method P9 as described herein.

[0326] The patient described herein can be a human.In some embodiments, the administration of the compound described herein in the method provided herein is by oral route.In some embodiments, the administration is by injection.The method provided herein includes administering the compound as 1L of therapy. Embodiment

[0327] The following are exemplary embodiments.

[0328] Embodiment 1. A method for the preparation of a compound of formula (I), comprising: JPEG2025032093000209.jpg57170In formula, X 0 is hydrogen, halogen, OR 5A , S.R. 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 is 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; R1 is hydrogen or PG 1 and; Each R 2 are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 is 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 is cycloalkyl; R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; R 4 is R 4A -substituted or unsubstituted C 1-3 is haloalkyl; R 4A is unsubstituted C 1-3 is alkyl; R 5 is halogen, cyano, OH, NO2, R 5A -Substituted or unsubstituted C 1-6 Alkyl, R 5A -Substituted or unsubstituted C 1-6 Haloalkyl, R 5A -Substituted or unsubstituted C 1-6 Cyanoalkyl, R 5A -Substituted or unsubstituted C 3-6 Cycloalkyl, R 5A -substituted or unsubstituted 3- to 6-membered heterocycle, R 5A -substituted or unsubstituted phenyl, or R 5A -substituted or unsubstituted 6-membered heteroaryl; R 5A and R 5B are each independently R 5C -Substituted or unsubstituted C 1-6 Alkyl, R 5C -Substituted or unsubstituted C1-6 Haloalkyl, R 5C -Substituted or unsubstituted C 3-7 Cycloalkyl; R 5C -Substituted or unsubstituted 3- to 7-membered heterocycle; R 5C -Substituted or unsubstituted C 5-7 Aryl or R 5C -Substituted or unsubstituted C 5-7 is 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 Heterocycle; R 5D -Substituted or unsubstituted C 5-7 Aryl or R 5D -Substituted or unsubstituted C 5-7 is 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 Heterocycle; Unsubstituted C 5-7 Aryl or unsubstituted C 5-7 is heteroaryl; R 6 is halogen, OH, CN, NO2, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Haloalkyl or unsubstituted C 3-7 is cycloalkyl; n is 0, 1 or 2; Each PG is independently an amino protecting group, or two PGs together form C 3-7 forming a nitrogen heterocycle; and PG 1 is an amino protecting group; (a) reacting a compound of formula (II) JPEG2025032093000210.jpg45170(in the formula, 2 is a halogen); contacting the organomagnesium compound and the zinc complex; and Reacting the mixture of step (a) with a compound of formula (III), JPEG2025032093000211.jpg30170(in the formula, 4 is a halogen); A process comprising contacting a transition metal (e.g., Pd or Ni) catalyst precursor, and a chiral ligand, thereby synthesizing a compound of formula (I).

[0329] Embodiment 2. The method according to embodiment 1, wherein the compound of formula (II) is prepared by the following method: (a) Formula (IVa) The compound of formula JPEG2025032093000212.jpg30170 is JPEG2025032093000213.jpg27170(in the formula, 3 is a halogen) to form a compound having the formula (IVb): JPEG2025032093000214.jpg27170 compounds to be produced; (d) reacting a compound of formula (IVb) with a compound of formula (V) cyclization to compound JPEG2025032093000215.jpg29170; (d) contacting the compound of formula (V) with a chlorinating agent to obtain a compound of formula (Va) producing a compound of formula JPEG2025032093000216.jpg31170; and (d) reacting a compound of formula (Va) with JPEG2025032093000217.jpg28170, by contacting with a piperazinyl moiety having the formula (IIa) producing a compound of formula JPEG2025032093000218.jpg47170; and (f) reacting a compound of formula (IIa) with X 0 to form a compound of formula (II).

[0330] Embodiment 3. The method of embodiment 2, further comprising the steps of: (a0) In the presence of CO2 gas, the reaction product of formula (IV) contacting the compound of formula (IVa) with a base to aminated the compound forming a compound of formula JPEG2025032093000220.jpg30170.

[0331] Embodiment 4. The method according to any one of embodiments 1 to 3, wherein the compound of formula (III) is prepared by the following method: (a) Formula (VII) contacting the compound of formula 26170 with a compound having the formula NH2(PG), thereby producing a compound of formula (VIIa) Producing a compound of formula (VIIa); (b) reacting a compound of formula (VIIa) with a compound of formula X a PG (wherein X a is a halogen, to form a compound having the formula (VIIb): To generate compound JPEG2025032093000222.jpg27170; (c) reacting a compound of formula (VIIb) with JPEG2025032093000223.jpg26170(in the formula, 5 is a halogen) to form a compound having the formula (VIIc) JPEG2025032093000224.jpg27170 compounds to be produced; (d) haloalkylating a compound of formula (VIIc) with a haloalkylating agent to produce a compound of formula (VIId). JPEG2025032093000225.jpg29170(e) Brominating a compound of formula (VIId) to give a compound of formula (VIIe) producing a compound of formula JPEG2025032093000226.jpg23170; and (f) reacting a compound of formula (VIIe) with Xa with PG to produce a compound of formula (III).

[0332] Embodiment 5 The method according to embodiment 1, wherein the compound of formula (III) is prepared by the following method: (a) Formula (VIII) JPEG2025032093000227.jpg25170 compound (wherein X 6 is Cl or I) with a halogenating agent to obtain a compound of formula (VIIIa) forming a compound of JPEG2025032093000228.jpg23170; (b) brominating a compound of formula (VIIIa) to obtain a compound of formula (VIIIb) forming a compound of formula JPEG2025032093000229.jpg22170; and (c) contacting a compound of formula (VIIIb) with a compound having the formula NH(PG)2, thereby producing a compound of formula (III).

[0333] Embodiment 6. The method according to embodiment 1, wherein the compound of formula (III) is prepared by the following method: (a) Formula (VIIIc) JPEG2025032093000230.jpg23170 is contacted with a brominating agent to obtain a compound of formula (VIIId) forming a compound of JPEG2025032093000231.jpg22170; (b) contacting a compound of formula (VIIId) with a halogenating agent to obtain a compound of formula (VIIIb) forming a compound of JPEG2025032093000232.jpg22170; (c) contacting a compound of formula (VIIIb) with a compound having the formula NH(PG)2, thereby producing a compound of formula (III).

[0334] Embodiment 7.X 1 The method of any one of the preceding embodiments, wherein is a halogen.

[0335] Embodiment 8.X 1 The method of any one of the preceding embodiments, wherein is F or Cl.

[0336] Embodiment 9.X 1 7. The method of any one of embodiments 1-6, wherein is hydrogen or halogen.

[0337] Embodiment 10.X 3 But halogen, unsubstituted C 1-4 Alkyl or unsubstituted C 1-3 The method of any one of the preceding embodiments, wherein haloalkyl.

[0338] Embodiment 11.X 3 is halogen or unsubstituted C 1-3 The method of any one of the preceding embodiments, wherein haloalkyl.

[0339] Embodiment 12.X 3 is unsubstituted C 1-3 The method of any one of the preceding embodiments, wherein is alkoxy or unsubstituted cyclopropyl.

[0340] Embodiment 13.X 3 The method of any one of the preceding embodiments, wherein is a halogen.

[0341] Embodiment 14.X 3 The method of any one of the preceding embodiments, wherein is Cl or F.

[0342] Embodiment 15.X 3 The method of any one of the preceding embodiments, wherein is Cl, F, CF3, CHF2, or CH2F.

[0343] Embodiment 16.X 3 The method of any one of the preceding embodiments, wherein is CF3, CHF2, or CH2F.

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

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

[0346] Embodiment 19.R 1 17. The method of any one of the preceding embodiments, wherein is Boc (tert-butyloxycarbonyl).

[0347] Embodiment 20.R 2 20. The method of any one of the preceding embodiments, wherein is halogen or cyano.

[0348] Embodiment 21.R 2 But non-substituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 The method of any one of the preceding embodiments, wherein haloalkyl.

[0349] Embodiment 22.R 2 is unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 20. The method of any one of the preceding embodiments, wherein the alkyl group is cyanoalkyl.

[0350] Embodiment 23.R 2 is unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 The method of any one of the preceding embodiments, wherein haloalkyl.

[0351] Embodiment 24.R 2 20. The method of any one of the preceding embodiments, wherein is methyl or ethyl.

[0352] Embodiment 25.R 2 20. The method of any one of the preceding embodiments, wherein is methyl.

[0353] Embodiment 26.R 2 The method of any one of the preceding embodiments, wherein is CF3, CHF2, or CH2F.

[0354] Embodiment 27.R 2 The method of any one of the preceding embodiments, wherein is CH2.

[0355] Embodiment 28.R 3 is hydrogen or R 3A -Substituted or unsubstituted C 1-3 The method of any one of the preceding embodiments, wherein the alkyl group is alkyl.

[0356] Embodiment 29.R 3 But R 3A -Substituted or unsubstituted C 1-3 Alkyl, R 3A -Substituted or unsubstituted C 1-3 The method of any one of embodiments 1-27, wherein the aryl group is haloalkyl, or cyclopropyl.

