Synthesis of RAS inhibitors

Abstract

The present invention relates to Ras inhibitors and methods for preparing Ras inhibitors.

Description

[Technical Field]

[0001] This invention relates to the synthesis of RAS inhibitors. [Background technology]

[0002] The vast majority of small molecule drugs act by binding to functionally important pockets on target proteins, thereby regulating the activity of those proteins. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrate. The fact that many such drug / target interaction pairs are known may have led some to mistakenly believe that, with reasonable time, effort, and resources, small molecule modulators can be discovered for most, if not all, proteins. This is far from the truth. Current estimates suggest that only about 10% of all human proteins are targetable by small molecules (Non-Patent Literature 1). The other 90% are currently considered refractory or refractory to the small molecule drug discovery described above. Such targets are commonly referred to as "undruggable." These undruggable targets represent a vast and untapped reservoir of clinically important human proteins. Therefore, there is considerable interest in discovering novel molecular modalities that can control the function of such undruggable targets.

[0003] Ras proteins (K-Ras, H-Ras, and N-Ras) play essential roles in various human cancers, and are therefore well-established in the literature as appropriate targets for anti-cancer therapies. In fact, mutations in the Ras protein account for approximately 30% of all human cancers in the United States, many of which are lethal. Dysregulation of the Ras protein due to mutation activation, overexpression, or upstream activation is common in human tumors, and mutation activation in Ras is frequently found in human cancers. For example, activation of a mutation at codon 12 in the Ras protein functions by inhibiting both the GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly distorting the population of Ras mutant proteins into an "on" (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. In particular, Ras exhibits picomolar affinity for GTP, allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations in codon 13 of Ras (e.g., G13C) and codon 61 (e.g., Q61K) also contribute to oncogenic activity in some cancers. Despite extensive drug discovery efforts against Ras over the past several decades, only two drugs targeting the K-Ras G12C variant (sotrasib and adaglav) have been approved in the United States. Further efforts are needed to identify additional drugs for cancers driven by various Ras mutations. There is also still a need for simple and scalable synthetic methods for this purpose. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019) [Overview of the Initiative]

[0005] The present invention is characterized by a method for preparing compound A, an intermediate useful for the synthesis of compound A, and a method for preparing the intermediate. Compound A, which is a RAS inhibitor, has the following structure: [ka]

[0006] In the first aspect, this disclosure relates to compound 1: [ka] A method for preparing, a) Reacting compound 1a and compound 1b to form compound 1c: [ka] b) Oxidizing and hydrolyzing compound 1c to form compound 1d: [ka] Furthermore c) Cyclizing compound 1d to form compound 1: [ka] This provides a method that includes [something].

[0007] In some embodiments, reaction step (a) includes contacting compounds 1a and 1b with a base. In some embodiments, the base is sodium hydroxide. In some embodiments, reaction step (a) is carried out in the presence of hydroquinone.

[0008] In some embodiments, the oxidation and hydrolysis step (b) is carried out in the presence of sulfuric acid and nitric acid. In some embodiments, the oxidation and hydrolysis step (b) includes a first step of oxidizing compound 1c to compound 1e and a second step of hydrolyzing compound 1e to compound 1d: [ka]

[0009] In some embodiments, the oxidation step includes contacting NaClO2 with compound 1c. In some embodiments, the hydrolysis step includes contacting potassium hydroxide with compound 1e. In some embodiments, the second step further includes protonating compound 1d by contacting the reactants with hydrochloric acid.

[0010] In some embodiments of the method for preparing compound 1, the cyclization step (c) includes contacting acetic anhydride with compound 1d.

[0011] In some embodiments, the method further includes purifying compound 1 by decolorization using activated carbon. In some embodiments, compound 1 is purified by recrystallization. In some embodiments, recrystallization is repeated multiple times. In some embodiments, recrystallization is carried out under methyl tert-butyl ether and n-heptane.

[0012] In another embodiment, the present disclosure relates to a compound of formula II: [ka] or its salt (wherein R 1 This includes optionally substituted C1-C6 alkyl groups, optionally substituted 3-10 member cycloalkyl groups, or optionally substituted C6-C 10 Provides (which is an arrow). In some embodiments, R 1 This is a C1-C6 alkyl group (e.g., methyl) that has been optionally substituted.

[0013] In some embodiments, the compound has the structure of formula IIa: [ka] It has or is a salt thereof, in the formula R 1 This is a C1-C6 alkyl group that is optionally substituted, a 3-10 member cycloalkyl group that is optionally substituted, or a C6-C6 alkyl group that is optionally substituted. 10 It is an arrow. In some embodiments, R 1 This is a C1-C6 alkyl group (e.g., methyl) that has been optionally substituted.

[0014] In a further embodiment, the present disclosure provides a method for preparing compound 2a. The method is as follows: a) Esterilizing compound 2b to form compound 2c: [ka] b) Protecting and tosyling compound 2c to form compound 2d: [ka] Furthermore c) Iodinating compound 2d to form compound 2a: [ka] Includes.

[0015] In some embodiments of the method for preparing compound 2a, the esterification step (a) includes contacting compound 2b with a protic solvent of thionyl chloride (e.g., a methanol solution).

[0016] In some embodiments, the protection and tosylation step (b) includes a first step of protecting compound 2c to form compound 2e and a second step of tosyling compound 2e to form compound 2d: [ka]

[0017] In some embodiments, the first protection step includes contacting di-tert-butyl dicarbonate with compound 2c, and the second tosylation step includes contacting tosyl chloride with compound 2e.

[0018] In some embodiments, the iodination step (c) includes contacting compound 2d with sodium iodide.

[0019] In one embodiment, the present disclosure provides a method for preparing compound 3: [ka] The method is, a) Contacting compound 3a and compound 3b in the presence of a base to form compound 3c: [ka] Furthermore b) Hydrolyzing compound 3c to form compound 3: [ka] Includes.

[0020] In some embodiments, the base in step (a) is n-butyllithium. In some embodiments, the contact step (a) is carried out using a flow process.

[0021] In another aspect, the present disclosure relates to a compound having the structure of compound 4: [ka] or its salt (wherein R is H or [ka] It provides (which is). In some embodiments, R is H. In some embodiments, R is [ka] That is the case.

[0022] In some embodiments, the compound has the structure of formula IIIa: [ka] It has or is a salt thereof, where R is H or [ka] In some embodiments, R is H. In some embodiments, R is [ka] That is the case.

[0023] In yet another aspect, the present disclosure relates to a compound having the structure of compound 5: [ka] or provide a salt thereof.

[0024] In some embodiments, the compound has the structure of compound 5a: [ka] It has or is a salt thereof.

[0025] In yet another aspect, the present disclosure relates to a compound having the structure of compound 6: [ka] or provide a salt thereof.

[0026] In some embodiments, the compound has the structure of compound 6a: [ka] It has or is a salt thereof.

[0027] In another aspect, the present disclosure provides a method for preparing compound 6a. The method is as follows: a) Borylating compound 7 to form compound 4a: [ka] b) Coupling compound 4a and compound 6b to form compound 5a: [ka] Furthermore c) Borylating compound 5a to form compound 6a: [ka] Includes.

[0028] In some embodiments, the method for preparing compound 6a is as follows: a) Borylating compound 7 to form compound 4a: [ka] b) Coupling compound 4a and compound 6b to form compound 5a: [ka] Furthermore c) Borylating compound 5a to form compound 6a: [ka] comprising.

[0029] In some embodiments, the borylation step (a) comprises contacting compound 7 with an iridium catalyst. In some embodiments, the coupling step (b) comprises contacting compound 4a and compound 5a with a copper source. In some embodiments, the copper source is Cu(OAc)2. In some embodiments, the coupling step (b) comprises a reaction in batch mode. In some embodiments, the coupling step (b) comprises a reaction in flow mode. In some embodiments, the borylation step (c) comprises contacting compound 5a with a palladium catalyst and a boron source.

[0030] In another aspect, the present disclosure provides a compound having the structure of formula I:

Chem.

[0031] In some embodiments, the compound has the structure of formula Ia:

Chem.

[0032] In some embodiments, R 1 is H. In some embodiments, R 1 is CH3.

[0033] In one aspect, the present disclosure provides a method for preparing compound 9:

Chem.

[0034] The method comprises a) Coupling compound 2a with compound 9a to form compound 9b: [ka] b) Hydrolyzing compound 9b to form compound 9c: [ka] c) Coupling compound 9c and compound 9d to form compound 9e: [ka] d) Deprotecting compound 9e to form compound 9f: [ka] e) Couple compound 9f with compound 3 to form compound 9g: [ka] Furthermore f) Hydrolyze 9g of compound to form compound 9: [ka] Includes.

[0035] In some embodiments, the coupling step (a) includes contacting compound 2a with a zinc source to form compound 2a-Zn: [ka]

[0036] In some embodiments, the coupling step (a) includes contacting compound 2a-Zn and compound 9a with a palladium catalyst.

[0037] In some embodiments, the coupling step (c) includes contacting compound 9c and compound 9d with EDCI.

[0038] In some embodiments, the coupling step (e) includes contacting compound 9f and compound 3 with EDCI.

[0039] In a further embodiment, the present disclosure provides a method for preparing compound A. The method is as follows: a) Contact compound 6a with pinacol to form compound 10: [ka] b) Esterilizing compound 9 with compound 10 to form compound 11: [ka] Furthermore c) Cyclizing compound 11 to form compound A: [ka] Includes.

[0040] In some embodiments, the esterification step (b) includes contacting compounds 9 and 10 with EDCI. In some embodiments, the cyclization step (c) includes contacting compound 11 with a palladium catalyst.

[0041] In another aspect, the present disclosure relates to a method for preparing compound A, a) Coupling compound 6a and compound 9 to form compound 12: [ka] Furthermore b) Lactonizing compound 12 to form compound A: [ka] This provides a method that includes [something].

[0042] In some embodiments, the coupling step (a) includes contacting compound 6a and compound 9 with a palladium catalyst.

[0043] In some embodiments, the lactonization step (b) includes contacting compound 12 with EDCI.

[0044] In some embodiments of the method for preparing compound A, the method further comprises purifying compound A. In some embodiments, the purification comprises forming a salt of compound A. In some embodiments, the salt of compound A is the hydrochloride salt of compound A. In some embodiments, the salt of compound A is the lactate salt of compound A.

[0045] In some embodiments, purification involves converting a salt of compound A to the free base form of compound A. In some embodiments, converting a salt of compound A to the free base form of compound A involves contacting the salt of compound A with a base. In some embodiments, the base is sodium carbonate. In some embodiments, the method further includes precipitating the free base form of compound A from a solution. In some embodiments, precipitation involves adding heptane to the solution of the free base form of compound A. In some embodiments, the free base form of compound A is dried under humidity and nitrogen gas.

[0046] In some embodiments, purification involves recrystallizing compound A. In some embodiments, recrystallization involves adding a first solvent, followed by the addition of a second solvent. In some embodiments, the first solvent is a protic solvent. In some embodiments, the first solvent is methanol. In some embodiments, the second solvent is water.

[0047] In yet another aspect, the present disclosure relates to a compound having the structure of compound 10: [ka] or provide a salt thereof.

[0048] In some embodiments, the present disclosure relates to a compound having the structure of formula IV: [ka] The formula provides (wherein X is a boronic acid, a boronic acid ester, or a halogen).

[0049] In a further embodiment, the present disclosure relates to a compound having the structure of compound 11: [ka] or provide a salt thereof.

[0050] In another aspect, the present disclosure relates to a compound having the structure of compound 12: [ka] or provide a salt thereof.

[0051] Definitions and Chemical Terms In this application, unless otherwise clearly indicated by the context, (i) the term “one (a)” means “one or more”; (ii) the term “or” is used to mean “and / or” unless it is explicitly indicated that it means only alternative expressions or that such alternative expressions are mutually exclusive, however this disclosure supports the definitions that refer only to alternative expressions and to “and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or processes, whether presented by themselves or together with one or more additional components or processes; and (iv) where a scope is indicated, it includes endpoints.

[0052] As used herein, the term “approximately” is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value. In certain embodiments, unless otherwise stated or evident from the content (for example, if such a number may exceed 100% of the possible values), the term “approximately” refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% or less in either direction (above or below) the stated value.

[0053] As used herein, the term "adjacent" in the context of describing adjacent atoms means divalent atoms directly bonded by a covalent bond.

[0054] As used herein, “compounds of the present invention” and similar terms mean, whether expressly stated or not, the Ras inhibitors described herein (e.g., compound A) and intermediates in their synthesis, as well as their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers.

[0055] Those skilled in the art will understand that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., hydrogen substituted with deuterium, in which one or more atoms are substituted with different isotopes of that atom). Unless otherwise specified or made clear from the context, the described structures can be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0056] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Any stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active forms or as racemates. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers, such as olefins and C=N double bonds, may also exist among the compounds described herein, and all such stable isomers are intended in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure are described and may be isolated as mixtures of isomers or as separated isomers.

[0057] In some embodiments, one or more compounds described herein may exist in different tautomerized forms. As will be apparent from the context, unless explicitly excluded, references to such compounds encompass all such tautomerized forms. In some embodiments, the tautomerized form arises from the exchange of a single bond with an adjacent double bond and the accompanying transfer of a proton. In certain embodiments, the tautomerized form may be a prototropic tautomer, which is a protonated state of an isomer having the same empirical formula and total charge as the reference form. Examples of moieties having a prototropic tautomerized form include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. In some embodiments, the tautomer morphs can be sterically fixed to one morph either in equilibrium or by appropriate substitution. In certain embodiments, the tautomer morphs arise from acetal interconversion.

[0058] Unless otherwise specified, the structures shown herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include: 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 Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. Isotope-labeled compounds (e.g.,3 H and 14 Compounds labeled with 1C may be useful in compound or substrate tissue distribution assays. Tritium labeling (i.e., 3 H), and carbon-14 (i.e., 14 C) Isotopes may be useful due to their ease of preparation and detection. Furthermore, heavier isotopes, such as deuterium (i.e., 2 Substitution with H) etc. can lead to greater metabolic stability, which may result in certain therapeutic benefits (e.g., longer in vivo half-life or reduced dosage). In some embodiments, one or more hydrogen atoms are 2 H or 3 Replaced by H, or one or more carbon atoms 13 C or 14 It is replaced by carbon-rich carbon. 15 O, 13 N, 11 C and 18 Positron-emitting isotopes such as fluorine are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents, following a procedure similar to the procedure disclosed for the compounds of the present invention as described herein.

[0059] As is known from the prior art, many chemical components can be used in various different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including any solid form. In some embodiments, the compounds described or explained herein can be provided or used in hydrate or solvate form.

[0060] In various parts of this specification, substituents of the compounds of this disclosure are disclosed by group or range. This disclosure is specifically intended to include each individual partial combination of members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. Furthermore, where a compound includes multiple positions in which substituents are disclosed by group or range, this disclosure is intended to include individual compounds and groups of compounds (e.g., genus and sub-genus) including each and all individual member subcombinations at each position, unless otherwise specified.

[0061] The term “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X which is optionally substituted” (e.g., “alkyl which is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) itself is optional. As described herein, a particular compound of interest may contain one or more “optionally substituted” moieties. In general, “substituted” means that one or more hydrogens of a given moiety are replaced by a suitable substituent, e.g., one of the substituents or groups described herein, regardless of whether the term “optionally” precedes it. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each of its substitutable positions, and if two or more positions of any given structure can be replaced by two or more substituents selected from a particular group, the substituents are either the same at all positions or different at all positions. For example, in the term "optionally substituted C1-C6 alkyl-C2-C9 heteroaryl," the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The substituent combinations conceivable in this disclosure preferably result in the formation of stable or chemically suitable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions anticipating the production, detection, and, in certain embodiments, their recovery, purification, and use for one or more purposes disclosed herein.

[0062] The preferred monovalent substituents on the replaceable carbon atoms of the "optionally substituted" groups are, independently, deuterium, halogen, -(CH2)O-4R°, -(CH2)O-4OR°, -O(CH2)O-4R°, -O-(CH2)O-4C(O)OR°, -(CH2)O-4CH(OR°)2, -(CH2)O-4SR°, -(CH2)O-4Ph[R°], -(CH2)O-4O(CH2)O-1Ph[R°], -CH=CHPh[R°], and -(CH2)O-4O(CH2)O-1-pyridyl[R°]. ]; 4-8 member saturated or unsaturated heterocycloalkyl (e.g., pyridyl); 3-8 member saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(R °)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2)0-4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)N R°2;-N(R°)N(R°)C(O)OR°;-(CH2)0-4C(O)R°;-C(S)R°;-(CH2)0-4C(O)OR°;-(CH2)0-4-C(O)-N(R o )2;-(CH2)O-4-C(O)-N(R o )-S(O)2-R o;-C(NCN)NR°2;-(CH2)0-4C(O)SR°;-(CH2)0-4C(O)OSiR°3;-(CH2)0-4OC(O)R°;-OC(O)(CH2)0-4SR°;-SC(S)SR°;-(CH2)0- 4SC(O)R°;-(CH2)0-4C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2)0-4OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R °;-C(NOR°)R°;-(CH2)0-4SSR°;-(CH2)0-4S(O)2R°;-(CH2)0-4S(O)2OR°;-(CH2)0-4OS(O)2R°;-S(O)2NR°2;-(CH2)0-4S(O )R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NOR°)NR°2;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-P(O)(OR°)2;-OP(O) R°2;-OP(O)(OR°)2;-OP(O)(OR°)R°, -SiR°3;-(C1-4 linear or branched alkylene)ON(R°)2; or -(C1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° may be substituted as defined below, independently of hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2-(5-6 membered heteroaryl ring), or nitrogen, oxygen, or A 3-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from sulfur, or, notwithstanding the above definition, two independently existing R°s, together with the atom(s) between them, form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0063] Suitable monovalent substituents on R° (or a ring formed by using two independently existing R° atoms together with the atoms in between) are, independently, halogens, -(CH2)O-2R ● ,-(HaroR ●), -(CH2)O-2OH, -(CH2)O-2OR ● ,-(CH2)0-2CH(OR ● )2;-O(HaroR ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ● ,-(CH2)0-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● ,-(CH2)0-2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● -(C1-4 linear or branched alkylene)C(O)OR ● , or -SSR ● It can be, and in the formula, each R ● It is either unsubstituted or, if preceded by "halo", substituted by only one or more halogens, and independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents on the saturated carbon atom of R° include =O and =S.

[0064] Suitable divalent substituents on the saturated carbon atoms of the "optionally substituted" groups include: =O, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2))2-3O-, or -S(C(R * 2))2-3S-(In the formula, each independent R *(The group is selected from hydrogen, a C1-6 aliphatic group which can be substituted as defined below, or an unsubstituted, 5-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.) A preferred divalent substituent bonded to the vicinal substituteable carbon of the "optionally substituted" group is -O(CR * 2) 2-3O- is an example, and in the formula, each R exists independently. * This is selected from hydrogen, a C1-6 aliphatic which can be substituted as defined below, or an unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0065] R * Suitable substituents on the aliphatic group include halogens and -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, and in the formula, each R ● It is either unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, and is independently a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or nitrogen, oxygen, or sulfur.

[0066] A suitable substituent on the substituted nitrogen of the "optionally substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR †2. -C(NH)NR † 2. or -N(R † )S(O)2R † is exemplified, where each R † is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-6 membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two independently present R † together with the intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0067] R † Suitable substituents on the aliphatic group of are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, where "halo" precedes, is substituted only by one or more halogens and is independently C_{1}-C_{4} aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered, saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom of R † include =O and =S.

[0068] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0069] As used herein, the term "alkoxy" refers to -O-C1-C 20Alkyl groups are formed when alkoxy groups are bonded to the rest of the compound via an oxygen atom.

