Process for producing IRAK4 inhibitors

Abstract

This disclosure relates, in general, to a process for preparing compounds that are inhibitors of the kinase IRAK4, and to synthetic intermediates prepared thereby. IRAK4 inhibitors may be useful in the treatment of inflammatory and fibrous disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, inflammation associated with gastrointestinal infections including C. difficile, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and renal diseases, including chronic kidney disease and diabetic kidney disease.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application asserts the interests under Section 119(e) of U.S. Provisional Application No. 63 / 511,558, filed on 30 June 2023, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates, in general terms, to a process for preparing compounds that are inhibitors of the kinase IRAK4, and to synthetic intermediates prepared thereby. [Background technology]

[0003] Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine-threonine kinase that acts as a mediator in the interleukin-1 / Toll-like receptor (IL-1 / TLR) signaling cascade. More specifically, IRAK4 is involved in the activation of the adapter protein myelodifferentiation primary response gene 88 (MyD88) signaling cascade and is hypothesized to play a role in inflammatory and fibrotic disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and renal diseases, including chronic kidney disease and diabetic kidney disease. Furthermore, IRAK4 is hypothesized to play a role in certain cancers and in inflammation associated with gastrointestinal infections, including C. difficile. IL-1R / TLR-mediated signaling leads to the activation of MyD88, which recruits IRAK4 and IRAK1 to form a signaling complex. This complex then interacts with a series of kinases, adapter proteins, and ligases, ultimately leading to the activation of nuclear factor-activated B cell κ light chain enhancers (NF-κB), activator protein 1 (API), cyclic AMP response element-binding protein (CREB), and interferon regulators (IRFs), including IRF5 and IRF7, inducing the production of pro-inflammatory cytokines and type I interferons.

[0004] Therefore, IRAK4 inhibitors may be useful in the treatment of inflammatory and fibrotic disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, inflammation associated with gastrointestinal infections including C. difficile, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and renal diseases, including chronic kidney disease and diabetic kidney disease. [Overview of the Initiative] [Means for solving the problem]

[0005] This specification describes a process for preparing compound I or a salt thereof, [ka] Under conditions suitable for providing compound I, compound II or a salt thereof [ka] Compound III or its salt [ka] A process is provided that includes bringing it into contact with.

[0006] Compound I: [ka] The citrate is also provided.

[0007] Compound II: [ka] The methanesulfonate is also provided.

[0008] A process for preparing compound II or a salt thereof, [ka] Under conditions suitable for providing compound I, the compound of formula IV or a salt thereof [ka] Compounds of formula V or salts thereof [ka] A process that involves contacting [In the formula, X is a halo, R , , , 1~6 , ,

[0010] , , , 3 , 3 , , , , 3 , , , , is a protecting group, R 2 is hydrogen or -B(OR 3 )2, each R 3 is independently hydrogen or C 1~6 alkyl, or two Rs 3 are cyclized to form a cyclic boronate ester] is also provided.

[0009] A process for preparing compound I or a salt thereof,

Chemical formula

Chemical formula

Chemical formula

[0010] A process for preparing a compound of formula VI or a salt thereof,

Chemical formula

Chemical formula

[0011] A process for preparing a compound of formula VI or a salt thereof, [ka] Under conditions suitable for providing the compound of formula VI, the compound of formula VII or a salt thereof [ka] A process (wherein X is a halo) is also provided, which involves contact with a dehydrating agent.

[0012] In some embodiments, the dehydrating agent is something other than anhydrous trifluoroacetic acid.

[0013] A process for preparing a compound of formula IX or a salt thereof, [ka] Under conditions suitable for providing compound IX, the compound of formula VII or a salt thereof [ka] Compounds of formula V or salts thereof [ka] A process that involves contacting [In the formula, X is a halo, R 2 is hydrogen or -B(OR 3 )2, Each R 3 These are independently hydrogen or C 1~6 Alkyl or two R 3 [It is also provided that it cyclizes to form a cyclic boronate ester.]

[0014] A process for preparing compound I or a salt thereof, [ka] Under conditions suitable for providing compound I, the compound of formula IX or a salt thereof. [ka] A process including contact is also provided.

[0015] below, [ka] Compounds or salts thereof, selected from the above, are also provided. [Modes for carrying out the invention]

[0016] definition When used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0017] The term "comprise" and its variations, such as "comprises" and "comprising," should be interpreted in an open and comprehensive sense, meaning "including, but not limited to." Furthermore, the singular forms "a," "an," and "the" include multiple referents unless otherwise clearly indicated in the context. Thus, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes one or more assays and their equivalents known to those skilled in the art.

[0018] References to values ​​or parameters of “approximately” in this specification include (and are described) embodiments that apply to the value or parameter itself. In certain embodiments, the term “approximately” includes the indicated amount ± 10%. In other embodiments, the term “approximately” includes the indicated amount ± 5%. In certain other embodiments, the term “approximately” includes the indicated amount ± 2.5%. In certain other embodiments, the term “approximately” includes the indicated amount ± 1%. Furthermore, “approximately X” for that term includes a description of “X”.

[0019] Throughout this disclosure, descriptions of numerical ranges of values ​​are intended to serve as a simplified notation for referring individually to each individual value within the range that defines that range, and each individual value is incorporated herein as it would be if it were described individually herein.

[0020] As used herein, the term “contact” refers to the process of bringing at least two distinct species into contact so that they can react. However, it should be understood that the reaction product obtained may be produced directly from the reaction between the added reagents, or from intermediates derived from one or more of the added reagents that may be produced in the reaction mixture.

[0021] The term “reaction conditions” is intended to refer to the physical and / or environmental conditions under which a chemical reaction takes place. Examples of reaction conditions include, but are not limited to, one or more of the following: reaction temperature, solvent, pH, pressure, reaction time, molar ratio of reactants, presence of a base or acid, one or more protecting groups, or catalysts, radiation, etc. Reaction conditions may be named based on the specific chemical reaction in which conditions such as coupling conditions, hydrogenation conditions, acylation conditions, and reduction conditions are used. The reaction conditions for most reactions are generally known to those skilled in the art or readily available from the literature. Sufficient exemplary reaction conditions for carrying out the chemical transformations provided herein can be found throughout, and in particular, throughout the examples below. It is also intended that reaction conditions may include reagents in addition to those enumerated in a particular reaction.

[0022] As used herein, “under suitable conditions” is intended to refer to reaction conditions under which the desired chemical reaction can proceed.

[0023] A “protecting group” refers to a part of a compound that shields or alters the properties of a functional part. “Deprotection” refers to the step of removing a protecting group so that the functional part returns to its original state. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See also Protective Groups in Organic Chemistry, Peter GMWuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often used to shield the reactivity of a particular functional part and to help the efficiency of a desired chemical reaction, for example, to create and break chemical bonds in an orderly and planned manner. For example, a “carboxylic acid protecting group” refers to a protecting group that is useful for shielding a carboxylic acid part to make the carboxylic acid group unreactive, for example, during an intermediate step in a synthetic process. Exemplary carboxylic acid protecting groups include alkyl protecting groups such as methyl, ethyl, benzyl, or tert-butyl; silyl groups such as 2-(trimethylsilyl)ethyl; and thioesters such as tert-butyl thioesters. In some embodiments, the protecting group is tert-butyl.

[0024] A "catalyst" refers to a chemical reactant that increases the reaction rate without being consumed itself. Similarly, a "pre-catalyst" refers to a compound that is converted into a catalyst during the catalytic reaction process.

[0025] As used herein, “dehydrating agent” is a chemical reaction product capable of converting amide groups to nitrile groups through the removal of water. Exemplary dehydrating agents include cyanuryl chloride, anhydrides such as acetic anhydride, trifluoromethanesulfonic anhydride or trifluoroacetic anhydride, ethyl chloroformate, phosphorus oxychloride, and phosphorus pentoxide.

[0026] As used herein, "hydrolysis" refers to the decomposition of a carboxylic acid ester into a carboxylic acid and an alcohol by water. Exemplary hydrolysants include inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, as well as alkoxide bases such as sodium methoxide and potassium methoxide.

[0027] As used herein, "ligand" refers to an ion or molecule that bonds to a metal atom to form a coordination complex. The denticity of a ligand refers to the number of times the ligand bonds to the metal via discontinuous donor sites. A ligand may be monodentate (i.e., having one bonding site) or bidentate (i.e., having two bonding sites).

[0028] As used herein, the term “salt” refers to a compound formed by the reaction of an acid and a base, resulting in the formation of a positively charged cation and a negatively charged anion. Generally, a salt is defined as a compound formed by a combination of positively and negatively charged ions, the charge of which determines whether the compound is neutral. Salts can be inorganic or organic. As used herein, the term “salt” includes partially or completely ionized salt forms. In some embodiments, the salt is completely ionized.

[0029] Definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. (inside front cover), and specific functional groups are generally defined as described in the said literature. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987, and the entire contents of each of these are incorporated herein by reference.

[0030] As used herein, the term “alkyl” means a linear or branched saturated hydrocarbon chain containing 1 to 30 carbon atoms. The terms “lower alkyl” or “C1-C6-alkyl” mean a linear or branched hydrocarbon chain containing 1 to 6 carbon atoms. The term “C1-C3-alkyl” means a linear or branched hydrocarbon chain containing 1 to 3 carbon atoms. Representative examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0031] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0032] As used herein, the term “aryl” refers to a phenyl group, or a bicyclic aryl or tricyclic aryl fused ring system. A bicyclic fused ring system is exemplified by a phenyl group attached to a parent molecule and fused to a phenyl group. A tricyclic fused ring system is exemplified by a phenyl group attached to a parent molecule and fused to two other phenyl groups. Representative examples of bicyclic aryls include, but are not limited to, naphthyl. Representative examples of tricyclic aryls include, but are not limited to, anthracenyl. Monocyclic, bicyclic, and tricyclic aryls are connected to the parent molecule via any carbon atoms contained within the ring, and may be unsubstituted or substituted.

[0033] As used herein, the terms "halogen" or "halo" mean Cl, Br, I, or F.

[0034] As used herein, the term "amine base" generally refers to primary, secondary, or tertiary amines, such as alkylamines, dialkylamines, trialkylamines, nitrogen-containing heterocyclics, or nitrogen-containing heteroaryls, each of which is optionally substituted, for example, with alkyl.

[0035] As used herein, the term “nitrogen-containing heterocyclic” base refers to a saturated or partially unsaturated cyclic alkyl group having at least one ring nitrogen atom and, optionally, one or more additional ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclic” includes heterocycloalkenyl rings (i.e., heterocycles having at least one double bond), bridging heterocycles, fused heterocycles, and spiroheterocycles. The heterocycle may be monocyclic or polycyclic, which may be fused, bridging, or spiro, and may contain one or more (e.g., 1 to 3 or 1 or 2) oxo (=O) or N-oxide (-O) atoms. - ) may include a portion. Any non-aromatic ring containing at least one nitrogen atom capable of accepting a proton is considered a nitrogen-containing heterocyclic base. Furthermore, the term heterocyclic is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be fused with a cycloalkyl, aryl, or heteroaryl ring, regardless of the position of the heteroatom. As used herein, a nitrogen-containing heterocyclic ring contains 2 to 20 ring carbon atoms (i.e., C 2~20 Heterocyclic rings), 2 to 12 ring carbon atoms (i.e., C 2~12 Heterocyclic rings), 2 to 10 ring carbon atoms (i.e., C 2~10 Heterocyclic rings), 2 to 8 ring carbon atoms (i.e., C 2~8 Heterocyclic rings), 3 to 12 ring carbon atoms (i.e., C 3~12 Heterocyclic rings), 3 to 8 ring carbon atoms (i.e., C 3~8 Heterocyclic rings, or rings with 3 to 6 carbon atoms (i.e., C 3~6 It has a heterocycle and at least one nitrogen atom capable of accepting a proton, and optionally has 1 to 5 further ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, sulfur, or oxygen.

[0036] The term "nitrogen-containing heteroaryl" base refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic ring having at least one nitrogen atom capable of accepting a proton, and optionally one or more further ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, a nitrogen-containing heteroaryl has 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3~12 Heteroaryls), or 3 to 8 carbon ring atoms (i.e., C 3~8 The heteroaryl comprises a heteroaryl ring having at least one nitrogen atom and optionally having 1 to 5 further ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In certain cases, the heteroaryl comprises a 5 to 10-membered ring system, a 5 to 7-membered ring system, or a 5 to 6-membered ring system, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur.

[0037] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, up to one-tenth of the lower limit unit unless otherwise clearly indicated by the context, and any other referred or intervening values ​​within that range, are included in this disclosure. The upper and lower limits of these smaller ranges may independently be included in smaller ranges, are included in this disclosure, and are subject to any specifically excluded limits within the range referred to. If the range referred to includes one or both of the limit values, the range excluding one or both of those included limit values ​​is also included in this disclosure.

[0038] In descriptions of numerical ranges in this specification, each number intervening within that range is explicitly intended with the same degree of precision. For example, in the range 6 to 9, the numbers 7 and 8 are intended in addition to 6 and 9, and in the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly intended.

[0039] For clarity, it is understood that certain features of the Disclosure described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the Disclosure described in the context of a single embodiment may also be provided separately or in any preferred partial combination. All combinations of embodiments relating to the Disclosure are encompassed by the Disclosure and are disclosed herein in the same way as any combination is explicitly disclosed individually, insofar as such combinations encompass subject matter that is, for example, a stable compound (i.e., a compound that can be prepared, isolated, characterized, and tested for biological activity). Furthermore, all partial combinations of various embodiments and their elements (e.g., elements of chemical groups enumerated in embodiments describing such variable elements) are also encompassed by the Disclosure and are disclosed herein in the same way as any combination is explicitly disclosed individually.

[0040] process The process described herein provides compounds that are inhibitors of the kinase IRAK4.

[0041] This specification describes a process for preparing compound I or a salt thereof, [ka] Under conditions suitable for providing compound I, compound II or a salt thereof [ka] Compound III or its salt [ka] A process is provided that includes bringing it into contact with.

[0042] In some embodiments, the conditions include a coupling agent and a base.

[0043] In some embodiments, the base is an amine base or a carbonate base. In some embodiments, the base is N-methylimidazole, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, potassium carbonate, or sodium carbonate.

[0044] In some embodiments, the base is an amine. In some embodiments, the amine is N-methylimidazole, N,N-diisopropylethylamine, triethylamine, or N-methylmorpholine. In some embodiments, the base is N-methylimidazole. In some embodiments, the base is N,N-diisopropylethylamine.

[0045] In some embodiments, the base is a carbonate base. In some embodiments, the carbonate base is potassium carbonate or sodium carbonate.