[0357] Embodiment 30.R 3 But R 3A -Substituted or unsubstituted C 1-3 Alkyl or R 3A -Substituted or unsubstituted C 1-3 The method of any one of embodiments 1-27, wherein haloalkyl.

[0358] Embodiment 31.R 3 R 3A -Substituted or unsubstituted C 1-3 The method of any one of the preceding embodiments, wherein the alkyl group is alkyl.

[0359] Embodiment 32.R 3 The method of any one of the preceding embodiments, wherein is methyl.

[0360] Embodiment 33.R 4 The method of any one of the preceding embodiments, wherein is CF3, CHF2, or CH2F.

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

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

[0363] Embodiment 36 The method according to any one of embodiments 1 to 34, wherein the two PGs taken together have the following structure: A method for forming a portion having JPEG2025032093000233.jpg26170.

[0364] Embodiment 37.X 2 The method of any one of the preceding embodiments, wherein is Br.

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

[0366] Embodiment 39. The method 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.

[0367] Embodiment 40. The transition metal catalyst precursor is a Pd or Ni catalyst precursor, and is selected from the group consisting of Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl 2、 40. The method of any one of the preceding claims, wherein the compound is selected from the group consisting of Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(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.

[0368] Embodiment 41. The method according to any one of embodiments 1 to 40, wherein the chiral ligand is: JPEG2025032093000234.jpg80170, During the ceremony, Y is O or NR 7 and; Z is O or N; R 7 and R 8 are independently unsubstituted C 1-6 is alkyl; R 9 and R 10 are independently 11 -Substituted or unsubstituted C 5-6 Cycloalkyl or R 11 - substituted or unsubstituted phenyl; Each R 11 are independently hydrogen, C 1-6 Unsubstituted alkyl, or C 1-6 unsubstituted haloalkyl; R 12 and R 13 are each independently 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 is heteroaryl; Each R 14 are independently unsubstituted C 1-4 The method wherein the is alkyl.

[0369] Embodiment 42.R 7 and R 8 42. The method of embodiment 41, wherein:

[0370] Embodiment 43.R 7 and R 8 is methyl, ethyl, or phenyl.

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

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

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

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

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

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

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

[0378] Embodiment 51. The method of embodiment 1, wherein the compound of formula (II) has the formula: JPEG2025032093000235.jpg has 45170 (In the formula, X 3 is a halogen), method.

[0379] Embodiment 52. The method of embodiment 1, wherein the compound of formula (II) has the formula: JPEG2025032093000236.jpg has 44170 (In the formula, X 3 is a halogen), method.

[0380] Embodiment 53. The method of embodiment 1, wherein the compound of formula (II) has the formula: The method has JPEG2025032093000237.jpg46170.

[0381] Embodiment 54. The method of embodiment 1, wherein the compound of formula (III) has the formula: The method has JPEG2025032093000238.jpg27170.

[0382] Embodiment 55.R 3 is unsubstituted C 1-3 55. The method of embodiment 54, wherein said alkyl is alkyl.

[0383] Embodiment 56.R 4 is unsubstituted C 1-3 The method of embodiment 54 or 55, wherein haloalkyl.

[0384] Embodiment 57. The method of embodiment 1, wherein the compound of formula (III) has the formula: The method has JPEG2025032093000239.jpg27170.

[0385] Embodiment 58. The method of embodiment 1, wherein the compound of formula (I) has the formula: The method has JPEG2025032093000240.jpg51170.

[0386] Embodiment 59. The method of embodiment 1, wherein the compound of formula (I) has the formula: The method has JPEG2025032093000241.jpg52170.

[0387] Embodiment 60.R 3 is unsubstituted C 1-3 The method of embodiment 58 or 59, wherein the alkyl group is alkyl.

[0388] Embodiment 61.R 4 is unsubstituted C 1-3 The method of any one of embodiments 58-60, wherein haloalkyl.

[0389] Embodiment 62. The method of embodiment 1, wherein the compound of formula (I) has the formula: The method has JPEG2025032093000242.jpg49170.

[0390] Embodiment 63.R 2 But non-substituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 The method of any one of embodiments 58-62, wherein the alkyl group is haloalkyl.

[0391] Embodiment 64.R 2 is methyl, ethyl, CN, CHCN, CF, CHF, or CHF.

[0392] Embodiment 65.R 2is methyl, ethyl, CN, or CHCN.

[0393] Embodiment 66. The method of embodiment 1, wherein the compound of formula (I) has the formula: JPEG2025032093000243.jpg50170 (In the formula, X 3 is a halogen), method.

[0394] Embodiment 67. The method of embodiment 1, wherein the compound of formula (I) has the formula: The method has JPEG2025032093000244.jpg52170.

[0395] Embodiment 68. The method according to embodiment 1, comprising: 0 is hydrogen, halogen, CF3, CHF2, CH2F, or a moiety having the structure: JPEG2025032093000245.jpg249170JPEG2025032093000246.jpg32170

[0396] Embodiment 69. A compound having the formula (Id): JPEG2025032093000247.jpg52170, X 3 is a halogen compound.

[0397] Embodiment 70. A compound having the formula (1): JPEG2025032093000248.jpg51170

[0398] Embodiment 71. The method according to embodiment 2, wherein step (f) comprises: The process further comprising step (g) fluorinating the compound of formula (IIa) to a compound of formula (IIa1). JPEG2025032093000249.jpg45170

[0399] Embodiment 72. The method according to embodiment 2, wherein step (f) comprises: The process further comprising step (h) alkoxylating the compound of formula (IIa) to a compound of formula (IIa2). JPEG2025032093000250.jpg44170

[0400] Embodiment 73. The method according to embodiment 2, wherein step (f) comprises: The method further comprising step (j) thiolating the compound of formula (IIa) to a compound of formula (IIe). JPEG2025032093000251.jpg45170

[0401] Embodiment 74 The method of any one of embodiments 1-6, wherein the compound of formula (I) is a compound of Table 1.

[0402] Embodiment 75. A compound having the formula: 1. A method for the synthesis of JPEG2025032093000252.jpg57170 or a pharma- ceutically acceptable salt thereof, comprising: (a) Equation (2) JPEG2025032093000253.jpg42170 or a salt thereof is contacted with ZnCl2 and i-PrMgCl·LiCl to obtain a compound represented by the formula (3) Contact with the compound of JPEG2025032093000254.jpg24170, (b) contacting the mixture of step (a) or a salt thereof with a transition metal (e.g., Pd or Ni) catalyst precursor and a chiral ligand, thereby producing a compound of formula (1) synthesizing JPEG2025032093000255.jpg52170 or a solvate or salt thereof; (c) reacting a compound of formula (1) or a solvate or salt thereof with a compound of formula HO-X A (In the formula, X A is the formula JPEG2025032093000256.jpg16170) and a base, thereby producing a compound of formula (1d); synthesizing JPEG2025032093000257.jpg47170 or a solvate or pharma- ceutically acceptable salt thereof; (d) contacting a compound of formula (1d) with MsOH in an acid, thereby producing a compound of formula (1e); synthesizing JPEG2025032093000258.jpg43170 or a solvate or a pharma- ceutically acceptable salt thereof; and (e) reacting a compound of formula (1e) or a solvate or a pharma- ceutically acceptable salt thereof in the presence of a base and, optionally, an activating agent as described herein, JPEG2025032093000259.jpg23170, thereby producing a compound of formula (A) or a pharma- ceutically acceptable salt thereof.

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

[0404] Embodiment 77. Step (e) comprises reacting a compound of formula (1e) or a solvate or pharma- ceutically acceptable salt thereof, 76. The method of embodiment 75, comprising contacting with JPEG2025032093000260.jpg21170.

[0405] Embodiment 78. In one embodiment of the method (P9) described herein, step (e) comprises reacting a compound of formula (1e) or a solvate or pharma- ceutically acceptable salt thereof with: This includes contacting with JPEG2025032093000261.jpg25170.

[0406] The following examples are offered by way of illustration and not by way of limitation. EXAMPLES

[0407] Example 1

[0408] Synthesis of 2-amino-4-bromo-3-fluorobenzoic acid. Compound 4a JPEG2025032093000262.jpg21170

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

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

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

[0412] NH3 .A mixture of 4-bromo-2,3-difluorobenzoic acid (500 g, 2.11 mol) in H2O (1500 mL, 25% w / w) was heated to 150° C. in a 5 L autoclave and stirred for 35 h. The reaction mixture was cooled to 0° C. and acidified in an ice bath with concentrated HCl until pH=3. 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 vol.) at 75° C., then water (5 vol.) was added dropwise. The mixture was cooled to room temperature and the precipitate was filtered and dried in air at 50° C. overnight. The resulting solid was triturated with DCM (5 vol.) 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)δ13.09(brs,1H),7.50(dd,J=8.8Hz,1.6Hz,1H),6.80(brs,1H),6.78(dd,J=8.8Hz,6.4Hz,1H).