[0070] As used herein, the term “alkyl” means a saturated, linear, or branched monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10, or 1 to 6) carbon atoms. In some embodiments, the alkyl group is unbranched (i.e., linear), and in some embodiments, the alkyl group is branched. Alkyl groups are exemplified by, but are not limited to, methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0071] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a saturated hydrocarbon, either linear or branched, by removing two hydrogen atoms, exemplified by methylene, ethylene, isopropylene, and the like. x -C y "Alkylene" refers to an alkylene group having x to y carbon atoms. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C 10 , C2-C 20 , C2-C6, C2-C 10 , or C2-C 20 Alkylene). In some embodiments, the alkylene may be further substituted with one, two, three, or four substituents as defined herein.

[0072] As used herein, the term “alkenyl” refers, unless otherwise specified, to a monovalent, linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds, exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyls include both cis and trans isomers. As used herein, the term “alkenylene” refers, unless otherwise specified, to a divalent, linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds.

[0073] As used herein, the term "alkynyl" refers to a monovalent linear or branched group consisting of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbon atoms) containing a carbon-carbon triple bond, as exemplified by ethynyl and 1-propynyl.

[0074] As used herein, the term "amino" means -N(R † )2, for example, represents -NH2 and -N(CH3)2.

[0075] As used herein, the term "aminoalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more amino moieties.

[0076] As used herein, the term “aryl” refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, wherein the ring bonded to the pendant group is aromatic. Examples of aryl groups include phenyl, naphthyl, phenantrenyl, and anthracenyl. The aryl ring may be bonded to its pendant group by any heteroatom or carbocyclic atom that provides a stable structure, and unless otherwise specified, any of the ring atoms may be optionally substituted.

[0077] As used herein, the term "C0" represents a bond. For example, part of the term -N(C(O)-(C0-C5alkylene-H)- includes -N(C(O)-(C0alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0078] As used herein, the terms "carbocyclic" and "carbocyclyl" refer to a monovalent C3- compound with optional substitution. 12 This refers to monocyclic, bicyclic, or tricyclic structures, which may be bridged, condensed, or spirocyclic, where all rings are formed of carbon atoms and at least one ring is non-aromatic. Examples of carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups include cyclohexyl, cyclohexenyl, cyclooctinyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, and dekalinyl. A carbocyclic ring can be bonded to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms may be optionally substituted.

[0079] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0080] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or the corresponding aprotonated group.

[0081] As used herein, the term "cyano" refers to the -CN group.

[0082] As used herein, the term "cycloalkyl" means a monovalent saturated cyclic hydrocarbon group, which may be crosslinked, condensed, or a spirocyclic group having 3 to 8 carbon atoms, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0083] As used herein, the term "cycloalkenyl" means a monovalent non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specified, may be crosslinked, condensed, or a spirocyclic group having 3 to 8 carbon atoms and containing one or more carbon-carbon double bonds.

[0084] As used herein, the term “diastereomer” means a stereoisomer that is not a mirror image of another and cannot be superimposed on another.

[0085] As used herein, “enantiomer” means each individual optically active form of the compound of the present invention having at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98% optical purity or enantiomer excess (measured by methods standard in the art).

[0086] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen atom is substituted with a halogen.

[0087] As used herein, the term "haloalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more identical or different halogen moieties.

[0088] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0089] As used herein, the term “heteroalkyl” refers to an “alkyl” group (as defined herein) in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may appear in the middle or at the ends of the radical.

[0090] As used herein, the term “heteroaryl” refers to a monovalent monocyclic or polycyclic cyclic structure containing at least one complete aromatic ring. That is, these contain 4n+2 π electrons within the monocyclic or polycyclic ring system and contain at least one ring heteroatom selected from N, O, or S within the aromatic ring. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term “heteroaryl” also includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings, such as a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindylol. The heteroaryl ring can be bonded to its pendant group at any ring atom that provides a stable structure, and unless otherwise specified, any of the ring atoms may be optionally substituted. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0091] As used herein, the term “heterocycloalkyl” refers to a monovalent monocyclic, bicyclic, or polycyclic ring system, which may be bridged, condensed, or spirocyclic, in which at least one ring is non-aromatic, and the non-aromatic ring contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have 0 to 2 double bonds, and six-membered and seven-membered rings have 0 to 3 double bonds. Exemplary unsubstituted heterocycloalkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term “heterocycloalkyl” also refers to heterocyclic compounds having a bridged polycyclic structure in which one or more carbons or heteroatoms bridge two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term "heterocycloalkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, pyridine ring, or pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthilidinyl. Heterocycloalkyl rings can be bonded to their pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms may be optionally substituted.

[0092] As used herein, the term "hydroxy" refers to the -OH group.

[0093] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more -OH moieties.

[0094] As used herein, the term “isomer” means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the present invention. Compounds of the present invention may have one or more chiral centers or double bonds and are therefore recognized to exist as stereoisomers, e.g., double bond isomers (i.e., geometric E / Z isomers), or diastereomers (e.g., enantiomers (i.e., (+) or (-), or cis / trans isomers)). According to the present invention, the chemical structures illustrated herein, i.e., compounds of the present invention, are recognized to exist as all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure forms, enantiomerically pure forms, or diastereoisomerically pure forms) and enantiomers. The present invention encompasses both thiomeric and stereoisomer mixtures, such as racemic compounds. Mixtures of enantiomers and stereoisomers of the compounds of the present invention can typically be separated into their constituent enantiomers or stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, recrystallization of the compound as a chiral salt complex, or recrystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0095] As used herein, the term “stereoisomer” means all possible different isomeric and structural forms that a compound may have (e.g., any compound of any formula described herein), in particular all possible stereochemical and structural isomeric forms of the basic molecular structure, including atropisomers, all diastereomers, enantiomers, or conformational isomers. Some of the compounds of the present invention may exist in different tautomers, all of which are included in the scope of the present invention.

[0096] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0097] As used herein, the term "thiocarbonyl" means a -C(S)- group.

[0098] The term "Boc" refers to structure [ka] This refers to a tert-butyloxycarbonyl or tert-butoxycarbonyl protecting group having a tert-butyloxycarbonyl protecting group.

[0099] The term "BPin" is structured as follows: [ka] This refers to a pinacolborane group having a pinacolborane group.

[0100] Those skilled in the art reading this disclosure will understand that certain compounds described herein may be provided or available in any of a variety of forms, such as salts, protected forms, prodrugs, esters, isomers (e.g., optical or structural isomers), and isotopic forms. In some embodiments, reference to a particular compound may relate to a particular form of that compound. In some embodiments, reference to a particular compound may relate to that compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound from a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt form of the compound; a preparation containing one structural isomer of a double bond ((Z) or (E)) may be considered a different form from one containing the other structural isomer of the double bond ((E) or (Z)); and a preparation in which one or more atoms are isotopes different from those present in the reference preparation may be considered a different form. [Modes for carrying out the invention]

[0101] Provided herein are a synthetic method for preparing Ras inhibitor compound A or a salt thereof and intermediates thereof. The method and intermediates can be useful for achieving higher yields, higher chemical purity, and / or higher stereoisomeric purity, as well as lower costs, with respect to the preparation of compound A. Further details of the synthesis are provided in the Examples. The structure of compound A is shown below.

Chemical formula

[0102] The compounds described herein can be prepared using the methods described herein and / or using known organic, inorganic, or enzymatic processes. The synthetic methods may employ the use of commercially available starting materials or starting materials prepared by processes known to those skilled in the art of organic synthesis. These methods include, but are not limited to, the methods described in the following schemes and the methods described in WO2021 / 091967 and WO2022 / 060836, the disclosures of each document being incorporated herein by reference.

[0103] In one aspect, the present disclosure provides a method for preparing compound 1:

Chemical formula

[0104] The method of preparation is a) reacting compound 1a and compound 1b to form compound 1c:

Chemical formula

Chemical formula

[0105] In some embodiments, reaction step (a) includes contacting compound 1a and compound 1b with a base. In some embodiments, the base is sodium hydroxide. In some embodiments, an excess of compound 1b is used relative to the amount of compound 1a. In some embodiments, 1.25 equivalents of compound 1b are used relative to compound 1a. In some embodiments, reaction step (a) is carried out in the presence of hydroquinone. In some embodiments, less than 1 equivalent (e.g., less than 0.9 equivalents, less than 0.5 equivalents, less than 0.25 equivalents, less than 0.1 equivalent, or less than 0.01 equivalent) of hydroquinone is used relative to the amount of compound 1a. In some embodiments, less than 0.01 equivalents of hydroquinone are used relative to the amount of compound 1a. In some embodiments, reaction step (a) is carried out under a solvent. In some embodiments, the solvent is an etheric solvent. In some embodiments, the solvent is dioxane. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, reaction step (a) is carried out above room temperature (e.g., above 20°C, above 30°C, above 40°C, above 50°C, above 60°C, or above 70°C). In some embodiments, reaction step (a) is carried out at 65°C. In some embodiments, reaction step (a) is carried out at 70-75°C.

[0106] In some embodiments, reaction step (a) is carried out according to the following scheme: [ka]

[0107] In some embodiments, reaction step (a) is carried out according to the following scheme: [ka]

[0108] In some embodiments, the oxidation and hydrolysis step (b) is carried out in the presence of sulfuric acid and nitric acid. In some embodiments, the reaction in the presence of sulfuric acid and nitric acid is carried out above room temperature (e.g., above 20°C, above 30°C, above 40°C, above 50°C, above 60°C, or above 70°C). In some embodiments, the reaction in the presence of sulfuric acid and nitric acid is carried out at 70–75°C.

[0109] In some embodiments, the oxidation and hydrolysis step (b) is carried out according to the following scheme: [ka] In some embodiments, the oxidation and hydrolysis step (b) includes a first step of oxidizing compound 1c to compound 1e and a second step of hydrolyzing compound 1e to compound 1d: [ka]

[0110] In some embodiments, the oxidation step includes contacting NaClO2 with compound 1c. In some embodiments, the oxidation step includes contacting compound 1c with NaClO2 and KH2PO4. In some embodiments, the oxidation step includes contacting compound 1c with NaClO2, KH2PO4, and DMSO. In some embodiments, the oxidation step is carried out under a solvent. In some embodiments, the solvent is water.

[0111] In some embodiments, the hydrolysis step comprises contacting potassium hydroxide and compound 1e. In some embodiments, compound 1e is contacted with more than 1 equivalent (e.g., more than 3 equivalents) of potassium hydroxide. In some embodiments, compound 1e is contacted with potassium hydroxide at a temperature above 30 °C (e.g., above 40 °C, above 50 °C, above 60 °C, above 70 °C, above 80 °C, or above 90 °C). In some embodiments, compound 1e is contacted with potassium hydroxide at 90 - 100 °C. In some embodiments, the second step further comprises protonating compound 1d by contacting the reaction product with hydrochloric acid.

[0112] In some embodiments of the method for preparing compound 1, the cyclization step (c) comprises contacting acetic anhydride and compound 1d. In some embodiments, the cyclization step (c) comprises contacting compound 1d with acetic anhydride for at least 1 hour. In some embodiments, the cyclization step (c) comprises contacting compound 1d with acetic anhydride at a temperature above 80 °C (e.g., 80 - 85 °C or 110 °C).

[0113] In some embodiments, the oxidation and hydrolysis step (b) and the cyclization step (c) are carried out according to the following scheme:

Chemical Formula

[0114] In some embodiments, the method further comprises purifying compound 1 by decolorization using activated carbon. In some embodiments, compound 1 is purified by recrystallization. In some embodiments, the recrystallization is repeated multiple times. In some embodiments, the recrystallization is carried out under methyl tert-butyl ether and n-hexane.

[0115] In a further aspect, the present disclosure provides a method for preparing compound 2a. The method comprises a) esterifying compound 2b to form compound 2c: [ka] b) Protecting and tosyling compound 2c to form compound 2d: [ka] Furthermore c) Iodinating compound 2d to form compound 2a: [ka] Includes.

[0116] In some embodiments of the method for preparing compound 2a, the esterification step (a) includes contacting compound 2b with a methanol solution of thionyl chloride. In some embodiments, compound 2b is contacted with a methanol solution of thionyl chloride at room temperature (e.g., 15–25°C, 20°C, or 25°C).

[0117] In some embodiments, the protection and tosylation step (b) includes a first step of protecting compound 2c to form compound 2e and a second step of tosyling compound 2e to form compound 2d: [ka]

[0118] In some embodiments, the first protection step includes contacting di-tert-butyl dicarbonate with compound 2c, and the second tosylation step includes contacting tosyl chloride with compound 2e. In some embodiments, the first protection step further includes contacting compound 2c with a base. In some embodiments, the base is sodium bicarbonate. In some embodiments, the second tosylation step further includes contacting compound 2e with a base. In some embodiments, the base is pyridine.

[0119] In some embodiments, the iodination step (c) includes contacting compound 2d with sodium iodide. In some embodiments, the iodination step (c) further includes contacting compound 2d with an acid. In some embodiments, the acid is citric acid.

[0120] In some embodiments, the method for preparing compound 2a is carried out according to the following scheme: [ka]

[0121] In one embodiment, the present disclosure provides a method for preparing compound 3: [ka] The method is, a) Contacting compound 3a and compound 3b in the presence of a base to form compound 3c: [ka] Furthermore b) Hydrolyzing compound 3c to form compound 3: [ka] Includes.

[0122] In some embodiments, the base in step (a) is n-butyllithium. In some embodiments, the contact step (a) is carried out using a flow process. In some embodiments, the hydrolysis step (b) includes contacting compound 3c with a hydroxide base. In some embodiments, the hydroxide base is sodium hydroxide. In some embodiments, the hydrolysis step (b) further includes contacting compound 3c with dicyclohexylamine. In some embodiments, the hydrolysis step (b) first forms a dicyclohexylamine salt of compound 3. In some embodiments, the hydrolysis step (b) further includes contacting the dicyclohexylamine salt of compound 3 with (R)-(+)-N-benzyl-1-phenylethylamine.

[0123] In some embodiments, the contact step (a) is carried out according to the following scheme: [ka]

[0124] In some embodiments, the hydrolysis step (b) is carried out according to the following scheme: [ka]

[0125] In some embodiments, this disclosure provides a method for preparing compound 6a. The method is as follows: a) Borylating compound 7 to form compound 4a: [ka] b) Coupling compound 4a and compound 6b to form compound 5a: [ka] Furthermore c) Borylating compound 5a to form compound 6a: [ka] Includes.

[0126] In some embodiments, the borylation step (a) includes contacting compound 7 with an iridium catalyst. In some embodiments, the borylation step (a) further includes contacting compound 7 with bis-(pinacolato)diborone. In some embodiments, the borylation step (b) is carried out according to the following scheme: [ka]

[0127] In some embodiments, coupling step (b) includes contacting compounds 4a and 6b with a copper source. In some embodiments, the copper source is Cu(OAc)2. In some embodiments, coupling step (b) includes a batch mode reaction. In some embodiments, coupling step (b) includes a flow mode reaction. In some embodiments, coupling step (b) further includes contacting compounds 4a and 6b with oxygen gas.

[0128] In some embodiments, the coupling step (b) is carried out according to the following scheme: [ka]

[0129] In some embodiments, the borylation step (c) includes contacting compound 5a with a palladium catalyst and a boron source. In some embodiments, the boron source is B2(OH)4. In some embodiments, the borylation step (c) is carried out according to the following scheme: [ka]

[0130] In some embodiments of the above reaction, 1.5 equivalents of B2(OH)4 are used. In some embodiments of the above reaction, 2.1 equivalents of KOPiv are used.

[0131] In some embodiments, the present disclosure provides a method for preparing compound 9: [ka]

[0132] The method is, a) Coupling compound 2a with compound 9a to form compound 9b: [ka] b) Hydrolyzing compound 9b to form compound 9c: [ka] c) Coupling compound 9c and compound 9d to form compound 9e: [ka] d) Deprotecting compound 9e to form compound 9f: [ka] e) Couple compound 9f with compound 3 to form compound 9g: [ka] Furthermore f) Hydrolyze 9g of compound to form compound 9: [ka] Includes.

[0133] In some embodiments, the present disclosure relates to compound 9c: [ka] The present invention provides a method for preparing a salt thereof.

[0134] The method is, a) Formylating compound 9c-1 to form compound 9c-2: [ka] b) Condensing compound 9c with malonic acid to form compound 9c-3: [ka] c) Amination of compound 9c-3 to form compound 9c-4 H2O: [ka] Furthermore d) Protecting compound 9c-4 to form compound 9c: [ka] Includes.

[0135] In some embodiments, the amination step c) is carried out using an enzyme. In some embodiments, the enzyme is phenylalanine ammonia lyase (PAL). PAL is well known in the art and can be obtained from Pharmaron (e.g., PH-AML-18), as well as from various suppliers such as Hande, Apeloa, and WuXi STA. In some embodiments, compound 9c prepared by this method can be used in a method for preparing compound 9.

[0136] In some embodiments, compound 9c is synthesized according to the following scheme: [ka]

[0137] In some embodiments, the coupling step (a) includes contacting compound 2a with a zinc source to form compound 2a-Zn: [ka]

[0138] In some embodiments, contacting compound 2a with a zinc source further includes contacting 2a with 1,2-dibromoethane. In some embodiments, contacting 2a with a zinc source further includes contacting compound 2a with trimethylsilyl chloride.

[0139] In some embodiments, the coupling step (a) includes contacting compound 2a-Zn and compound 9a with a palladium catalyst. In some embodiments, the coupling step (a) is carried out according to the following scheme: [ka]

[0140] In some embodiments, the hydrolysis step (b) is carried out according to the following scheme: [ka]

[0141] In some embodiments, coupling step (c) includes contacting compounds 9c and 9d with EDCI. In some embodiments, coupling step (c) further includes contacting compounds 9c and 9d with HOBt. In some embodiments, coupling step (c) is carried out according to the following scheme: [ka]

[0142] In some embodiments, deprotection step (d) includes contacting compound 9e with thionyl chloride. In some embodiments, deprotection step (d) is carried out according to the following scheme: [ka]

[0143] In some embodiments, the coupling step (e) includes contacting compound 9f and compound 3 with EDCI. In some embodiments, the coupling step (e) further includes contacting compound 9f and compound 3 with NMM. In some embodiments, the coupling step (e) further includes contacting compound 9f and compound 3 with HOBt.

[0144] In some embodiments, the coupling step (e) is carried out according to the following scheme: [ka]

[0145] In some embodiments, the hydrolysis step (f) is carried out according to the following scheme: [ka]

[0146] In a further embodiment, the present disclosure provides a method for preparing compound A. The method is as follows: a) Contact compound 6a with pinacol to form compound 10: [ka] b) Esterilizing compound 9 with compound 10 to form compound 11: [ka] Furthermore c) Cyclizing compound 11 to form compound A: [ka] Includes.

[0147] In some embodiments, the esterification step (b) includes contacting compounds 9 and 10 with EDCI. In some embodiments, the esterification step (b) further includes contacting compounds 9 and 10 with a base (e.g., DMAP).

[0148] In some embodiments, the esterification step (e) is carried out according to the following scheme: [ka]

[0149] In some embodiments, the cyclization step (c) includes contacting compound 11 with a palladium catalyst. In some embodiments, the cyclization step (c) is carried out according to the following scheme: [ka]

[0150] In another aspect, the present disclosure relates to a method for preparing compound A, a) Coupling compound 6a and compound 9 to form compound 12: [ka] Furthermore b) Lactonizing compound 12 to form compound A: [ka] This provides a method that includes [something].