[0046] Suitable coupling agents (or activators) are known in the art, for example, carbonyl diimidazole (e.g., N,N'-dicyclohexylcarbodiimide (DCC), N,N'-dicyclopentylcarbodiimide, N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Nt-butyl-N-methylcarbodiimide (BMC), Nt-butyl-N-ethylcarbodiimide (BEC), 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl) Lubodiimide (BDDC, etc.), anhydrides (e.g., symmetric, mixed, or cyclic anhydrides), activated ester-forming agents (e.g., phenyl activated ester derivatives, p-hydroxam activated esters, hexafluoroacetone (HFA), etc.), acyluazole-forming agents (acylimidazoles using CDI, acylbenzotriazoles, etc.), acyluazide-forming agents, acid halide-forming agents, phosphonium salts (HOBt, PyBOP, HOAt, etc.), aminonium / uronium salts (e.g., tetramethylaminonium salt, bispyrrolidinium aminonium salt, bispyperi (e.g., dinoaminium salts, imidazolium uronium salts, pyrimidinium uronium salts, uronium salts derived from N,N,N'-trimethyl-N'-phenylurea, morpholino-based aminium / uronium coupling reagents, uronium antimonate salts, etc.), organophosphorus reagents (e.g., phosphinic acid and phosphoric acid derivatives), organosulfur reagents (e.g., sulfonic acid derivatives), triazine coupling reagents (e.g., 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4methyl Examples include methylmorpholinium chloride, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium tetrafluoroborate, pyridinium coupling reagents (e.g., Mukaiyama reagent, pyridinium tetrafluoroborate coupling reagent, etc.), and polymer-supported reagents (e.g., polymer-bound carbodiimide, polymer-bound TBTU, polymer-bound 2,4,6-trichloro-1,3,5-triazine, polymer-bound HOBt, polymer-bound HOSu, polymer-bound IIDQ, polymer-bound EEDQ, etc.).

[0047] In some embodiments, the coupling agent provides an acid halide intermediate, such as an acid chloride. In some embodiments, the coupling agent is thionyl chloride, oxalyl chloride, or phosphorus(V) oxychloride.

[0048] In some embodiments, the coupling agent provides a mixed acid anhydride intermediate. In some embodiments, the coupling agent is acetic anhydride, pivaloyl chloride, diphenylphosphinic anhydride, propanephosphinic anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, or p-toluenesulfonyl chloride.

[0049] In some embodiments, the coupling agent provides an activated ester. In some embodiments, the coupling agent is 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 2-chloro-4,6,-dimethoxy-1,3,5-triazine, cyanuryl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0050] In some embodiments, the coupling agent is a carbonyl diimidazole, such as N,N'-dicyclohexylcarbodiimide (DCC), N,N'-dicyclopentylcarbodiimide, N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Nt-butyl-N-methylcarbodiimide (BMC), Nt-butyl-N-ethylcarbodiimide (BEC), or 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC).

[0051] In some embodiments, the conditions further include a solvent. In some embodiments, the conditions further include a solvent at a temperature of about -20°C to about 60°C. In some embodiments, the conditions further include a solvent at a temperature of about -10°C to about 10°C. In some embodiments, the conditions further include a solvent at a temperature of about 10°C to about 30°C.

[0052] In some embodiments, the solvent is a polar aprotic solvent, an ether, an ester, a halogenated solvent, or a combination thereof, or a combination thereof with water. In some embodiments, the solvent is acetonitrile, N-methyl-2-pyrrolidone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, or a combination thereof, or a combination thereof with water.

[0053] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is N-methyl-2-pyrrolidone, dimethylformamide, dimethyl sulfoxide, or a combination thereof, or a combination thereof with water.

[0054] In some embodiments, the solvent is ether. In some embodiments, the ether is tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof, or a combination thereof with water.

[0055] In some embodiments, the solvent is an ester. In some embodiments, the ester is ethyl acetate, isopropyl acetate, or a combination thereof, or a combination thereof with water.

[0056] In some embodiments, the solvent is a halogenated solvent. In some embodiments, the halogenated solvent is dichloromethane, or a combination thereof, or a combination thereof with water.

[0057] In some embodiments, the solvent is acetonitrile.

[0058] In some embodiments, the conditions include N-methylimidazole and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate.

[0059] In some embodiments, the conditions further include acetonitrile at a temperature of about -10°C to about 10°C.

[0060] In some embodiments, the conditions further include acetonitrile at a temperature of about 0°C.

[0061] In some embodiments, the conditions include N-methylimidazole and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate at a temperature of about 0°C, and an acetonitrile solvent.

[0062] In some embodiments, the conditions include N,N-diisopropylethylamine and diphenylphosphinate chloride. In some embodiments, the conditions further include acetonitrile at a temperature of about 10°C to about 30°C. In some embodiments, the conditions further include acetonitrile at a temperature of about 20°C.

[0063] In some embodiments, the conditions include N,N-diisopropylethylamine, diphenylphosphinate chloride, and acetonitrile at a temperature of about 20°C.

[0064] In some embodiments, the process involves the citrate of compound I: [ka] The further step involves contacting compound I with citric acid under conditions suitable for providing [the desired result].

[0065] In some embodiments, the conditions include a solvent. In some embodiments, the conditions include a solvent at a temperature of about 0°C to about 90°C. In some embodiments, the conditions include a solvent at a temperature of about 45°C to about 55°C. In some embodiments, the conditions include a solvent at a temperature of about 50°C.

[0066] In some embodiments, the solvent is an alcohol, ether, ester, ketone, nitrile, or polar aprotic solvent. In some embodiments, the solvent is ethanol, methanol, 1-propanol, 2-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, ethyl acetate, isopropyl acetate, acetone, 2-butanone, 4-methyl-2-pentanone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methyl-2-pyrrolidone.

[0067] In some embodiments, the solvent is an alcohol. In some embodiments, the alcohol is ethanol, methanol, 1-propanol, or 2-propanol.

[0068] In some embodiments, the solvent is an ether. In some embodiments, the ether is tetrahydrofuran, 2-methyltetrahydrofuran, or tert-butylmethyl ether.

[0069] In some embodiments, the solvent is an ester. In some embodiments, the ester is ethyl acetate or isopropyl acetate.

[0070] In some embodiments, the solvent is a ketone. In some embodiments, the ketone is acetone, 2-butanone, or 4-methyl-2-pentanone.

[0071] In some embodiments, the solvent is a nitrile. In some embodiments, the nitrile is acetonitrile.

[0072] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, or N-methyl-2-pyrrolidone.

[0073] In some embodiments, the solvent is ethanol.

[0074] In some embodiments, the conditions include ethanol at a temperature of about 45°C to about 55°C. In some embodiments, the conditions include ethanol at a temperature of about 50°C.

[0075] In some embodiments, the conditions include contacting compound I with about 1.5 equivalents of citric acid.

[0076] In some embodiments, the conditions include contacting compound I with about 1.5 equivalents of citric acid, with ethanol at a temperature of about 50°C.

[0077] A process for preparing compound II or a salt thereof, [ka] Under conditions suitable for providing compound II, the compound of formula IV or a salt thereof [ka] Compounds of formula V or salts thereof [ka] A process including bringing into contact with [in the formula, X is a halo, R 1 It is a protecting group, R 2 is hydrogen or -B(OR 3 )2, Each R 3 These are independently hydrogen or C 1~6 Alkyl or two R 3[It is also provided that it cyclizes to form a cyclic boronate ester.]

[0078] In some embodiments, R 1 is a carboxyl protecting group. In certain embodiments, the carboxyl protecting group is C 1~6 Alkoxy, cyano, -Si(C 1~6 C is optionally substituted with alkyl)3 or aryl. 1~6 It is alkyl, and the aryl is halo, nitro, C 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected independently of the alkoxy. In a particular embodiment, R 1 R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, t-butoxymethyl, benzyl, p-methoxybenzyl, or p-nitrobenzyl. In some embodiments, R 1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or benzyl. In some embodiments, R 1 is methyl, ethyl, tert-butyl, or benzyl. In some embodiments, R 1 C 1~6 It is alkyl. In some embodiments, R 1 is methyl, ethyl, or tert-butyl. In some embodiments, R 1 is tert-butyl. In some embodiments, R 2 is -B(OR 3 )2. In some embodiments, two R 3 It cyclizes to form a cyclic boronate ester. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 It is hydrogen.

[0079] In some embodiments, the conditions include a catalyst.

[0080] In some embodiments, the catalyst is a palladium(II) salt, a palladium(O) salt, copper(II) trifluoromethanesulfonate, or a combination thereof. In some embodiments, the catalyst is palladium(II) 2,4-pentanedione, allylpalladium(II) chloride dimer, bis(acetonitrile)dichloropalladium(II), palladium(II) trifluoroacetate, palladium(II) chloride, tetrakis(triphenylphosphine)palladium(O), tris(dibenzylideneacetone)dipalladium(O), copper(II) trifluoromethanesulfonate, or a combination thereof. In some embodiments, the catalyst is a palladium(II) salt or a palladium(O) salt.

[0081] In some embodiments, the catalyst is a palladium(II) salt. In some embodiments, the palladium(II) salt is palladium(II) 2,4-pentanedione, allylpalladium(II) chloride dimer, bis(acetonitrile)dichloropalladium(II), palladium(II) trifluoroacetate, or palladium(II) chloride.

[0082] In some embodiments, the catalyst is a palladium(O) salt. In some embodiments, the palladium(O) salt is tetrakis(triphenylphosphine)palladium(O) or tris(dibenzylideneacetone)dipalladium(O).

[0083] In some embodiments, the catalyst is copper(II) trifluoromethanesulfonate. In some embodiments, the catalyst is a combination of copper(II) trifluoromethanesulfonate, a palladium(II) salt, and a palladium(O) salt.

[0084] In some embodiments, the catalyst is palladium(II) acetate.

[0085] In some embodiments, the conditions include a catalyst and a ligand.

[0086] In some embodiments, the ligand is a dialkylbiarylphosphine ligand, a bidentate phosphine ligand, or a monodentate phosphine ligand. In some embodiments, the ligand is 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettP The ligands are 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf), triphenylphosphine, tri-tert-butylphosphine, or tricyclohexylphosphine. In some embodiments, the ligands are 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), dialkylbiarylphosphine ligands, monodentate phosphine ligands, or bidentate phosphine ligands.

[0087] In some embodiments, the ligand is a dialkylbiarylphosphine ligand. In some embodiments, the dialkylbiarylphosphine ligand is 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos), or 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos).

[0088] In some embodiments, the ligand is a bidentate phosphine ligand. In some embodiments, the bidentate phosphine ligand is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (XantPhos), 1,1'-bis(di-tert-butylphosphine)ferrocene (dtbpf), or 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf).

[0089] In some embodiments, the ligand is a monodentate phosphine ligand. In some embodiments, the monodentate phosphine ligand is triphenylphosphine, tri-tert-butylphosphine, or tricyclohexylphosphine.

[0090] In some embodiments, the ligand is 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos).

[0091] In some embodiments, the conditions include a catalyst, a ligand, and a base.

[0092] In some embodiments, the base is an inorganic base, an alkoxide base, a tertiary amine, or a nitrogen-containing heteroaryl base.

[0093] In some embodiments, the base is an amine, an inorganic base, an alkoxide base, an alkyl Grignard reagent, an alkyllithium, or a diorganilamide base. In some embodiments, the base is N,N-diisopropylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, N-methylimidazole, sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, monobasic / dibasic / tribasic sodium phosphate, monobasic / dibasic / tribasic lithium phosphate, monobasic / dibasic / tribasic potassium phosphate, monobasic / dibasic / tribasic calcium phosphate, monobasic / dibasic / tribasic magnesium phosphate, monobasic / dibasic / tribasic tetramethylammonium phosphate These are monobasic / dibasic / tribasic tetrabutylammonium phosphate, sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, calcium tert-butoxide, methylmagnesium bromide, methylmagnesium chloride, isopropylmagnesium chloride, methyllithium, n-butyllithium, sodium diethylamide, potassium diethylamide, lithium diethylamide, sodium diisopropylamide, potassium diisopropylamide, or lithium diisopropylamide.

[0094] In some embodiments, the base is an amine. In some embodiments, the amine is N,N-diisopropylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, or N-methylimidazole.

[0095] In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a hydroxide, carbonate, tribasic phosphate, dibasic phosphate, or monobasic phosphate of sodium, lithium, potassium, calcium, magnesium, tetramethylammonium, or tetrabutylammonium salt.

[0096] In some embodiments, the base is an alkoxide base. In some embodiments, the alkoxide base is a sodium, lithium, potassium, magnesium, or calcium salt of a methoxide, ethoxide, or tert-butoxide.

[0097] In some embodiments, the base is an alkyl Grignard reagent. In some embodiments, the alkyl Grignard reagent is methylmagnesium bromide, methylmagnesium chloride, or isopropylmagnesium chloride.

[0098] In some embodiments, the base is alkyllithium. In some embodiments, the alkyllithium is methyllithium or n-butyllithium.

[0099] In some embodiments, the base is a diorganilamide. In some embodiments, the diorganilamide base is a sodium, potassium, or lithium salt of diethylamide or diisopropylamide.

[0100] In some embodiments, the base is potassium carbonate.

[0101] In some embodiments, the conditions further include a solvent. In some embodiments, the conditions further include a solvent at a temperature of about 45°C to about 110°C. In some embodiments, the conditions further include a solvent at a temperature of about 65°C to about 85°C.

[0102] In some embodiments, the solvent is an alcohol, ether, hydrocarbon, ester, aqueous surfactant, or a combination thereof, or a combination thereof with water. In some embodiments, the solvent is methanol, ethanol, 2-propanol, 2-methyltetrahydrofuran, tert-butyl methyl ether, n-heptane, toluene, ethyl acetate, isopropyl acetate, Coolade (CAS No. 2306441-11-0), TPGS-750-M (DL-α-tocopherol methoxypolyethylene glycol succinate), hydroxypropyl methylcellulose, or a combination thereof, or a combination thereof with water.

[0103] In some embodiments, the solvent is an alcohol. In some embodiments, the alcohol is methanol, ethanol, 2-propanol, or a combination thereof, or a combination of them with water.

[0104] In some embodiments, the solvent is an ether. In some embodiments, the ether is 2-methyltetrahydrofuran, tert-butylmethyl ether, or a combination thereof, or a combination thereof with water.

[0105] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is n-heptane, toluene, or a combination thereof, or a combination thereof with water.

[0106] In some embodiments, the solvent is an ester. In some embodiments, the ester is ethyl acetate, isopropyl acetate, or a combination thereof, or a combination thereof with water.

[0107] In some embodiments, the solvent is an aqueous surfactant. In some embodiments, the aqueous surfactant is Coolade (CAS No. 2306441-11-0), TPGS-750-M (DL-α-tocopherol methoxypolyethylene glycol succinate), hydroxypropyl methylcellulose, or a combination thereof, or a combination thereof with water.

[0108] In some embodiments, the solvents are tetrahydrofuran and water.