[0413] Example 2

[0414] tert-Butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate Compound 2: JPEG2025032093000263.jpg63170

[0415] Step 1: JPEG2025032093000264.jpg33170

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

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

[0418] Step 2: JPEG2025032093000265.jpg32170

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

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

[0421] Step 3: JPEG2025032093000266.jpg33170

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

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

[0424] Step 4: JPEG2025032093000267.jpg47170

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

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

[0427] Approximately 500 kg of water was charged to a 1000 L reactor and cooled to 0-10°C. The reactants containing 5a were added to the water and stirred at 0-10°C for 1 h. The cake was filtered, washed with water (4 vol x 2) and then dissolved in DCM (10 vol) and the phases were separated. The organic phase was washed with water (5 vol) and the water was extracted with DCM. The combined organic phase was added to a 500 L reactor and concentrated under vacuum at 45-50°C to approximately 20-25 L. Approximately 53 kg of n-heptane was charged to the reactor and the contents were concentrated under vacuum at 45-50°C to approximately 50-60 L and repeated. An additional 53 kg of n-heptane was slowly dripped into the 500 L reactor over 10 min at 20-30°C. The mixture was stirred at 20-30°C for 0.5 h. The mixture was cooled to 5-10 °C and stirred at 5-10 °C for 0.5 h. The cake was filtered, washed with n-heptane (5 volumes) and then dried in a vacuum oven at 45-50 °C for 10 h. 35.8 kg of compound 2d (98.0 A%) was isolated as an off-white solid in 94% (corrected) yield.

[0428] Step 5: JPEG2025032093000268.jpg46170

[0429] To a 500 L reactor, under N2 atmosphere, 274 kg of DMF was added 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 before stirring at room temperature for 5 min. The mixture was heated to 51.5-52.5 °C and stirred for 10 h. Additional CsF (23.7 mol) was added and the mixture was stirred under N2 atmosphere at 51.5-52.5 °C for 16 h.

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

[0431] Example 3

[0432] Compound 3 (6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine) JPEG2025032093000269.jpg73170

[0433] Step 1: 6-chloro-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (Compound 7a) JPEG2025032093000270.jpg32170

[0434] Charge PMBNH2 (175.0 L, 183.75 kg, 5 V) to the reactor. Charge 2,6-dichloro-4-methylpyridine (compound 7, 35.0 kg, 1.0 equiv.) to the reactor and stir below 30 °C. Heat to 120 ± 10 °C and stir at 120 ± 10 °C for 32 h. After cooling the reaction to sample for LCMS, add soft water / isopropanol = 2 / 1 (350.0 L, 10 V) dropwise at 85-130 °C. Cool the reaction to 85-95 °C and stir for 30-60 min. Cool to 5 ± 5 °C (cool 10 ± 5 °C every hour) and stir at 5 ± 5 °C for at least 1 h. Centrifuge and wash the cake twice with water / isopropanol = 2 / 1 (3 V). The cake was collected and dried at 45±5° C. for at least 16 hours. Yield: 52.0 kg, 91.6%

[0435] Step 2: 6-chloro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (compound 7b) JPEG2025032093000271.jpg32170

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

[0437] Step 3: 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine JPEG2025032093000272.jpg41170

[0438] DMF (353.5 L, 5.0 V), compound 7b (70.70 kg, 1.0 equiv.) were charged into the reactor and clarified by stirring at 25 ± 5 °C. NIS (49.9 kg, 1.2 equiv.) solid was charged into the reactor in 10 batches, one batch every at least 3 hours. Stirred at 25 ± 5 °C for at least 8 hours. After cooling to 0 ± 5 °C, 5 wt% Na2SO3 aqueous solution (353.5 L, 5.0 V) was added dropwise at -5 to 25 °C. Stirred at 5 ± 5 °C for at least 30 minutes. Centrifuged, cake was washed twice with soft water. The volume of elution is 2 V each time. Figure cake was collected and slurried with soft water / isopropanol = 2 / 1 (373.5 L, 5.0 V) at 70 ± 5 °C for at least 30 minutes. Cool to 20±5°C and stir at 20±5°C for at least 1 hour. Centrifuge again and wash the cake twice with water / isopropanol=2 / 1. The volume of elution is 3V each time. Collect the solid and dry at 45±5°C for at least 16 hours. Yield: 86.56 kg, 92.1%.

[0439] Step 4: 6-(1,3-bis(4-methoxyphenyl)propan-2-yl)-2-chloro-4-methyl-3-(trifluoromethyl)pyridine (compound 7d) JPEG2025032093000273.jpg34170

[0440] Charge DMF (432.5 L, 5.0 V) and HMPA (152.3 kg, 5.0 equiv.) to reactor. Charge compound 7c (86.5 kg, 1.0 equiv.) to reactor under nitrogen atmosphere. Charge reactor with CuI (80.9 kg, 2.5 equiv.). Sparge with N2 at 25±5°C for at least 40 min. Heat to 90±5° and add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (98.0 kg, 3.0 equiv.) dropwise to reactor. Stir at 90±5°C for at least 2 h. Cool and filter through diatomaceous earth. Wash with EtOAc (865.0 L, 10.0 V). Evaporate in vacuum to 4-8 V. After cooling to 5±5°C, soft water (865.0L, 10.0V) was added dropwise to the reactor at 0-25°C. Stirred at 20±5°C for at least 30 minutes. Centrifuged and cake washed twice with water. The volume of elution is 4V each time. The cake was collected and EtOAc (865.0L, 10.0V) was added. Stirred at 25±5°C for at least 30 minutes, filtered through diatomaceous earth, and washed with EtOAc (865.0L, 10.0V). Retained, separated, and the organic phase was collected and concentrated to 2-4V. Isopropanol (432.5L, 5.0V) was added to the reactor and concentrated to 2-4V. Charging isopropanol (432.5L, 5.0V) and concentrating to 2-4V were repeated until the area % of EtOAc was below 5.0% by GC. Heat to 60±5°C, add water (4-6V) dropwise to the vessel and stir at 60±5°C for at least 0.5 h. Cool to 20±5°C and stir at 25±5°C for at least 1 h. Centrifuge and wash cake twice with water / isopropanol = 2 / 1 (3V). Collect solid and dry at 50±5°C for at least 16 h. Yield: 70.45 kg, 91.9%.

[0441] Step 5: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine JPEG2025032093000274.jpg32170

[0442] MeCN (176.0 L, 2.5 V), compound 7d (70.4 kg, 1.0 equiv.) were charged to the reactor and stirred at 15 ± 5 °C to form a suspension. HBr (176.0 L, 2.5 V, 48% in water) was added dropwise to the reactor at 10-40 °C. Adjust to 80 ± 5 °C and stir for at least 2 h. Cool before charging IPAC (211.2 L, 3.0 V). Cool to 0 ± 5 °C and neutralize with 15 wt% NaOH aqueous solution at T ≤ 25 °C until pH = 7-8. The aqueous layer was extracted three times with IPAC (211.2 L, 3.0 V), and the organic layer was collected and concentrated to 2-4 V at T ≤ 45 °C. MeCN (352.0 L, 5.0 V) was added to the reactor and concentrated to 2-4 V at T≦45° C. to give a solution of 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine in MeCN.

[0443] Step 6: N-(6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide JPEG2025032093000275.jpg31170

[0444] AcBr (287.9 ​​kg, 15.0 equiv.) was charged to the reactor at -10~40°C, and the temperature was adjusted to 70±5°C, followed by stirring for at least 10 h. The reactor was cooled to 0±5°C and quenched with EtOH (176.0 L, 2.5 V) at T≦25°C. The reactor was cooled to 0±5°C and neutralized with 15 wt% aqueous NaOH at T≦25°C until pH=7~8. The reactor was extracted three times with EtOAc (281.6 L, 3.0 V), and the organic layer was collected and concentrated to 2~4 V at T≦45°C. MeCN (352.0 L, 5.0 V) was added to the reactor and concentrated to 2~4 V at T≦45°C. The reactor was charged with AcBr (287.9 ​​kg, 15.0 equiv.) at -10~40°C, and the temperature was adjusted to 70±5°C, followed by stirring for at least 10 h. Cooled to 0±5°C and quenched with EtOH (176.0 L, 2.5 V) at T≦25°C. Cooled to 0±5°C and neutralized with 15 wt% aqueous NaOH at T≦25°C until pH=7-8. Extracted 3 times with EtOAc (281.6 L, 3 V), collected organic layer and concentrated to 1-4 V at T≦45°C. Cooled to 5-10°C and stirred at 5-10°C for 1-2 h. Centrifuged, washed cake twice with EtOAc (1 V) and collected cake for next step without further purification. Yield: 34.50 kg crude product.