[0151] In some embodiments, the coupling step (a) includes contacting compounds 6a and 9 with a palladium catalyst. In some embodiments, the palladium catalyst is Pd(dtbpf)Cl2. In some embodiments, the coupling step (a) further includes contacting compounds 6a and 12 with a base (e.g., potassium carbonate). In some embodiments, the coupling step (a) is carried out above room temperature (e.g., above 20°C, above 30°C, above 40°C, above 50°C, above 60°C, or above 70°C). In some embodiments, the coupling step (a) is carried out at 70-80°C.

[0152] In some embodiments, the coupling step (a) is carried out according to the following scheme: [ka]

[0153] In some embodiments, lactonization step (b) includes contacting compound 12 with EDCI. In some embodiments, lactonization step (b) further includes contacting compound 12 with one or more bases (e.g., DMAP and / or DIPEA). In some embodiments, lactonization step (b) further includes contacting compound 12 with HOBt. In some embodiments, lactonization step (b) is carried out according to the following scheme: [ka]

[0154] In some embodiments of the method for preparing compound A, the method further comprises purifying compound A. In some embodiments, the purification comprises forming a salt of compound A. In some embodiments, the salt of compound A is the hydrochloride salt of compound A. In some embodiments, the salt of compound A is the lactate salt of compound A. In some embodiments, the lactate salt of compound A is formed by contacting compound A with lactic acid (e.g., 1 equivalent, 2 equivalents, 3 equivalents, or 4 equivalents of lactic acid). In some embodiments, the contact of compound A with lactic acid is carried out in a solvent (e.g., acetonitrile).

[0155] In some embodiments, purification involves converting a salt of compound A to the free base form of compound A. In some embodiments, converting a salt of compound A to the free base form of compound A involves contacting the salt of compound A with a base. In some embodiments, the base is sodium carbonate. In some embodiments, contacting the salt of compound A with a base is carried out in an organic solvent (e.g., an etheric solvent such as 2-methyltetrahydrofuran). In some embodiments, the method further includes precipitation of the free base form of compound A from a solution. In some embodiments, precipitation involves adding heptane to the solution of the free base form of compound A.

[0156] In some embodiments, purification involves recrystallizing compound A. In some embodiments, recrystallization involves adding a first solvent, followed by the addition of a second solvent. In some embodiments, the first solvent is a protic solvent. In some embodiments, the first solvent is methanol. In some embodiments, the second solvent is water.

[0157] Compounds and intermediates This disclosure provides compounds and intermediates useful for the preparation of compound A. For example, in some embodiments, this disclosure provides compounds having the structure of compound 2: [ka] or provide a salt thereof.

[0158] In some embodiments, the compound has the structure of compound 2a: [ka] It has or is a salt thereof.

[0159] In another aspect, the present disclosure relates to a compound having the structure of compound 4: [ka] or provide a salt thereof.

[0160] In some embodiments, the compound has the structure of compound 4a: [ka] It has or is a salt thereof.

[0161] In yet another aspect, the present disclosure relates to a compound having the structure of compound 5: [ka] or provide a salt thereof.

[0162] In some embodiments, the compound has the structure of compound 5a: [ka] It has or is a salt thereof.

[0163] In yet another aspect, the present disclosure relates to a compound having the structure of compound 6: [ka] or provide a salt thereof.

[0164] In some embodiments, the compound has the structure of compound 6a: [ka] It has or is a salt thereof.

[0165] In another aspect, the present disclosure relates to a compound having the structure of formula I: [ka] or its salt (wherein R 1 It provides (which is H or C1-C6 alkyl).

[0166] In some embodiments, the compound has the structure of formula Ia: [ka] It has or is a salt thereof.

[0167] In some embodiments, R 1 H is H. In some embodiments, R 1 This is CH3.

[0168] In some embodiments, the present disclosure relates to a compound having the structure of compound 9c: [ka] or provide a salt thereof.

[0169] In some embodiments, the present disclosure describes a compound having the structure of compound 10: [ka] or provide a salt thereof.

[0170] In some embodiments, the present disclosure describes a compound having the structure of compound 11: [ka] or a salt thereof is provided. In some embodiments, Br can be replaced with a halogen suitable for the Suzuki reaction (e.g., iodide or chloride). In some embodiments, BPin can be replaced with a boronic acid ester suitable for the Suzuki reaction (e.g., neopentyl and catechol boronic acid esters).

[0171] In some embodiments, the present disclosure describes a compound having the structure of compound 12: [ka] or provide a salt thereof. [Examples]

[0172] This disclosure is further illustrated by the following examples and synthesis examples, which should not be considered to limit the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to imply any limitation on the scope of this disclosure. It should also be understood that various other embodiments, modifications, and equivalents can be taken, which themselves may be suggested to those skilled in the art, without departing from the spirit of this disclosure or the appended claims.

[0173] Example 1. Synthesis procedure for compound 13b-(S)-3-bromo-2-(1-methoxyethyl)pyridine.

[0174] The general synthesis procedure for compound 13b-(S)-3-bromo-2-(1-methoxyethyl)pyridine is described in detail below.

[0175] Synthesis of compound 13b-(S)-3-bromo-2-(1-methoxyethyl)pyridine. [ka] Part 1 - Synthesis of compound 13-1-(3-bromopyridine-2-yl)ethane-1-one. [ka] Toluene (2,100 L, 7V) and 3-bromopiccolinonitrile (300 kg, 1,639 mol, 1 equivalent) were added to the reactor. The resulting mixture was cooled to -20°C and maintained at -20°C. MeMgCl (3M in THF, 601 L, 1,803 mol, 1.1 equivalents) was then added. The resulting mixture was heated to 10-20°C and maintained at 10-20°C for 16 hours. At that point, HPLC analysis indicated that the reaction was complete.

[0176] The reaction mixture was added at -10 to 10°C to a pre-cooled 4M HCl aqueous solution (-10 to 0°C) (1,070 L, 2.6 equivalents), and the resulting mixture was maintained at 15 to 25°C for 30 minutes. The phases were separated, and the aqueous phase was extracted with toluene (600 L x 5, 2V x 5). The combined organic layers were washed with saturated NaHCO3 aqueous solution (100 L, 0.3V), and then concentrated to approximately 200 L (0.7V) (50 to 60°C, -0.08 MPa) to obtain crude 1-(3-bromopyridine-2-yl)ethane-1-one (compound 13) (346 kg, area specific purity 93.7%, weight specific assay value 83.4%, yield 88%, Table 1) as a brown oily substance, which was used directly in the next step. [Table 1] LRMS (ESI+) C7H7BrNO (M+H +Calculated value for ): 199.97110 Measured value: 200.0 1 H NMR (400 MHz, DMSO-d6, 25℃) δ 8.66 (dd, J = 4.6, 1.3 Hz, 1H), 8.22 (dd, J = 8.2, 1.3 Hz, 1H), 7.52 (dd, J = 8.2, 4.6 Hz, 1H), 2.61 (s, 3H).

[0177] Part 2 - Synthesis of compound 13a-(S)-1-(3-bromopyridine-2-yl)ethane-1-ol. [ka] A solution of 1-(3-bromopyridine-2-yl)ethane-1-one (compound 13) (200 kg, 999.83 mol, 1 equivalent) in potassium phosphate buffer (0.2 M, pH 6-8-7.2, 2,000 L, 10 V), glucose (594 kg, 3,297 mol, 3.3 equivalents), GDH (4 kg, 2 w / w%), NADP (2 kg, 1 w / w%), KRED (2 kg, 1 w / w%), and 1-(3-bromopyridine-2-yl)ethane-1-one (compound 13) (200 kg, 999.83 mol, 1 equivalent) in DMSO (200 L, 1 V) was added to the reactor at 25-30°C. Note: If necessary, 2 M NaOH aqueous solution was used to maintain the pH at 6-5-7. The reaction mixture was maintained at 28-32°C for 6 hours. At that point, HPLC analysis indicated completion of the reaction.

[0178] Diatomaceous earth (40 kg, 20 w / w%) and MTBE (800 L, 4V) were added to the reaction mixture. The resulting mixture was filtered, and the cake was washed with MTBE (200 L, 1V). The resulting phase was separated, and the aqueous phase was extracted again with MTBE (500 L x 3, 2.5V x 3). The combined organic phase was washed with brine (100 L, 0.5V), concentrated (45~55°C, -0.08 MPa), and (S)-1-(3-bromopyridine-2-yl)ethane-1-ol (compound 13a) (204 kg, area specific purity 97.8%, weight specific assay value 89.6%, yield 90%).

[0179] Part 3 - Alternative synthesis of compound 13a-(S)-1-(3-bromopyridine-2-yl)ethane-1-ol. [ka] Triethylamine (47 kg, 464.46 mol, 2.8 equivalents) was added to the reactor. This was cooled to 0-10°C and maintained at 0-10°C. Formic acid (19 kg, 412.82 mol, 2.5 equivalents) and RuCl(p-cymene)[(S,S)-Ts-DPEN] (0.55 kg, 864.49 mmol, 0.005 equivalents) were added. The resulting mixture was heated to 30-35°C and maintained at 30-35°C. 1-(3-bromopyridine-2-yl)ethane-1-one (compound 13) (36.7 kg, 165.12 mol, 1 equivalent) was added, and the input port was rinsed with additional triethylamine (2 kg, 19.76 mol, 0.12 equivalents). The temperature of the reaction mixture was maintained at 30-35°C for 6 hours. At that point, the HPLC analysis indicated that the reaction was complete.

[0180] The reaction mixture was concentrated (30-35°C) to remove triethylamine. Water (170 kg) and pharmaceutically acceptable HCl (310 kg) were added to the resulting mixture at 15-25°C. The phases were separated, and the aqueous phase was extracted with pharmaceutically acceptable HCl (160 kg x 2). The combined organic phase was washed with brine (158 kg x 2), dried over anhydrous Na2SO4, filtered, and the used desiccant cake was washed with pharmaceutically acceptable HCl (40 kg). The combined filtrate was cooled to 0-10°C and maintained at 0-10°C, to which 35 w / w% HCl (55 kg, 3.2 equivalents) in MeOH was added. The resulting mixture was maintained at 0-10°C for 12 hours, filtered, and the product was washed with pharmaceutically acceptable HCl (40 kg). The product was dissolved in water (66 kg) and pharmaceutically acceptable HCl (170 kg), and the resulting solution was cooled to 5-15°C and maintained at 5-15°C. A solution of NaHCO3 (33 kg) in water (170 kg) was added to this. The phases were separated, and the aqueous phase was extracted with ELISA (170 kg x 3). The combined organic phase was washed with brine (158 kg x 2), dried with anhydrous Na2SO4, filtered, and the used desiccant cake was washed with ELISA (120 kg). The filtrate was concentrated (40~45°C) to obtain (S)-1-(3-bromopyridine-2-yl)ethane-1-ol (compound 13a) (30.0 kg, area specific purity >99.9%, weight specific assay value 95%, yield 86%, Table 2) as a dark brown oily substance. [Table 2] LRMS (ESI+) C7H9BrNO (M+H + Calculated value for ): 201.98675 Actual value: 202.0 1 H NMR (400 MHz, DMSO-d6, 25℃) δ 8.56 (dd, J = 4.6, 1.4 Hz, 1H), 8.02 (dd, J = 8.0, 1.4 Hz, 1H), 7.26 (dd, J = 8.0, 4.6 Hz, 1H), 5.13 - 5.04 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H).

[0181] Part 4 - Synthesis of compound 13b-(S)-3-bromo-2-(1-methoxyethyl)pyridine. [ka] THF (2,025 L, 5V) and t-BuONa (231 kg, 2,404 mol, 1.2 equivalents) were added to the reactor. The resulting mixture was cooled to 0-10°C and maintained at 0-10°C. To this, a solution of (S)-1-(3-bromopyridine-2-yl)ethane-1-ol (405 kg, 2,004 mol, 1 equivalent) in THF (800 L, 2V) and MeI (340 kg, 2,395 mol, 1.2 equivalents) were added. The resulting reaction mixture was maintained at 0-10°C for 16 hours. At that point, HPLC analysis indicated that the reaction was complete.

[0182] To the reaction mixture, a 7.5 w / w% aqueous solution of NH3 (520 L, 1.3V) at 0-10°C and MTBE (1,200 L, 3V) were added. The phases were separated, and the aqueous layer was extracted with MTBE (1,200 L, 3V). The combined organic phase was washed with brine (200 L, 0.5V), concentrated (50-60°C, -0.08 MPa) to obtain crude (S)-3-bromo-2-(1-methoxyethyl)pyridine (compound 13b). Crude (S)-3-bromo-2-(1-methoxyethyl)pyridine was distilled (120°C, 600 Pa) to obtain (S)-3-bromo-2-(1-methoxyethyl)pyridine (445 kg, area specific purity 99.3%, weight specific assay value 90.2%, yield 93%, Table 3) as a colorless solid (solidified after packaging). [Table 3] LRMS (ESI+) C8H 11 BrNO (M+H + Calculated value for ): 216.00240 Actual value: 216.00 1 1H NMR (400 MHz, CDCl3, 25℃) δ 8.61 (d, J = 3.2 Hz, 1H), 7.83 (q, J = 1.6, 6.8 Hz, 1H), 7.08 (q, J = 3.6, 4.8 Hz, 1H), 4.92 (q, J = 6.4 Hz, 1H), 3.31 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H).

[0183] Example 2.3,3-Dimethyldihydro-2H-pyran-2,6(3H)-dione synthesis procedure. [ka] Part 1 - Synthesis of 4,4-dimethyl-5-oxopentannitrile. [ka] 1,4-dioxane (1,552 L, 5V), hydroquinone (1.55 kg, 14.1 mol, 0.0033 equivalents), and 5 w / w% NaOH aqueous solution (341.4 kg, 426.78 mol, 0.1 equivalents) were added to the reactor. The resulting mixture was heated to 70-75°C and maintained at 70-75°C. Isobutyraldehyde (310.6 kg, 4,307.3 mol, 1 equivalent) and acrylonitrile (2) (285.7 kg, 5,384.5 mol, 1.25 equivalents) were added over 8 hours. The reaction mixture was maintained at 70-75°C for 8 hours. At that point, GC analysis indicated that the reaction was complete.

[0184] Next, the reaction mixture was cooled to 20-25°C and maintained at 20-25°C. The pH was adjusted to 5-6 with a 3.5 w / w% HCl aqueous solution (172.5 kg required) and concentrated until the organic solvent was completely evaporated (45°C, approximately 0.03 atm). The remaining residue was cooled to 20-25°C and maintained at 20-25°C. DCM (1,552 L, 5V) and water (620 L, 2V) were added to this. The phases were separated, and the organic phase was concentrated until the solvent was completely evaporated (45°C, approximately 0.03 atm) to obtain crude 4,4-dimethyl-5-oxopentannitrile as a brown oily substance (626.6 kg, area specific purity 70.8%, weight specific assay value 43.5%, yield 51%, Table 4). [Table 4] LRMS (ESI+) C7H 12 NO (M+H + Calculated value for ): 126.09189 Actual value: 126.0 1 1H NMR (400 MHz, CDCl3, 25℃) δ 9.37 (s, 1H), 2.30 - 2.19 (m, 2H), 1.88 - 1.77 (m, 2H), 1.06 (s, 6H).

[0185] Part 2 - Synthesis of crude 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione. [ka] Water (1,115 kg, 5V), KH2PO4 (13.8 kg, 101.4 mol, 0.057 equivalents), DMSO (164.0 kg, 2,099.1 mol, 1.2 equivalents), and crude 4,4-dimethyl-5-oxopentannitrile (455.3 kg, weight-to-assay value 49.0%, 1,782.3 mol, 1 equivalent) were added to the reactor. The resulting mixture was cooled to 10-20°C and maintained at 10-20°C. 20 w / w% NaClO2 aqueous solution (1,185.0 kg, 2,620.5 mol, 1.5 equivalents) was added over 20 hours. The reaction mixture was then maintained at 10-20°C for 1 hour. At this point, GC analysis indicated completion of the reaction. Crude 4-cyano-2,2-dimethylbutanoic acid was obtained and used directly in the next step.

[0186] A mixture of crude 4-cyano-2,2-dimethylbutanoic acid was mixed with KOH (361.5 kg, 6,442.7 mol, 3.6 equivalents). The resulting mixture was extracted with MTBE (800 kg x 2, 4.9 V x 2). The aqueous phase was then heated to 90-100°C and maintained at 90-100°C for 15 hours. At that point, GC analysis indicated that the reaction was complete.

[0187] The reaction mixture was cooled to 15-25°C and maintained at that temperature. The pH was adjusted to 1-2 with a 30 w / w% HCl aqueous solution (1,058 kg, 4.9 equivalents). The resulting mixture was extracted with MTBE (1,058 kg x 2, 6.4V x 2). The combined organic phase was washed with a 5 w / w% NaCl aqueous solution (378 kg x 2, 1.7V x 2), concentrated to 670 L (3V) (40-45°C, approximately 0.03 atm) to obtain crude 2,2-dimethylpentanediic acid, which was used directly in the next step.

[0188] To a mixture of crude 2,2-dimethylpentanedioic acid, Ac2O (614.6 kg, 6,020.1 mol, 3.4 equivalents) was added at 40-45°C. The resulting mixture was concentrated (40-45°C, approximately 0.03 atm) to remove MTBE. The reaction mixture was heated to 80-85°C and maintained at 80-85°C for 2 hours. At this point, GC analysis indicated completion of the reaction.

[0189] Next, the reaction mixture was concentrated until the solvent completely evaporated (70-75°C, approximately 0.03 atm) to remove AcOH and Ac2O. This yielded crude 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (390.5 kg, area specific purity 86.3%, weight specific assay value 69.3%, crude yield 107%), which was used directly in the next step.

[0190] Part 3 - Synthesis of 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione. [ka] n-heptane (574.0 kg, 1.86 V relative to crude weight) was added to the reactor. This was cooled to -10 to -5°C and maintained at -10 to -5°C. A solution of crude 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (454.0 kg, weight-specific assay value 84.1%) in MTBE (667.2, 2 V relative to crude weight) was added to this over 10 hours. The resulting mixture was maintained at -10 to -5°C for 1.5 hours and then filtered.

[0191] The filtration cake was dissolved in MTBE (572 kg, 2V relative to the assay weight). Activated carbon (19.1 kg, 0.05 w / w%) relative to the assay weight was added to the resulting solution. This was maintained at 15-25°C for 8 hours. The resulting solution was then filtered, and the used carbon cake was washed with MTBE (18 kg, 0.05V). The filtrate was then added to pre-cooled n-heptane (-10 to -5°C) (518.4 kg, 2V relative to the assay weight) over 9 hours. The resulting mixture was maintained at -10 to -5°C for 2 hours. This was then filtered at -10 to -5°C. The product was dried for 16 hours (25-30°C, approximately 0.03 atm) to obtain 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (212.0 kg, area specific purity 100%, weight specific assay value 98.3%, yield 55%) as an off-white solid.

[0192] Part 4 - Alternative synthesis of 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione. [ka] Ac2O (5.4 L) and 2,2-dimethylpentanedioc acid (2,573 g, weight ratio assay value 98.8% and 506 g, weight ratio assay value 90.9%, 18.74 mol, 1 equivalent) were added to the reactor. The resulting reaction mixture was heated to 110°C and maintained at 110°C for 1 hour. At that point, GC analysis indicated that the reaction was complete.