[0109] In some embodiments, the conditions include potassium carbonate, palladium(II) acetate, and 2-dicyclohexylphosphin-2',6'-diisopropoxybiphenyl (RuPhos). In some embodiments, the conditions further include tetrahydrofuran and water at a temperature of about 65°C to about 85°C. In some embodiments, the conditions further include tetrahydrofuran and water at a temperature of about 75°C.

[0110] In some embodiments, the conditions include potassium carbonate, palladium(II) acetate, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), tetrahydrofuran, and water at a temperature of about 75°C.

[0111] A process for preparing compound II or a salt thereof, [ka] Under conditions suitable for providing compound I, the compound of formula IV or a salt thereof [ka] Compounds of formula V or salts thereof [ka] A process that involves contacting [In the formula, X is a halo, R 1 It is a protecting group, R 2 It is also provided that [it is hydrogen].

[0112] In some embodiments, R 1 is a carboxyl protecting group. In certain embodiments, the carboxyl protecting group is C 1~6 Alkoxy, cyano, -Si(C 1~6 C is optionally substituted with alkyl)3 or aryl. 1~6 It is alkyl, and the aryl is halo, nitro, C 1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected independently of the alkoxy. In a particular embodiment, R 1 R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, t-butoxymethyl, benzyl, p-methoxybenzyl, or p-nitrobenzyl. In some embodiments, R 1 R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or benzyl. In some embodiments, R 1 These are methyl, ethyl, tert-butyl, or benzyl.

[0113] In some embodiments, R 1 C 1~6 It is alkyl. In some embodiments, R 1 is methyl, ethyl, or tert-butyl. In some embodiments, R 1 It is tert-butyl.

[0114] In some embodiments, the conditions include a catalyst, a ligand, and an acid.

[0115] In some embodiments, the catalyst is a palladium catalyst or a palladium pre-catalyst. In some embodiments, the catalyst is palladium acetate, allyl palladium chloride dimer, cinnamyl palladium chloride dimer, (η3-clotyl)palladium chloride tri-tert-butylphosphine, or 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0116] In some embodiments, the catalyst is an allyl palladium chloride dimer.

[0117] In some embodiments, the ligand is a monodentate phosphine or a bidentate phosphine. In some embodiments, the ligand is tri-tert-butylphosphine, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), triphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), or 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP).

[0118] In some embodiments, the ligand is a monodentate phosphine. In some embodiments, the monodentate phosphine is tri-tert-butylphosphine, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), or triphenylphosphine.

[0119] In some embodiments, the ligand is a bidentate phosphine. In some embodiments, the bidentate phosphine is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (XantPhos) or 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP).

[0120] In some embodiments, the ligand is tri-tert-butylphosphonium tetrafluoroborate.

[0121] In some embodiments, the acid is a carboxylic acid or a sulfonic acid. In some embodiments, the acid is acetic acid, isobutyric acid, pivalic acid, 1-adamantanecarboxylic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.

[0122] In some embodiments, the acid is a carboxylic acid. In some embodiments, the carboxylic acid is acetic acid, 2,2-dimethylbutyric acid, isobutyric acid, pivalic acid, 1-adamantanecarboxylic acid, or benzoic acid.

[0123] In some embodiments, the acid is a sulfonic acid. In some embodiments, the sulfonic acid is methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.

[0124] In some embodiments, the acid is 2,2-dimethylbutyric acid.

[0125] In some embodiments, the conditions further include a base. In some embodiments, the base is an amine, an inorganic base, an alkoxide base, an alkyl Grignard reagent, an alkyllithium, or a diorganilamide base. In some embodiments, the base is N,N-diisopropylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, N-methylimidazole, sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, monobasic / dibasic / tribasic sodium phosphate, monobasic / dibasic / tribasic lithium phosphate, monobasic / dibasic / tribasic potassium phosphate, monobasic / dibasic / tribasic calcium phosphate, monobasic / dibasic / tribasic magnesium phosphate, monobasic / dibasic / tribasic tetramethylammonium phosphate These are monobasic / dibasic / tribasic tetrabutylammonium phosphate, sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, calcium tert-butoxide, methylmagnesium bromide, methylmagnesium chloride, isopropylmagnesium chloride, methyllithium, n-butyllithium, sodium diethylamide, potassium diethylamide, lithium diethylamide, sodium diisopropylamide, potassium diisopropylamide, or lithium diisopropylamide.

[0126] In some embodiments, the base is potassium carbonate.

[0127] In some embodiments, the conditions further include a solvent. In some embodiments, the conditions further include a solvent at a temperature of about 60°C to about 140°C. In some embodiments, the temperature is about 70°C to about 110°C. In some embodiments, the temperature is about 90°C.

[0128] In some embodiments, the solvent is an alcohol, ether, hydrocarbon, ester, or aqueous surfactant. In some embodiments, the solvent is methanol, ethanol, 2-propanol, 2-methyltetrahydrofuran, tert-butyl methyl ether, n-heptane, toluene, ethyl acetate, isopropyl acetate, Coolade (CAS No. 2306441-11-0), TPGS-750-M (DL-α-tocopherol methoxypolyethylene glycol succinate), or hydroxypropyl methylcellulose.

[0129] In some embodiments, the solvent is an alcohol. In some embodiments, the alcohol is 2-butanol, methanol, ethanol, or 2-propanol.

[0130] In some embodiments, the solvent is an ether. In some embodiments, the ether is 2-methyltetrahydrofuran or tert-butylmethyl ether.

[0131] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is n-heptane or toluene.

[0132] In some embodiments, the solvent is an ester. In some embodiments, the ester is ethyl acetate or isopropyl acetate.

[0133] In some embodiments, the solvent is an aqueous surfactant. In some embodiments, the aqueous surfactant is Coolade (CAS No. 2306441-11-0), TPGS-750-M (DL-α-tocopherol methoxypolyethylene glycol succinate), or hydroxypropyl methylcellulose.

[0134] In some embodiments, the solvent is 2-butanol.

[0135] In some embodiments, the conditions include allyl palladium chloride dimer, tri-tert-butylphosphonium tetrafluoroborate, and 2,2-dimethylbutyric acid. In some embodiments, the conditions further include potassium bicarbonate. In some embodiments, the conditions further include 2-butanol at a temperature of about 70°C to about 110°C. In some embodiments, the conditions further include 2-butanol at a temperature of about 90°C.

[0136] In some embodiments, the conditions include allyl palladium chloride dimer, tri-tert-butylphosphonium tetrafluoroborate, 2,2-dimethylbutyrate, potassium bicarbonate, and 2-butanol, at a temperature of about 90°C.

[0137] In some embodiments, the conditions further include a deprotection step.

[0138] In some embodiments, the deprotection step involves a compound of formula IIA: [ka] This includes converting to compound II.

[0139] In some embodiments, R 1 is a carboxyl protecting group. In certain embodiments, the carboxyl protecting group is C 1~6 Alkoxy, cyano, -Si(C 1~6 C is optionally substituted with alkyl)3 or aryl. 1~6 It is alkyl, and the aryl is halo, nitro, C1~6 Alkyl and C 1~6 It is optionally substituted with one or more substituents selected independently of the alkoxy. In a particular embodiment, R 1 These are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, t-butoxymethyl, benzyl, p-methoxybenzyl, or p-nitrobenzyl.

[0140] In some embodiments, R 1 R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or benzyl. In some embodiments, R 1 These are methyl, ethyl, tert-butyl, or benzyl.

[0141] In some embodiments, R 1 C 1~6 It is alkyl. In some embodiments, R 1 is methyl, ethyl, or tert-butyl. In some embodiments, R 1 It is tert-butyl.

[0142] In some embodiments, the deprotection step includes a reagent and an optional additive. In some embodiments, the deprotection step includes methanesulfonic acid.

[0143] In some embodiments, the reagent is an inorganic acid, an organic acid, an acid chloride, or a Lewis acid. In some embodiments, the reagent is hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, citric acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, acetyl chloride, aluminum chloride, aluminum bromide, lithium chloride, magnesium chloride, boron trichloride, boron tribromide, samarium iodide, or lanthanum triflate.

[0144] In some embodiments, the reagent is an inorganic acid. In some embodiments, the inorganic acid is hydrobromic acid, hydroiodic acid, sulfuric acid, or phosphoric acid.

[0145] In some embodiments, the reagent is an organic acid. In some embodiments, the organic acid is formic acid, acetic acid, trifluoroacetic acid, citric acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, or camphorsulfonic acid.

[0146] In some embodiments, the reagent is an acid chloride. In some embodiments, the acid chloride is an acyl halide (e.g., acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, chloroacetyl chloride, trifluoroacetyl chloride, or p-toluenesulfonyl chloride), thionyl chloride, or phosphorus pentachloride. In some embodiments, the acyl halide is acetyl chloride.

[0147] In some embodiments, the reagent is a Lewis acid. In some embodiments, the Lewis acid is aluminum chloride, aluminum bromide, lithium chloride, magnesium chloride, boron trichloride, boron tribromide, samarium iodide, or lanthanum triflate.

[0148] In some embodiments, the reagent is methanesulfonic acid.

[0149] In some embodiments, the optional additive is a trialkylsilane. In some embodiments, the additive is trimethylsilane or triethylsilane. In some embodiments, there is no optional additive.

[0150] In some embodiments, the solvent is an ether, hydrocarbon, nitrile, ester, halogenated solvent, polar aprotic solvent, alcohol, ketone, or carboxylic acid. In some embodiments, the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, 1,4-dioxane, n-heptane, toluene, butyronitrile, ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N-methyl-2-pyrrolidone, ethanol, isopropanol, 1-butanol, 2-butanol, acetone, formic acid, or acetic acid.

[0151] In some embodiments, the deprotection step further comprises a solvent. In some embodiments, the deprotection step further comprises a solvent at a temperature of about 0°C to about 120°C. In some embodiments, the deprotection step further comprises a solvent at a temperature of about 55°C to about 75°C. In some embodiments, the deprotection step further comprises a solvent at a temperature of about 65°C.

[0152] In some embodiments, the solvent is an ether. In some embodiments, the ether is tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, or 1,4-dioxane.

[0153] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is n-heptane or toluene.

[0154] In some embodiments, the solvent is a nitrile. In some embodiments, the nitrile is butyronitrile or acetonitrile.

[0155] In some embodiments, the solvent is an ester. In some embodiments, the ester is ethyl acetate or isopropyl acetate.

[0156] In some embodiments, the solvent is a halogenating solvent. In some embodiments, the halogenating solvent is dichloromethane or 1,2-dichloroethane.

[0157] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is N,N-dimethylformamide or N-methyl-2-pyrrolidone.

[0158] In some embodiments, the solvent is an alcohol. In some embodiments, the alcohol is methanol, ethanol, isopropanol, 1-butanol, or 2-butanol.

[0159] In some embodiments, the solvent is a ketone. In some embodiments, the ketone is acetone.

[0160] In some embodiments, the solvent is a carboxylic acid. In some embodiments, the carboxylic acid is formic acid or acetic acid.

[0161] In some embodiments, the solvent is acetonitrile.

[0162] In some embodiments, the deprotection step includes methanesulfonic acid. In some embodiments, the deprotection step further includes acetonitrile at a temperature of about 55°C to about 75°C. In some embodiments, the deprotection step further includes acetonitrile at a temperature of about 65°C.

[0163] In some embodiments, the deprotection step includes methanesulfonic acid and acetonitrile at a temperature of about 65°C.

[0164] In some embodiments, the process involves the methanesulfonate of compound II. [ka] To provide.

[0165] This specification describes a process for preparing compound I or a salt thereof, [ka] Under conditions suitable for providing compound I, the compound of formula VI or a salt thereof [ka] Compounds of formula V or salts thereof [ka] This includes making contact with However, the condition does not include microwave radiation in the process [in the formula, X is a halo, R 2 is hydrogen or -B(OR 3 )2, Each R 3 These are independently hydrogen or C 1~6 Alkyl or two R 3 [It is also provided that it cyclizes to form a cyclic boronate ester.]

[0166] In some embodiments, R 2 is -B(OR 3 )2.

[0167] In some embodiments, the compound of formula V is represented by the compound of formula VA. [ka]

[0168] In some embodiments, two R 3 It cyclizes to form a cyclic boronate ester. In some embodiments, R 2 teeth, [ka] That is the case.

[0169] In some embodiments, the conditions include a catalyst, a ligand, and a base.

[0170] In some embodiments, the catalyst is a palladium(II) salt or a palladium(0) salt. In some embodiments, the catalyst is palladium(II) acetate, palladium(II) 2,4-pentanedionate (Pd(acac)2), allylpalladium(II) chloride dimer ([Pd(allyl)Cl2]), bis(acetonitrile)dichloropalladium(II) (Pd(MeCN)2Cl2), tris(dibenzylideneacetone)dipalladium(0) (Pd(dba)3), palladium(II) trifluoroacetate (Pd(TFA)2), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), or palladium(II) chloride (PdCl2).

[0171] In some embodiments, the catalyst is a palladium(II) salt. In some embodiments, the palladium(II) salt is palladium(II) acetate, palladium(II) 2,4-pentanedionate (Pd(acac)2), allylpalladium(II) chloride dimer ([Pd(allyl)Cl2]), bis(acetonitrile)dichloropalladium(II) (Pd(MeCN)2Cl2), palladium(II) trifluoroacetate (Pd(TFA)2), palladium(II) chloride (PdCl2).

[0172] In some embodiments, the catalyst is a palladium(0) salt. In some embodiments, the palladium(0) salt is tris(dibenzylideneacetone)dipalladium(0) (Pd(dba)3) or tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4).

[0173] In some embodiments, the catalyst is palladium(II) acetate.

[0174] In some embodiments, the ligand is a dialkylbiarylphosphine ligand, a monodentate phosphine ligand, or a bidentate phosphine ligand. In some embodiments, the ligand is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos), 2-dicyclohexylphosphino- These are 2',6'-diisopropoxybiphenyl (RuPhos), triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), or 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf).

[0175] In some embodiments, the ligand is a dialkylbiarylphosphine ligand. In some embodiments, the dialkylbiarylphosphine ligand is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos), or 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos).

[0176] In some embodiments, the ligand is a monodentate phosphine ligand. In some embodiments, the monodentate phosphine ligand is triphenylphosphine, tri-tert-butylphosphine, or tricyclohexylphosphine.

[0177] In some embodiments, the ligand is a bidentate phosphine ligand. In some embodiments, the bidentate phosphine ligand is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (XantPhos), 1,1'-bis(di-tert-butylphosphine)ferrocene (dtbpf), or 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf).

[0178] In some embodiments, the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos).