[0445] Step 7: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Compound 7e) JPEG2025032093000276.jpg30170

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

[0447] Step 8: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (compound 3) JPEG2025032093000277.jpg30170

[0448] NMP (255.0 L, 10.0 V), PMBCl (47.0 kg, 3.0 equiv.) and compound 7e (25.5 kg, 1.0 equiv.) were charged to a reactor under N2. Cooled to 0 ± 5 °C. Solid CH3ONa (16.2 kg, 3.0 equiv.) was charged in 5 batches at 0 ± 5 °C. One batch was added at least every 0.5 h. Stirred at 0 ± 5 °C for at least 4 h. Water (20.0 V) was added dropwise at -10 to 10 °C and stirred at 5 ± 5 °C for at least 30 min. Filtered and washed the filter cake twice with water (3 V). Collected the filter cake and slurried in water / isopropanol = 1 / 1 (127.5 L, 5.0 V) at 60 ± 5 °C for at least 2 h. Cool to 20±5°C (cool 10±5°C every hour) and stir at 20±5°C for at least 1 hour. Centrifuge and wash cake twice with water / isopropanol = 1 / 1 (3V). Collect cake and add DCM (255.0L, 10.0V) to reactor. Adjust temperature to 25±10°C and stir at least 0.5 hour. Filter through activated charcoal and wash with DCM (51.0L, 2.0V). Collect filtrate and concentrate to 2-4V at T≦45°C. Add n-heptane (255.0L, 10.0V) to reactor and concentrate to 2-4V at T≦45°C. Add n-heptane (255.0L, 10.0V) to reactor and adjust temperature to 70±5°C. Stirred at 70±5° C. for at least 10 min. Cooled to 20±5° C. (cooled 10±5° C. every hour) and stirred at 20±5° C. for at least 1 h. Centrifuged and washed cake twice with n-heptane (3 V). Centrifuged and washed cake with n-heptane / EtOAc 10 / 1 (51.0 L, 2 V). Collected solid and dried at 45±5° C. for at least 16 h. Yield: 31.20 kg, 63.0%.

[0449] Step 8: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (compound 3) JPEG2025032093000278.jpg29170

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

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

[0452] Example 4

[0453] Compound 3 (6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine) JPEG2025032093000279.jpg87170

[0454] Step 1: 6-chloro-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (Compound 7a) JPEG2025032093000280.jpg31170

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

[0456] Step 2: 6-chloro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (compound 7b) JPEG2025032093000281.jpg32170

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

[0458] Step 3: 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine JPEG2025032093000282.jpg40170

[0459] To a solution of compound 7b (assay corrected 150 kg, 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 15-25 °C for 24 h. NIS (3 kg, 0.02X, 0.03 equiv.) was added to the reaction. The solution was stirred at 15-25 °C for 20 h. The solution was stirred at 15-25 °C for an additional 4.5 h. The reaction was cooled to 0-10 °C and 5 wt% aqueous AlSO (~845 kg) was added. The mixture was stirred at 0-10 °C for 2 h. The wet cake was filtered and washed with water (~466 kg) to give 224.85 kg of wet cake. The wet cake was poured into EtOH (~768 kg) and stirred at 45-55 °C for 2 h. The mixture was cooled to 15-25 °C for 3 h and stirred for 3 h, after which the wet cake was filtered and washed with EtOH (about 460 kg) to give 208.25 kg of wet cake. After drying at 45-55 °C for 18.5 h, 198.15 kg of compound 7c was obtained with an assay of 98.3 wt%, a corrected yield of 98%, and a purity of 99.4 A%.

[0460] Step 4: 6-(1,3-bis(4-methoxyphenyl)propan-2-yl)-2-chloro-4-methyl-3-(trifluoromethyl)pyridine (compound 7d) JPEG2025032093000283.jpg34170

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

[0462] Step 5A: 6-Bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine JPEG2025032093000284.jpg35170

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

[0464] Steps 5B and 5C: N-(6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-yl)acetamide JPEG2025032093000285.jpg28170

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

[0466] Step 6: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (compound 3) JPEG2025032093000286.jpg32170

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

[0468] Example 5

[0469] 2,6-Dibromo-4-methyl-3-(trifluoromethyl)pyridine (compound 8b) JPEG2025032093000287.jpg32170

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

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

[0472] Example 6

[0473] Step 1: 2,6-Dichloro-4-methyl-3-(trifluoromethyl)pyridine (Compound 8a) JPEG2025032093000288.jpg30170

[0474] 2,6-Dichloro-4-methylnicotinic acid (compound 8, 1.0 equiv.) was charged to an autoclave at ambient temperature (20-30°C), followed by anhydrous HF (1.37 rel. wt.) at -20°C, and SF4 (2.5 equiv.) at -78°C. The reaction mixture was allowed to warm to ambient temperature and then heated at 70-80°C for 17-24 hours. The reaction was cooled to ambient temperature (25-30°C) before being purged with KOH (alkaline scrubber). The solvent was exchanged to MTBE, the reaction was cooled to 0-10°C, and DM water (1 rel. vol.) and K2CO3 (4 rel. wt.) in DM water (8 rel. vol.) were added.

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

[0476] 2,6-Dichloro-4-methyl-3-(trifluoromethyl)pyridine (compound 8a) JPEG2025032093000289.jpg30170

[0477] Nicotinic acid substrate (compound 8, 1.0 equiv.) was charged to an autoclave at ambient temperature, followed by anhydrous HF (1.37 rel. wt.) at -20°C, and SF4 (3.5 equiv.) at -78°C. The reaction mixture was allowed to warm to ambient temperature and then heated at 90-100°C for 24 h. Conversion was checked by HPLC analysis. Upon completion, DCM was charged to the reaction, then the mixture was unloaded with ice, neutralized with K2CO3, filtered through celite, and extracted with DCM (3 x 3V). The combined organic layers were concentrated to give a black semi-solid.

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

[0479] 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Compound 3) JPEG2025032093000290.jpg28170

[0480] Step 1: Compound 8b JPEG2025032093000291.jpg27170

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

[0482] Step 2: JPEG2025032093000292.jpg26170

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

[0484] Recrystallization: A reactor was charged with crude product (1115 g) and THF (4.46 L, 4 L), the mixture solution was stirred to clear, and then decolorized with activated carbon (110 g, 10 wt%). The decolorized solution was concentrated under reduced pressure to 1.2 v below 40° C., and then methanol (2.23 L, 1.2 v) was added. The mixture solution was heated to 50° C., at which point it was stirred for 0.5 h to obtain a clear solution. MeOH (4.65 L, 4.2 v) was charged to the solution, and then crystal seeds (1 wt%) were added. The mixture solution was stirred at 50° C. for 1 h. MeOH (2.23 L, 1.2 v) was added to the suspension at 50° C. and stirred at that temperature for 0.5 h. The suspension was then cooled to 0° C. over 1 h and stirred at that temperature for 16 h. The suspension was filtered and washed with MeOH (2.23 L, 1.2 v). The filter cake was dried under vacuum at 45° C. for 20 hours to give the product as an off-white solid (931.6 g, HPLC purity: 99.7 A%, Assay: 102.3 wt %, Yield: 68.4%). 1 H NMR(400MHz,CHLOROFORM-d)δ2.24-2.45(m,3H),3.73-3.90(s,6H),4.57-4.85(s ,4H),6.11-6.22(s,1H),6.80-6.93(m,4H),7.10-7.23(m,4H),7.24-7.34(s,1H)

[0485] Example 7

[0486] Compound 1: tert-butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate JPEG2025032093000293.jpg41170

[0487] A dry flask (1 L) was charged with compound 2 (50.0 g, 104.7 mmol, 1.1 equiv) and THF (350 mL, 7v, 100-200 ppm HO). i-PrMgCl·LiCl (1.3 M in THF, 93.0 mL, 1.265 equiv) was added dropwise over 30 min at -78 to -70 °C under argon. The reaction mixture was stirred at -78 °C for 10 min. ZnCl2 (1.9 M in Me-THF, 72 mL, 1.43 equiv, ca. 230 ppm HO) was added dropwise over 20 min at -78 to -70 °C and then gradually warmed to 10 °C over 2 h. The mixture was stirred at 10 °C for ca. 0.5 h. After addition of ZnCl2, the reaction mixture was stirred at -70 to -30 °C for at least 1 h. In a separate dry flask (1 L) was added compound 3 (47.1 g, 95.2 mmol, 1.0 equiv) and 1,4-dioxane (8 v). The Zn reagent was added under an argon atmosphere. The reaction mixture was sparged with argon at 0.3 L / min for 2 h. A solution of [PdCinnamylCl]2 (0.5 mol%), (R,R)-chiraphite ligand (1.0 mol%) in 1,4-dioxane (ca. 14 mL, ca. 0.27 v) was added under an argon atmosphere. The mixture was stirred at ca. 48° C. for 21 h.

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

[0489] Example 8 JPEG2025032093000294.jpg39170

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

[0491] [Table 3] JPEG2025032093000296.jpg210170JPEG2025032093000297.jpg65170

[0492] Example 9 JPEG2025032093000298.jpg43170

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

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

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

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

[0497] Example 10

[0498] Compound 1: tert-butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate JPEG2025032093000299.jpg65170

[0499] To the reactor was added ultra-dry THF (53 L, 8.4v) and compound 2 (8.5 kg, 17.79 mol, 1.4 equiv) under argon atmosphere. The mixture was degassed by three vacuum / argon cycles and cooled to -78 °C by liquid N2 bath. i-PrMgCl·LiCl solution (1.3 M in THF, 15.74 L, 20.46 mol, 1.61 equiv) was added dropwise over 15 min at -78 to -70 °C under argon. The reaction mixture was stirred at -78 °C for 15 min. ZnCl2 (1.9 M in Me-THF, 12.2 L, 23.18 mmol, 1.82 equiv, ca. 1300 ppm) was added dropwise over 15 min at -78 to -70 °C and then gradually warmed to -10 °C over 3.0 h. After the addition of ZnCl2, the reaction mixture was stirred at -70 to -30 °C for at least 1 h.