[0193] The reaction mixture was concentrated until the solvent completely evaporated (70°C, approximately 0.03 atm) to remove AcOH and Ac2O. The residue was combined with another batch (2,2-dimethylpentanedioic acid (6,610 g, weight-specific assay value 90.8%)) and distilled until the product was completely distilled (110-120°C, approximately 0.005 atm). The resulting fraction was triturated with n-heptane (35 L), filtered, and the product was dried (25°C, approximately 0.005 atm) to obtain 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (6.66 kg, area-specific purity 99.6%, weight-specific assay value 98.56%, yield 82%, Table 5) as an off-white solid. [Table 5] LRMS (ESI+) C7H 11 O3(M+H + Calculated value for ): 143.07082 Measured value: 143.0 1 1H NMR (300 MHz, CDCl3, 25℃) δ 2.82 (t, J = 7.0 Hz, 2H), 1.85 (t, J = 7.0 Hz, 2H), 1.35 (s, 6H).

[0194] Part 5 - Alternative synthesis of 2,2-dimethylpentanedioic acid. [ka] 3.3 L of 65 w / w% HNO3 aqueous solution and 500 mL of concentrated H2SO4 were added to the reactor at 25°C. The resulting mixture was heated to 70-80°C and maintained at that temperature. 4,4-dimethyl-5-oxopentannitrile (2.21 kg, weight-to-assay value 90.5%, 15.98 mol, 1 equivalent) was added in portions over 24 hours. The reaction mixture was then maintained at 70-75°C for 1 hour. At that point, GC analysis indicated that the reaction was complete.

[0195] The reaction mixture was cooled to 25°C and then added to ice-cold water (10 kg). During this time, a solid precipitate formed. The resulting mixture was extracted with MTBE (10 L x 1, followed by 5 L x 2). The combined organic phase was washed with water (2 L x 1), then with brine (2 L x 1), dried over anhydrous Na2SO4, filtered, and then concentrated until the solvent had completely evaporated (45°C, approximately 0.03 atm). This yielded 2,2-dimethylpentanedioic acid (2.6 kg, weight-to-assay value 98.8%, yield 100%, Table 6) as a white solid. [Table 6] LRMS (ESI-) C7H 11 O4(Mon + Calculated value for ): 159.06573 Measured value: 159.2 1 1H NMR (400 MHz, CDCl3, 25℃) δ 2.42 (t, J = 7.5 Hz, 2H), 1.92 (t, J = 7.5 Hz, 2H), 1.23 (s, 6H).

[0196] Example 3. Synthesis procedure for compound 2a-(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate methyl. [ka] Part 1 - Synthesis of compound 2c-L-serine methyl hydrochloride. [ka] MeOH (1,650 L, 3V) and L-serine (compound 2b) (550 kg, 5,233 mol, 1 equivalent) were added to the reactor. The resulting mixture was cooled to 0-10°C and maintained at 0-10°C. SOCl2 (695 kg, 5,842 mol, 1.1 equivalents) was then added over 12 hours. The resulting reaction mixture was heated to 20-30°C and maintained at 20-30°C for 5 hours. At that point, HPLC monitoring indicated that the reaction was complete.

[0197] The reaction mixture was concentrated to 1.5V (40-45°C, -0.09MPa). MTBE (1,650L, 3V) was added to the resulting residue, and the mixture was concentrated to 1.5V (40-45°C, -0.09MPa). MTBE (1,650L, 3V) was added to the resulting residue, and the mixture was cooled to 5-15°C and maintained at 5-15°C for 1 hour. This was then filtered at 5-15°C, and the cake was washed with MTBE (203.5kg, 0.5V). The cake was dried (40-50°C, -0.09MPa) to obtain L-serine methyl hydrochloride (compound 2c) (814.0kg, area-specific purity 99.7%, yield 100%, Table 7). [Table 7] LRMS (ESI+) C4H 11 NO3 (M+H) + Calculated value for ): 120.06607 Measured value: 120.1 1 1H NMR (400 MHz, CD3OD, 25℃) δ 4.16-4.10 (m, 1H), 4.03-3.88 (m, 2H), 3.83 (s, 3H).

[0198] Part 2 - Synthesis of compound 2e-(tert-butoxycarbonyl)-L-serinemethyl. [ka] Water (813 kg, 2V) and L-serine methyl hydrochloride (compound 2c) (407 kg, 2,616 mol, 1 equivalent) were added to the reactor. The resulting mixture was cooled to 10-20°C and maintained at 10-20°C.

[0199] In a separate reactor, THF (723 kg, 2V) and NaHCO3 (659 kg, 7,844 mol, 3 equivalents) were added. The resulting mixture was cooled to 10-20°C and maintained at 10-20°C. To this, a solution of L-serine methyl hydrochloride (compound 2c) was added over 1 hour. Boc2O (627 kg, 2,873 mol, 1.1 equivalents) was added to the resulting mixture over 2.5 hours. The resulting reaction mixture was heated to 20-30°C and maintained at 20-30°C for 1 hour. At this point, HPLC monitoring indicated that the reaction was complete.

[0200] The reaction mixture was filtered, and the cake was washed with DCM (541.3 kg × 2, 1V × 2). The filtrate was then concentrated to 1.5V (45-55°C). DCM (2,706 kg, 5V) was added to the resulting residue. The phases were separated, and the aqueous phase was extracted with DCM (2,706 kg, 5V). The combined organic phase was washed with water (1,221 kg × 3, 3V × 3), washed with brine (1,628 kg, 3V), dried over anhydrous Na2SO4, filtered, and the cake was washed with DCM (272.7 kg, 0.5V). The resulting filtrate was concentrated to 5V (≤40°C) to obtain crude (tert-butoxycarbonyl)-L-serinemethyl (compound 2e, Table 8), which was used directly in the next step. [Table 8] LRMS (ESI+) C9H 17 NNaO5(M+Na + Calculated value for ): 242.10044 Measured value: 242.1 1 1H NMR (400 MHz, CDCl3, 25℃) δ 5.56 (d, J = 8.1 Hz, 1H), 4.32 (d, J = 7.8 Hz, 1H), 3.95-3.78 (m, 2H), 3.73 (s, 3H), 2.83 (s, 1H), 1.40 (s, 9H).

[0201] Part 3 - Synthesis of compound 2d-N-(tert-butoxycarbonyl)-O-tosyl-L-serinemethyl. [ka] To a DCM solution of crude (tert-butoxycarbonyl)-L-serinemethyl (compound 2e) (estimated 573.54 kg, 2,616 mol, 1 equivalent), TsCl (472.14 kg, 2,477 mol, 0.95 equivalents) was added. The resulting mixture was cooled to -5 to 5°C and maintained at -5 to 5°C. Pyridine (268.6 kg, 3,396 mol, 1.3 equivalents) was then added over 3.5 hours. The reaction mixture was then heated to 20 to 30°C and maintained at 20 to 30°C for 5 hours. At this point, HPLC monitoring indicated that the reaction was complete.

[0202] The reaction mixture was diluted with DCM (2,706 kg, 5V). A 5 w / w% NaHCO3 aqueous solution (3V, 61 kg NaHCO3, 1,221 kg water) was added over 0.5 hours. The phases were separated, and the organic phase was washed twice with 10 w / w% citric acid (3V, 133 kg citric acid, 1,219 kg water), washed with brine (3V, 407 kg NaCl, 1,221 kg water), and concentrated to 1.5V (≤40°C). MTBE (903.5 kg, 3V) was added to the resulting residue and concentrated to 1.5V. MTBE (602.3 kg, 2V) was added to the resulting residue and cooled to -15 to -5°C, where it was maintained. Next, n-heptane (1,443 kg, 5V) was added over 1 hour, and the resulting slurry was maintained at -15 to -5°C for 6 hours. Then, it was filtered, and the cake was washed with pre-cooled n-heptane (-15 to -5°C) (138 kg x 2, 0.5V x 2). The cake was dried for 8 hours (35 to 45°C, -0.09 MPa) to obtain N-(tert-butoxycarbonyl)-O-tosyl-L-serinemethyl (compound 2d) (444 kg, area-specific purity 92.8%, yield 45% from L-serinemethyl hydrochloride (compound 2c), Table 9). [Table 9] LRMS (ESI+) C 16 H 23 NNaO7S (M+Na + Calculated value for ): 396.10929 Actual value: 396.0 1 1H NMR (400 MHz, CDCl3, 25℃) δ 7.81-7.72 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.28 (d, J = 8.1 Hz, 1H), 4.53-4.45 (m, 1H), 4.38 (dd, J = 10.2, 3.1 Hz, 1H), 4.27 (dd, J = 10.1, 3.1 Hz, 1H), 3.69 (s, 3H), 2.44 (s, 3H), 1.41 (s, 9H).

[0203] Part 4 - Synthesis of compound 2a-(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate methyl. [ka] NaI (201.6 kg, 1,345 mol, 1.1 equivalents), citric acid (119.0 kg, 619 mol, 0.5 equivalents), N-(tert-butoxycarbonyl)-O-tosyl-L-serinemethyl (compound 2d) (458.2 kg, 1,227 mol, 1 equivalent), and acetone (2,433 kg, 7V) were added to the reactor. The reaction mixture was heated to 35-45°C and maintained at 35-45°C for 20 hours. At that point, HPLC monitoring indicated that the reaction was complete.

[0204] The reaction mixture was filtered, and the cake was washed with RINKAN (824 kg, 2V). The filtrate was concentrated to 2.5V and diluted with RINKAN (2,061 kg, 5V). A 5 w / w% Na2S2O3 aqueous solution (5V, 114 kg of Na2S2O3, 2,290 kg of water) was added. The phases were separated, and the aqueous phase was extracted with RINKAN (1,236 kg, 3V). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the cake was washed with RINKAN (207 kg x 2, 0.5V x 2). The filtrate was concentrated to 1.5V (35-45°C). n-heptane (622 kg, 2V) was added, and this was concentrated to 1.5V (35-45°C). MTBE (33 kg, 0.1V) and n-heptane (590 kg, 1.9V) were added. The resulting mixture was heated to 30°C, then cooled to -15 to -5°C, and maintained at -15 to -5°C for 6 hours. This was filtered, and the cake was washed with pre-cooled n-heptane (-5°C) (155 kg x 2, 0.5 V x 2). The cake was dried for 8 hours (35°C, -0.09 MPa) to obtain crude (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate methyl (compound 2a).

[0205] Next, crude (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate methyl (compound 2a) was dissolved in MeCN (288 kg, 0.8 V) and filtered. The filtrate was extracted with n-heptane (124 kg, ×5, 0.4 V ×5). The MeCN phase was then cooled to -5°C and maintained at -5°C. Water (1,833 kg, 4 V) was added to it. The resulting mixture was maintained at -5°C for 2 hours, filtered, and the cake was washed with water (916 kg, 2 V). This cake was dissolved in MTBE (33 kg, 0.1 V) and n-heptane (280 kg, 0.9 V) at 30°C. The resulting mixture was then cooled to -5°C and maintained at -5°C for 2 hours. Next, the mixture was filtered, and the cake was washed with pre-cooled n-heptane (-5°C) (155 kg x 2, 0.5 V x 2). The cake was dried for 8 hours (35°C, -0.09 MPa) to obtain (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate methyl (compound 2a) (144.6 kg, area-specific purity 99.7%, yield 36%, Table 10) as a white solid. [Table 10] HRMS (ESI+) C4H9INO2(M+H + Calculated value for (des-Boc): 229.96780 Actual value: 229.9673 1 1H NMR (600 MHz, CDCl3, 25℃) δ 5.39 (d, J = 6.6 Hz, 1H), 4.53 (t, J = 3.6 Hz, 1H), 3.80 (s, 3H), 3.60-3.55 (m, 2H), 1.46 (s, 9H).

[0206] Example 4. Synthesis procedure for compound 3-(1S,2S)-2-methylcyclopropane-1-carboxylic acid. [ka] Part 1 - Synthesis of compound 3c-(1S,2S)-2-methylcyclopropane-1-carboxylate ethyl. [ka] n-BuLi (1.6 M, 9.79 L, 15.67 mol, 0.91 equivalents in hexane), 2-(diethoxyphosphoryl)ethyl acetate (3.74 kg, 16.70 mol, 0.97 equivalents), and 2-MeTHF (10 L, 10V) were added to the reactor. This was maintained at 10-25°C for 1 hour. Next, (R)-2-methyloxirane (compound 3a) (1.00 kg, 17.22 mol, 1 equivalent) was added, and the resulting mixture was maintained at 10-25°C for 0.5 hours. NMP (10 L, 10V) was added, and the resulting mixture was maintained at 10-25°C for 10 minutes. The reaction mixture was then passed through a flow reactor (143°C, residence time = 30 minutes). At this point, GC monitoring indicated that the reaction was complete. From this reaction mixture, crude (1S,2S)-2-methylcyclopropane-1-carboxylate ethyl (compound 3c, Table 11) was obtained. This was used directly in the next step. [Table 11] HRMS (ESI+) C7H 13 O2(M+H + Calculated value for ): 129.09155 Measured value: 129.1.

[0207] Part 2 - Synthesis of compound 3-(1S,2S)-2-methylcyclopropane-1-carboxylic acid. [ka] To a crude (1S,2S)-2-methylcyclopropane-1-carboxylate ethyl (compound 3) reaction mixture (starting from (R)-2-methyloxirane (compound 3a) (1.00 kg, 17.22 mol, 1 equivalent)), NaOH (2.07 kg, 51.73 mol, 3 equivalents), water (3 L, 3V), and MeOH (3 L, 3V) were added. The resulting reaction mixture was heated to 40°C and maintained at 40°C for 14 hours. At that point, GC monitoring indicated that the reaction was complete.

[0208] The reaction mixture was concentrated (40°C) until no distillate was observed (final volume approximately 20 L, approximately 20 V). This residue was cooled to ≤30°C and maintained at ≤30°C, to which water (10 L, 10 V) was added. The pH was adjusted to 1 with concentrated HCl (approximately 6 L required). The resulting mixture was extracted with MTBE (10 L x 3, 10 V x 3). The combined organic phase was washed with brine (10 L, 10 V), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated (30°C) to a final volume of approximately 12 L (approximately 12 V). Dicyclohexylamine (2.64 kg, 14.56 mol, 0.84 equivalents) was added, and the resulting mixture was maintained at room temperature for 12 hours. This was then filtered, and the cake was washed with MTBE (1 L, 1 V). The cake was dissolved in water (20 L, 20 V) and the pH was adjusted to 1 with concentrated HCl (approximately 1 L required). Next, MTBE (10 L, 10 V) was added, the two-phase mixture was filtered, and the cake was washed with MTBE (2 L, 2 V). The phases were separated, and the aqueous phase was extracted with MTBE (10 L, 10 V). The combined organic phase was washed with brine (10 L, 10 V), dried over anhydrous MgSO4, filtered, concentrated (30°C), and crude (1S,2S)-2-methylcyclopropane-1-carboxylic acid (compound 3) (711.5 g, yield 41% from (R)-2-methyloxirane (1)) was obtained as a yellow oil.

[0209] Crude (1S,2S)-2-methylcyclopropane-1-carboxylic acid (compound 3) was dissolved in MeCN (9 L, 9 V), and (R)-(+)-N-benzyl-1-phenylethylamine (1.50 kg, 1 equivalent) was added. The resulting mixture was heated to 40°C and maintained at 40°C for 1 hour. Then it was cooled to 20°C and maintained at 20°C for 2 hours. The resulting mixture was filtered, and the cake was washed with MeCN (2 L, 2 V). The cake was dried and then placed in a pre-cooled solution (5-10°C) of NaOH (200 g) and water (1.3 kg). The resulting mixture was extracted with MTBE (2.6 L × 3, 2.6 V × 3). The aqueous phase was adjusted to pH 1 with concentrated 3 M HCl, and then extracted with MTBE (2.6 L × 3, 2.6 V × 3). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated (at 40°C) to obtain (1S,2S)-2-methylcyclopropane-1-carboxylic acid (compound 3) (397.4 g, yield 56%, Table 12). [Table 12] LRMS (ESI-) C5H7O2(MH + Calculated value for ): 99.04460 Actual value: 99.1 1 1H NMR (400 MHz, CDCl3, 25℃) δ 11.43 (br s, 1H), 1.49-1.43 (m, 1H), 1.35-1.30 (m, 1H), 1.25-1.22 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H), 0.77-0.73 (m, 1H).

[0210] Example 5 - Compound 6a-(1 2 The synthesis procedure for M)-(S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)boronic acid. [ka] Part 1 - Compound 7 - (1 2 Synthesis of M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol. [ka] In the reactor, add water (19L, 3V), MTBE (51L, 8V), (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol hydrochloride (HCl of compound 7) (6.35 kg, 13.18 mol, equivalent) and K2CO3 (1.27 kg, 9.19 mol, 0.7 equivalent) were added. The resulting mixture was maintained at 15-25°C for 30 minutes.

[0211] The phases were separated. The organic phase was washed with water (19 L, 3 V) and combined with the organic phase from another reaction of the same scale, and concentrated to approximately 25 L (approximately 2 V). This was then solvent-changed to n-heptane (63 L x 2, 5 V x 2, concentrated to 25 L, 2 V). The resulting mixture was filtered, and the cake was washed with n-heptane (12 L, 1 V). The cake was dried, and (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (compound 7) (11.3 kg, yield 96%, Table 13) was obtained. [Table 13] LRMS (ESI+) C 23 H 30 BrN2O2(M+H + Calculated value for ): 445.14907 Actual value: 445.2 11H NMR (400 MHz, CDCl3, 25℃) δ 8.82 (dd, J = 4.8, 1.8 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 7.7, 1.8 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.24 (d, J = 8.6 Hz, 1H), 4.10 (q, J = 6.2 Hz, 1H), 4.06 - 3.93 (m, 1H), 3.93 - 3.80 (m, 1H), 3.33 - 3.17 (m, 2H), 3.07 (s, 3H), 2.72 (d, J = 14.2 Hz, 1H), 2.24 (d, J = 14.3 Hz, 1H), 1.47 (d, J = 6.3 Hz, 3H), 1.29 (s, 1H), 1.18 (t, J = 7.2 Hz, 3H), 0.77 (s, 6H).

[0212] Part 2a - Compounds Compound 4a-(1 2 Synthesis of M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-1H-indole. [ka] The reactor contains n-heptane (17.7 L, 3.3 V), THF (9.1 L, 1.7 V), and (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (compound 7) (5.37 kg, 12.06 mol, 1 equivalent) was added. To this, HBpin (2.32 kg, 18.13 mol, 1.5 equivalents) was added over 2.5 hours. The resulting mixture was heated to 50°C and maintained at 50°C for 4 hours. At that point, it was cooled to 25°C.

[0213] B2pin2 (3.67 kg, 14.47 mol, 1.2 equivalents), Me4phen (22.8 g, 96.48 mmol, 0.008 equivalents), and [Ir(OMe)(COD)]2 (16.0 g, 24.14 mmol, 0.002 equivalents) were added to the reaction mixture. The resulting mixture was heated to 50°C and maintained at 50°C for 14 hours. At that point, HPLC monitoring indicated that the reaction was complete.

[0214] The reaction mixture was cooled to 15°C and maintained at 15°C for 1 hour, then concentrated to approximately 13.4 L (approximately 2.5 V). The solvent was changed to n-heptane (16 L x 2, 3 V x 2, concentrated to approximately 13.4 L, approximately 2.5 V). The resulting mixture was cooled to 10-15°C and maintained at 10-15°C for 15 hours. Then it was filtered and the cake was washed with n-heptane (5 L, 1 V). The cake was dried, and (1 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-1H-indole (compound 4a) (8.37 kg, area specific purity 98.7%, weight specific assay value 91.5%, yield 91%, Table 14) was obtained as a light brown solid.

[0215] Part 2b - Compounds Compound 4a-(1 2 Alternative synthesis of M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-1H-indole.