[0179] In some embodiments, the base is an inorganic base, an alkoxide base, or an organic base, for example, an amine base, for example, a tertiary amine, or a nitrogen-containing heterocyclic base or nitrogen-containing heteroaryl base. In some embodiments, the base is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, monobasic / dibasic / tribasic sodium phosphate, monobasic / dibasic / tribasic lithium phosphate, monobasic / dibasic / tribasic potassium phosphate, monobasic / dibasic / tribasic calcium phosphate, monobasic / dibasic / tribasic magnesium phosphate, These are monobasic / dibasic / tribasic tetramethylammonium phosphate, monobasic / dibasic / tribasic tetrabutylammonium phosphate, sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, N-methylmorpholine, triethylamine, N-methylmorpholine, triethylamine, pyridine, or N-methylimidazole.

[0180] In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, monobasic / dibasic / tribasic sodium phosphate, monobasic / dibasic / tribasic lithium phosphate, monobasic / dibasic / tribasic potassium phosphate, monobasic / dibasic / tribasic calcium phosphate, monobasic / dibasic / tribasic magnesium phosphate, monobasic / dibasic / tribasic tetramethylammonium phosphate, or monobasic / dibasic / tribasic tetrabutylammonium phosphate.

[0181] In some embodiments, the base is an alkoxide base. In some embodiments, the alkoxide base is sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, or potassium tert-butoxide.

[0182] In some embodiments, the base is an amine base. In some embodiments, the amine base is triethylamine, diisopropylethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, or N-methylimidazole. In some embodiments, the base is a tertiary amine. In some embodiments, the tertiary amine is N-methylmorpholine or triethylamine.

[0183] In some embodiments, the base is a nitrogen-containing heterocyclic base or a nitrogen-containing heteroaryl base. In some embodiments, the nitrogen-containing heterocyclic base or nitrogen-containing heteroaryl base is N-methylmorpholine, pyridine, or N-methylimidazole.

[0184] In some embodiments, the base is tribasic potassium phosphate.

[0185] In some embodiments, the conditions further include a solvent. In some embodiments, the conditions further include a solvent at a temperature of about 45°C to about 110°C. In some embodiments, the conditions further include a solvent at a temperature of about 70°C to about 80°C. In some embodiments, the conditions further include a solvent at a temperature of about 75°C.

[0186] In some embodiments, the solvent is an ether, ketone, polar aprotic solvent, hydrocarbon, nitrile, or a combination thereof, or a combination thereof with water. In some embodiments, the solvent is tetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether (CPME), acetone, 2-butanone, 4-methyl-2-pentanone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, toluene, n-heptane, acetonitrile, or a combination thereof, or a combination thereof with water.

[0187] In some embodiments, the solvent is an ether. In some embodiments, the ether is tetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether (CPME), or a combination thereof, or a combination thereof with water.

[0188] In some embodiments, the solvent is a ketone. In some embodiments, the ketone is acetone, 2-butanone, 4-methyl-2-pentanone, or a combination thereof, or a combination thereof with water.

[0189] In some embodiments, the solvent is an aprotic polar solvent. In some embodiments, the aprotic polar solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or a combination thereof, or a combination thereof with water.

[0190] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is toluene, n-heptane, or a combination thereof, or a combination thereof with water.

[0191] In some embodiments, the solvent is a nitrile. In some embodiments, the nitrile is acetonitrile, or a combination thereof, or a combination thereof with water.

[0192] In some embodiments, the solvent is 2-methyltetrahydrofuran and water.

[0193] In some embodiments, the conditions include palladium(II) acetate, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), and tribasic potassium phosphate. In some embodiments, the conditions further include 2-methyltetrahydrofuran and water at a temperature of about 70 °C to about 80 °C. In some embodiments, the conditions further include 2-methyltetrahydrofuran and water at a temperature of about 75 °C.

[0194] In some embodiments, the conditions include palladium(II) acetate, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), tribasic potassium phosphate, 2-methyltetrahydrofuran, and water at a temperature of about 75 °C.

[0195] In some embodiments, the process further comprises contacting Compound I with citric acid to form the citrate salt of Compound I:

Chemical formula

[0196] In some embodiments, the conditions include a solvent. In some embodiments, the conditions include a solvent at a temperature of about 0°C to about 90°C. In some embodiments, the conditions include a solvent at a temperature of about 45°C to about 55°C. In some embodiments, the conditions include a solvent at a temperature of about 50°C.

[0197] In some embodiments, the solvent is an alcohol, ether, ester, ketone, nitrile, or polar aprotic solvent. In some embodiments, the solvent is ethanol, methanol, 1-propanol, 2-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, ethyl acetate, isopropyl acetate, acetone, 2-butanone, 4-methyl-2-pentanone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methyl-2-pyrrolidone.

[0198] In some embodiments, the solvent is an alcohol. In some embodiments, the alcohol is ethanol, methanol, 1-propanol, or 2-propanol.

[0199] In some embodiments, the solvent is an ether. In some embodiments, the ether is tetrahydrofuran, 2-methyltetrahydrofuran, or tert-butylmethyl ether.

[0200] In some embodiments, the solvent is an ester. In some embodiments, the ester is ethyl acetate or isopropyl acetate.

[0201] In some embodiments, the solvent is a ketone. In some embodiments, the ketone is acetone, 2-butanone, or 4-methyl-2-pentanone.

[0202] In some embodiments, the solvent is a nitrile. In some embodiments, the nitrile is acetonitrile.

[0203] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, or N-methyl-2-pyrrolidone.

[0204] In some embodiments, the solvent is ethanol.

[0205] In some embodiments, the conditions include ethanol at a temperature of about 45°C to about 55°C. In some embodiments, the conditions include ethanol at a temperature of about 50°C.

[0206] In some embodiments, the process involves contacting compound I with about 1.5 equivalents of citric acid.

[0207] In some embodiments, the conditions include contacting compound I with about 1.5 equivalents of citric acid, with ethanol at a temperature of about 50°C.

[0208] This specification describes a process for preparing a compound of formula VI or a salt thereof, [ka] A compound of formula VII or a salt thereof [ka] Compounds of formula VIII: [ka] Under conditions suitable for providing, contact with trifluoroacetic anhydride in the absence of an organic base, (In the equation, X is the halo.) A process is also provided which includes hydrolyzing a compound of formula VIII to provide a compound of formula VI.

[0209] In some embodiments, the hydrolysis involves an inorganic base or an alkoxide base.

[0210] In some embodiments, the inorganic base is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, monobasic / dibasic / tribasic sodium phosphate, monobasic / dibasic / tribasic lithium phosphate, monobasic / dibasic / tribasic potassium phosphate, monobasic / dibasic / tribasic calcium phosphate, monobasic / dibasic / tribasic magnesium phosphate, monobasic / dibasic / tribasic tetramethylammonium phosphate, or monobasic / dibasic / tribasic tetrabutylammonium phosphate.

[0211] In some embodiments, the alkoxide base is sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, or potassium tert-butoxide.

[0212] In some embodiments, the base is potassium carbonate.

[0213] In some embodiments, the conditions include a solvent. In some embodiments, the conditions include a solvent at a temperature of about -20°C to about 60°C. In some embodiments, the conditions include a solvent at a temperature of about -10°C to about 10°C. In some embodiments, the conditions include a solvent at a temperature of about 0°C.

[0214] In some embodiments, the solvent is an ester, ether, ketone, nitrile, hydrocarbon, halogenated solvent, polar aprotic solvent, or a combination thereof, or a combination thereof with water. In some embodiments, the solvent is ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tert-butylmethyl ether, acetone, 2-butanone, 4-methyl-2-pentanone, toluene, n-heptane, dichloromethane, 1,2-dichloroethane, chlorobenzene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or a combination thereof, or a combination thereof with water.

[0215] In some embodiments, the solvent is an ester. In some embodiments, the ester is ethyl acetate, isopropyl acetate, or a combination thereof, or a combination thereof with water.

[0216] In some embodiments, the solvent is an ether. In some embodiments, the ether is tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, or a combination of these with water.

[0217] In some embodiments, the solvent is a ketone. In some embodiments, the ketone is acetone, 2-butanone, 4-methyl-2-pentanone, or a combination thereof, or a combination thereof with water.

[0218] In some embodiments, the solvent is a nitrile. In some embodiments, the nitrile is acetonitrile, a combination thereof, or a combination thereof with water.

[0219] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is toluene or n-heptane, or a combination thereof, or a combination of them with water.

[0220] In some embodiments, the solvent is a halogenating solvent. In some embodiments, the halogenating solvent is dichloromethane, 1,2-dichloroethane, chlorobenzene, or a combination thereof, or a combination thereof with water.

[0221] In some embodiments, the solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or a combination thereof, or a combination thereof with water.

[0222] In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is tetrahydrofuran and water. In some embodiments, the solvent is tetrahydrofuran and water at a temperature of about -10°C to about 10°C. In some embodiments, the solvent is tetrahydrofuran and water at a temperature of about 0°C.

[0223] In some embodiments, the conditions include tetrahydrofuran at a temperature of about 0°C, and the hydrolysis step includes potassium carbonate, tetrahydrofuran, and water at a temperature of about 0°C.

[0224] In some embodiments, X is chloro or bromo.

[0225] This specification describes a process for preparing a compound of formula VI or a salt thereof, [ka] Under conditions suitable for providing the compound of formula VI, the compound of formula VII or a salt thereof [ka] A process is also provided which includes contact with a dehydrating agent (wherein X is a halo), wherein the dehydrating agent is other than trifluoroacetic anhydride.

[0226] In some embodiments, the dehydrating agent is cyanuryl chloride, carboxylic acid anhydride, sulfonic acid anhydride, alkyl chloroformate, phosphorus oxychloride, phosphorus pentoxide, thionyl chloride, phosphoryl chloride, sulfonyl chloride, oxalyl chloride, aluminum trichloride, or dichlorophosphate. In some embodiments, the dehydrating agent is cyanuryl chloride, carboxylic acid anhydride (e.g., acetic anhydride), sulfonic acid anhydride (e.g., trifluoromethanesulfonic anhydride), alkyl chloroformate (e.g., ethyl chloroformate), phosphorus oxychloride, or phosphorus pentoxide. In some embodiments, the dehydrating agent is acetic anhydride, trifluoromethanesulfonic anhydride, ethyl chloroformate, phosphorus oxychloride, phosphorus pentoxide, thionyl chloride, phosphoryl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, oxalyl chloride, aluminum trichloride, or ethyl dichlorophosphate.

[0227] In some embodiments, the conditions further include a base.

[0228] In some embodiments, the base is an amine base. In some embodiments, the amine base is N,N-diisopropylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, or N-methylimidazole.

[0229] In some embodiments, the amine base is triethylamine.

[0230] In some embodiments, the process further includes a hydrolysis step.

[0231] In some embodiments, the hydrolysis involves an inorganic base or an alkoxide base.

[0232] In some embodiments, the inorganic base is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, monobasic / dibasic / tribasic sodium phosphate, monobasic / dibasic / tribasic lithium phosphate, monobasic / dibasic / tribasic potassium phosphate, monobasic / dibasic / tribasic calcium phosphate, monobasic / dibasic / tribasic magnesium phosphate, monobasic / dibasic / tribasic tetramethylammonium phosphate, or monobasic / dibasic / tribasic tetrabutylammonium phosphate.

[0233] In some embodiments, the alkoxide base is sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, or potassium tert-butoxide.

[0234] In some embodiments, the conditions and hydrolysis step further include a solvent. In some embodiments, the conditions and hydrolysis step further include a solvent at a temperature of about -20°C to about 60°C. In some embodiments, the conditions and hydrolysis step further include a solvent at a temperature of about 0°C to about 20°C. In some embodiments, the conditions and hydrolysis step further include a solvent at a temperature of about 10°C.

[0235] In some embodiments, the solvent is an ester, ether, ketone, nitrile, hydrocarbon, halogenated solvent, or polar aprotic solvent. In some embodiments, the solvent is ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tert-butylmethyl ether, acetone, 2-butanone, 4-methyl-2-pentanone, toluene, n-heptane, dichloromethane, 1,2-dichloroethane, chlorobenzene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methyl-2-pyrrolidone.

[0236] In some embodiments, the solvent is an ester. In some embodiments, the ester is ethyl acetate or isopropyl acetate.

[0237] In some embodiments, the solvent is an ether. In some embodiments, the ether is tetrahydrofuran, 2-methyltetrahydrofuran, or tert-butylmethyl ether.

[0238] In some embodiments, the solvent is a ketone. In some embodiments, the ketone is acetone, 2-butanone, or 4-methyl-2-pentanone.

[0239] In some embodiments, the solvent is a nitrile. In some embodiments, the nitrile is acetonitrile.

[0240] In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is toluene or n-heptane.

[0241] In some embodiments, the solvent is a halogenating solvent. In some embodiments, the halogenating solvent is dichloromethane, 1,2-dichloroethane, or chlorobenzene.

[0242] In some embodiments, the solvent is an aprotic polar solvent. In some embodiments, the aprotic polar solvent is N,N-dimethylformamide, N,N-dimethylacetamide, or N-methyl-2-pyrrolidone.

[0243] In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is acetonitrile at a temperature of about 0°C to about 20°C. In some embodiments, the solvent is acetonitrile at a temperature of about 10°C.

[0244] In some embodiments, the conditions include triethylamine and acetonitrile at a temperature of about 10°C.

[0245] A process for preparing a compound of formula IX or a salt thereof, as described herein,

Chemical formula

Chemical formula

Chemical formula

[0246] In some embodiments, two Rs 3 cyclize to form a cyclic boronate ester. In some embodiments, the moiety

Chemical formula

[0247] In some embodiments, X is chloro.

[0248] In some embodiments, the conditions include a base.

[0249] In some embodiments, the base is an inorganic base, an alkoxide base, or an organic base, for example, but not limited to, an amine base, such as a tertiary amine, or a nitrogen-containing heterocyclic base or nitrogen-containing heteroaryl base. In some embodiments, the base is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, monobasic / dibasic / tribasic sodium phosphate, monobasic / dibasic / tribasic lithium phosphate, monobasic / dibasic / tribasic potassium phosphate, monobasic / dibasic / tribasic calcium phosphate, monobasic / dibasic / tribasic magnesium phosphate, These are monobasic / dibasic / tribasic tetramethylammonium phosphate, monobasic / dibasic / tribasic tetrabutylammonium phosphate, sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, N-methylmorpholine, triethylamine, N-methylmorpholine, triethylamine, pyridine, or N-methylimidazole.

[0250] In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, monobasic / dibasic / tribasic sodium phosphate, monobasic / dibasic / tribasic lithium phosphate, monobasic / dibasic / tribasic potassium phosphate, monobasic / dibasic / tribasic calcium phosphate, monobasic / dibasic / tribasic magnesium phosphate, monobasic / dibasic / tribasic tetramethylammonium phosphate, or monobasic / dibasic / tribasic tetrabutylammonium phosphate.

[0251] In some embodiments, the base is an alkoxide base. In some embodiments, the alkoxide base is sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, or potassium tert-butoxide.