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

[0501] Cooled to 20°C and then added to saturated NH4Cl (64 L, 10v) solution at <20°C. Filtered through 3.2 kg of diatomaceous earth and separated two phases (filtrate). The aqueous phase was extracted twice with EtOAc (32 L, 5 vol). The combined organic phase was washed with brine (32 L, 5v) and then concentrated to ca. 2v (ca. 17 L) at 40°C and then solvent-swapped with EtOAc (ca. 30 L x 3) to give an EtOAc solution (ca. 17 L). The above solution was concentrated under high vacuum at ca. 40°C to remove most of the EtOAc and then solvent-swapped with DCM (ca. 30 L x 3) to give a DCM solution (ca. 17 L, DCM / EtOAc = 5-6 / 1).

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

[0503] About 60 L of EtOAc was added, and the resulting mixture was warmed to about 40° C. to form a solution (EtOAc / n-heptane=about 2 / 1) after about 1 hour. The solution was then naturally cooled to about 15° C. About 680 g of C941 (8 wt % relative to the amount of compound) was added, and the resulting mixture was stirred at about 15° C. for about 1 hour. Filtered, the cake was washed with EtOAc (2.5 L×2), and the filtrate and washings were concentrated to 2-3v (17-25 L), and then further dried on a rotary evaporator at 40° C. to obtain the final compound 1. 1 H NMR(600MHz,DMSO-d6)δppm 7.97(s,1H),7.15(d,J=8.7Hz,4H),6.87(br d,J=8.2Hz,4H),6.84(s,1H),4.71-4.88(m,3H),4.56(br d,J=15.7Hz,2H),4.19-4.25(m,1H),3.86-4.02(m,1H),3.79-3.86(m,1H),3.74(br d,J=5.8Hz,1H),3.72(s,6H),2.94-3.30(m,2H),2.40(d,J=1.7Hz,3H),1.43(s,8H),1.33-1.36(m,3H).HR-MS(ESI): Calculated value C 41 H 42 ClF5N6 m / z ([M+H] + )813.2965;Actual value 813.2963.

[0504] Example 11 JPEG2025032093000300.jpg44170

[0505] A solution of tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2,8-difluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (50.0 g, 53.7 mmol, 1.00 eq., 87.3% assay) and [(2S)-1-methylpyrrolidin-2-yl]methanol (7.44 g, 64.6 mmol, 1.20 eq.) in 2-Me-THF (320 g) was concentrated under reduced pressure (235 mbar) to a volume of 250 mL. The solution was cooled to -10°C. Sodium tert-pentoxide (27.5 g, 64.6 mmol, 1.20 equiv, 25% w / w) as a solution in toluene was then charged over 10-20 min. The reaction mixture was stirred at 0 °C until complete conversion was achieved (typically 1 h). The reaction mixture was then diluted with 2-Me-THF (214 g), warmed to 15-25 °C and quenched by addition of aqueous potassium carbonate (200 g, 10% w / w solution). The biphasic mixture was stirred for 1 h and the layers separated. The organic layer was further washed with aqueous potassium carbonate (200 g, 10% w / w). The biphasic mixture was stirred for 15 min and the layers separated. The organic layer was concentrated under reduced pressure (235 mbar) to a solution of 250 mL, cooled to 20-25 °C and polish filtered. The filtrate was further concentrated under reduced pressure (235 mbar) to a solution of 175 mL. 1-PrOH (100 g) was added and continuous exchange of 2-Me-THF to 1-PrOH was performed under reduced pressure (150 to 60 mbar). Water (100 g) was then added at 50° C. and the solution was seeded at this temperature. The resulting mixture was further stirred at this temperature for 2 h and water (100 g) was added over at least 2 h. The crystal slurry was cooled to 20° C. over at least 3 h and further stirred at this temperature for at least 5 h. The crystals were filtered off, washed with a solution of 1-PrOH / water and dried under reduced pressure to constant weight. The title compound is isolated in 96% yield (47.5 g) as off-white crystals. 1H NMR(600MHz,DMSO-d6)δ ppm 7.82(s,1H),7.16(d,J=8.7Hz,4H),6.87(br d,J=8.3Hz,4H),6.82(s,1H),4.62-4.89(m,3H),4.56(br d,J=15.6Hz,2H),4.39(dd,J=10.7,4.7Hz,1H),4.12-4.25(m,1H),4.05(br d, J = 13.4 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 907.3811; found: 907.3808.

[0506] Example 12 JPEG2025032093000301.jpg46170

[0507] To a mixture of acetic acid (46.2 g), methanesulfonic acid (52.9 g) and toluene (34.7 g) at 40° C., a solution of tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (20.0 g, 22.0 mmol) in toluene (86.7 g) was added 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 were separated. The acidic layer was quenched slowly (typically over 1 h) with a mixture of aqueous sodium hydroxide (211.5 g, 28% w / w), water (80.0 g) and toluene (121.4 g) at 40° C. Once the quench was complete, acetic acid (10.0 g) was added to rinse the lines. The biphasic mixture was warmed to 50° C. and the layers were separated. The organic layer was washed twice with aqueous sodium hydroxide (2×90.0 g, 0.1 N solution). The toluene layer was then vacuum distilled at constant volume (90 mbar; typically, 69 g of toluene is exchanged). After polish filtration, the resulting toluene solution was concentrated under reduced pressure (90 mbar) to a 94 mL solution, which was then warmed to 60° C. n-heptane (34.6 g) was then added over at least 30 min 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 solution (1:1 v / v) and dried under reduced pressure to constant weight. The title compound was isolated in 89% yield (11.7 g) as off-white crystals. 1H NMR(600MHz,DMSO-d6)δ ppm 7.74(d,J=0.9Hz,1H),6.84(s,2H),6.49(s,1H),4.54-4.65(m,1H),4.38(dd,J=10.8,4.6Hz,1H),4.14(dd,J=10.7,6.5Hz,1H),3.96(br d, J = 13.1 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.

[0508] Example 13 JPEG2025032093000302.jpg47170

[0509] A 250 mL round bottom flask equipped with overhead stirring and a nitrogen line was charged with compound 1e (8.00 g, 14.1 mmol, 1.0 equiv), 3-(phenylsulfonyl)propanoic acid (3.66 g, 16.9 mmol, 1.20 equiv), and acetonitrile (48 mL, 6 v). The mixture was stirred for 5 min, after which N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI·HCl) (3.11 g, 16.2 mmol, 1.15 equiv) was added and rinsed forward with acetonitrile (16 mL, 2 v). The reaction was stirred at 20 °C for a minimum of 3 h. Once the reaction was complete and the sulfone intermediate had formed, the pH was adjusted to 13.0-13.5 by adding water (32 mL, 4 v) and sodium hydroxide pellets (1.60 g, 39.9 mmol, 2.85 equiv). The reaction mixture was stirred for a minimum of 2 hours to give compound A, which was isolated by first adding water (24 mL, 3v) and seed crystals (0.5 wt%). Precipitation was then completed by slowly charging additional water (24 mL, 3v) over 2 hours, aging at 20° C. for 2 hours, followed by slowly charging water (64 mL, 8v) over 5 hours. The resulting slurry was held at 20° C. for 2 hours, filtered, and washed with 1:1 acetonitrile / water (64 mL, 8v), followed by water (64 mL, 8v). Upon drying, compound A (7.42 g) was obtained as an off-white solid in 89.6% yield (corrected for purity).

[0510] Example 14 JPEG2025032093000303.jpg86170

[0511] To a 400 mL reactor, compound 1e (10.0 g, 17.6 mmol, 1.00 equiv.) was added followed by 2-MeTHF (50.0 mL, 5 mL / g) and the materials were stirred at room temperature until complete dissolution was observed. Then, 10% aqueous Na2CO3 (50.0 mL, 5 mL / g) was added, the reactor was cooled to 0° C. (internal temperature control) and the overhead stirrer was set at 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 over 30 minutes to the biphasic solution while maintaining the internal temperature at 0° C. The mixture was then stirred at 0° C. for 1 hour (97.8% conversion).

[0512] Next, 10% aqueous NaOH (50.0 mL / 5 mL / g) was added, the reactor was set to 40° C. (internal temperature control) and stirred for 16 h. The reactor was then cooled to 25° C., the mixture was transferred to a 500 mL separatory funnel and the lower (aqueous) layer was removed. The upper (organic) layer was transferred back to the 400 mL reactor, 10% aqueous NaOH (50.0 mL / 5 mL / g) was added, the reactor was set to 40° C. (internal temperature control) and stirred (350 RPM) for 4 h. The reactor was then cooled to 25° C., the mixture was transferred to a 500 mL separatory funnel and the lower (aqueous) layer was removed. The organic layer was then transferred to a 250 mL round bottom flask, concentrated to approximately 20 mL and refilled with 60 mL MeCN, this process was repeated six times and the solvent composition was confirmed by headspace GC (0.03% MeTHF after solvent exchange). The mixture in the round bottom flask was then placed in a 5° C. refrigerator for 2 days, filtered, and washed with two 20 mL portions of MeCN (pre-chilled to −10° C.).