[0216] In the reactor, add water (601 kg, 3V), MTBE (1186.9 kg, 8V), (1 2HCl salt (200 kg, 1.0 equivalent) of M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (compound 7) and K2CO3 (37.29 kg, 0.65 equivalents) were added. The solution was stirred at 20°C for 0.5 hours, and then allowed to stand undisturbed for 0.5 hours. The phases were separated, and the organic phase was washed with water (600.5 kg, 3V). The MTBE solution was concentrated under reduced pressure until the residual volume was approximately 400 L. THF (354.3 kg, 2V) was added to the solution. The resulting solution was concentrated under reduced pressure until the residual volume was approximately 400 L. Solvent exchange was repeated two more times. n-heptane (407.7 kg, 3.05 V) was added to a solution of compound 7 in THF. N2 was bubbled under the surface of the solution for 1 hour. HBpin (59.5 kg, 1.1 equivalents) was added dropwise to the reactor under an N2 atmosphere at 20°C. The reaction mixture was heated at 30°C for 2 hours and cooled to 20°C. B2pin2 (126 kg, 1.2 equivalents) and Me4phen (779 g, 0.8 mol%) were added to the reactor under an N2 atmosphere. N2 was bubbled under the surface of the solution for 1 hour. [IrOMe(COD)]2 (545 g, 0.2 mol%) was added to the reactor under an N2 atmosphere. The reaction mixture was heated at 45°C for 6 hours and cooled to 20°C. After the reaction, EtOH (28.6 kg, 1.5 equivalents) was added to the reaction mixture and stirred at 20°C for 17 hours. The reaction mixture was concentrated under reduced pressure until the residual volume was approximately 400 L. The suspension was replaced with n-heptane (273.10 kg, 2V). The resulting suspension was concentrated under reduced pressure until the residual volume was approximately 400 L. The solvent exchange was repeated once more. The resulting suspension was cooled to 5°C, stirred for 20 hours, and filtered to obtain a wet cake. This was washed with n-heptane (14 kg). The washed wet cake was dried at below 45°C for 16 hours and 277.74 kg of (1 22M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-1H-indole (compound 4a) was obtained as an off-white solid with a purity of 97.0%, an assay value of 96.4%, and a yield of 92.5%. [Table 14] LRMS (ESI+) C 23 H 31 BBrN2O4(M+H + Calculated value for (free alcohol, free boronic acid): 489.15603 Actual value: 489.2 1 1H NMR (400 MHz, CDCl3, 25℃) δ 9.11 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.6, 1.9 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 4.08 (q, J = 6.3 Hz, 1H), 4.02 - 3.91 (m, 1H), 3.90 - 3.80 (m, 1H), 3.55 - 3.43 (m, 2H), 3.09 (s, 3H), 2.76 (d, J = 14.2 Hz, 1H), 2.14 (d, J = 14.2 Hz, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.35 (d, J = 2.9 Hz, 12H), 1.25 (s, 12H), 1.17 (t, J = 7.2 Hz, 3H), 0.76 (s, 3H), 0.68 (s, 3H).

[0217] Part 3 - Compound 5a-(1 2Synthesis of M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol. [ka] In the reactor, (1 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-1H-indole (compound 4a) (11.88 kg, 17.04 mol, 1 equivalent), 1-methylpiperazine (compound 6b) (17.11 kg, 170.82 mol, 10 equivalents), Cu(OAc)2 (19.01 kg, 104.66 mol, 6 equivalents), TMP (8.91 kg, 63.01 mol, 3.7 equivalents), and DCM (238 L, 20V) were added. The resulting mixture was maintained at 20-25°C, and 21% O2 in N2 was bubbled in for 16 hours. At that point, HPLC monitoring indicated that the reaction was complete.

[0218] The reaction mixture was concentrated to 119 L (10V). The resulting mixture was added to a mixture of 28 w / w% NH3 aqueous solution (35.6 L, 3V) and water (71.3 L, 6V). This two-phase mixture was filtered, and the filtrate phase was separated. The organic phase was washed with 28 w / w% NH3 aqueous solution (35.6 L, 3V), then washed with 0.1 M EDTA aqueous solution (35.6 L, 3V), and concentrated to 17.8 L (1.5V). 2-MeTHF (35.6 L, 3V) and water (11.9 L, 1V) were added to this residue. The pH was adjusted to 1-2 with 6 M HCl aqueous solution (23.5 L as needed). The phases were separated, and the aqueous phase was extracted with 2-MeTHF (35.6 L x 2, 3V x 2). DCM (35.6 L, 3V) was added to the aqueous phase. The pH was adjusted to 8-9 with a 30 w / w% NaOH aqueous solution (4.5 L required). The phases were separated, and the organic phase was concentrated to 12 L (1 V). To this, n-heptane (65.3 L, 5.5 V) was added. The resulting mixture was maintained at 35°C for 3 hours, then cooled to -5°C and maintained at -5°C for 12 hours. This mixture was filtered, and the cake was washed with n-heptane (5.9 L, 0.5 V). The cake was dried, and (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (compound 5a) (7.28 kg, area specific purity 98.7%, weight specific assay value 91.7%, yield 72%) was obtained as an off-white solid.

[0219] Part 4a - Compound 5a - (1 2 Alternative synthesis of M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol. [ka] (1) 2M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-1H-indole (compound 4a) (6.5 kg, 9. A 32 mol (1 equivalent) solution and separate solutions of 1-methylpiperazine (compound 6b) (12.53 kg, 125.09 mol, 13.4 equivalents), Cu(OAc)2 (11.36 kg, 62.54 mol, 6.7 equivalents), and TMP (8.84 kg, 62.58 mol, 6.7 equivalents) in DCM (65 L, 10 V) were passed through a flow reactor (35-45°C, residence time = 1.5 hours). At that point, HPLC monitoring indicated that the reaction was complete.

[0220] The reaction mixture was combined with another reaction mixture (total input amount 13.2 kg, 18.93 mol, 1 equivalent (1 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-1H-indole (compound 4a)).

[0221] The reaction mixture was concentrated to 132 L (10V). The resulting mixture was added to a mixture of 28 w / w% NH3 aqueous solution (43.6 L, 3.3V) and water (87.1 L, 6.6V). This two-phase mixture was filtered, and the filtrate phase was separated. The organic phase was washed with 28 w / w% NH3 aqueous solution (43.6 L, 3.3V), then washed with 0.1 M EDTA aqueous solution (43.6 L, 3.3V), and concentrated to approximately 20 L (approximately 1.5V). 2-MeTHF (39.6 L, 3V) and water (13 L, 1V) were added to this residue. The pH was adjusted to 1-2 with 6 M HCl aqueous solution. The phases were separated, and the aqueous phase was extracted with 2-MeTHF (39.6 L × 2, 3V × 2). DCM (39.6 L, 3V) was added to the aqueous phase. The pH was adjusted to 8-9 with an aqueous solution of $M NaOH. The phases were separated, and the organic phase was concentrated to approximately 20 L (approximately 1.5 V). To this, n-heptane (73 L, 5.5 V) was added over 2 hours. The resulting mixture was maintained at 35°C for 3 hours, then cooled to 0°C and maintained at 0°C for 15 hours. This mixture was filtered, and the cake was washed with n-heptane (7 L, 0.5 V). The cake was dried, and (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (compound 5a) (7.2 kg, area specific purity 98.2%, weight specific assay value 83.4%, yield 58%, Table 15)) was obtained as an off-white solid.

[0222] Part 4b - Compound 5a - (1 2 Alternative synthesis of M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol. [ka] DCM (2493 kg, 16V), Cu(OAc)2 (143 kg, 5.0 equivalents), N-methylpiperazine (160 kg, 10 equivalents), and TMP (83 kg, 3.7 equivalents) were added to the reactor at 23°C. The solution was stirred at 23°C for 0.5 hours. A mixture of N2-O2 (21% O2) gas was bubbled subsurface of the reaction mixture at 23°C for 2 hours. Compound 4a (114.5 kg, 1.0 equivalent) was added to the reactor at 23°C. A mixture of N2-O2 (21% O2) gas was bubbled subsurface of the reaction mixture at 23°C for 6 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure until the residual volume was approximately 1100 L. In a separate reactor, the concentrated reaction mixture containing water (306 kg, 6V) and 28% ammonium hydroxide (306 kg, 3V) was added at 20°C. The phases were separated. The organic layer was recovered and washed at 20°C with EDTA-Na2 aqueous solution (340 kg (0.1N), 3V) to remove the copper salts. The DCM solution was concentrated to a residual volume of approximately 220 L.

[0223] Two other Chan-Lam batches (with a net input of 400 kg of compound 4a to these two batches) were prepared and washed with NH3 and EDTA to obtain DCM solutions. Three batches of DCM solutions of crude compound 5a were combined and subjected to acidic MeTHF washing, liberation basing, DCM extraction, water washing, and ACN crystallization.

[0224] 2-MeTHF (1333 kg, 3V) and water (510 kg, 1V) were added to the reactor. The two-phase solution was adjusted to a pH of 1.29 with 6N HCl. The two-phase solution was stirred at 20°C for 30 minutes. The phases were separated. The aqueous phase was recovered and washed twice with 2-MeTHF (1340 kg x 2, 3V x 2). DCM (2029 kg, 3V) and NaOH aqueous solution (30 W / W%) were added to the aqueous layer to adjust the pH to 8.39. The DCM phase was separated and washed with water (1533 kg, 3V). The DCM solution was concentrated under vacuum until the residual volume was 1250 L. The resulting solution was changed three times with ACN (835.9 kg x 3, V x 3). The resulting solution was heated to 75°C and stirred at 75°C until the solid dissolved. The solution was slowly cooled to 60°C over 2 hours. Seed crystals of compound 5a were added to the reactor at 60°C. The suspension was stirred at 60°C for 2 hours, cooled to 25°C over 5 hours, and stirred at 25°C for 3 hours. The suspension was concentrated under vacuum until the residual volume was approximately 230 L. The suspension was further cooled to 5°C over 4 hours. The resulting suspension was stirred at 5°C for 12 hours. The suspension was filtered and washed with pre-cooled ACN (481 kg). The wet cake was dried under vacuum at 45°C for 15 hours to obtain 307.6 kg of compound 5a as an off-white solid with a purity of 99.3%, an assay value of 98.0%, and a yield of 75.8%. [Table 15] LRMS (ESI+) C 28 H 40 BrN4O2(M+H + Calculated value for ): 543.23346 Actual value: 543.2 1 1H NMR (400 MHz, CDCl3, 25℃) δ 8.51 (d, J = 2.9 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.7, 1.9 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 4.06 - 3.85 (m, 3H), 3.35 - 3.17 (m, 6H), 3.05 (s, 3H), 2.70 (d, J = 14.2 Hz, 1H), 2.60 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H), 2.27 (d, J = 14.2 Hz, 1H), 1.44 (d, J = 6.2 Hz, 3H), 1.35 (s, 1H), 1.20 (t, J = 7.2 Hz, 3H), 0.78 (s, 6H).

[0225] Part 5a - Compound 6a - (1 2 Synthesis of M)-(S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)boronic acid. [ka] In the reactor, 2-MeTHF (18.7 L, 6.6 V), MeOH (6.2 L, 2.2 V), KOPiv (1.60 kg, 11.41 mol, 2.2 equivalents), (1 2M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (compound 5a) (2.85 kg, 5.25 mol, 1 equivalent), XPhos (54.3 g, 113.90 mmol, 0.02 equivalents), XPhos Pd G3 (48.2 g, 56.94 mmol, 0.01 equivalents), and B2(OH)4 (307 g, 3.42 mol, 0.7 equivalents) were added. The resulting mixture was heated to 30°C and maintained at 30°C for 2 hours. An additional 307g, 3.42mol, 0.7 equivalents of B2(OH)4 were added, and the resulting mixture was maintained at 30°C for 2 hours. At that point, HPLC monitoring indicated that the reaction was complete.

[0226] The reaction mixture was concentrated to approximately 11 L (approximately 4 V) and then cooled to 20°C. Water (3.1 L, 1 V) was added. The resulting mixture was maintained at 20°C for 12 hours, at which point it was filtered, and the cake was washed with water (6.2 L, 2 V). The cake was combined with a cake from another reaction of the same scale and then slurryed in MeOH (37.2 L, 6.5 V) and water (12.4 L, 2.2 V) at 20°C for 12 hours. The resulting mixture was then filtered, and the cake was washed with a mixture of MeOH:water (3:1, v / v, 6 L, 1 V). The cake was dried, and (1 2 M)-(S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)boronic acid (compound 6a) (5.19 kg, purity 97.2%, weight ratio assay value 92.7%, yield 90%, Table 16) was obtained as an off-white solid.

[0227] Part 5b - Compound 6a - (1 2 Alternative synthesis of M)-(S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)boronic acid.

[0228] In the reactor, (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (compound 5a) (287.6 kg, 529.79 mol, 1 equivalent), KOPiv (148 kg, 2025 mol, 2.1 equivalents), XPhos (4.0 kg, 8.39 mol, 0.02 equivalents), XPhos G3 Pd (3.4 kg, 4.02 mol, 0.01 equivalents), and B2(OH)4 (71.0 kg, 791 mol, 1.5 equivalents) were added in 2-MeTHF (870 L, 3.03 V). A solution of compound 5a in 2-MeTHF (870 L, 3.03 V) and MeOH (580 L, 2.02 V) was added to the reactor at 30°C for 1 hour. The resulting mixture was maintained at 30°C for 3 hours. At that point, HPLC monitoring indicated that the reaction was complete.

[0229] Water (28 L, 0.1 V) was added to the reactor. The reaction mixture was concentrated to 987 L (approximately 3.5 V) and then cooled to 20°C. Water (256 L, 0.9 V) was added to the mixture. The resulting mixture was maintained at 20°C for 16 hours. At that point, it was filtered and the cake was washed with water (471 L, 1.7 V). The cake was slurryed in MeOH (1690 L, 6.0 V) and water (571 L, 2.0 V) at 15°C for 8 hours. The resulting mixture was then filtered and the cake was washed with a mixture of MeOH:water (3:1, v / v, 674 L, 2.4 V). The cake was dried to obtain (12M)-(S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)boronic acid (compound 6a) (250.18 kg, purity 99.0%, weight ratio assay value 97.5%, yield 94.2%) as an off-white solid. [Table 16] LRMS (ESI+) C 28 H 42 BN4O4(M+H + Calculated value for ): 509.32991 Actual value: 509.5 1 1H NMR (400 MHz, CD3OD, 25℃) δ 8.40 (d, J = 2.9 Hz, 1H), 8.06 (s, 1H), 7.53 (s, 1H), 7.45 - 7.35 (m, 2H), 4.17 - 4.05 (m, 1H), 4.01 (q, J = 6.3 Hz, 1H), 3.92 - 3.80 (m, 1H), 3.40 - 3.30 (m, 6H), 3.28 (d, J = 12.0, 1H), 3.17 (d, J = 12.0 Hz, 1H), 2.99 (s, 3H), 2.80 (d, J = 14.0 Hz, 1H), 2.64 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H), 2.27 (d, J = 14.1 Hz, 1H), 1.40 (d, J = 6.3 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.76 (d, J = 23.5 Hz, 6H).

[0230] Example 6. Synthesis procedure for compound 9-(S)-1-((S)-3-(4-bromothiazole-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylic acid [ka] Part 1 - Compound 9b: Preparation of Methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate [ka] DMF (689 kg, 5 volumes, water content approximately 100 ppm by KF titration) and Zn (57.6 kg, 881.1 mol, 2.0 equivalents) were added to reactor 1. Reactor 1 was evacuated and refilled with argon (Ar) three times, and then bubbling with Ar for 1 hour. 1,2-Dibromoethane (24.8 kg, 132.2 mol, 0.3 equivalents) was added to reactor 1. The resulting mixture was heated to 85-95°C and maintained at that temperature for 30 minutes. TMSCl (2.87 kg, 26.4 mol, 0.06 equivalents) was added to reactor 1 at 20-30°C and stirred for 30 minutes. DMF (276 kg, 2 volumes, water content approximately 100 ppm by KF titration) and (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate methyl (compound 2a) (145.0 kg, 440.6 mol, 1.0 equivalent) were added to reactor 2. Reactor 2 was evacuated and filled with Ar three times, and then bubbling with Ar for 1 hour. The DMF solution of compound 2a in reactor 2 was added to reactor 1 at 20-30°C. The resulting mixture in reactor 1 was heated to 30-40°C and maintained at that temperature for another 30 minutes. MeTHF (624 kg, 5 volumes) and 2,4-dibromothiazole (compound 9a) (96 kg, 359.2 mol, 0.9 equivalent) were added to reactor 3. Reactor 3 was evacuated and refilled with Ar three times, and then bubbling with Ar for 1 hour. Pd(PPh3)2Cl2 (6.2 kg, 8.81 mol, 0.02 equivalents) was added to reactor 3. The Reformatsky reagent in reactor 1 was filtered, and the filtrate was added directly to reactor 3 at 20-40°C. The mixture in reactor 3 was heated to 60-70°C and maintained for 4 hours. A sample was taken for IPC (HPLC: 45.6 A% compound 9b was produced). The reaction mixture was concentrated to approximately 300 L (approximately 2 vols) under reduced pressure at 60-70°C. MTBE (537 kg, 5 vols) and 10 wt% NaCl aqueous solution (1450 kg, 10.0 vols) were added to the mixture at 20-30°C. The mixture was separated, and the aqueous phase was extracted with MTBE (537 kg, 5.0 vols). The MTBE solutions were combined and washed with 10 wt% NaCl aqueous solution (1450 kg x 3, 10 vol x 3). The MTBE phase was concentrated to approximately 200 L (1.5 vol) under reduced pressure at 35-45°C. The resulting solution was subjected to two solvent exchanges with THF at 35-45°C (645 kg x 2, 5 vol x 2).A THF solution of compound 9b totaling 290.4 kg was obtained with an HPLC purity of 59.5A%, a gravimetric assay value of 32.8%, and an assay-corrected yield of 61.4% (Table 17). The crude product was not further purified before proceeding to the next step. [Table 17] MS (ESI+): C 12 H 17 BrN2O4S (M+H + Calculated value for ): 365.01 Actual value: 365.10 1 1H NMR (400 MHz, CDCl3): δ 7.12 (s, 1H), 5.47 (d, J = 7.2 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H), 3.75 (s, 3H), 3.51 (d, J = 5.1 Hz, 2H), 1.43 (s, 9H).