[0252] In some embodiments, the base is an amine base. In some embodiments, the amine base is triethylamine, diisopropylethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, or N-methylimidazole. In some embodiments, the base is a tertiary amine. In some embodiments, the tertiary amine is N-methylmorpholine or triethylamine.

[0253] In some embodiments, the base is a nitrogen-containing heterocyclic base or a nitrogen-containing heteroaryl base. In some embodiments, the nitrogen-containing heterocyclic base or nitrogen-containing heteroaryl base is N-methylmorpholine, pyridine, or N-methylimidazole.

[0254] In some embodiments, the base is tribasic potassium phosphate.

[0255] In some embodiments, the conditions include a catalyst. In some embodiments, the conditions include a base and a catalyst.

[0256] In some embodiments, the catalyst is a palladium(II) salt, a palladium(O) salt, copper(II) trifluoromethanesulfonate, or a combination thereof. In some embodiments, the catalyst is a palladium(II) salt or a palladium(O) salt. In some embodiments, the catalyst is palladium(II) 2,4-pentanedione (Pd(acac)2), allylpalladium(II) chloride dimer ([Pd(allyl)Cl2]), bis(acetonitrile)dichloropalladium(II) (Pd(MeCN)2Cl2), tris(dibenzylideneacetone)dipalladium(O) (Pd(dba)3), palladium(II) trifluoroacetate (Pd(TFA)2), tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4), palladium(II) chloride (PdCl2), or a combination thereof.

[0257] In some embodiments, the catalyst is a palladium(II) salt. In some embodiments, the palladium(II) salt is palladium(II) 2,4-pentanedione, allylpalladium(II) chloride dimer, bis(acetonitrile)dichloropalladium(II), palladium(II) trifluoroacetate, or palladium(II) chloride.

[0258] In some embodiments, the catalyst is a palladium(O) salt. In some embodiments, the palladium(O) salt is tetrakis(triphenylphosphine)palladium(O) or tris(dibenzylideneacetone)dipalladium(O).

[0259] In some embodiments, the conditions include a catalyst, a ligand, and a base.

[0260] In some embodiments, the catalyst is palladium(II) acetate.

[0261] In some embodiments, the ligand is a dialkylbiarylphosphine ligand, a monodentate phosphine ligand, or a bidentate phosphine ligand. In some embodiments, the ligand is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos), 2-dicyclohexylphosphino- These are 2',6'-diisopropoxybiphenyl (RuPhos), triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 1,1'-bis(di-tert-butylphosphino)ferrocene (dtbpf), or 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf).

[0262] In some embodiments, the ligand is a dialkylbiarylphosphine ligand. In some embodiments, the dialkylbiarylphosphine ligand is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos), or 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos).

[0263] In some embodiments, the ligand is a monodentate phosphine ligand. In some embodiments, the monodentate phosphine ligand is triphenylphosphine, tri-tert-butylphosphine, or tricyclohexylphosphine.

[0264] In some embodiments, the ligand is a bidentate phosphine ligand. In some embodiments, the bidentate phosphine ligand is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (XantPhos), 1,1'-bis(di-tert-butylphosphine)ferrocene (dtbpf), or 1,1'-ferrocenediyl-bis(diphenylphosphine) (dppf).

[0265] In some embodiments, the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos).

[0266] In some embodiments, the catalyst is a pre-catalyst, for example, a pre-formed mixture of a palladium catalyst and a ligand, for example, other Pd pre-catalysts (e.g., 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate, in addition to those listed above.

[0267] In some embodiments, the conditions further include a solvent. In some embodiments, the conditions further include a solvent at a temperature of about 45°C to about 110°C. In some embodiments, the conditions further include a solvent at a temperature of about 70°C to about 80°C. In some embodiments, the conditions further include a solvent at a temperature of about 75°C.

[0268] In some embodiments, the solvent is an ether, ketone, polar aprotic solvent, hydrocarbon, nitrile, or a combination thereof, or a combination thereof with water. In some embodiments, the solvent is tetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether (CPME), acetone, 2-butanone, 4-methyl-2-pentanone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, toluene, n-heptane, acetonitrile, or a combination thereof, or a combination thereof with water.

[0269] In some embodiments, the solvent is ether. In some embodiments, the solvent is 2-methyltetrahydrofuran and water, and the temperature is about 70°C to about 80°C, or about 75°C.

[0270] This specification describes a process for preparing compound I or a salt thereof, [ka] Under conditions suitable for providing compound I, the compound of formula IX or a salt thereof. [ka] A process including contact is also provided.

[0271] In some embodiments, the conditions include the dehydrating agents described herein.

[0272] In some embodiments, the dehydrating agent is cyanuryl chloride, carboxylic acid anhydride, sulfonic acid anhydride, alkyl chloroformate, phosphorus oxychloride, or phosphorus pentoxide.

[0273] In some embodiments, the dehydrating agent is acetic anhydride, trifluoroacetic anhydride, trifluoromethanesulfonic acid anhydride, ethyl chloroformate, phosphorus oxychloride, or phosphorus pentoxide.

[0274] In some embodiments, the dehydrating agent is anhydrous trifluoroacetic acid.

[0275] In some embodiments, the conditions include a dehydrating agent and a base, such as an amine base. In some embodiments, the amine base is N-methylimidazole, N,N-diisopropylamine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, or N-methylmorpholine.

[0276] In some embodiments, the conditions include trifluoroacetic anhydride and pyridine.

[0277] In some embodiments, the conditions include a dehydrating agent, a base, and a solvent.

[0278] In some embodiments, the solvent is an ester, ether, ketone, nitrile, hydrocarbon, halogenated solvent, or polar aprotic solvent, or a mixture thereof.

[0279] In some embodiments, the solvent is ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, acetone, 2-butanone, 4-methyl-2-pentanone, acetonitrile, toluene, n-heptane, dichloromethane, 1,2-dichloroethane, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or a mixture thereof.

[0280] In some embodiments, the conditions include trifluoroacetic anhydride and pyridine in tetrahydrofuran.

[0281] In some embodiments, the conditions include temperatures ranging from about -20°C to about 20°C. In some embodiments, the conditions include temperatures ranging from about -10°C to about 10°C. In some embodiments, the conditions include temperatures ranging from about 0°C.

[0282] In some embodiments, the conditions include a hydrolysis step.

[0283] In some embodiments, the conditions include a dehydrating agent and an optional hydrolysis step. In some embodiments, the conditions include a hydrolysis step following the dehydrating agent.

[0284] In some embodiments, the hydrolysis step includes a base.

[0285] In some embodiments, the base is an inorganic base or an alkoxide base. In some embodiments, the base is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, tetramethylammonium carbonate, tetrabutylammonium carbonate, tribasic sodium phosphate, dibasic sodium phosphate, monobasic sodium phosphate, tribasic lithium phosphate, dibasic lithium phosphate, monobasic lithium phosphate, tribasic potassium phosphate, dibasic potassium phosphate, monobasic potassium phosphate, tribasic calcium phosphate, dibasic calcium phosphate, monobasic calcium phosphate These are magnesium tribasic phosphate, magnesium dibasic phosphate, magnesium monobasic phosphate, tetraalkylammonium tribasic phosphate, tetraalkylammonium dibasic phosphate, tetraalkylammonium monobasic phosphate, sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, calcium tert-butoxide, or mixtures thereof.

[0286] In some embodiments, the base is sodium carbonate.

[0287] In some embodiments, the hydrolysis step includes a solvent, for example, an ester (e.g., ethyl acetate, isopropyl acetate, etc.), an ether (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), or a ketone (e.g., acetone, 2-butanone, etc.).

[0288] In some embodiments, the conditions include temperatures ranging from about -20°C to about 60°C. In some embodiments, the conditions include temperatures ranging from about -10°C to about 10°C. In some embodiments, the conditions include temperatures ranging from about 0°C.

[0289] compound In certain embodiments, this disclosure provides intermediate compounds useful in the processes described herein.

[0290] It can be understood that straight thick or dashed lines are used to indicate relative stereochemistry, and wedge-shaped thick or dashed lines are used to indicate absolute stereochemistry. When a composition is identified as enantiomerically enriched, it is intended that the composition contains more than 50% of a single enantiomer, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 99% ee.

[0291] In this specification, Compound I: [ka] The citrate is provided.

[0292] In this specification, the citrate of compound I: [ka] It will be provided.

[0293] In certain embodiments, the citrate of Compound I is the monocitrate of Compound I.

[0294] Compound II: [Chemical formula] The methanesulfonate of is also provided.

[0295] The methanesulfonate of Compound II: [Chemical formula] Is also provided.

[0296] Compound of formula IIA: [Chemical formula] (where R 1 is a protecting group) is also provided.

[0297] In some embodiments, R 1 is a carboxy protecting group. In certain embodiments, the carboxy protecting group is C 1~6 alkoxy, cyano, -Si(C 1~6 alkyl)3, or aryl, optionally substituted C 1~6 alkyl, and the aryl is optionally substituted with one or more substituents independently selected from halo, nitro, C 1~6 alkyl, and C 1~6 alkoxy. In certain embodiments, R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, t-butoxymethyl, benzyl, p-methoxybenzyl, or p-nitrobenzyl.

[0298] In some embodiments, R 1R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or benzyl. In some embodiments, R 1 These are methyl, ethyl, tert-butyl, or benzyl.

[0299] In some embodiments, R 1 C 1~6 It is alkyl. In some embodiments, R 1 is methyl, ethyl, or tert-butyl. In some embodiments, R 1 It is tert-butyl.

[0300] Compounds of formula IV: [ka] (In the formula, R 1 X and X are also provided (each independently as defined herein).

[0301] In some embodiments, R 1 C 1~6 It is alkyl. In some embodiments, X is halo. In some embodiments, X is chloro or bromo. In some embodiments, X is chloro.

[0302] Compounds of formula V: [ka] [In the formula, R 2 is hydrogen or -B(OR 3 )2, Each R 3 These are independently hydrogen or C 1~6 Alkyl or two R 3 [It is also provided that it cyclizes to form a cyclic boronate ester.]

[0303] In some embodiments, R 2 It is hydrogen.

[0304] Several embodiments, each R 3 These are, independently, hydrogen or C 1~6 It is alkyl. In some embodiments, each R 3 is hydrogen. In some embodiments, each R 3 C 1~6 It is alkyl. In some embodiments, two R 3 It cyclizes to form a cyclic boronate ester. In some embodiments, two R 3 It cyclizes to form a 5-10 membered cyclic boronate ester. In some embodiments, R 2 teeth, [ka] That is the case.

[0305] below, [ka] Compounds or salts thereof, selected from the above, are also provided.

[0306] structure: [ka] Compounds or salts thereof having the same property are also provided.

[0307] structure: [ka] Compounds or salts thereof having the same property are also provided.

[0308] structure: [ka] Compounds or salts thereof having the same property are also provided.

[0309] For clarity, it should be understood that certain features described herein, as described in the context of a separate embodiment, may also be provided in combination in a single embodiment. Conversely, for brevity, various features described herein, as described in the context of a single embodiment, may also be provided separately or in any preferred partial combination. [Examples]

[0310] The compounds of this disclosure may also be prepared using the methods disclosed herein and their routine modifications, which will be apparent given the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well known synthetic methods may be used. The synthesis of typical compounds described herein can be achieved as described in the following examples. Where available, reagents may be purchased commercially from, for example, Sigma Aldrich or other chemical suppliers. Unless otherwise noted, the starting materials for the following reactions can be obtained from commercial suppliers.

[0311] List of abbreviations and acronyms Abbreviations and their meanings ℃ Celsius temperature DMSO (Dimethyl Sulfoxide) EtOH Ethanol HCl (hydrochloric acid) KHCO3 (potassium bicarbonate) K2CO3 potassium carbonate K3PO4 Tripotassium Phosphate MeCN acetonitrile MeOH methanol MTBE methyl tert-butyl ether MIBK Methyl isobutyl ketone NaOH (Sodium Hydroxide) Nf Perfluorobutanesulfonyl Pd / C Palladium Carbon RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl TCFH N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate TEA (Triethylamine) TFAA (Trifluoroacetic Acid) THF (Tetrahydrofuran) XPhos Dicyclohexyl[2',4',6'-Tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane

[0312] Procedure A: Synthesis of (R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride [ka] Methyl L-serinate hydrochloride (1.0 equivalent, scaling factor), N,N-dimethylformamide (8.0 vol), potassium carbonate (2.0 equivalent), and potassium iodide (0.5 equivalent) were added to the reactor. The temperature was adjusted to approximately 5°C, and while maintaining the temperature at approximately 5°C, benzyl bromide (1.95 equivalent) was added over approximately 4 hours. The mixture was heated to approximately 25°C and stirred for approximately 16 hours. The mixture was cooled to approximately 5°C, and tert-butyl methyl ether (6.0 vol) and water (10.0 vol) were added. The mixture was heated to approximately 25°C and stirred for approximately 2 hours. The aqueous layer was removed, and the organic layer was washed with water (5.0 vol) and washed twice (4.0 vol each) with 10% w / w sodium sulfate aqueous solution. The mixture was concentrated to approximately 3 volumes at approximately 50°C, and the solvent was changed to tetrahydrofuran (8.0 volumes) to obtain a solution of methyldibenzyl-L-serinate.

[0313] A solution of methyl dibenzyl-L-serinate in tetrahydrofuran (1.0 equivalent, standard dilution) was added to the reactor, and the temperature was adjusted to approximately 25°C. Next, while maintaining the temperature at approximately 25°C, triethylamine trihydrofluoride (1.3 equivalents) was added to the reactor over approximately 2 hours, followed by diisopropylethylamine (2.8 equivalents) over approximately 2 hours. While maintaining the temperature at approximately 25°C, perfluorobutanesulfonyl fluoride (1.3 equivalents) was added to the reactor over approximately 3 hours. The reaction mixture was adjusted to approximately 40°C, and the reactants were stirred for approximately 15 hours. The reaction mixture was adjusted to approximately 20°C over approximately 2 hours. While maintaining the temperature at approximately 20°C, water (5.0 volume) was added to the mixture. Methylcyclohexane (4.0 volume) was added to the mixture, and the mixture was stirred at approximately 25°C for approximately 1 hour. The stirring was stopped, and three layers were obtained. The upper layer was removed, the lower two layers were returned to the reactor, methylcyclohexane (4.0 vol) was added, and the mixture was stirred at approximately 25°C for approximately 1 hour. The stirring was stopped to obtain three layers. The upper and lower layers were removed, the intermediate layer was returned to the reactor, and washed with 7% w / w aqueous potassium bicarbonate (4.5 vol) and water (4.0 vol). The mixture was concentrated to approximately 3 vol, and the solvent was changed to 2-methyltetrahydrofuran (7.0 vol) to obtain a solution of methyl(R)-3-(dibenzylamino)-2-fluoropropanoate.