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

[0514] Example 15 JPEG2025032093000304.jpg46170

[0515] A 250 mL round bottom flask equipped with overhead stirring and a nitrogen line was charged with 3-(phenylsulfonyl)propanoic 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 a forward acetonitrile rinse (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 min and rinsed forward with acetonitrile (8 mL, 1 v). The mixture was stirred at -10 °C for a minimum of 1 h, then compound 1e (8.00 g, 14.1 mmol, 1.0 equiv) was added and rinsed forward with acetonitrile (8 mL, 1 v). The reaction was stirred at -10 °C for a minimum of 30 min. Once the reaction was complete and the sulfone intermediate was formed, the mixture was warmed to 20°C. Water (32mL, 4v) and sodium hydroxide pellets (2.11g, 52.8mmol, 3.75eq) were added to adjust the pH to 13.0-13.5. The reaction mixture was stirred for a minimum of 2h to give compound A, which was isolated by first adding water (24mL, 3v) and seed crystals (0.5wt%). Precipitation was then completed by slowly charging additional water (24mL, 3v) over 2h, aging at 20°C for 2h, followed by slowly charging water (48mL, 6v) over 4h. The resulting slurry was held at 20°C for 2h, filtered, and washed with 1:1 acetonitrile / water (64mL, 8v) followed by water (64mL, 8v). Upon drying, compound A (7.10g) was obtained as an off-white solid in 87.4% yield (corrected for purity).

[0516] Example 16 JPEG2025032093000305.jpg104170

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

[0518] Example 17 JPEG2025032093000306.jpg47170

[0519] To a solution of compound 1e (3.02 kg, 5.32 mol, 1.0 equiv) in DCM (in a 100 L reactor) was charged 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, 7V) was added slowly over 140 min while maintaining the temperature below -20°C. The reaction mixture was stirred for a minimum of 10 min, warmed to 5°C, and quenched with 10 wt% aqueous potassium bicarbonate (12.1 kg, 4V).

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

[0521] Example 18 JPEG2025032093000307.jpg51170

[0522] Compound A (2.32 kg, 3.53 mol) and ground filtered 2-butanone (17.42 L, 7.5 L / kg) were combined in a 25 L reactor equipped with an active nitrogen line, overhead stirring, and temperature probe. Adipic acid (0.46 kg, 3.17 mol, 0.9 equiv.) and ground filtered 2-butanone (1.16 L, 0.5 L / kg) were charged to a separate 5 L vial. The reactor was then heated to 50° C.±10° C., and once the desired internal temperature target of >45° C. was reached, the adipic acid slurry in 2-butanone was charged to the reactor by pulling a vacuum. Compound B seed (0.02 kg, 1 wt %) was charged to a 5 L vial, followed by ground filtered butanone (2.32 L, 1.0 L / kg). Again, the slurry was charged to the reactor by pulling a vacuum. Finally, the 5 L glass bottle was rinsed with ground filtered 2-butanone (1.16 L, 0.5 L / kg) and then charged to the reactor by vacuum. The reactor contents were aged for a minimum of 1 hour, cooled to 0° C. for a minimum of 2 hours, and then aged at 0° C. overnight (15 hours). The contents were transferred to a pre-cooled filter dryer at 0° C. In parallel, ground filtered 2-butanone (9.29 L, 4.0 L / kg) was charged to the reactor at 0° C. and then stirred for 30 minutes. The material in the filter dryer was then filtered and the resulting cake was washed with chilled 2-butanone. After drying for a minimum of 8 hours using vacuum and nitrogen sweep, the filter dryer contents were discharged to give compound B (2.137 kg, 77%) as an off-white solid. 11H NMR (600 MHz, DMSO-d6) δ 7.77 (s, 1H), 6.81 (s, 2H), 6.76 (dd, J = 16.8, 10.6 Hz, 1H), 6.45 (s, 1H), 6.18 - 6.10 (m, 1H), 5.70 (dd, J = 10.4, 2.3 Hz, 1H), 4.75 - 4.66 (m, 1H), 4.38 - 4.30 (m, 2H), 4.25 - 3.89 (m, 4H), 3.61 (dq, J = 21.3, 12.4, 10.9 Hz, 2H), 3.20 (dd, J = 13.4, 3.8 Hz, 1H), 3.00 (td, J = 12.6, 3.7 Hz, 1H), 2.91 (ddd, J = 9.0, 6.0, 2.8 Hz, 1H), 2.59 - 2.51 (m, 1H), 2.32 (d, J = 6.2 Hz, 6H), 2.15 (td, J = 8.6, 7.7, 4.7 Hz, 5H), 1.94 - 1.85 (m, 1H), 1.61 (dddd, J = 20.8, 12.3, 8.0, 4.1 Hz, 3H), 1.45 (h, J = 3.4 Hz, 4H), 1.22 (dd, J = 12.4, 6.6 Hz, 3H); 13 C{ 1 H, 19 F} NMR (151 MHz, DMSO-d6) δ 174.9, 165.5, 164.8, 162.2, 161.4, 153.2, 148.8, 147.7, 143.0, 131.1, 128.5, 128.4, 128.3, 128.2, 125.6, 125.3, 121.0, 114.7, 112.2, 110.5, 69.8, 63.9, 57.4, 52.5, 52.4, 49.4, 45.9, 45.2, 44.9, 44.3, 42.0, 41.7, 40.6, 34.0, 29.1, 24.6, 23.1, 20.3, 15.9, 15.3; 19 19F NMR (565 MHz, DMSO-d6) δ -53.5, -125.9.

[0523] Example 19 JPEG2025032093000308.jpg54170

[0524] Compound A (1 molar equivalent) and adipic acid (1 molar equivalent) were suspended in 2-butanol and 2-methyltetrahydrofuran and dissolved by heating to about 70°C. The polished filtered solution was cooled to about 25°C. Jet milled compound B material was used for seeding. Seeding material Compound B material was suspended in 2-butanol / n-heptane. This suspension was used to seed the solution at about 25°C. The seeding equipment was rinsed with n-heptane, which was then added to the seeding suspension. N-heptane was added within 15-30 minutes at about 25°C. The suspension was stirred at about 25°C for about 3 hours. The suspension was cooled to about 0°C and stirred for at least 5 hours. The solid was isolated by solid / liquid separation and rinsed with a mixture of 2-butanol / n-heptane followed by n-heptane. The solid was dried under reduced pressure at about 40° C. to give a white to off-white powder in 88-95% yield.

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

[0526] Example 20: Cyclohexane crystalline solvate compound 1

[0527] X-ray quality crystals were grown from hot cyclohexane solution and slowly cooled to room temperature and left to diffract for 72 hours before deposition. Colorless rods measuring 0.110x0.090x0.050 mm were mounted on a Cryoloop using paratone oil. Data were collected in a nitrogen gas stream at 90(2) K using phi and omega scanning. The crystal to detector distance was 40 mm and the exposure time was 0.15 seconds per frame using a scan width of 0.5°. Data collection was 100.0% complete up to 67.000° (θ). A total of 112434 reflections were collected covering indices -11<=h<=11, -16<=k<=17, -40<=l<=41. 8888 reflections had an R of 0.0352. int The structure was found to be symmetry independent, with the lattice indexing and unit cell refinement indicating a simple 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. Solution by iterative methods (SHELXT-2014) produced a full heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using a riding model. Their positions were restrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[0528] [Table 4]

[0529] Example 21: Methylcyclohexane crystalline solvate compound 1

[0530] X-ray quality crystals were grown from hot methylcyclohexane solution, slowly cooled to room temperature and left to rest for 48 hours. A colorless prism measuring 0.206x0.097x0.068mm was mounted on a Cryoloop with paratone oil. Data were collected in a nitrogen gas stream at 90(2)K using phi and omega scanning. The crystal to detector distance was 40mm and the exposure time was 0.1 seconds per frame using a scan width of 0.5°. Data collection was 100.0% complete up to 67.000°(θ). A total of 128902 reflections were collected covering indices -17<=h<=17, -11<=k<=12, -41<=l<=40. 17535 reflections had an R of 0.0912. int The symmetry of the nucleus was found to be independent, with the symmetry being 0.01, 0.0 ...