[0231] Part 2a - Compound 9c: Preparation of (S)-3-(4-bromothiazole-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid [ka] (S)-3-(4-bromothiazole-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (compound 9b) (290.4 kg of THF solution, purity 59.5 A%, 32.8 wt%, 260.8 mol, 1.0 equivalent) and THF (847.7 kg, 10.0 vol) were added to the reactor. The reactor was evacuated and filled with nitrogen three times. LiOH·H2O (16.4 kg, 391.2 mol, 1.5 equivalent) in water (667 kg, 7.0 vol) was added dropwise to the mixture at -2 to 2°C. The mixture was stirred at 0 to 5°C for 3 hours, and then sampled for IPC (HPLC purity: compound 9c 58.3 A% and compound 9b 0.3 A%). The reaction mixture was adjusted to pH 8-9 with 1M HCl (approx. 100 kg) at 2-10°C (IT). Water (667 kg, 7.0 vol) was added to the mixture. The resulting mixture was concentrated under reduced pressure at 30-40°C until the residual volume reached 1300 L (14.0 vol). HCl (429 kg, 7.0 vol) was added to the mixture at 15-20°C and stirred for 30 minutes. The mixture was filtered, and the filtrate was separated to remove the organic layer. The aqueous phase was washed with HCl (429 kg x 2). The aqueous phase was adjusted to pH 2.8-3.0 with 3M HCl aqueous solution (approx. 300 kg) at 5-10°C. The aqueous phase was extracted with DCM (633 kg x 4). The DCM phases were combined and washed with water (476 kg, 5.0 vol). The DCM phase was concentrated under reduced pressure at 30-40°C to approximately 7 vol (approx. 660 L). Next, (S)-1-phenylethylamine (44.2 kg, 364.7 mol, 1.4 equivalents) was added to the solution at 15-20°C. The mixture was stirred at 15-20°C for 30 minutes. n-heptane (1557 kg, 25 volumes) was added at 15-20°C (IT) and stirred for 60 minutes, then stirred for another 60 minutes at 0-10°C. The mixture was filtered, and the filtered cake was rinsed with n-heptane / DCM in a ratio of 2.5:1 (vol / vol). The wet filtered cake was dried under reduced pressure at 40-45°C for 12 hours. A total of 129.0 kg of the (S)-1-phenylethylamine salt of compound 9c was obtained as a white solid (HPLC purity 96.7% and HPLC gravimetric assay value 65.3%).The (S)-1-phenylethylamine salt of compound 9c was dissolved in water (1684 kg, 20.0 vol) and DCM (1120 kg, 10.0 vol) was added. The mixture was adjusted to pH 10-10.5 with 1 M NaOH aqueous solution (270 kg) at 5-10°C. The phases were separated, and the aqueous phase was washed with DCM (560 kg x 2) to remove (S)-1-phenethylamine. The sample was taken for IPC (no (S)-1-phenethylamine residue). The aqueous phase was adjusted to pH 2.8-3.0 with 1 M HCl aqueous solution (300 kg) at 5-10°C. The aqueous phase was extracted with DCM (560 kg x 3). The DCM phases were combined and washed with water (421 kg, 5.0 vol). The DCM phase was dried with Na2SO4 (84 kg, 1.0 w). After filtration, the filtrate cake was rinsed with DCM (168 kg, 2.0 vol). The filtrate was concentrated under reduced pressure at 30-40°C. A total of 1176.1 kg of free acid compound 9c was obtained as a DCM solution (corresponding to 83.5 kg of pure compound 9c based on the HPLC assay) with an HPLC purity of 97.4%, a gravimetric assay value of 7.1%, and an assay-corrected yield of 91.6% (Table 18). [Table 18] MS (ESI+): C6H 14 N2O2(M+H + Calculated value for ): 350.99 Actual value: 350.80 1 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 7.16 (s, 1H), 5.63 (d, J = 6.3 Hz, 1H), 4.68 (d, J = 5.0 Hz, 1H), 3.58 (d, J = 4.7 Hz, 2H), 1.44 (s, 9H).

[0232] Part 2b - Compound 9c: Alternative preparation of (S)-3-(4-bromothiazole-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid [ka] Steps 1 and 2: Preparation of compound 9c [ka] The following three solutions were prepared: i) Solution 1: THF (10 L, 5.0 volume) and compound 9c-1 (2.0 kg, 8.2 mol, 1.0 equivalent) were added to the reactor to obtain a clear solution; ii) Solution 2: 2M i-PrMgCl in THF (14.4L, 7.2mol, 0.875 eq); and iii) Solution 3: DMF (1.2 kg, 16.5 mol, 2.0 eq.).

[0233] The flow rate of pump 1 for solution 1 was adjusted to 44.1 mL / min, the flow rate of pump 2 for solution 2 was adjusted to 15.9 mL / min, and the flow rate of pump 3 for solution 3 was adjusted to 5.4 mL / min. After heating the oil bath to 20°C, pumps 1 and 2 were started simultaneously, followed by pump 3. After 2 minutes, the reaction mixture was collected. After 5 minutes, the reaction was monitored by IPC (HPLC purity: 3.6 A% for compound 9c-1; 92.9 A% for compound 9c-2). DCM (30 L, 15 volumes), followed by hydrochloric acid (628.5 g, 17.2 mol, 2.1 equivalents) in water (10 L, 5.0 volumes) was added to the reactor. The reaction mixture was then added to 1.5 M HCl solution (12 L, 6 volumes) at 15 ± 5°C. The organic phase was then collected and washed with water (20 L × 3). The organic phase was concentrated under reduced pressure at NMT 35°C until the residual volume reached 6 L (3.0 vol), and then the solvent was replaced with MeCN (6.0 L × 2). A total of 4.95 kg of compound 9c-2 solution in MeCN (26 wt%) was obtained. Compound 9c-2 (4.95 kg of MeCN solution, 26 wt%, 6.7 mol, 1.0 equivalent) and MeCN (6.5 L, 5.0 vol) were added to the reactor. Malonic acid (766.5 g, 1.1 equivalent) and pyridine (2.1 kg, 4.0 equivalent) were added to the reactor at 15-25°C, followed by pyrrolidine (95 g, 0.2 equivalent). The mixture was stirred at 80 ± 5°C for 10 hours. After confirming completion of the reaction, the reaction mixture was cooled to 5 ± 5°C. DCM (650 mL, 0.5 vol) was added to the mixture. Diluted HCl (980 g of HCl in water (32.5 L, 25.0 vol)) was added dropwise to the mixture at 5±5°C until the pH was adjusted to approximately 2. The mixture was stirred at 5±5°C for 2 hours. The mixture was filtered, and the cake was rinsed with water (2.6 L, 2.0 vol). The cake was rinsed with DCM (650 mL, 0.5 vol). The wet cake was dried under reduced pressure at 50-55°C for 12 hours. A total of 1.45 kg of compound 9c-3 was obtained as an off-white solid with HPLC purity of 99.7% (Table 18b). 1 H NMR (400 MHz, DMSO-d6): δ 12.92 (s, 1H), 8.03 (s, 1H), 7.67 (d, 1H), 6.70 (d, 1H). [Table 19]

[0234] Step 3: Synthesis of compound 9c-4·H2O [ka] (NH4)2CO3 buffer (600 mL, 10.0 vol, pH 9.8) was added to the reactor under stirring at 34±2°C. Enzyme PH-AML-118 (600 mg, 1.0 wt%) and compound 9c-3 (60 g, 257.6 mmol, 1.0 equivalent) were added to the reactor. The mixture was stirred at 34±2°C for 10 hours, and the reaction was monitored by IPC (HPLC purity: 96.3 A% of compound 9c-4 and 2.4 A% of compound 9c-3, ee: 97.4%). The mixture was cooled to 25±5°C and maintained at that temperature for 10 minutes. The mixture was then adjusted to a pH of 1.0±0.2 with 12M HCl (382 mL, 4.7 vol). The mixture was filtered, and the cake was rinsed with water (30 mL, 0.5 vol). The filtrate was collected and added to the reactor. The pH of the filtrate was adjusted to 1.8±0.1 with a 50% NaOH aqueous solution. Then, the crystalline species of compound 9c-4 was added to the mixture, and the mixture was stirred for 2 hours. The pH of the mixture was adjusted to 5.0±0.5 with a 50% NaOH aqueous solution (6 mL, 0.2 vol). The mixture was heated to 50±5°C and stirred for 2 hours, then cooled to 40±5°C and stirred for 30 minutes. The temperature of the mixture was gradually decreased by 10±5°C increments, stirring for 30 minutes four times until a temperature of 0±5°C was reached. Then, the mixture was stirred at 0±5°C for 5 hours. The mixture was filtered, and the cake was rinsed with water (60 mL, 1.0 vol). The wet cake was dried under reduced pressure at 45±5°C for 16 hours. A total of 57.5 g of compound 9c-4 H2O was obtained as a solid (HPLC purity 99.9%, ee≧99.9%) (Table 18c). [Table 20] 1H NMR (400 MHz, DO): δ 7.49 (s, 1H), 4.13 (dd, 1H), 3.58 (dd, 1H).

[0235] Step 4: Synthesis of Compound 9c [ka] K2CO3 (14.4 g, 104 mmol, 1.4 equivalents) and water (60 mL, 3.0 vols) were added to the reactor. The mixture was adjusted to 20±5°C. Compound 9c-4 H2O (20.0 g, 74.3 mmol, 1.0 equivalent) was added to the reactor. The mixture was heated to 45±5°C and stirred to obtain a clear solution. (Boc)2O solution (17.8 g, 81.7 mmol, 1.1 equivalents in 20 mL of THF) was added to the reactor. The mixture was stirred at 45±5°C for 1 hour, and the reaction was monitored by IPC (HPLC purity: 98.8A%, compound 9c, compound 9c-4 was not detected). The mixture was cooled to 20±5°C. DCM (40 mL, 2.0 vols) was added to the reactor. The mixture was adjusted to pH 2-3 with 3M HCl and stirred for 30 minutes. The mixture was separated and the organic phase was recovered. The aqueous phase was extracted with DCM (40 mL, 2.0 vol.) and combined with the organic phase. DCM (100 mL, 5.0 vol.) was added to the organic phase, and the mixture was concentrated under reduced pressure at NMT 40°C to 4-5 vol. DCM (100 mL, 5.0 vol.) was added to the residue. The mixture was concentrated under reduced pressure at NMT 40°C until 4-5 vol. DCM (100 mL, 5.0 vol.) was added to the residual mixture, and a DCM solution of 180 g of compound 9c was obtained as free acid (HPLC purity 99.92% and 14 wt%, assay corrected yield 90%). 1 H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 7.16 (s, 1H), 5.63 (d, 1H), 4.68 (d, 1H), 3.58 (d, 2H), 1.44 (s, 9H).

[0236] Part 3 - Preparation of Compound 9d (S)-Hexahydropyridazine-3-carboxylate methyl dihydrochloride [ka] MeOH (371 kg, 5.0 vol) and (S)-1,2-bis(tert-butoxycarbonyl)hexahydropyridazine-3-carboxylic acid (compound 9h) (93.9 kg, 284.2 mol, 1.0 equivalent) were added to the reactor.

[0237] SOCl2 (67.6 kg, 568.4 mol, 2.0 equivalents) was added dropwise to the mixture at 10-20°C. The reaction mixture was heated to 35-40°C and stirred for 43 hours. Samples were taken for IPC (indicated HPLC purity: compound 9d 98.5A% and compound 9h 0A%). The reaction mixture was concentrated to 2 volumes (approximately 190 L) under reduced pressure at 35-40°C. Dioxane (193 kg, 2 volumes) was added to the mixture and concentrated to 2 volumes (approximately 190 L) under reduced pressure at 35-40°C. Dioxane (193 kg, 2 volumes) was added to the mixture and concentrated to 2 volumes (approximately 190 L) under reduced pressure at 35-40°C (OT). Dioxane (193 kg, 2 volumes) was added to the mixture and concentrated to 2 volumes (approximately 190 L) under reduced pressure at 35-40°C. The resulting mixture was diluted with DCM (250 kg, 2 volumes). A dioxane / DCM solution of compound 9d was obtained with an HPLC purity of 95.7%, a gravimetric assay value of 10.3%, and a quantitative yield (Table 19). [Table 21] MS (ESI+): C6H 14 N2O2(M+H + Calculated value for ): 145.09 Measured value: 145.10 1 1H NMR (400 MHz, DMSO-d6): δ 3.96 (dd, J = 10.5, 2.5 Hz, 1H), 3.63 (s, 3H), 3.06 (s, 1H), 2.91 (dd, J = 16.2, 7.4 Hz, 1H), 1.89 (d, J = 10.6 Hz, 2H), 1.78 (dd, J = 9.8, 3.4 Hz, 1H), 1.65 - 1.47 (m, 1H).

[0238] Part 4 - Preparation of Compound 9e (S)-1-((S)-3-(4-bromothiazole-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate methyl [ka] Compound 9d (598.0 kg of dioxane / DCM solution, 10.3 wt%, 284.1 mol, 1.2 equivalents) and DCM (553 kg, 5.0 vol) were added to the reactor. The reactor was evacuated and filled with nitrogen three times. The mixture was cooled to 0-5°C. NMM (38.3 kg, 378.8 mol, 1.6 equivalents) was added dropwise to the mixture at 0-5°C and stirred for a further 30 minutes. Compound 9c (1176 kg of DCM solution, 7.1 wt%, 236.7 mol, 1.0 equivalent) was added dropwise to the mixture at 0-5°C and stirred for a further 30 minutes. HOBt (0.64 kg, 4.7 mol, 0.02 equivalents) and EDCI (81.7 kg, 426.1 mol, 1.8 equivalents) were added to the mixture at 0-5°C and stirred for a further 1 hour. Samples were collected for IPC (HPLC purity: compound 9e was 86.5A%, and compound 9c was not present). The reaction mixture was washed with water (831 kg x 4, 10 vols x 4). The DCM phase was concentrated to 2 volumes (approximately 200 L) under reduced pressure at 25-30°C. MTBE (307 kg, 5 vols) was added to the above DCM solution. The organic phase was concentrated to 2 volumes (approximately 200 L) under reduced pressure at 25-30°C. MTBE (307 kg, 5 vols) was added to the above solution. The mixture was concentrated to 2 volumes (approximately 200 L) under reduced pressure at 25-30°C. MTBE (307 kg, 5 vols) was added to the above solution. The mixture was concentrated to 2 volumes (approximately 200 L) under reduced pressure at 25-30°C. MTBE (184 kg, 3 vols) was added to the above solution. n-heptane (141 kg, 2.5 vols) was added dropwise to the above solution at 25-30°C. The resulting mixture was stirred at 15-20°C for 30 minutes. The resulting mixture was cooled to 0-10°C and stirred for a further 60 minutes. The resulting slurry was filtered, and the filtered cake was rinsed with 1:1 (volt / volt) n-heptane / MTBE (141 kg, 2 vols). The filtered cake was dried under reduced pressure at 35-40°C. A total of 105.5 kg of compound 9e was obtained as a white solid (HPLC purity 99.6% and HPLC gravimetric assay value 99.4%, assay corrected yield 92.8%) (Table 20). [Table 22] MS (ESI+): C17 H 25 BrN4O5S (M+H + Calculated value for ): 477.07 Actual value: 477.20 1 1H NMR (400 MHz, CD3OD-d4): δ 7.44 (s, 1H), 5.64 - 5.31 (m, 1H), 3.92 (s, 1H), 3.74 (s, 3H), 3.61 (d, J = 3.9 Hz, 1H), 3.39 (dd, J = 14.5, 5.0 Hz, 1H), 3.29 - 3.18 (m, 2H), 1.99 (dd, J = 8.4, 5.0 Hz, 1H), 1.86 - 1.62 (m, 3H), 1.40 (d, J = 18.6 Hz, 9H).

[0239] Part 5 - Preparation of Compound 9f((S)-1-((S)-2-amino-3-(4-bromothiazole-2-yl)propanoyl)hexahydropyridazine-3-carboxylate methyl) [ka] MeOH (960 kg, 10 volumes) and (S)-1-((S)-3-(4-bromothiazole-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate methyl (compound 9e) (121.5 kg, 254.5 mol, 1.0 equivalent) were added to the reactor. The reactor was evacuated and filled with nitrogen three times. SOCl2 (90.8 kg, 763.6 mol, 3.0 equivalents) was added dropwise to the mixture at 0-10°C. The resulting mixture was heated to 30-40°C and stirred at this temperature for 2 hours. Samples were taken for IPC (HPLC: 98.2 A% compound 9f and 0 A% compound 9e). The reaction mixture was concentrated to 150-250 L at 30-40°C and diluted with DCM (808 kg, 5 volumes). The mixture was adjusted to pH 10.0–10.4 with a 15% by weight Na₂CO₃ aqueous solution (2673 kg, 22 wts) at 0–10°C. After phase separation, the aqueous phase was extracted with DCM (808 kg × 2, 2 × 5 vols). The DCM phases were combined and washed with a 26% NaCl aqueous solution (3 × 1215 kg, 3 × 10 vols). The DCM phase was concentrated to 1200–1500 L under reduced pressure at 30–40°C. A DCM solution of compound 9f (1612.3 kg, 5.35 wt%) was obtained with a purity of 99.3 A% and a corrected yield of 91.1% (Table 21). [Table 23] LCMS (ESI+) C 12 H 17 BrN4O3S (M+H + Calculated value for ): 377.02 Actual value: 377.10 1 1H NMR (400 MHz, CD3OD) δ 7.57 (s, 1H), 5.45 (br, 1H), 3.80 (br, 1H), 3.77 (s, 3H), 3.67 (dd, J = 16.1, 4.3 Hz, 2H), 3.51 (dd, J = 16.1, 8.0 Hz, 2H), 1.91-2.09 (m, 2H), 1.83 - 1.67 (m, 2H).

[0240] Part 6 - Preparation of Compound 9g - (S)-1-((S)-3-(4-bromothiazole-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylate methyl [ka] (S)-1-((S)-2-amino-3-(4-bromothiazole-2-yl)propanoyl)hexahydropyridazine-3-carboxylate methyl (compound 9f) (1612.3 kg of DCM solution, HPLC gravimetric assay value 5.4%, 230.8 mol, 1.0 equivalent) and 212.4 kg of DCM were added to the reactor. The reactor was evacuated and filled with nitrogen three times. NMM (37.3 kg, 369.2 mol, 1.6 equivalents) was added dropwise to the mixture at 0-10°C and stirred at this temperature for 10 minutes. Compound 3 (30.0 kg, 300.0 mol, 1.3 equivalents) was added dropwise to the mixture at 0-10°C and stirred at this temperature for 10 minutes. HOBt (0.62 kg, 4.6 mol, 0.02 equivalents) and EDCI (79.6 kg, 415.4 mol, 1.8 equivalents) were added to the mixture at 0-10°C. The mixture was stirred at 0-10°C for 1-3 hours. Samples were taken for IPC (HPLC: 9 g of compound at 92.5 A% and 9 f of compound at 0 A%). The DCM phase was washed three times with water (871 kg × 3, 10 volumes × 3). The DCM phase was concentrated under reduced pressure at 30-40°C to 2-3 volumes (180-270 L). n-heptane (355 kg, 6 volumes) was added dropwise to the above solution at 20-40°C. The resulting mixture was stirred at 10-20°C for 30 minutes and then stirred at 0-5°C for 5 hours. The resulting mixture was filtered, and the filtered cake was rinsed with 2:1 (vol / vol) n-heptane / DCM (174 kg, 2 vol). The filtered cake was dried under reduced pressure at 30-40°C for 12 hours. A total of 94.8 kg of the compound yielded 9 g as a white solid (HPLC purity 99.8% and gravimetric assay value 99.5%, assay corrected yield 89%) (Table 22). [Table 24] LCMS (ESI+): C 17 H 23 BrN4O4S (M+H + Calculated value for ): 459.06 Actual value: 459.30 1 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 5.59 (td, J = 8.0, 5.3 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 3.93 - 3.76 (m, 1H), 3.66 (s, 3H), 3.50 (dd, J = 15.9, 7.8 Hz, 1H), 3.33 - 3.24 (m, 1H), 3.23 - 2.92 (m, 2H), 1.95 - 1.76 (m, 1H), 1.78 - 1.39 (m, 4H), 1.17 - 0.93 (m, 4H), 0.83 (dt, J = 7.8, 3.9 Hz, 1H), 0.47 (dt, J = 8.1, 4.4 Hz, 1H).