[0314] A solution of methyl(R)-3-(dibenzylamino)-2-fluoropropanoate in 2-methyltetrahydrofuran (1.0 equivalent, standard dilution) was added to a reactor and cooled to approximately -30°C. While maintaining the temperature at approximately -30°C, a solution of 3M methylmagnesium chloride in tetrahydrofuran (2.4 equivalents) was added over approximately 5 hours. The mixture was stirred for approximately 6 hours. A 1N aqueous HCl solution (7.0 vol) was added to a separate reactor and cooled to approximately 5°C. The mixture from the first reactor was added to the HCl solution over approximately 2 hours while maintaining the temperature at approximately 5°C. The mixture was heated to approximately 25°C and stirred for approximately 1 hour. The layers were separated, and the organic layer was extracted twice (6.0 vol, then 3.0 vol) with 1N aqueous HCl. The two acidic extracts were combined, and potassium carbonate was added until the pH was approximately 9. The basic aqueous layer was extracted with ethyl acetate (5.0 vol), the aqueous layer was removed, and the organic mixture was concentrated to about 3 vol at about 45°C. The mixture was azeotropically dried by continuously adding ethyl acetate (6.0 vol) and concentrated to about 3 vol at about 45°C. Ethyl acetate (6.0 vol) was added to obtain a solution of (R)-4-(dibenzylamino)-3-fluoro-2-methylbutan-2-ol.

[0315] Ethyl acetate (2.0 vol) was placed in a reactor and adjusted to approximately -10°C. Hydrogen chloride gas was passed through the ethyl acetate for approximately 2 hours. In a separate reactor, (R)-4-(dibenzylamino)-3-fluoro-2-methylbutan-2-ol solution (1.0 equivalent, standard dilution) in ethyl acetate was placed and adjusted to approximately 25°C. The hydrogen chloride solution in ethyl acetate was added over approximately 30 minutes. The mixture was stirred at approximately 25°C for approximately 12 hours. The mixture was then degassed by passing nitrogen through it for approximately 1 hour. The slurry was filtered, washed twice with ethyl acetate (1.0 vol), and dried at approximately 45°C for approximately 20 hours to obtain (R)-4-(dibenzylamino)-3-fluoro-2-methylbutan-2-ol hydrochloride.

[0316] 1H NMR (400MHz, MeOD-d4) δ7.51-7.56(m,10H),4.65(ddd,J=2.6,7.4,47.9Hz,1H),4.37-4.56(bm,4H),3.47-3.66(m,2H),1.17(s,3H),1.03(s,3H)ppm.

[0317] [ka] (R)-4-(dibenzylamino)-3-fluoro-2-methylbutan-2-ol hydrochloride (1.0 equivalent), isopropyl alcohol (8.0 vol), and 10% wet Pd / C (approximately 7% w / w) were placed in the reactor. The reactor was flushed three times with hydrogen, and the mixture was heated to approximately 45°C. The reactor was pressurized with hydrogen (approximately 45 psi) and stirred at approximately 45°C for approximately 20 hours. The mixture was adjusted to approximately 25°C, filtered through diatomaceous earth, and the cake was washed twice with isopropyl alcohol (2.0 vol each time). The mixture was concentrated to approximately 2 vol under vacuum at less than approximately 50°C. The mixture was azeotropically dried by continuously adding isopropyl alcohol (4.0 vol) and concentrated to approximately 2 vol at approximately 50°C. Isopropyl alcohol (2.0 vol) was placed in the reactor. The mixture was adjusted to approximately 45°C over approximately 1 hour and stirred for approximately 8 hours. The mixture was adjusted to approximately 25°C over approximately 4 hours, and isopropyl acetate (5.0 vol) was added over approximately 2 hours. The mixture was stirred at approximately 25°C for approximately 20 hours. The mixture was filtered, and the filtrate was stirred at approximately 25°C for approximately 4 hours to form a second crop, which was filtered together with the first crop. The cake was washed with a 5:1 mixture of isopropyl acetate and isopropyl alcohol (1.0 vol) and dried at approximately 45°C for approximately 20 hours to obtain (R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride.

[0318] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,3H),5.03(s,1H),4.42-4.57(m,1H),2.97-3.20(m,2H),1.12-1.13(d,J=4.0Hz,6H)ppm.

[0319] Procedure B: Synthesis of pyrrolo[1,2-b]pyridazine-3-carbonitride [ka] A solution of potassium(Z)-2-cyano-3,3-diethoxypropane-1-oleate in methanol (1.1 equivalents) and a concentrated aqueous solution of HCl (1.7 equivalents) were added to the reactor. At approximately 25°C, tert-butyl(1H-pyrrole-1-yl)carbamate (1.0 equivalent, standard dilution) was added to the reaction mixture. The mixture was stirred at approximately 25°C for approximately 2 hours. Water (4.5 vols) was added to the reactor, and the pH of the mixture was adjusted to approximately 8-9 with a 2N NaOH solution to form a slurry. The mixture was stirred at approximately 25°C for approximately 30 minutes. The slurry was filtered, and the filtered cake was washed with water (1.3 vols). The wet cake was transferred to the reactor and slurryed in water (3.0 vols) at approximately 25°C for approximately 2 hours. The slurry was filtered, the cake was washed with water (1.0 volume), and dried at approximately 40°C to obtain pyrrolo[1,2-b]pyridazine-3-carbonitride.

[0320] 1 ¹H NMR (400MHz, chloroform-d): δ 8.03-8.16 (m, 2H), 7.93 (ddd, J=2.6, 1.4, 0.6Hz, 1H), 7.04 (dd, J=4.5, 2.7Hz, 1H), 6.84 (dd, J=4.6, 1.4Hz, 1H) ppm.

[0321] Procedure C: Synthesis of 7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile [ka] Pyrrolo[1,2-b]pyridazine-3-carbonitride (1.0 equivalent, standard ratio) and acetonitrile (20 volumes) were placed in a reactor. N-bromosuccinimide (1.1 equivalents) and acetonitrile (12 volumes) were placed in a separate reactor. The N-bromosuccinimide solution was added to the first reactor at approximately 15°C over approximately 9 hours to form a slurry. The mixture was aged at approximately 15°C for approximately 30 minutes, and then cooled to approximately 5°C. Water (33 volumes) was added at approximately 5°C over approximately 6 hours, and the mixture was aged at approximately 5°C for approximately 1 hour. The slurry was filtered, the cake was washed with water (2.0 volumes), and dried at approximately 50°C to obtain 7-bromopyrrolo[1,2-b]pyridazine-3-carbonitride.

[0322] 1 ¹H NMR (400MHz, chloroform-d): δ 8.28 (d, J=2.1Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.12 (d, J=4.8Hz, 1H), 6.93 (d, J=4.8Hz, 1H) ppm.

[0323] Procedure D: Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile [ka] Toluene (10.0 vol) was added to the reactor and heated under reflux using a Dean-Stark trap for approximately 11 hours to azeotropically dry the mixture. The contents were cooled to approximately 20°C and degassed with nitrogen for approximately 2 hours. 7-Bromopyrrolo[1,2-b]pyridazine-3-carbonitride (1.0 equivalent, standard ratio) was added to the reactor, followed by pinacol diboron (1.2 equivalents) and potassium acetate (3.0 equivalents). The mixture was degassed with nitrogen for approximately 1 hour. The mixture was heated under reflux using a Dean-Stark trap for approximately 2 hours to azeotropically dry it, and then cooled to approximately 20°C. Bis(triphenylphosphine)palladium(II) chloride (0.02 equivalents) was added to the mixture and the mixture was heated to approximately 100°C for approximately 16 hours. The mixture was cooled to approximately 25°C, n-heptane (6.0 vol) was added, and the mixture was stirred for approximately 2 hours to form a slurry. The slurry was filtered through Celite and activated carbon, and washed with a 2:1 mixture of toluene and n-heptane (6.0 vol). The mixture was solvent-changed to n-heptane (5.0 vol). The slurry was adjusted to approximately 30°C, filtered, and the cake was washed with n-heptane (1.0 vol). The wet cake, MTBE (1.0 vol), and n-heptane (5.0 vol) were placed in the reactor. The slurry was stirred at approximately 70°C for approximately 1 hour and then at approximately 30°C for approximately 1 hour. The slurry was filtered and washed with n-heptane (1.0 vol). The wet cake, MTBE (1.0 vol), and n-heptane (5.0 vol) were placed in the reactor. The slurry was stirred at approximately 70°C for approximately 1 hour and then at approximately 30°C for approximately 1 hour. The slurry was filtered and washed with n-heptane (1.0 vol). The cake was dried at approximately 50°C to obtain 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile.

[0324] 1 ¹H NMR (400MHz, chloroform-d): δ 8.31 (d, J=2.3Hz, 1H), 8.14 (d, J=2.2Hz, 1H), 7.52 (d, J=4.6Hz, 1H), 6.84 (d, J=4.6Hz, 1H), 1.41 (s, 12H) ppm.

[0325] Procedure E: Synthesis of tert--butyl(R)-6-chloro-4-((1-cyanoethyl)amino)nicotinate [ka] 4,6-dichloronicotinic acid (1.0 equivalent, standard dilution), di-tert-butyl dicarbonate (1.2 equivalents), and 2-methyltetrahydrofuran (6.0 vol) were added to the reactor. The mixture was heated to approximately 60°C, and 4-dimethylaminopyridine (0.05 equivalents) in 2-methyltetrahydrofuran (1.0 vol) was added. The reaction mixture was aged for approximately 2 hours, then water (5.0 vol) was added, and the mixture was stirred for approximately 15 minutes. The lower aqueous layer was removed, and the mixture was washed with water (6.0 vol). The contents of the reactor were concentrated to approximately 3 vol, and then 2-methyltetrahydrofuran (10.0 vol) was added. The mixture was concentrated to approximately 3 vol at approximately 50°C, and acetonitrile (2.0 vol) was added to obtain tert-butyl 4,6-dichloronicotinate.

[0326] In a reactor, 1.0 equivalent of tert-butyl 4,6-dichloronicotinate solution in 2-methyltetrahydrofuran and acetonitrile (standard dilution), 2.5 equivalents of (R)-2-aminopropanamide hydrochloride, and 4.5 equivalents of N,N-diisopropylamine were added. The reaction mixture was heated to approximately 80°C for approximately 18 hours. The resulting slurry was cooled to approximately 60°C and washed twice with water (2.5 volumes, then 2.0 volumes). Acetonitrile (10.0 volumes) was added to the mixture, and it was concentrated to approximately 2 volumes at approximately 50°C to obtain tert-butyl(R)-4-((1-amino-1-oxopropan-2-yl)amino)-6-chloronicotinate.

[0327] 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.44(d,J=7.0Hz,1H),7.62(s,1H),7.31(s ,1H),6.57(s,1H),4.16(p,J=6.8Hz,1H),1.55(s,9H),1.36(d,J=6.7Hz,3H)ppm.

[0328] 13C NMR (101MHz, DMSO-d6) δ173.15,165.78,154.30,154.12,152.66,108.12,104.86,82.04,50.41,27.81,18.49ppm.

[0329] In a reactor, 1.0 equivalent of tert-butyl(R)-4-((1-amino-1-oxopropan-2-yl)amino)-6-chloronicotinate solution (standard dilution) and 1.0 equivalent of triethylamine were added, and the mixture was cooled to approximately 10°C. Anhydrous trifluoroacetic acid (2.1 equivalents) was added over approximately 30 minutes, and the reaction mixture was stirred for approximately 2 hours. 15.0 volumes of 10% w / w aqueous KHCO3 solution was added over approximately 1 hour. The slurry was filtered, the cake was washed with water (4.0 volumes), and dried under vacuum at approximately 50°C to obtain tert-butyl(R)-6-chloro-4-((1-cyanoethyl)amino)nicotinate.

[0330] 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),8.20(d,J=7.7Hz,1H),7.07(s,1H),5.01(p,J=7.1Hz,1H),1.67(d,J=7.0Hz,3H),1.56(s,9H)ppm.

[0331] 13 C NMR (101MHz, DMSO-d6) δ166.1,155.2,154.3,153.2,119.9,109.3,106.4,83.1,37.6,28.2,18.6ppm.

[0332] Procedure F: Synthesis of tert-butyl(R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate [ka] In the reactor, tert-butyl(R)-6-chloro-4-((1-cyanoethyl)amino)nicotinate (1.0 equivalent, reference ratio), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.3 equivalents), RuPhos (0.05 equivalents), and palladium(II) acetate (0.025 equivalents) were added. The reactor was inactivated with nitrogen, and tetrahydrofuran (20.0 vol) and 2M aqueous potassium carbonate solution (2.0 equivalents) were added. The resulting mixture was stirred under reflux for about 3 hours and then cooled to about 40°C. Diatomaceous earth (150% w / w), trisodium trithiocyanurate hydrate (0.3 equivalents), Darco G-60 (50% w / w), and 2-methyltetrahydrofuran (5.0 vol) were added to the reaction mixture. The resulting mixture was stirred at approximately 40°C for approximately 17 hours and then filtered. The reactor and filter cake were rinsed with water (10.0 vol) and then rinsed three times with 2-methyltetrahydrofuran (10.0 vol). The combined filtrate was washed twice with water at approximately 40°C (10.0 vol each). The layers were separated, and the organic layer was concentrated to approximately 10 vol at approximately 70°C and the solvent was changed to toluene (10.0 vol). The mixture was cooled to approximately 55°C, n-heptane (12.0 vol) was added over approximately 2 hours, and the resulting slurry was aged at approximately 55°C for approximately 1 hour, and then cooled to approximately 20°C over approximately 4 hours. The reaction mixture was stirred at 20°C for approximately 16 hours and then filtered. The filtered cake was washed twice (3.0 volume each time) with a 5:6 toluene:n-heptane mixture. The cake was dried at approximately 50°C for approximately 24 hours to obtain tert-butyl(R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate.

[0333] 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.85(d,J=2.2Hz,1H),8.65(d,J=2.2Hz,1H),8.29(s,1H),8.19(d,J=7.1Hz ,1H),7.86(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),4.94(p,J=7.0Hz,1H),1.73(d,J=6.9Hz,3H),1.57(s,9H)ppm.