[0531] [Table 5]

[0532] Example 22: Chlorobenzene crystalline solvate compound 1

[0533] X-ray quality crystals were grown from a saturated chlorobenzene solution, followed by slow vapor diffusion of heptane to deposit the diffracting crystals. A colorless prism measuring 0.130x0.110x0.060 mm was mounted on a Cryoloop with paratone oil. Data were collected in a nitrogen gas stream at 90(2)K using phi and omega scanning. The crystal to detector distance was 40 mm and the exposure time was 0.05 seconds per frame using a scan width of 0.5°. Data collection was 100.0% complete up to 67.000° (θ). A total of 110828 reflections were collected, covering indices -12<=h<=12, -16<=k<=16, -41<=l<=41. 8734 reflections had an R of 0.0384. int The structure was found to be symmetry independent, with the lattice indexing and unit cell refinement indicating a simple orthorhombic lattice. The space group was found to be P 21 21 21 (No. 19). The data were integrated and scaled using CrysAlisPro 1.171.41.71a. Solution by iterative methods (SHELXT-2014) produced a full heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using a riding model. Their positions were restrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[0534] [Table 6]

[0535] Example 23: Ethylbenzene crystalline solvate compound 1

[0536] X-ray quality crystals were grown from a saturated ethylbenzene solution, followed by slow vapor diffusion of heptane to deposit the diffracting crystals. A colorless prism measuring 0.162x0.103x0.067mm was mounted on a Cryoloop with paratone oil. Data were collected in a nitrogen gas stream at 90(2)K using phi and omega scanning. The crystal to detector distance was 40mm and the exposure time was 0.25 seconds per frame using a scan width of 0.5°. Data collection was 100.0% complete up to 67.000°(θ). A total of 20385 reflections were collected, covering indices -16<=h<=16, -12<=k<=12, -42<=l<=42. The 20385 reflections had an R of 0.1540. int The structure was found to be symmetry independent, with a . Indexing and unit cell refinement indicated a simple monoclinic lattice. The space group was found to be P 21 (No. 4). Data were integrated and scaled using CrysAlisPro 1.171.41.71a. Solution by iterative methods (SHELXT-2014) produced a full heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using a riding model. Their positions were restrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[0537] [Table 7]

[0538] Example 24: m-Xylene Crystalline Solvate Compound 1

[0539] X-ray quality crystals were grown from saturated m-xylene solutions followed by slow vapor diffusion of heptane to deposit diffracting crystals. A colorless prism measuring 0.190x0.170x0.130 mm was mounted on a Cryoloop using paratone oil. Data were collected in a nitrogen gas stream at 90(2)K using phi and omega scanning. The crystal to detector distance was 40 mm and the exposure time was 0.1 sec per frame using a scan width of 0.5°. Data collection was 100.0% complete up to 67.000° (θ). A total of 115184 reflections were collected covering indices -11<=h<=12, -16<=k<=16, -40<=l<=40. 8996 reflections had an R of 0.0373. int The structure was found to be symmetry independent, with the lattice indexing and unit cell refinement indicating a simple orthorhombic lattice. The space group was found to be P 21 21 21 (No. 19). Data were integrated and scaled using CrysAlisPro 1.171.41.71a. Solution by iterative methods (SHELXT-2014) produced a full heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using a riding model. Their positions were restrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was determined to be S at C12.

[0540] [Table 8]

[0541] Example 25: Toluene crystalline solvate compound 1

[0542] X-ray quality crystals were grown from saturated toluene solution, followed by slow vapor diffusion of heptane to deposit the diffracting crystals. A colorless prism measuring 0.150x0.130x0.110 mm was mounted on a Cryoloop using paratone oil. Data were collected in a nitrogen gas stream at 90(2)K using phi and omega scanning. The crystal to detector distance was 40 mm and the exposure time was 0.1 seconds per frame using a scan width of 0.5°. Data collection was 100.0% complete up to 67.000° (θ). A total of 329491 reflections were collected, covering indices -12<=h<=12, -41<=k<=41, -50<=l<=49. 26769 reflections had an R of 0.0335. int The structure was found to be symmetry independent, with the lattice indexing and unit cell refinement indicating a simple orthorhombic lattice. The space group was found to be P 21 21 21 (No. 19). The data were integrated and scaled using CrysAlisPro 1.171.41.70a. Solution by iterative methods (SHELXT-2014) produced a full heavy atom phasing model. All non-hydrogen atoms were anisotropically refined by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using a riding model. Their positions were restrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018. The absolute stereochemistry was unambiguously determined to be S at all chiral centers.

[0543] [Table 9]

[0544] All technical and scientific terms used herein have the same meaning. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0545] Throughout this specification and the claims, the words "comprise," "comprises," and "comprising" are used in their non-exclusive sense, unless the context requires otherwise. It is understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0546] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of the range and any other stated or intervening value in that stated range is included herein. The upper and lower limits of these smaller ranges that may be independently included in the smaller ranges are also included herein, subject to any specifically excluded limit in the stated range. Where one or both of the limits are included in the stated range, ranges excluding either or both of those included limits are also included herein.

[0547] Many modifications and other embodiments of the inventions described herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that 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.

Claims

1. Formula (I) (In the formula, X ０ is hydrogen, halogen, OR ５Ａ , S.R. 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 is heteroaryl; X １ is hydrogen or halogen; X ３ is hydrogen, halogen, R ６ -substituted or unsubstituted C １－３ Alkyl, R ６ -substituted or unsubstituted C １－３ Haloalkyl, R ６ -substituted or unsubstituted C １－３ Alkoxy or R ６ - substituted or unsubstituted cyclopropyl; R １ is hydrogen or PG １ and 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 is cycloalkyl; R ３Ａ is halogen, OH, CN, unsubstituted C １－３ Alkyl or unsubstituted C １－３ haloalkyl; R ４ is R ４Ａ - substituted or unsubstituted C １－３ haloalkyl; R ４Ａ is unsubstituted C １－３ is alkyl; R ５ is halogen, cyano, OH, NO ２ , 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- to 6-membered heterocycle, R ５Ａ - substituted or unsubstituted phenyl, or R ５Ａ - substituted or unsubstituted 6-membered heteroaryl; R ５Ａ and R ５Ｂ are each independently 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- to 7-membered heterocycle, R ５Ｃ -substituted or unsubstituted C ５－７ Aryl, or R ５Ｃ -substituted or unsubstituted C ５－７ is heteroaryl; R ５Ｃ are independently halogen, OH, CN, NO ２ , R ５Ｄ -substituted or unsubstituted C １－６ Alkyl, R ５Ｄ -substituted or unsubstituted C １－６ Haloalkyl, R ５Ｄ -substituted or unsubstituted C ３－７ Cycloalkyl, R ５Ｄ -substituted or unsubstituted C ３－７ Heterocycle R ５Ｄ -substituted or unsubstituted C ５－７ Aryl, or R ５Ｄ -substituted or unsubstituted C ５－７ is heteroaryl; R ５Ｄ are independently halogen, OH, CN, NO ２ , unsubstituted C １－６ Alkyl, unsubstituted C １－６ Haloalkyl, unsubstituted C ３－７ Cycloalkyl, unsubstituted C ３－７ Heterocycle, unsubstituted C ５－７ Aryl or unsubstituted C ５－７ is heteroaryl; R ６ is halogen, OH, CN, NO ２ , unsubstituted C １－６ Alkyl, unsubstituted C １－６ Haloalkyl, or unsubstituted C ３－７ is cycloalkyl; n is 0, 1 or 2; Each PG is independently an amino protecting group, or two PGs together form C ３－７ forming a nitrogen heterocycle; and P.G. １ is an amino protecting group) 1. A process for the preparation of a compound of the formula (a) a compound represented by formula (II) (In the formula, X ２ is a halogen) with an organomagnesium compound and a zinc complex; and (b) reacting the mixture of step (a) with a solution of the formula (III) (In the formula, X ４ is a halogen), a transition metal catalyst precursor, and a chiral ligand, thereby synthesizing a compound of formula (I).

2. The compound of formula (II) may be prepared by the following process: (a) Formula (IVa) The compound of formula (In the formula, X ３ is a halogen, to form a compound having the formula (IVb): producing a compound of formula (I); (d) reacting said compound of formula (IVb) with a compound of formula (V) cyclizing to a compound of formula (I); (d) contacting said compound of formula (V) with a chlorinating agent to obtain a compound of formula (Va): and (e) reacting said compound of formula (Va) with a compound of formula by contacting a piperazinyl moiety having the formula (IIa) and (f) reacting said compound of formula (IIa) with X ０ to form a compound of formula (II); The method of claim 1 , wherein the compound is prepared by

3. The following steps: (a0) CO ２ In the presence of a gas, with a base to amine said compound to form a compound of formula (IVa) forming said compound of The method of claim 2 , further comprising:

4. The compound of formula (III) may be prepared by the following process: (a) a compound represented by formula (VII) The compound of formula NH ２ (PG), thereby contacting the compound having the formula (VIIa) producing a compound of formula (I); (b) reacting said compound of formula (VIIa) with a compound of formula X ａ PG (wherein X ａ is a halogen, to obtain a compound having the formula (VIIb): producing a compound of formula (I); (c) reacting said compound of formula (VIIb) with (In the formula, X ５ is a halogen, to obtain a compound having the formula (VIIc): producing a compound of formula (I); (d) haloalkylating said compound of formula (VIIc) with a haloalkylating agent to produce a compound of formula (VIId). (e) brominating said compound of formula (VIId) to obtain a compound of formula (VIIe) and (f) reacting said compound of formula (VIIe) with X ａ with PG to produce a compound of formula (III); The method according to any one of claims 1 to 3, wherein the composition is prepared by