[0241] Part 7 - Preparation of Compound 9-(S)-1-((S)-3-(4-bromothiazole-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylic acid [ka] ((S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylate methyl) (9g of compound) (94.0kg, 204.6mol, 1.0 equivalent) and MeOH (743kg, 10 volumes) were added to the reactor. Aqueous LiOH solution was added dropwise to the mixture at 2-4°C. The mixture was stirred at 0-5°C for 7 hours. Sample 1 was taken for IPC (HPLC: 99.4A% of compound 9g and 0.2A% of compound 9g). The solution was filtered through a filtration tank and an online microfilter. Sample 2 was taken for IPC (HPLC: 99.4A% of compound 9g and 0.2A% of compound 9g). The reaction mixture was adjusted to pH 6.2–7.2 with a 1M HCl aqueous solution at 0–5°C, and then concentrated under reduced pressure at 25–35°C (OT) until the residual volume reached 650–750 L. HCl (846 kg, 10 volumes) was added to the reactor. The reaction mixture was adjusted to pH 2.8–3.2 with a 1M HCl aqueous solution at 0–5°C. The phases were separated. The aqueous phase was extracted twice with HCl (846 kg, 10 volumes and 423 kg, 5 volumes). The HCl phases were combined and washed with a 26 wt% NaCl aqueous solution (1050 kg, 10 volumes). The HCl phase was filtered through a filtration tank. The HCl phase was concentrated under reduced pressure at 35–45°C (OT) to 380–470 L. Seed crystals (45 g) were added to the mixture and stirred at 5–15°C for 10 minutes. n-heptane (320 kg, 5 volumes) was added to the above alkyl solution. The resulting mixture was concentrated under reduced pressure at 35-45°C to 380-470 L. n-heptane (320 kg, 5 volumes) was added to the above alkyl solution. The resulting mixture was concentrated under reduced pressure at 35-45°C to 380-470 L. n-heptane (320 kg, 5 volumes) was added to the above alkyl solution. The resulting mixture was concentrated under reduced pressure at 35-45°C to 380-470 L. The resulting mixture was stirred at 10-20°C for 0.5-1.5 hours, and then stirred at 1-5°C for 2-4 hours. The mixture was filtered, and the filtered cake was rinsed with n-heptane (128 kg, 2 volumes). The filtered cake was dried under reduced pressure at 35-45°C for 10 hours.A total of 87.7 kg of compound 9 was obtained as a white solid (HPLC purity 99.2%, HPLC gravimetric assay value 97.9%, assay-corrected yield 94.2%) (Table 23). [Table 25] LCMS (ESI+): C 16 H 21 BrN4O4S (M+H + Calculated value for ): 445.05 Actual value: 445.20 1 1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 5.3 Hz, 1H), 5.70 (dd, J = 6.9, 5.8 Hz, 1H), 4.05 (d, J = 7.3 Hz, 1H), 3.46 (dd, J = 9.5, 3.6 Hz, 1H), 3.39 (dd, J = 14.6, 5.6 Hz, 1H), 3.27 (dt, J = 3.3, 2.0 Hz, 1H), 2.99 (s, 1H), 2.06 - 1.91 (m, 1H), 1.79 (td, J = 9.0, 4.2 Hz, 1H), 1.73 - 1.60 (m, 2H), 1.36 (dt, J = 8.3, 4.3 Hz, 1H), 1.18 (dtd, J = 10.0, 6.1, 4.0 Hz, 1H), 1.04 (d, J = 6.0 Hz, 3H), 0.97 (dt, J = 8.6, 4.2 Hz, 1H), 0.55 (ddd, J = 8.1, 6.2, 3.9Hz, 1H).

[0242] Example 7. Synthesis procedure for compound A-(1S,2S)-N-[(7S,13S)-21-ethyl-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1^{2,5}.1^{9,13}.0^{22,26}]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methylcyclopropane-1-carboxamide [ka] Part 1 - Synthesis of Compound 10 (3-(1-ethyl-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine-3-yl}-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-yl)-2,2-dimethylpropane-1-ol) [ka] DCM (36.25 kg), MeOH (7.05 kg), [1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine-3-yl}-1H-indole-5-yl]boronic acid (compound 6a) (8.90 kg, 17.50 mol, 1.0 equivalent), and pinacol (3.12 kg, 26.40 mol, 1.5 equivalents) were added to the reactor. The solution was stirred at 25°C for 18 hours. A sample was taken, diluted with DMSO, and analyzed by HPLC (reference: area % of compound 6a ≤ 3%, result: area % of compound 6a = 0.4%). The solution was concentrated under reduced pressure until the residual volume was approximately 11 L. DCM (36.10 kg) was added, and the resulting solution was concentrated under reduced pressure until the residual volume was approximately 11 L. The same process was repeated nine more times to obtain residual MeOH within an acceptable range. A sample was taken for GC analysis to confirm the residual MeOH (reference: MeOH content ≤ 100 ppm, result: MeOH content = 60 ppm). The solution of compound 10 in the obtained DCM was used in the next step without further purification (weight of DCM solution: 30.74 kg, area-specific purity 95.2%, content of compound 10: weight-specific assay value 32.0%, 16.66 mol, yield 95.2%, Table 24). [Table 26] LCMS (ESI+) C 34 H 51 Calculated value for BN4O4(M+H+): 591.40 Actual value: 591.40 1 1H NMR (400 MHz, CDCl) 3) δ 8.51 (d, J = 2.9 Hz, 1H), 8.23 ​​(s, 1H), 7.72 (dd, J = 8.3, 1.0 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 2.9 Hz, 1H), 4.12 - 3.88 (m, 3H), 3.30 (dt, J = 11.7, 3.9 Hz, 6H), 3.04 (s, 3H), 2.81 (d, J = 14.1 Hz, 1H), 2.63 (t, J = 5.0 Hz, 3H), 2.38 (s, 3H), 2.33 (d, J = 14.1 Hz, 1H), 1.44 (d, J = 6.2 Hz, 3H), 1.39 (s, 12H), 1.22 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 6.8 Hz, 2H), 0.83 (d, J = 7.3 Hz, 6H).

[0243] Part 2 - Synthesis of Compound 11-2-[(1-ethyl-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine-3-yl}-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-yl)methyl]-2-methylpropyl(3S)-1-[(2S)-3-(4-bromo-1,3-thiazole-2-yl)-2-{[(1S,2S)-2-methylcyclopropyl]formamide}propanoyl]-1,2-diadinane-3-carboxylate [ka] In the reactor, 3-(1-ethyl-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine-3-yl}-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-yl)-2,2-dimethylpropane-1-ol (compound 10) (30.56 kg, compound 10 content: weight ratio assay value 32.0%, 16.56 mol, 1.0 A solution of DCM containing (3S)-1-[(2S)-3-(4-bromo-1,3-thiazole-2-yl)-2-{[(1S,2S)-2-methylcyclopropyl]formamide}propanoyl]-1,2-diadinane-3-carboxylic acid (compound 9) (8.52 kg, 19.13 mol, 1.16 equivalents) and DMAP (3.05 kg, 2.50 mol, 1.5 equivalents) was added. The solution was cooled to 19°C, and EDCI (6.39 kg, 3.33 mol, 2.0 equivalents) was gradually added while stirring at 15-20°C. The resulting solution was stirred at 15-20°C for 14 hours. A sample was taken, diluted with MeCN, and the IPC purity was confirmed by HPLC analysis (reference: area % of compound 10 ≤ 5%, actual result: area % of compound 10: 3%). The reaction mixture was quenched with water and sequentially washed with aqueous HCl (0.2 M, 171.5 kg), aqueous NaHCO3 (8 w / w%, 155.7 kg), and water (98.4 kg). The DCM phase was then separated and concentrated under reduced pressure until the residual volume was approximately 25 L. MTBE (37.05 kg, 3V) was added, and the resulting solution was concentrated under reduced pressure until the residual volume was approximately 25 L. The solvent exchange process was repeated three more times. The resulting MTBE solution was added dropwise to pre-cooled n-heptane (25 L) at -10°C. The resulting suspension was then stirred at -10°C for 12.5 hours. The slurry was filtered, and the filter cake was washed with n-heptane (6.8 kg). The wet cake was dried under vacuum at 30°C to obtain compound 11 as a white solid (17.29 kg, area specific purity 86.5%, weight specific assay value 81.9%, 13.91 mol, yield 84%, Table 25). [Table 27] LCMS (ESI+) C 50 H 70 Calculated value for BBrN8O7S (M+H+): 1017.44 Measured value: 1017.4 1 1H NMR (400 MHz, CDCl 3) δ: 8.52 (d, J = 2.8 Hz, 1H), 8.12 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 7.09 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H), 5.50 (dt, J = 7.0, 4.9 Hz, 1H), 4.32 (d, J = 12.9 Hz, 1H), 4.03 (dd, J = 12.7, 7.8 Hz, 2H), 3.95 (d, J = 6.1 Hz, 1H), 3.88 (dd, J = 14.6, 7.3 Hz, 1H), 3.73 (d, J = 4.8 Hz, 1H), 3.68 (dd, J = 10.9, 3.1 Hz, 1H), 3.62 (d, J = 11.6 Hz, 1H), 3.43 (d, J = 4.8 Hz, 2H), 3.31 (t, J = 5.1 Hz, 4H), 2.99 (s, 3H), 2.84 (d, J = 14.2 Hz, 1H), 2.61 (t, J = 5.0 Hz, 4H), 2.37 (s, 3H), 2.32 (d, J = 14.2 Hz, 1H), 2.04 - 1.95 (m, 1H), 1.85 - 1.75 (m, 2H), 1.41 (d, J = 6.2 Hz, 3H), 1.37 (s, 12H), 1.25 (d, J = 7.3 Hz, 2H), 1.21 (d, J = 7.1 Hz, 3H), 1.19 - 1.08 (m, 3H), 1.06 (d, J = 6.0 Hz, 3H), 0.90 (s, 3H), 0.85 (s, 3H), 0.61 - 0.55 (m, 1H).

[0244] Part 3 - Synthesis of the free base of compound A - (1S,2S)-N-[(7S,13S)-21-ethyl-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1^{2,5}.1^{9,13}.0^{22,26}]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methylcyclopropane-1-carboxamide [ka] In the reactor, add 1,4-dioxane (134.65 kg), 2-[(1-ethyl-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine-3-yl}-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-yl)methyl]-2-methylpropyl(3S)-1-[(2S)-3-(4-bromo -1,3-thiazole-2-yl)-2-{[(1S,2S)-2-methylcyclopropyl]formamide}propanoyl]-1,2-diadinane-3-carboxylate (compound 11) (5.50 kg, weight ratio assay value 81.9%, 4.43 mol, 1.0 equivalent) and P(t-Bu)3-HBF4 (256.5 g, 0.089 mol, 0.2 equivalents) were added at 25°C.

[0245] Nitrogen was bubbled under the surface of the mixture at 25°C for 1 hour. P(t-Bu)3Pd G3 (504.0 g, 0.089 mol, 0.2 equivalents) was added to this mixture. Nitrogen was again bubbled under the surface of the mixture at 25°C for 1 hour. The resulting reaction mixture was then heated to 45°C. A solution of K2CO3 (1.22 kg, 8.84 mol, 2.0 equivalents) in water (27.00 kg) was added dropwise over 1 hour. The resulting reaction mixture was stirred at 45-50°C for 7 hours. A sample was taken, diluted with MeOH, and the IPC purity was tested by HPLC analysis (reference: area % of compound 11: ≤3%, actual result: area % of compound 11 = 0.1%). The reaction mixture was then concentrated under reduced pressure to 25 L. The mixture was then diluted with RINKAN (49.0 kg) and water (45.5 kg). The organic phase was separated and washed three times with water (22.8 kg x 3). The organic phase was concentrated and co-distilled with butyl under reduced pressure to remove 1,4-dioxane (GC area % for dioxane: ≤3%, result: GC area % for dioxane: 1.3%). The product in the resulting butyl solution was stored and combined with two other batches for further workup.

[0246] Suzuki coupling of two other batches was carried out using the same procedure as above. Water (11.00 kg) and ethyl acetate (33.50 kg) were added to the combined three batches. The resulting two-phase solution was then cooled to 10°C. To this solution, aqueous HCl (prepared by mixing 13.9 kg of water and 2.4 kg of hydrochloric acid) was slowly added over 90 minutes at 10°C. Seed crystals (136.5 g) were then added, and the resulting suspension was stirred for a further 1 hour at 10°C. The slurry was further cooled to 0°C for 1 hour and held for 1 hour. This 10-0°C temperature cycle was repeated three more times. The suspension was stirred at 0°C for 10 hours, and the resulting slurry was filtered. The filtered cake was washed with water (5.00 kg). The wet cake was suspended in a mixed solvent of ethyl acetate (20.0 kg) and water (5.0 kg) at 5°C and stirred for 1 hour. The suspension was filtered and washed with cold water (5.0 kg, pre-cooled to 5°C) to obtain the wet HCl salt of compound A as a yellow solid (6.1 kg, area specific purity 97.6%, LOD: 29.2%, Pd: 595 ppm).

[0247] The HCl salt of compound A was suspended at 5°C in a mixture of 2-MeTHF (35.70 kg) and water (24.10 kg), and the pH of the aqueous solution was adjusted to 8-9 by adding a 10% sodium carbonate aqueous solution. The organic phase was then separated and washed twice with water (2 × 24 kg). Water (16.1 kg) was added to the organic phase, and the pH was adjusted to 3.7 with a 1 M HCl solution. The aqueous phase was then separated and washed twice with 2-MeTHF (2 × 13.5 kg). 27.7 kg of 2-MeTHF was added to the aqueous phase, and the pH was adjusted to 5.5 by adding a 1 M sodium hydroxide aqueous solution. The organic phase was separated and washed with water and NaCl solution. SiliaMets thiol (1.290 kg) was added to the organic phase, and the resulting suspension was stirred at 25°C for 22 hours. The slurry was filtered, and the filtered cake was washed with 2-MeTHF (2 × 5.5 L). The combined organic phases were concentrated under reduced pressure to 12 L. The resulting MeTHF solution was added to pre-cooled n-heptane (55.80 kg, pre-cooled to -10°C) over 1 hour at -10°C. The resulting suspension was stirred at -10°C for 12 hours. The suspension was filtered, and the wet cake was washed twice with n-heptane (2 × 2.3 kg). The wet cake was dried under reduced pressure at 40°C to obtain the free base of compound A as an off-white solid (2.46 kg, area specific purity 99.2%, 3.03 mol, yield 22.8%, Table 26). [Table 28] LCMS (ESI+) C44H58N8O5S (M+H + Calculated value for ): 811.43 Measured value: 811.4 1 1H NMR (400 MHz, DMSO-d 6) δ 8.54 (d, J = 9.2 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.73 (dd, J = 8.8, 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.60 (t, J = 8.8 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.32-4.15 (m, 5H), 3.60 (br s, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.27 (br s, 4H), 3.22 (s, 3H), 3.19-3.15 (m, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.49-2.45 (m, 5H), 2.21(s, 3H), 2.10 (d, J = 9.6 Hz, 1H), 1.80 (br s, 2H), 1.56-1.52 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.08 (s, 4H), 0.92-0.89 (m, 7H), 0.56 (d, J = 5.2 Hz, 1H), 0.37 (s, 3H).

[0248] Part 4 - Purification of Compound A-(1S,2S)-N-[(7S,13S)-21-ethyl-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1^{2,5}.1^{9,13}.0^{22,26}]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methylcyclopropane-1-carboxamide [ka] MeOH (7.76 kg) and the free base of compound A (2.46 kg, 3.03 mol, 1.0 equivalent) were added to the reactor at 25°C. The resulting suspension was stirred until the solid was completely dissolved. The resulting methanol solution was filtered through a microporous filter and transferred to another reactor. The reactor temperature was then maintained at 25°C, and water (2.41 kg, 1.0 V) was slowly added over 30 minutes. The resulting turbid solution was stirred at 25°C for a further 30 minutes. Then, a methanol and water solution (3.42 kg, 1:2, v / v) was slowly added over 1 hour. The resulting suspension was stirred at 25°C for 2 hours. Additional water (2.48 kg) was slowly added to the suspension over 1 hour. The final suspension was stirred for a further 1 hour. Water (9.29 kg, 3.75 V) was slowly added to the suspension over 2 hours, and the mixture was stirred at 25°C for at least 16 hours. The resulting suspension was filtered and washed twice (2 × 2.2 kg) with a water:MeOH mixed solvent (3:2, v / v), followed by washing with water (4.91 kg). The wet cake was dried under reduced pressure and humidity control (temperature: 25 ± 5°C, vacuum ≥ -0.085 MPa, humidity: 10% ~ 20%) for 37 hours to obtain compound A as a white solid (2.68 kg, area specific purity 99.4%, weight specific assay value 93.0%, KF: 6.7%, 3.07 mol, yield 92%, Table 27). [Table 29] MS (ESI+) C 44 H 58 Calculated value for N8O5S (M+H): 811.43 Measured value: 811.40 1 1H NMR (400 MHz, DMSO-d 6) δ 8.54 (d, J = 9.2 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.73 (dd, J = 8.8, 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.60 (t, J = 8.8 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.32-4.15 (m, 5H), 3.60 (br s, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.27 (br s, 4H), 3.22 (s, 3H), 3.19-3.15 (m, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.49-2.45 (m, 5H), 2.21(s, 3H), 2.10 (d, J = 9.6 Hz, 1H), 1.80 (br s, 2H), 1.56-1.52 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.08 (s, 4H), 0.92-0.89 (m, 7H), 0.56 (d, J = 5.2 Hz, 1H), 0.37 (s, 3H).

[0249] Example 8. Alternative synthesis of compound A [ka] Part 1a - Synthesis of Compound 12-(S)-1-((S)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)thiazole-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylic acid [ka] (S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)boronic acid (compound 6a) (54.5 kg, 95% by weight, 107.2 mol, 1.0 equivalent), (S)-1-((S)-3-(4-bromothiazole-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylic acid (compound 9, 49.0 kg, 110.3 mol, 1.03 equivalent), and dioxane (514.2 kg) were added to the reactor. Then, anhydrous potassium carbonate (45.4 kg) in purified water (166.5 kg) was added. The mixture was purged with nitrogen for approximately 1.5 hours. Then, 3.6 kg (0.06-0.07 x 0.05 equivalents) of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) was added to the mixture under nitrogen protection. Dioxane (70 kg) was sprayed into the reactor. The reaction mixture was again purged with nitrogen for a further 1.5 hours. Then, the reaction mixture was slowly heated to 75°C over 4 hours. The reaction mixture was stirred at 75°C for a further 10 hours. Reaction IPC showed that the starting material (compound 6a) was less than 1% by HPLC. The reaction mixture was cooled to room temperature and filtered through 10.2 diatomaceous earth to remove insoluble material. The filtrate cake was washed with 206.9 kg of 23% NaCl aqueous solution and 185 kg of dioxane. The filtrate was separated, the organic phase was separated and evaporated to 429 L. Water (272 kg) and 2-methyltetrahydrofuran (242 kg). The basic mixture was adjusted to pH 9.1 with 7% HCl (25.6 kg), and the aqueous phase was separated. The aqueous phase was acidified to pH 2-3 using 7% HCl (139 kg). The aqueous phase was then washed with MeTHF (277 kg). The aqueous phase was neutralized to pH 7-8 using 15% sodium carbonate aqueous solution (130 kg). The product was extracted from the aqueous phase using DCM-MeOH (twice, 563.4 kg + 100 kg). The combined organic phase was evaporated and diluted with IPA (275 L) and MeOH (6 kg). MTBE (1274 kg) was added slowly over 5 hours in three portions.During the addition process, the product began to crystallize. The resulting slurry was cooled to 0°C for 12 hours. The slurry was then filtered, and the wet compound was dried to obtain compound 12 as a gray solid (76.6 kg, area specific purity 95.9%, 87.9% by weight, yield 76%, Table 28).