[0334] Alternative synthesis of procedure G:tert-butyl(R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate [ka] In the reactor, tert-butyl(R)-6-chloro-4-((1-cyanoethyl)amino)nicotinate (1.0 equivalent, reference ratio), pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.5 equivalents), allyl palladium chloride dimer (0.05 equivalents), tri-tert-butylphosphonium tetrafluoroborate (0.30 equivalents), potassium bicarbonate (3.0 equivalents), 2-butanol (5.0 vol.), and 2,2-dimethylbutyric acid (0.30 equivalents) were added. The resulting mixture was stirred at approximately 90°C for approximately 4 hours. The contents of the reactor were cooled to approximately 50°C, and n-heptane (5.0 vol.) was added. The contents of the reactor were cooled to approximately 20°C over approximately 1 hour. The slurry was aged for approximately 30 minutes, then filtered, and washed twice with 2-butanol (1.0 vol., then 3.0 vol.). The cake, 2-MeTHF (20.0 vol.), and water (10.0 vol.) were placed in a reactor and mixed to dissolve. The aqueous phase was removed, and the organic phase was washed with water (10.0 vol.). The aqueous phase was removed, and the organic phase was concentrated to approximately 5 vol. at approximately 60°C. The mixture was solvent-changed to acetone (5.0 vol.), the contents of the reactor were adjusted to approximately 10°C, and the slurry was aged for approximately 1 hour. The slurry was filtered, washed with acetone (1.0 vol.), and dried at approximately 50°C to obtain tert-butyl(R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate.

[0335] 1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.85(d,J=2.2Hz,1H),8.65(d,J=2.2Hz,1H),8.29(s,1H),8.19(d,J=7.1Hz ,1H),7.86(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),4.94(p,J=7.0Hz,1H),1.73(d,J=6.9Hz,3H),1.57(s,9H)ppm.

[0336] Procedure H: Synthesis of (R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate methanesulfonate [ka] 1.0 equivalent of tert-butyl(R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate (standard ratio) and 5.0 volume of acetonitrile were added to the reactor. The mixture was cooled to approximately 10°C, and 2.0 equivalents of methanesulfonic acid were added. The resulting mixture was stirred at approximately 65°C for approximately 6 hours. The contents of the reactor were cooled to approximately 15°C over approximately 5 hours. The slurry was allowed to mature for approximately 1 hour, then filtered, and the filtered cake was washed with 5.0 volume of acetonitrile. The cake was dried at approximately 50°C to obtain (R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate methanesulfonate.

[0337] 1 H NMR (400MHz, DMSO-d6): δ9.37(d,J=8.0Hz,1H),9.02(d,J=4.0Hz,1H),8.93(s,1H),8.85(d,J=4.0Hz,1H),8.18(d ,J=4.0Hz,1H),8.09(s,1H),7.27(d,J=4.0Hz,1H),5.35(p,J=4.0Hz,1H),2.38(s,3H),1.79(d,J=4.0Hz,3H)ppm.

[0338] Procedure I: Synthesis of 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (Compound I) [ka] (R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate methanesulfonate (1.0 equivalent, reference ratio), (R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride (1.2 equivalents), and acetonitrile (15.0 volume) were added to the reactor. The resulting mixture was adjusted to approximately 0°C, and then 1-methylimidazole (5.0 equivalents) was added. The mixture was aged at approximately 0°C for approximately 30 minutes. A solution of TCFH (1.15 equivalents) in acetonitrile (5 volume) was added over approximately 2 hours. The reaction mixture was aged for approximately 1 hour, and then adjusted to approximately 20°C. Water (45.0 volume) was added to a separate reactor and adjusted to approximately 50°C. The reaction mixture was added to the reactor with water over approximately 2 hours. The obtained slurry was aged at approximately 50°C for about 2 hours, and then cooled to approximately 20°C over approximately 4 hours. The slurry was aged for approximately 16 hours, filtered, and the filtered cake was washed with water (10.0 vol). The cake was dried under vacuum at approximately 50°C to obtain 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0339] 1H NMR(400MHz,DMSO-d6):δ8.89(t,J=5.8Hz,1H),8.81(s,1H),8.78(d,J=7.2Hz,1H),8.6 1(d,J=2.4Hz,1H),8.22(s,1H),7.85(d,J=4.4Hz,1H),7.10(d,J=4.8Hz,1H),4.86(p,J= 6.9Hz,1H),4.40(ddd,J=49.2,9.2,2.0Hz,1H),3.75(dddd,J=37.2,14.4,5.2,2.0Hz,1 H),3.43(m,1H),1.72(d,J=7.2Hz,3H),1.19(d,J=1.6Hz,3H),1.18(d,J=1.2Hz,3H)ppm.

[0340] 13 C NMR(100MHz,DMSO-d6):δ167.5,152.0,149.7,149.2,141.7,133.8,130.6,127.3,119.7,118.5,117.2,110.1,106 .9,104.0,96.9(d,J=177.8Hz),93.5,69.5(d,J=19.9Hz),39.4(m),26.1(d,J=3.8Hz),24.7(d,J=3.8Hz),18.5ppm.

[0341] Procedure J: Alternative synthesis of 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (compound I) [ka] (R)-4-((1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)nicotinate methanesulfonate (1.0 equivalent, standard dilution) and acetonitrile (15.0 volume) were added to the reactor. The resulting slurry was adjusted to approximately 20°C, and N,N-diisopropylethylamine (5.0 equivalents) was added, followed by diphenylphosphinate chloride (1.2 equivalents). (R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride (1.2 equivalents) was added as a solid, and the mixture was rinsed forward with acetonitrile (1.0 volume). The resulting mixture was adjusted to approximately 0°C, and then 1-methylimidazole (5.0 equivalents) was added. The mixture was aged at approximately 20°C for approximately 1 hour. 30.0 vol. of 2-methyltetrahydrofuran was added to this mixture, and it was washed three times (15.0 vol. each) with approximately 10% w / w potassium bicarbonate aqueous solution, and twice (15.0 vol. each) with water. The organic layer was azeotropically dried in 2-methyltetrahydrofuran, and the solvent was changed to methanol (15.0 vol.) to adjust the reactor contents to approximately 45°C. The reactor contents were cooled to approximately 10°C over approximately 3 hours and stirred at approximately 10°C for approximately 15 hours. The reactor contents were filtered, and the cake was dried at approximately 55°C for approximately 21 hours. The cake was transferred to the reactor, and 15.0 vol. of ethanol was added. The slurry was stirred at approximately 50°C for approximately 23 hours, and then cooled to approximately 10°C over approximately 5 hours. The reactor contents were filtered, and the reactor and filtered cake were rinsed with ethanol (2.5 vol.) and transferred. The cake was dried at approximately 55°C to obtain 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0342] 1H NMR(400MHz,DMSO-d6):δ8.89(t,J=5.8Hz,1H),8.81(s,1H),8.78(d,J=7.2Hz,1H),8.6 1(d,J=2.4Hz,1H),8.22(s,1H),7.85(d,J=4.4Hz,1H),7.10(d,J=4.8Hz,1H),4.86(p,J= 6.9Hz,1H),4.40(ddd,J=49.2,9.2,2.0Hz,1H),3.75(dddd,J=37.2,14.4,5.2,2.0Hz,1 H),3.43(m,1H),1.72(d,J=7.2Hz,3H),1.19(d,J=1.6Hz,3H),1.18(d,J=1.2Hz,3H)ppm.

[0343] 13 C NMR (100MHz, DMSO-d6): δ167.5,152.0,149.7,149.2,141.7,133.8,130.6,127.3,119.7,118.5,117.2,110.1,106. 9,104.0,96.9(d,J=177.8Hz),93.5,69.5(d,J=19.9Hz),39.4,(m),26.1(d,J=3.8Hz),24.7(d,J=3.8Hz),18.5ppm.

[0344] Procedure K: Synthesis of (R)-4,6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide [ka] 4,6-Dichloronicotinic acid (1.1 equivalents), N,N-dimethylformamide (0.05 equivalents), and tetrahydrofuran (6.0 vol.) were placed in a reactor, and the mixture was cooled to approximately 10°C. Oxalyl chloride (1.3 equivalents) was added to this mixture over approximately 1 hour, and the reaction was stirred at approximately 10°C for approximately 1 hour. In a separate reactor, (R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride (1.0 equivalent, standard dilution), potassium carbonate (2.5 equivalents), 2-methyltetrahydrofuran (8.0 vol.), and water (8.0 vol.) were placed, and the temperature was adjusted to approximately 10°C. The mixture from the first reactor was added to the reactor containing (R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride, and the reaction was stirred for approximately 3 hours. The reaction mixture was then adjusted to approximately 22°C, and stirring was stopped. The lower aqueous layer was removed, and the organic layer was washed twice (5.0 vol each) with a 15% w / w sodium chloride aqueous solution. The organic layer was azeotropically dried in 2-methyltetrahydrofuran, and then removed by polish filtration to remove inorganic materials. The organic layer was concentrated to about 7 vol, and the reaction temperature was adjusted to about 55°C. Then, n-heptane (3.0 vol) was added over about 1 hour. The reaction temperature was adjusted to about 45°C, and the mixture was aged for about 1 hour, after which an additional n-heptane (13.0 vol) was added over about 3 hours. The resulting slurry was aged at about 45°C for about 1 hour, then cooled to about 0°C over about 8 hours and filtered. The cake was washed twice (3.0 vol each) with a 1:3 2-methyltetrahydrofuran:n-heptane solution. The cake was dried at approximately 45°C to obtain (R)-4,6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0345] 1 H NMR(400MHz,DMSO-d6)δ8.91(t,1H),8.47(s,1H),7.92(s,1H),4.86(s,1H),4.31(dd d,J=49.4,9.4,2.1Hz,1H),3.77(m,1H),3.34(m,1H),1.16(dd,J=6.3,1.7Hz,6H)ppm.

[0346] Procedure L: Synthesis of 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide [ka] (R)-4,6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (1.0 equivalent, standard dilution) and (R)-2-aminopropanamide hydrochloride (2.0 equivalents) were added to the reactor. 1-butanol (5.0 vol) and N,N-diisopropylethylamine (4.5 equivalents) were added. The resulting mixture was stirred at approximately 110°C for approximately 18 hours. The contents of the reactor were cooled to approximately 10°C and washed twice (5.0 vol each) with 10% w / w potassium bicarbonate aqueous solution. The organic phase was transferred to a container, the combined aqueous phase was returned to the reactor, and back-extracted with 1-butanol (3.0 vol). The aqueous phase was removed. The organic phases were combined and washed with 15% w / w sodium chloride aqueous solution (5.0 vol). The organic layer was concentrated to approximately 3 vol, and then 1-butanol (13.0 vol) was added. The contents of the reactor were adjusted to approximately 45°C, polished, and rinsed with 1-butanol (2.0 vol). The solution was concentrated to approximately 4 vol, then the internal temperature was adjusted to approximately 75°C and aged for approximately 1 hour. The slurry was cooled to approximately 20°C over approximately 5 hours. n-heptane (10.0 vol) was added over approximately 4 hours, then the slurry was stirred for approximately 1 hour, and then filtered. The cake was washed with a 3:1 mixture of n-heptane and 1-butanol (2.0 vol), dried under vacuum at approximately 50°C to obtain 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0347] 1H NMR(400MHz,DMSO-d6)δ8.71-8.81(m,2H),8.39(s,1H),7.59(s,1H),7.21(s,1H),6.48(s,1H),4.82(s,1H),4.31(ddd,J=49.4,9. ppm.

[0348] Procedure M: Synthesis of 6-chloro-4-(((R)-1-cyanoethyl)amino)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide [ka] 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (1.0 equivalent, standard dilution) and tetrahydrofuran (4.0 vol) were added to the reactor. The mixture was cooled to approximately 0°C and trifluoroacetic anhydride (2.1 equivalents) was added. The resulting mixture was stirred at approximately 0°C for approximately 1 hour. Potassium carbonate (6.0 equivalents) and water (6.0 vol) were added to a separate reactor and stirred until dissolved. The carbonate solution was then transferred to the reaction mixture and stirred at approximately 20°C for approximately 1 hour, after which isopropyl acetate (8.0 vol) was added. The layers were separated and the organic stream was washed twice with water (5.0 vol each). The resulting organic stream was solvent-changed with isopropanol (2.0 vol) and heated to approximately 50°C to obtain a homogeneous solution. n-heptane (2.0 vol) was added, and the reactor contents were cooled to approximately 20°C over approximately 6 hours. An additional n-heptane (3.2 vol) was added over approximately 2 hours, and the slurry was cooled to approximately 0°C over approximately 2 hours. After the slurry was aged for approximately 5 hours, the slurry was filtered, and the cake was washed with n-heptane (2.0 vol). The resulting cake was dried at approximately 50°C to obtain 6-chloro-4-(((R)-1-cyanoethyl)amino)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0349] 1 H NMR(400MHz,DMSO-d6):δ8.94(t,J=4.0Hz,1H),8.69(d,J=8.0Hz,1H),8.51 (s,1H),6.99(s,1H),4.94(p,J=4.0Hz,1H),4.85(s,1H),4.35(ddd,J=40.0, 8.0,4.0Hz,1H),3.70(dddd,J=40.0,16.0,8.0,4.0Hz,1H),3.39(tdd,J=16 .0,12.0,8.0Hz,1H),1.62(d,J=4.0Hz,3H),1.16(dd,J=4.0,8.0Hz,6H)ppm.

[0350] Procedure N: Synthesis of 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (compound I) [ka] In the reactor, 6-chloro-4-(((R)-1-cyanoethyl)amino)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (1.0 equivalent, reference ratio), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.7 equivalents), XPhos (0.05 equivalents), palladium acetate (0.025 equivalents), and 2-methyltetrahydrofuran (17.0 vols) were added. The resulting mixture was stirred, and a solution of tribasic potassium phosphate (2.0 equivalents) in water (2.5 vols) was added to the mixture. The reaction mixture was stirred and heated to approximately 75°C for approximately 4 hours, then cooled to approximately 40°C. Diatomaceous earth (200% w / w), trisodium trithiocyanurate hydrate (0.3 equivalents), Darco G-60 (50% w / w), and 2-methyltetrahydrofuran (21.0 vol) were added to the reaction mixture. The resulting mixture was stirred at approximately 40°C for approximately 17 hours and then filtered. The reactor and filter cake were rinsed three times with 2-methyltetrahydrofuran (10.0 vol each). The combined filtrate was washed three times with water at approximately 50°C (10.0 vol each), and the organic flow was concentrated to approximately 10 vol. 2-methyltetrahydrofuran (20.0 vol) was added to the reactor. The resulting solution was passed through a polish filter and then concentrated to approximately 10 vol under reduced pressure. The reaction mixture was solvent-changed with methanol (15.0 vol), and the reactor contents were adjusted to approximately 45°C. The reactor contents were cooled to approximately 10°C over approximately 3 hours and stirred at approximately 10°C for approximately 15 hours. The reactor contents were filtered, and the cake was dried at approximately 55°C for approximately 21 hours. The cake was transferred to the reactor, and ethanol (15.0 vol) was added. The slurry was stirred at approximately 50°C for approximately 23 hours, and then cooled to approximately 10°C over approximately 5 hours. The reactor contents were filtered, and the reactor and filtered cake were rinsed with ethanol (2.5 vol) and transferred. Toluene (10 vol) was added to the filter, the mixture was stirred for approximately 1 hour, and then filtered. The cake was then rinsed with toluene (5.0 vol) and dried at approximately 55°C to obtain 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0351] 1 H NMR(400MHz,DMSO-d6):δ8.89(t,J=5.8Hz,1H),8.81(s,1H),8.78(d,J=7.2Hz,1H),8.6 1(d,J=2.4Hz,1H),8.22(s,1H),7.85(d,J=4.4Hz,1H),7.10(d,J=4.8Hz,1H),4.86(p,J= 6.9Hz,1H),4.40(ddd,J=49.2,9.2,2.0Hz,1H),3.75(dddd,J=37.2,14.4,5.2,2.0Hz,1 H),3.43(m,1H),1.72(d,J=7.2Hz,3H),1.19(d,J=1.6Hz,3H),1.18(d,J=1.2Hz,3H)ppm.