5. The compound of formula (III) may be prepared by the following process: (a) Formula (VIII) (wherein X ６ is Cl or I) with a halogenating agent to obtain a compound of formula (VIIIa) forming a compound of (b) brominating said compound of formula (VIIIa) to give a compound of formula (VIIIb) forming a compound of the formula: (c) reacting said compound of formula (VIIIb) with a compound of formula NH(PG) ２ with a compound having formula (III) The method of claim 1 , wherein the compound is prepared by

6. The compound of formula (III) may be prepared by the following process: (a) Formula (VIIIc) with a brominating agent to obtain a compound of formula (VIIId): forming a compound of (b) contacting said compound of formula (VIIId) with a halogenating agent to produce a compound of formula (VIIIb): forming a compound of (c) reacting said compound of formula (VIIIb) with a compound of formula NH(PG) ２ with a compound having formula (III) The method of claim 1 , wherein the compound is prepared by

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

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

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

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

11. X ３ is halogen or unsubstituted C １－３ The method of any one of claims 1 to 8, wherein the alkyl group is haloalkyl.

12. X ３ is unsubstituted C １－３ The method of any one of claims 1 to 8, wherein the aryl group is alkoxy or unsubstituted cyclopropyl.

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

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

15. X ３ But Cl, F, CF ３ , C.H.F. ２ or CH ２ The method according to any one of claims 1 to 8, wherein F is

16. X ３ But, CF ３ , C.H.F. ２ or CH ２ The method according to any one of claims 1 to 8, wherein F is

17. R １ P.G. １ The method according to any one of claims 1 to 16, wherein

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

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

20. R ２ The method of any one of claims 1 to 19, wherein is halogen or cyano.

21. R ２ is unsubstituted C １－６ Alkyl, unsubstituted C １－６ Cyanoalkyl, or unsubstituted C １－６ The method of any one of claims 1 to 19, wherein the alkyl group is haloalkyl.

22. R ２ is unsubstituted C １－６ Alkyl or unsubstituted C １－６ The method of any one of claims 1 to 19, wherein the alkyl group is a cyanoalkyl group.

23. R ２ is unsubstituted C １－６ Alkyl or unsubstituted C １－６ The method of any one of claims 1 to 19, wherein the alkyl group is haloalkyl.

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

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

26. R ２ But, CF ３ , C.H.F. ２ or CH ２ The method according to any one of claims 1 to 19, wherein F is

27. R ２ CH ２ 20. The method according to any one of claims 1 to 19, wherein the compound is CN.

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

29. R ３ But, R ３Ａ -substituted or unsubstituted C １－３ Alkyl, R ３Ａ -substituted or unsubstituted C １－３ The method of any one of claims 1 to 27, wherein the aryl group is haloalkyl or cyclopropyl.

30. R ３ But, R ３Ａ -substituted or unsubstituted C １－３ Alkyl or R ３Ａ -substituted or unsubstituted C １－３ The method of any one of claims 1 to 27, wherein the alkyl group is haloalkyl.

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

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

33. R ４ But, CF ３ , C.H.F. ２ or CH ２ The method according to any one of claims 1 to 32, wherein F is

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

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

36. The two PGs together form the following structure: The method of any one of claims 1 to 34, further comprising forming a part having

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

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

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

40. The transition metal catalyst precursor is a Pd or Ni catalyst precursor, and Pd(OAc) ２ , PdCl ２ , PdCl ２ (MeCN) ２ , Pd(benzonitrile) ２ C ２、 Pd(dba) ２ , Pd ２ (dba) ３ , Pd(PPh ３ ) ４ , Pd(PCy ３ ) ２ , Pd(PtBu ３ ) ２ , Pd(TFA) ２ , [Pd(allyl)Cl] ２ [Pd(cinnamyl)Cl] ２ , [PdCl(crotyl)] ２ , PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl ２ , NiBr ２ , Ni(OAc) ２ and nickel(II) acetylacetonate.

41. The chiral ligand is and During the ceremony, Y is O or NR ７ and Z is O or N; R ７ and R ８ is independently an unsubstituted C １－６ is alkyl; R ９ and R １０ are independently R １１ -substituted or unsubstituted C ５－６ Cycloalkyl or R １１ - substituted or unsubstituted phenyl; Each R １１ are independently hydrogen, C １－６ Unsubstituted alkyl, or C １－６ unsubstituted haloalkyl; R １２ and R １３ are each independently 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 is heteroaryl; Each R １４ is independently an unsubstituted C １－４ The method of any one of claims 1 to 40, wherein the alkyl group is alkyl.

42. R ７ and R ８ 42. The method of claim 41 , wherein

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

44. 3. The method of claim 2, wherein the base is LDA or LiTMP.

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

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

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

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

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

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

51. The compound of formula (II) has the formula: (In the formula, X ３ The method of claim 1 , wherein

52. The compound of formula (II) has the formula: (In the formula, X ３ The method of claim 1 , wherein

53. The compound of formula (II) has the formula:

2. The method of claim 1, comprising:

54. The compound of formula (III) has the formula:

2. The method of claim 1, comprising:

55. R ３ is unsubstituted C １－３ 55. The method of claim 54, wherein said alkyl is alkyl.

56. R ４ is unsubstituted C １－３ 56. The method of claim 54 or 55, wherein the alkyl group is haloalkyl.

57. The compound of formula (III) has the formula:

2. The method of claim 1, comprising:

58. The compound of formula (I) has the formula:

2. The method of claim 1, comprising:

59. The compound of formula (I) has the formula:

2. The method of claim 1, comprising:

60. R ３ is unsubstituted C １－３ 60. The method of claim 58 or 59, wherein said alkyl is alkyl.

61. R ４ is unsubstituted C １－３ The method of any one of claims 58 to 60, wherein the alkyl group is haloalkyl.

62. The compound of formula (I) has the formula:

2. The method of claim 1, comprising:

63. R ２ is unsubstituted C １－６ Alkyl, unsubstituted C １－６ Cyanoalkyl, or unsubstituted C １－６ The method of any one of claims 58 to 62, wherein the alkyl group is haloalkyl.

64. R ２ Methyl, ethyl, CN, CH ２ C.N., C.F. ３ , C.H.F. ２ or CH ２ 64. The method of claim 63, wherein said amino acid is F.

65. R ２ is methyl, ethyl, CN or CH ２ CN. The method of claim 63.

66. The compound of formula (I) has the formula: (In the formula, X ３ The method of claim 1 , wherein

67. The compound of formula (I) has the formula:

2. The method of claim 1, comprising:

68. X ０ However, hydrogen, halogens, and CF ３ , C.H.F. ２ , C.H. ２ F, or the following structure: The method of claim 1 , wherein the moiety has the formula:

69. Formula (Id): (In the formula, X ３ is a halogen.

70. Formula (1): A compound having the formula:

71. Step (f) is Step (g) reacting the compound of formula (IIa) with a compound of formula (IIa1) 3. The method of claim 2, further comprising fluorinating the compound of formula:

72. Step (f) is Step (h) reacting the compound of formula (IIa) with a compound of formula (IId) The method of claim 2, further comprising alkoxylating the compound of formula (I).

73. Step (f) is Step (j) reacting the compound of formula (IIa) with a compound of formula (IIe) The method of claim 2, further comprising thiolating the compound of formula (I).

74. The method of any one of claims 1 to 6, wherein said compound of formula (I) is a compound of Table 1.

75. formula: or a pharma- ceutically acceptable salt thereof, comprising: (a) Formula (2) or a salt thereof in the presence of i-PrMgCl.LiCl and ZnCl ２ followed by contacting with NaTFA and a compound of formula (3) contacting the compound of (b) contacting the mixture of step (a) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand, thereby forming a compound of formula (1): or a solvate or salt thereof; (c) reacting the compound of formula (1) or a solvate or salt thereof with a compound of formula HO-X Ａ (In the formula, X Ａ is the formula and a base, whereby or a solvate or a pharma- ceutically acceptable salt thereof; (d) contacting said compound of formula (1d) with MsOH in an acid, thereby producing a compound of formula (1e): or a solvate or a pharma- ceutically acceptable salt thereof; and (e) reacting the compound of formula (1e) or a solvate or a pharma- ceutically acceptable salt thereof in the presence of a base and, optionally, an activating agent, thereby producing a compound of formula (A) or a pharma- ceutically acceptable salt thereof.

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

77. Step (e) comprises reacting said compound of formula (1e) or a solvate or a pharma- ceutically acceptable salt thereof with 76. The method of claim 75, comprising contacting said

78. Step (e) comprises reacting said compound of formula (1e) or a solvate or a pharma- ceutically acceptable salt thereof with 76. The method of claim 75, comprising contacting said

79. Step (e) is reacting, in the presence of a base and an activating agent, with a compound of formula 76. The method of claim 75, comprising the compound of formula:

80. Step (e) is a reaction of formula and a base.

81. Process:

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

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