[0250] Part 1b - Alternative synthesis of compound 12 (S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)boronic acid (compound 6a) (118.4 kg, 233 mol, 1.0 equivalent), (S)-1-((S)-3-(4-bromothiazole-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylic acid (compound 9, 108.8 kg, 244 mol, 1.04 equivalent), and dioxane (1,102 kg) were added to the reactor. Then, anhydrous potassium carbonate (91.7 kg; 5.5 equivalents) in purified water (352 kg) was added. The mixture was purged with nitrogen for approximately 1.5 hours. Then, 7.80 kg (0.065 x 0.05 equivalents) of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) was added to the mixture under nitrogen protection. Dioxane (125 kg) was sprayed into the reactor. The reaction mixture was again purged with nitrogen for a further 1.5 hours. Then, the reaction mixture was slowly heated to 75°C over 4 hours. The reaction mixture was stirred at 75°C for a further 6 hours. Reaction IPC showed that the starting material (compound 6a) was less than 1% by HPLC. The reaction mixture was cooled to room temperature, and the dark-colored reaction mixture was filtered through 10.2 diatomaceous earth to remove insoluble material. The filter cake was washed with additional dioxane (312 kg). In a separate reactor, aqueous solutions of sodium chloride (103 kg (312 kg) in water) and aqueous solutions of potassium carbonate (80 kg (122 kg) in water) were prepared. The filtrate (organic solution) was combined with a mixture of aqueous NaCl and aqueous K2CO3 solutions. The organic phase was then separated and concentrated to 1188 L (10V). The resulting solution was co-distilled with IPA (6 × 1191 L) to minimize the content of dioxane and water. The resulting organic phase was adjusted to 946 L (8V). The solution was slowly added to MTBE (3754 L, 31.8V) over 5 hours. Furthermore, the product began to crystallize / precipitate into a slurry. The resulting slurry was cooled to 0°C for 12 hours.Next, the slurry was filtered and the wet compound was dried to obtain the sodium salt of compound 12 as a gray solid (184.6 kg, area specific purity 96.1%, 87.7% by weight, yield 84%). [Table 30] LCMS (ESI+) C 44 H 60 N8O6S (M+H + Calculated value for ): 829.44 Actual value: 829.90 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=2.81 Hz, 1 H) ,8.32 (s, 1 H), 8.05 (d, J=8.19 Hz, 1 H), 7.74 - 7.71 (m, 2 H), 7.51 - 7.49 (m, 1 H), 7.30 - 7.27 (m, 1 H), 5.53 - 5.46 (m, 1 H), 4.53 - 4.50 (m, 1 H), 4.20 (br d, J=12.72 Hz, 1 H), 4.10 - 4.01 (m, 2 H), 3.92 - 3.84 (m, 1 H), 3.28 - 3.20 (m, 7 H), 3.12 (br d, J=10.72 Hz, 2 H), 3.08 (s, 3 H), 3.04 - 3.01 (m, 1 H), 2.88 (s, 3 H), 2.84 (m, 1 H), 2.72 (s, 1 H), 2.69 - 2.62 (m, 2 H),2.53 - 2.52 (m, 1 H), 2.46 (br t, J=4.77*(2) Hz, 5 H), 2.26-2.24 (m, 1 H), 2.21 - 2.16 (m, 4 H), 1.93 - 1.87 (m, 1 H), 1.68 (br dd, J=9.11, 3.00 Hz, 1 H), 1.58 (d, J=4.03 Hz, 1 H), 144 (d, J=6.68 Hz, 1 H), 1.36 - 1.34 (m, 2 H), 1.15 (t, J=7.15 Hz, 2 H), 0.93 - 0.85 (m, 1 H), 0.69 - 0.63 (m, 3 H), 0.63 - 0.58 (m, 3 H), 0.53 - 0.45 (m, 1 H)。

[0251] Part 2a - Synthesis of the lactate of compound A - (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide lactate [ka] In reactor 1, 1-hydroxy-1H-benzotriazole (21.1 kg, 156 mol, 2.0 equivalents), 4-dimethylaminopiridine (4.9 kg, 0.5 equivalents), N,N-diisopropylethylamine (21 kg, 2.0 equivalents), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl (45.5 kg, 237 mol, 3.0 equivalents) were added and dissolved in DCM (3601.3 kg). Subsequently, in reactor 2, (S)-1-((S)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)thiazole-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylic acid (compound 12, 65.7 kg, 87.9 wt%, 79 mol, 1.0 equivalent) was dissolved in DCM (920 kg). The solution was transferred from reactor 2 to reactor 1 over 25-35°C for 25 hours. The solution was stirred at 25-35°C for 2.0 hours. After the reaction was complete, the mixture was quenched with water (330 kg) and the solution was concentrated to 2000 kg. Water (330 kg) was added to the mixture to separate the organic phase. The organic phase was washed twice with water (720 kg), and the 1708.8 kg of organic phase was concentrated to 175 kg and evaporated twice with acetonitrile (460 kg). The concentrate in acetonitrile was adjusted to 300 kg. Then, 98% lactic acid (26.2 kg, 4.0 equivalents) was slowly added over 2 hours. Water (3.8 kg) was added to the solution. Then, seed crystals (0.54 kg) were added, and the resulting slurry was stirred at 25°C for 12 hours, then cooled to 0°C for 5 hours, and stirred at 0°C for 20 hours. The compound was isolated after filtration and drying. The crude wet cake was slurried in MeCN (340 kg) at 0°C for 18 hours. Next, the slurry was filtered and dried to obtain the lactate of compound A as a gray solid (35.6 kg, area specific purity 99.0%, 82.2% by weight, yield 48%, Table 29).

[0252] Part 2b - Synthesis of the lactate of compound A - (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide lactate 1-hydroxy-1H-benzotriazole (24 kg, 177 mol, 2.0 equivalents), 4-dimethylaminopiridine (5.6 kg, 45.9 mol, 0.5 equivalents), N,N-diisopropylethylamine (24 kg, 186 mol, 2.0 equivalents), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl (52 kg, 272 mol, 3.0 equivalents) were added to reactor 1. The reagents were then dissolved in DCM (4190 kg). In a separate reactor (reactor 2), (S)-1-((S)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-1H-indole-5-yl)thiazole-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamide)propanoyl)hexahydropyridazine-3-carboxylic acid (compound 12, 75.3 kg, 90.8 mol, 1.0 equivalent) was dissolved in DCM (1000 kg). The solution from reactor 2 was then transferred to reactor 1 at 25-35°C over 25 hours. The solution was stirred at 25-35°C for 2 hours. After the reaction was complete, the mixture was quenched with water (350 kg) and then concentrated to approximately 2000 kg. Water (350 kg) was added to the mixture and the organic phase was separated. Water (approximately 750 kg) was added to the organic phase and the pH of the aqueous phase was adjusted to 4-5 using 85% lactic acid. The organic phase was separated and concentrated to 232 L and evaporated three times with acetonitrile (740 L). The volume of the resulting organic phase was adjusted to approximately 300 kg. Then, 85% lactic acid (16.2 kg, 2.0 equivalents) was slowly added over 2 hours, and water (2.4 kg) was added to the solution. Then, seed crystals of compound 12 (0.23 kg) were added, and the resulting slurry was stirred at 25°C for 12 hours, then cooled to 0°C for 5 hours, and stirred at 0°C for 20 hours. Compound 12 was isolated after filtration. The crude wet cake was recrystallized again in MeCN (approximately 340 kg), heated to 60°C, and cooled to 0°C for 20 hours. The slurry was then filtered and dried to obtain the L-lactate of compound 12 as a gray solid (57.07 kg, area specific purity 99.0%, 81.1% by weight, yield 63%). [Table 31] LCMS (ESI+). C 44 H 58 N8O5S+C3H6O3(M+H + ) Calculated value for: 901.14 (as lactate) Measured value: 811.3 1 H NMR (400 MHz, CDCl3): δ ppm: 8.48 - 8.52 (m, 1 H), 8.39 - 8.45 (m, 1 H), 7.49 - 7.55 (m, 1 H), 7.24 - 7.29 (m, 1 H), 7.03 (d, J=2.50 Hz, 1 H), 6.40 - 6.55 (m, 1 H), 5.80 - 5.91 (m, 1 H), 5.15 - 5.22 (m, 1 H), 5.12 - 5.27 (m, 1 H), 4.47 - 4.56 (m, 1 H), 4.14 - 4.29 (m, 4 H) 4.01 - 4.12 (m, 4 H), 3.90 - 3.97 (m, 2 H), 3.71 - 3.77 (m, 1 H), 3.60 - 3.68 (m, 1 H),, 3.35 - 3.40 (m, 4 H), 3.27 - 3.33 (m, 3 H), 3.00 -3.12 (m, 2 H), 2.91 - 2.96 (m, 3 H), 2.57 - 2.66 (m, 1 H), 2.47 - 2.55 (m, 3 H), 2.32 - 2.41 (m, 1 H), 2.07 - 2.18 (m, 1 H), 1.85 - 1.91 (m, 1 H), 1.68 - 1.79 (m, 1 H),1.48 - 1.58 (m, 1 H), 1.31 - 1.39 (m, 6 H), 1.09 - 1.22 (m, 3 H), 0.87 - 0.92 (m, 3 H), 0.78 - 0.86 (m, 3 H), 0.52 - 0.60 (m, 1 H), 0.48 - 0.51 (m, 1 H), 0.47 - 0.51 (m, 1 H), 0.31 - 0.40 (m, 3 H).

[0253] Part 3a - Synthesis of the free base of compound A - (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide [ka] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide lactate (28.0 kg, 34.5 mol, 1.0 equivalent) was added to 2-MeTHF (292 kg) and water (113 kg) in a reactor. The mixture was cooled to 0-10°C. Next, 15 kg of 15% sodium carbonate aqueous solution was slowly added to the reactor to neutralize the pH to 8-9 at 0-10°C. The mixture was stirred for 30 minutes to separate the organic phase. The organic phase was washed with water (225 kg). Then it was washed with 25% NaCl (120 kg). 11.2 kg of silicathiol (0.38-0.42X) was added to the organic phase, and the slurry was stirred at room temperature for 12 hours to remove residual palladium. Then the silicathiol was removed by filtration. The filtrate was concentrated to 112 L. This solution was added to heptane (1200 kg) over 4 hours. The resulting slurry was filtered, and the filtration cake was dried to obtain the free base of crude compound A as a white solid (24.9 kg, area specific purity 98.9%, 96.4 w / w%, yield 85.6%, Table 30).

[0254] Part 3b - Synthesis of the free base of compound A - (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide lactate (lactate of compound A, 49.6 kg, 55 mol, 1.0 equivalent) was added to 2-MeTHF (440 kg, 8.9 V) and water (198 kg). The mixture was cooled to 0-10°C. Next, 27 kg of 15% aqueous sodium carbonate solution was slowly added to the reactor to neutralize the pH to 8-9 at 0-10°C. The mixture was stirred for 30 minutes to separate the organic phase. The organic phase was washed with water (398 kg), followed by 198 kg of 25% NaCl. 11.2 kg of silicathiol (0.38-0.42X) or 3-mercaptopropyl ethyl sulfide silica (SPM32) was added to the organic phase, and the slurry was stirred at room temperature for 12 hours to remove residual palladium. The silicathiol was then removed by filtration. The filtrate was concentrated to 349 L (7V). This solution was added to heptane (1857 L, 37.4V) over 4 hours. The obtained slurry was filtered, and the filtered cake was dried to obtain the free base of crude compound A as a white solid (44.2 kg, area specific purity 99.6%, 94.9 w / w%, yield 83%). [Table 32] LCMS (ESI+) C 44 H 58 N8O5S (M+H + ) Calculated value for: 811.43 Measured value: 811.3 1 H NMR (400 MHz, DMSO-d 6) δ 8.54 (d, J = 9.2 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.73 (dd, J = 8.8, 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.60 (t, J = 8.8 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.32 - 4.15 (m, 5H), 3.60 (br s, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.27 (br s, 4H), 3.22 (s, 3H), 3.19 - 3.15 (m, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.80 - 2.74 (m, 1H), 2.49 - 2.45 (m, 5H), 2.21(s, 3H), 2.10 (d, J = 9.6 Hz, 1H), 1.80 (br s, 2H), 1.56 - 1.52 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.08 (s, 4H), 0.92 - 0.89 (m, 7H), 0.56 (d, J = 5.2 Hz, 1H), 0.37 (s, 3H).

[0255] Part 4a - Compound A-(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide [ka] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide (compound A free base, 23.9 kg, 29.47 mol, 1.0 equivalent) and MeOH (76 kg) were added to reactor 1. To the resulting solution, purified water (29 kg) was added dropwise to reactor 2 at 20-30°C for 3 hours. Next, 0.29 kg of seed crystals were added and the mixture was stirred at 20-30°C for 2-4 hours. Additional purified water (67 kg) was added dropwise to the turbid solution in reactor 2 over 4-6 hours at 20-30°C. The resulting slurry was then stirred at 20-30°C for 8-12 hours. The slurry was filtered, and the wet cake was dried to obtain crude compound A as a white solid (23.9 kg, area specific purity 99.4%, weight specific assay value 96%, yield 96%, Table 31).

[0256] Part 4b - Compound A-(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazine-1-yl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazineacycloundecafan-4-yl)-2-methylcyclopropane-1-carboxamide (compound A free base, 41.9 kg, 51.7 mol, 1.0 equivalent) and MeOH (166 kg) were added to reactor 1. Purified water (50 kg) was added dropwise to the resulting solution at 20-30°C for 3 hours. Next, 0.42 kg of seed crystals were added to the mixture, and the resulting slurry was stirred at 20-30°C for 5 hours. Purified water (116 kg) was added dropwise at 20-30°C for 4-6 hours. The resulting slurry was then stirred at 20-30°C for 16-24 hours. The slurry was filtered, and the wet cake was washed with MeOH and water (30 kg; 34 kg). The wet cake was dried under a nitrogen stream at a relative humidity of 35-55% to obtain compound A as a white solid (44.12 kg, area specific purity 99.7%, weight specific assay value 92.5%, yield 97%). [Table 33] LCMS (ESI+) C44H58N8O5S (M+H + Calculated value for ): 811.43 Measured value: 811.3 1 1H NMR (400 MHz, DMSO-d 6) δ 8.54 (d, J = 9.2 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.73 (dd, J = 8.8, 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.60 (t, J = 8.8 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.32-4.15 (m, 5H), 3.60 (br s, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.27 (br s, 4H), 3.22 (s, 3H), 3.19-3.15 (m, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.49-2.45 (m, 5H), 2.21(s, 3H), 2.10 (d, J = 9.6 Hz, 1H), 1.80 (br s, 2H), 1.56-1.52 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.08 (s, 4H), 0.92-0.89 (m, 7H), 0.56 (d, J = 5.2 Hz, 1H), 0.37 (s, 3H).

[0257] Other Embodiments While the present invention is described in relation to its specific embodiments, it should be understood that the invention is subject to further modifications, and this application is intended to encompass any variations, uses, or adaptations of the invention, including any deviations from this disclosure that, generally in accordance with the principles of the invention, are included in known or customary practices of the relevant art and can be applied to the essential features described herein.

[0258] All publications, patents, and patent applications are incorporated herein by reference in their entirety, just as each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. A method for preparing compound 1, which includes: 【Chemistry 1】 a) Reacting compound 1a and compound 1b to form compound 1c: 【Chemistry 2】 b) Oxidizing and hydrolyzing compound 1c to form compound 1d: 【Transformation 3】 Furthermore c) Cyclizing compound 1d to form compound 1: 【Chemistry 4】 Methods that include...

2. The method according to claim 1, wherein the oxidation and hydrolysis step (b) includes a first step of oxidizing compound 1c to compound 1e and a second step of hydrolyzing compound 1e to compound 1d. 【Transformation 5】

3. Compounds having the structure of formula II: 【Transformation 6】 or its salt (wherein R １ C is replaced by an optional substitution. １ -C ６ Alkyl, optionally substituted 3- to 10-membered cycloalkyl, or optionally substituted C ６ -C １０ (It is an arrow.)

4. The compound has the structure of formula IIa: 【Transformation 7】 A compound or salt thereof according to claim 3, having the properties of claim 3.

5. A method for preparing compound 2a, a) Esterilizing compound 2b to form compound 2c: 【Transformation 8】 b) Protecting and tosyling compound 2c to form compound 2d: 【Chemistry 9】 Furthermore c) Iodinating compound 2d to form compound 2a: 【Chemistry 10】 Methods that include...

6. The method according to claim 5, wherein the protection and tosylation step (b) includes a first step of protecting compound 2c to form compound 2e and a second step of tosyling compound 2e to form compound 2d. 【Chemistry 11】

7. A method for preparing compound 3, which includes: 【Chemistry 12】 a) Contacting compound 3a and compound 3b in the presence of a base to form compound 3c: 【Chemistry 13】 Furthermore b) Hydrolyzing compound 3c to form compound 3: 【Chemistry 14】 Methods that include...

8. Compounds having the structure of formula III, compound 5, or compound 6: 【Chemistry 15】 or its salt (wherein R is H or 【Chemistry 16】 (That is the case.)

9. A method for preparing compound 6a, a) Borylating compound 7 to form compound 4a: 【Chemistry 17】 b) Coupling compound 4a and compound 6b to form compound 5a: [Chemistry 18] Furthermore c) Borylating compound 5a to form compound 6a: 【Chemistry 19】 Methods that include...

10. Compounds having the structure of formula I: 【Chemistry 20】 or its salt (wherein R １ is H or C １ -C ６ (It is alkyl.)

11. A method for preparing compound 9c or a salt thereof: 【Chemistry 21】 a) Formylating compound 9c-1 to form compound 9c-2: 【Chemistry 22】 b) Condensing compound 9c with malonic acid to form compound 9c-3: 【Chemistry 23】 c) Aminating compound 9c-3 to form compound 9c-4 H ２ O: 【Chemistry 24】 Furthermore d) Protecting compound 9c-4 to form compound 9c: 【Chemistry 25】 Methods that include...

12. A method for preparing compound 9, which is: 【Chemistry 26】 a) Coupling compound 2a with compound 9a to form compound 9b: 【Chemistry 27】 b) Hydrolyzing compound 9b to form compound 9c: 【Chemistry 28】 c) Coupling compound 9c and compound 9d to form compound 9e: 【Chemistry 29】 d) Deprotecting compound 9e to form compound 9f: 【Transformation 30】 e) Coupling compound 9f with compound 3 to form compound 9g: 【Chemistry 31】 Furthermore f) Hydrolyze 9g of compound to form compound 9: 【Chemistry 32】 Methods that include...

13. The method according to claim 12, wherein the coupling step (a) includes contacting compound 2a with a zinc source to form compound 2a-Zn. 【Transformation 33】

14. A method for preparing compound A: 【Transformation 34】 a) Contacting compound 6a with pinacol to form compound 10: 【Chemistry 35】 b) Esterilizing compound 9 with compound 10 to form compound 11: 【Transformation 36】 Furthermore c) Cyclizing compound 11 to form compound A: 【Chemistry 37】 Methods that include...

15. A method for preparing compound A: 【Transformation 38】 a) The step of coupling compound 6a and compound 9 to form compound 12: 【Chemistry 39】 Furthermore b) The step of lactonizing compound 12 to form compound A: 【Chemistry 40】 Methods that include...

16. The method according to claim 14 or 15, further comprising the step of purifying compound A.

17. The method according to claim 16, wherein the purification includes forming a salt of compound A.

18. The method according to claim 17, wherein the salt of compound A is the hydrochloride salt of compound A or the lactate salt of compound A.

19. The method according to claim 17 or 18, wherein the purification includes the step of converting the salt of compound A into the free base form of compound A.

20. Compounds having the structure of compound 10, compound 11, or compound 12: 【Chemistry 41】 or its salt.

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