[0352] 13 C NMR (100MHz, DMSO-d6): δ167.5,152.0,149.7,149.2,141.7,133.8,130.6,127.3,119.7,118.5,117.2,110.1,106. 9,104.0,96.9(d,J=177.8Hz),93.5,69.5(d,J=19.9Hz),39.4,(m),26.1(d,J=3.8Hz),24.7(d,J=3.8Hz),18.5ppm.

[0353] Procedure O: Coupling reaction of 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-3-carbonitrili to convert to 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide [ka] In a reactor, 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (1.0 equivalent, reference ratio), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile (1.6 equivalents), XPhos (0.05 equivalents), palladium acetate (0.025 equivalents), and 2-methyltetrahydrofuran (17.0 vols) were added. The resulting mixture was stirred, and a solution of tribasic potassium phosphate (2.0 equivalents) in water (2.5 vols) was added to the mixture. The reaction mixture was stirred and heated to about 75°C for about 4 hours, then cooled to about 40°C. The resulting slurry was filtered. The cake was washed with toluene (9.0 vol), acetonitrile (5.0 vol), and citric acid aqueous solution (10% w / w), and dried at approximately 40°C. The solid was placed in a reactor and slurried in N-methyl-2-pyrrolidinone (5.0 vol) at approximately 40°C. The slurry was filtered and washed with N-methyl-2-pyrrolidinone (2.0 vol), and the resulting organic saturate was concentrated to approximately 5 vol. The mixture was placed in a reactor, followed by diatomaceous earth (200% w / w), trisodium trithiocyanurate hydrate (0.3 equivalents), and Darco G-60 (50% w / w), and mixed at approximately 40°C for approximately 2 hours. The mixture was filtered, and the filtrate was concentrated to approximately 1 vol. Ethanol (18.0 vol) was added at approximately 40°C, and the mixture was aged at approximately 50°C for approximately 2 hours. Water (18.0 vol) was added at approximately 35°C, the mixture was allowed to mature for approximately 2 hours, and then cooled to approximately 20°C over approximately 3 hours. The slurry was filtered and washed with water (5.0 vol). The contents of the reactor were filtered, and the cake was dried at approximately 40°C for approximately 21 hours to obtain 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0354] 1H NMR (400MHz, methanol-d4) δ8.76(d,J=2.2Hz,1H),8.69-8.63(m,2H),8.05(d,J=4.8Hz,1H),7.88(s,1H),7.22(d,J=5.1Hz,1H),4.91(t,J=7.6 Hz,2H),4.73(dd,J=8.2,4.4Hz,2H),4.52-4.28(m,3H),3.80-3.40(m,5H),2.76(dd,J=13.9,7.0Hz,2H),2.24(s,2H),1.29(d,J=1.7Hz,6H).

[0355] Procedure P: Amide dehydration reaction to convert 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide to 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (compound I). [ka] 4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide and THF (17.0 vol) were added to the reactor. Pyridine (5.0 equivalents) was added and the mixture was cooled to approximately 0°C. Anhydrous trifluoroacetic acid (2.9 equivalents) was added and the resulting mixture was stirred at approximately 0°C for approximately 1 hour. Sodium carbonate solution (1 M, 15 vol) was added over approximately 1 hour and the mixture was heated to approximately 20°C over approximately 1 hour. Water (20.0 vol) and ethyl acetate (20.0 vol) were added, the mixture was filtered through Celite, and rinsed with ethyl acetate (20.0 vol). The layers were separated and the aqueous stream was extracted with 2-methyltetrahydrofuran (20.0 vol). The organic slurry was combined and washed with saturated ammonium chloride aqueous solution (20.0 vol). The resulting organic slurry was solvent-exchanged to ethanol (15.0 vol), and n-heptane (50.0 vol) was added over approximately 1 hour at approximately 20°C. After aging the slurry for approximately 3 hours, the slurry was filtered, and the cake was washed with n-heptane (2.0 vol). The resulting cake was dried at approximately 50°C to obtain 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (compound I).

[0356] 1 H NMR(400MHz,DMSO-d6):δ8.89(t,J=5.8Hz,1H),8.81(s,1H),8.78(d,J=7.2Hz,1H),8.6 1(d,J=2.4Hz,1H),8.22(s,1H),7.85(d,J=4.4Hz,1H),7.10(d,J=4.8Hz,1H),4.86(p,J= 6.9Hz,1H),4.40(ddd,J=49.2,9.2,2.0Hz,1H),3.75(dddd,J=37.2,14.4,5.2,2.0Hz,1 H),3.43(m,1H),1.72(d,J=7.2Hz,3H),1.19(d,J=1.6Hz,3H),1.18(d,J=1.2Hz,3H)ppm.

[0357] 13C NMR (100MHz, DMSO-d6): δ167.5,152.0,149.7,149.2,141.7,133.8,130.6,127.3,119.7,118.5,117.2,110.1,106. 9,104.0,96.9(d,J=177.8Hz),93.5,69.5(d,J=19.9Hz),39.4,(m),26.1(d,J=3.8Hz),24.7(d,J=3.8Hz),18.5ppm.

[0358] Procedure Q: Synthesis of 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide citrate (citrate of compound I) [ka] 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (compound I, 1.0 equivalent, standard dilution) and ethanol (10.0 volume) were added to the reactor. The resulting mixture was heated to approximately 50°C and stirred. In a separate reactor, citric acid (1.5 equivalents) and ethanol (20.0 volume) were added. The citric acid solution was stirred and heated to approximately 35°C for approximately 30 minutes to dissolve it, and then added to the reactor containing compound I. The reaction mixture was stirred at approximately 50°C for approximately 18 hours, and then cooled to approximately 20°C over approximately 3 hours. The contents of the reactor were filtered, and the reactor and filter cake were rinsed with ethanol (5.0 volume) and transferred. The cake was dried at approximately 40°C to obtain 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide citrate.

[0359] 1H NMR(400MHz,DMSO-d6)δ8.91(t,J=5.6Hz,1H),8.87(d,J=2.2Hz,1H),8.83(s,1H),8.78(d,J=7.1Hz,1H),8.66 (d,J=2.2Hz,1H),8.25(s,1H),7.88(d,J=4.8Hz,1H),7.14(d,J=4.8Hz,1H),4.89(dd,J=14.4,7.4Hz,2H),4.3 9(ddd,J=49.2,9.3,2.1Hz,1H),3.75(dddd,J=37.3,14.5,5.3,2.2Hz,1H),3.56-3.37(m,1H),2.77(d,J=15.4 Hz,2H),2.66(d,J=15.4Hz,2H),2.51(p,J=1.9Hz,3H),1.72(d,J=7.0Hz,3H),1.18(dd,J=5.3,1.6Hz,6H)ppm.

[0360] 13 C NMR(101MHz,DMSO-d6)δ174.5,171.2,167.4,152.0,149.7,149.2,141.8,134.0,130.5,127.4,119.7,118.5,117.2,110.2,1 07.0,104.1,96.9(d,J=177.8Hz),93.6,72.4,69.5(d,J=19.9Hz),42.7,38.6,26.1(d,J=3.8Hz),24.7(d,J=3.8Hz),18.5ppm.

[0361] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to whom this disclosure relates.

[0362] The embodiments described herein as exemplary may be suitably carried out in the absence of any or more elements, limitations, or restrictions not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and not limitably. Furthermore, the terms and expressions used herein are for illustrative purposes only and not limiting, and the use of such terms and expressions is not intended to exclude any equivalent or part thereof of the illustrated and described features, although it should be recognized that various modifications are possible within the scope of the claimed embodiments.

[0363] All publications, patent applications, patents, and other references referred to herein are incorporated in whole by reference to the same extent that each is incorporated by reference individually. In case of any conflict, this specification, including definitions, shall prevail.

[0364] While this disclosure has been described in conjunction with the embodiments described above, it should be understood that the foregoing description and examples are illustrative and not intended to limit the scope of this disclosure. Other aspects, advantages, and modifications within the scope of this disclosure will be apparent to those skilled in the art to whom this disclosure relates.

Claims

1. A process for preparing compound I or a salt thereof, 【Chemistry 83】 Under conditions suitable for providing compound I, compound II or a salt thereof 【Chemical 84】 Compound III or its salt 【Chemical 85】 A process that involves bringing something into contact with something.

2. Compound I is brought into contact with citric acid to obtain the citrate of Compound I: 【Chemical 86】 The process according to claim 1, further comprising providing

3. Compound I: 【Chemistry 87】 Citrate.

4. Compound II: 【Chemical 88】 methanesulfonate.

5. A process for preparing compound II or a salt thereof, 【Chemistry 89】 Under conditions suitable for providing compound I, the compound of formula IV or a salt thereof [Chemical 90] Compounds of formula V or salts thereof 【Chemistry 91】 A process that involves contacting [In the formula, X is a halo, R １ It is a protecting group, R ２ is hydrogen or -B (OR ３ ) ２ And, Each R ３ These are independently hydrogen or C １～６ Alkyl or two R ３ It undergoes cyclization to form a cyclic boronate ester.

6. The process according to claim 5, wherein the conditions further include a deprotection step.

7. The deprotection step involves the compound of formula IIA: 【Chemistry 92】 The process according to claim 6, comprising converting to compound II.

8. R １ The process according to any one of claims 5 to 7, wherein is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or benzyl.

9. The process according to claim 8, wherein the deprotection step comprises methanesulfonic acid.

10. Methanesulfonate of compound II: 【Chemistry 93】 The process according to claim 9, which provides

11. R ２ is - B(OR ３ ) ２ is, the process according to any one of claims 5 to 10.

12. R ２ but 【Chemical 94】 The process according to any one of claims 5 to 11.

13. The process according to any one of claims 5 to 12, wherein the conditions include a catalyst, a ligand, and a base.

14. The process according to claim 13, wherein the catalyst is a palladium(II) salt or a palladium(O) salt.

15. The process according to claim 13 or 14, wherein the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), a dialkylbiarylphosphine ligand, a monodentate phosphine ligand, or a bidentate phosphine ligand.

16. The process according to any one of claims 13 to 15, wherein the base is an inorganic base, an alkoxide base, a tertiary amine, or a nitrogen-containing heteroaryl base.

17. R ２ The process according to any one of claims 5 to 10, wherein is hydrogen.

18. The process according to claim 17, wherein the conditions include a catalyst, a ligand, and an acid.

19. The process according to claim 18, wherein the catalyst is a palladium catalyst or a palladium pre-catalyst.

20. The process according to claim 18 or 19, wherein the ligand is a monodentate phosphine or a bidentate phosphine.

21. The process according to any one of claims 18 to 20, wherein the acid is a carboxylic acid or a sulfonic acid.

22. A process for preparing compound I or a salt thereof, 【Chemical 95】 Under conditions suitable for providing compound I, the compound of formula VI or a salt thereof 【Chemistry 96】 Compounds of formula V or salts thereof 【Chemistry 97】 This includes making contact with However, the above conditions do not include microwave radiation in the process [in the formula, X is a halo, R ２ is hydrogen or -B (OR ３ ) ２ And, Each R ３ These are independently hydrogen or C １～６ Alkyl or two R ３ It undergoes cyclization to form a cyclic boronate ester.

23. Compound I is brought into contact with citric acid to obtain the citrate of Compound I: 【Chem.98】 The process according to claim 22, further comprising providing

24. The process according to claim 22, wherein the conditions include a catalyst, a ligand, and a base.

25. The process according to claim 22, wherein the conditions include palladium(II) acetate, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), and tribasic potassium phosphate.

26. The process according to any one of claims 22 to 25, wherein the conditions include 2-methyltetrahydrofuran and water at a temperature of about 70°C to 80°C.

27. A process for preparing a compound of formula VI or a salt thereof, 【Chem.99】 A compound of formula VII or a salt thereof 【Chemistry 100】 Compounds of formula VIII: 【Chemistry 101】 Under conditions suitable for providing, contact with trifluoroacetic anhydride in the absence of an organic base, (In the equation, X is the halo.) A process comprising hydrolyzing a compound of formula VIII to provide a compound of formula VI.

28. A process for preparing a compound of formula VI or a salt thereof, 【Chemical Engineering 102】 Under conditions suitable for providing a compound of formula VI, a compound of formula VII or a salt thereof 【Chemistry 103】 A process comprising contact with a dehydrating agent (wherein X is a halo), wherein the dehydrating agent is other than trifluoroacetic anhydride.

29. The process according to claim 28, wherein the dehydrating agent is cyanuryl chloride, carboxylic acid anhydride (e.g., acetic anhydride), sulfonic acid anhydride (e.g., trifluoromethanesulfonic acid anhydride), alkyl chloroformate (e.g., ethyl chloroformate), phosphorus oxychloride, or phosphorus pentoxide.

30. The process according to claim 28 or 29, further comprising a hydrolysis step.

31. The process according to claim 27 or 30, wherein the hydrolysis comprises an inorganic base or an alkoxide base.

32. The process according to claim 28, wherein the aforementioned condition includes a base.

33. The process according to claim 32, wherein the base is an amine base.

34. A process for preparing a compound of formula IX or a salt thereof, 【Chemical 104】 Under conditions suitable for providing compound IX, the compound of formula VII or a salt thereof 【Chemistry 105】 Compounds of formula V or salts thereof 【Chemistry 106】 A process that involves contacting [In the formula, X is a halo, R ２ is hydrogen or -B (OR ３ ) ２ And, Each R ３ These are independently hydrogen or C １～６ Alkyl or two R ３ It undergoes cyclization to form a cyclic boronate ester.

35. The compound of formula V is the compound of formula VA. 【Chemistry 107】 The process according to claim 34, as represented by [the specified method].

36. The process according to any one of claims 5 to 35, wherein X is chloro.

37. A process for preparing compound I or a salt thereof, 【Chemistry 108】 Under conditions suitable for providing compound I, the compound of formula IX or a salt thereof. 【Chemistry 109】 A process that involves bringing something into contact with something else.

38. The process according to claim 37, wherein the conditions include a dehydrating agent and an optional hydrolysis step.

39. below: 【Chemical 110】 A compound or a salt thereof, selected from the following.

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