The process for making CFTR modulators

Abstract

The present disclosure provides processes for synthesizing Compound I and its pharmaceutically acceptable salts. JPEG2022544769000442.jpg4674

Description

[Technical Field]

[0001] This application claims priority from U.S. Provisional Application No. 62 / 886,660, filed August 14, 2019, which is incorporated herein by reference in its entirety.

[0002] Disclosed herein are processes for making modulators of the cystic fibrosis transmembrane conductance regulator ("CFTR"). [Background technology]

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite advances in CF treatment, there is no cure.

[0004] In patients with CF, mutations in CFTR, which is endogenously expressed in respiratory epithelia, result in reduced apical anion secretion, causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lungs and associated microbial infections, which ultimately lead to death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, can lead to death. Additionally, the majority of men with CF are infertile, and women with CF have reduced fertility.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G.R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B.S. et al. (1989) Science 245:1073-1080; Kerem, B.S. et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, more than 2,000 mutations in the CFTR gene have been identified. Currently, the CFTR2 database contains information on 412 of these identified mutations, and sufficient evidence exists to define 346 mutations as disease-causing. The most common disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the △F508 mutation. This mutation occurs in the majority of cystic fibrosis cases and is associated with severe disease.

[0006] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This prevents the mutant protein from exiting the endoplasmic reticulum (ER) and transporting to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is much lower than that observed in cells expressing wild-type CFTR, i.e., CFTR without the mutation. In addition to impaired transport, this mutation also results in abnormal channel gating. The reduced number of channels in the membrane and the abnormal gating together result in reduced anion and fluid transport across epithelia. (Quinton, PM (1990), FASEB J. 4:2709-2727). While the abnormal channels resulting from the △F508 mutation are still functional, they are less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature London. 354:526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270:12347-50). In addition to ΔF508, other disease-causing mutations in CFTR that result in abnormalities in transport, synthesis, and / or channel gating alter anion secretion and can be up- or down-regulated to modify disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells. CFTR regulates anion flux across membranes and the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is crucial for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR is composed of approximately 1,480 amino acids, encoding a protein composed of tandem repeats of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. The two transmembrane domains are connected by a large, polar regulatory (R) domain with multiple phosphorylation sites that control channel activity and cellular trafficking. Chloride transport is mediated by ENaC and CFTR, which are present at the apical membrane, and Na + -K + -ATPase pump and Cl - This occurs through the coordinated activity of the channels. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which is then transported through the Cl - It can passively exit the cell through channels, resulting in vectorial transport. + / 2Cl - / K + Cotransporter, Na + -K + -ATPase pump, and basement membrane K + The positioning of the channel and luminal CFTR coordinates luminal CFTR-mediated chloride secretion. Because water is probably never actively transported itself, its flow across epithelia depends on the small transepithelial osmotic gradient generated by the bulk flow of sodium and chloride. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Cutting, GRet al. (1990) Nature 346:366-369 [Non-patent document 2] Dean, M. et al. (1990) Cell 61:863:870 [Non-patent document 3] Kerem, BS. et al. (1989) Science 245:1073-1080, Kerem [Non-patent document 4] BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451 [Non-patent document 5] Quinton, PM (1990), FASEB J.4:2709-2727 [Non-patent document 6] Dalemans et al. (1991), Nature Lond.354:526-528 [Non-Patent Document 7] Pasyk and Foskett (1995), J.Cell.Biochem.270:12347-50 Summary of the Invention [Means for solving the problem]

[0009] (14S)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound I) [ka] (also known as (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione) has been disclosed in PCT Application No. PCT / US2019 / 018042 (incorporated herein by reference in its entirety) as a modulator of CFTR activity and, as such, is useful for the treatment of CFTR-mediated diseases, such as CF. However, there remains a need for an efficient process for the synthesis of compound I that delivers this compound or a pharmaceutically acceptable salt thereof in higher yield, with higher selectivity, or with higher purity, for example, as compared to known processes.

[0010] (14S)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound I), [ka] and processes for making pharmaceutically acceptable salts thereof are disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0011] definition As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0012] As used herein, the terms "treatment," "treating," and the like refer to an improvement in CF or its symptoms, or a reduction in the severity of CF or its symptoms, or a delay in the onset of CF or its symptoms in a subject. As used herein, "treatment" includes, but is not limited to, enhancing growth, increasing weight gain, reducing mucus in the lungs, improving pancreatic and / or liver function, reducing lung infections, and / or reducing cough or shortness of breath in a subject. Improvement or reduction in severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0013] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0014] As used herein, "mutation" can refer to a mutation in the CFTR gene or CFTR protein. A "CFTR gene mutation" refers to a mutation in the CFTR gene, and a "CFTR protein mutation" refers to a mutation in the CFTR protein. Generally, a genetic defect or mutation, or a nucleotide change in a gene, results in a mutation or frameshift(s) in the CFTR protein translated from that gene.

[0015] The term "ΔF508" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508.

[0016] As used herein, the term " modulator " refers to a compound that increases the activity of biological compounds or molecules such as proteins.For example, CFTR modulator is a compound that increases the activity of CFTR.The increased activity resulting from CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize and / or amplify CFTR.

[0017] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are randomly arranged, such that there is no clearly defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions, and do not have a definite melting point. For example, an amorphous material is a solid material that does not have sharp, characteristic crystalline peak(s) in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237.

[0018] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order in the position of its molecules. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity or less than 5% crystallinity). Note that the term "substantially amorphous" also includes the descriptor "amorphous," which refers to a material that has no (0%) crystallinity.

[0019] As used herein, the term "stable" refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0020] As used herein, the term "chemically stable" means that a solid form of Compound I does not decompose into one or more different compounds when subjected to specified conditions, such as 40°C / 75% relative humidity, for a specified period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, or more. In some embodiments, less than 25% of the solid form of Compound I is decomposed. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, or less than about 0.5% of the form of Compound I is decomposed under the specified conditions. In some embodiments, no detectable amount of the solid form of Compound I is decomposed.

[0021] As used herein, the term "physically stable" means that a solid form of Compound I does not change into one or more different physical forms of Compound I (e.g., different solid forms as measured by XRPD, DSC, etc.) when subjected to specified conditions, such as 40°C / 75% relative humidity, for a specified period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, or more. In some embodiments, less than 25% of the solid form of Compound I changes into one or more different physical forms when subjected to specified conditions. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, or less than about 0.5% of the solid form of Compound I changes into one or more different physical forms of Compound I when subjected to specified conditions. In some embodiments, a detectable amount of the solid form of Compound I does not change into one or more physically different solid forms of Compound I.

[0022] As used herein, the terms "about" and "approximately," when used in connection with amounts, volumes, reaction times, reaction temperatures, and the like, refer to an acceptable error for a particular value as determined by one of ordinary skill in the art and will depend in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

[0023] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structure except that isotopic variations may exist among the constituent atoms of the molecules.

[0024] The compounds described herein may be optionally substituted with one or more substituents, typically as indicated above or as exemplified by the specific classes, subclasses, and species of the present disclosure. The phrase "optionally substituted" is understood to be used interchangeably with the phrase "substituted or unsubstituted." Generally, the term "substituted," whether preceded by the term "optionally," indicates that at least one hydrogen atom of the "substituted" group is replaced with a substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0025] As used herein, the term "stable compound" refers to a compound that is sufficiently stable to permit its manufacture and maintains its compound integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., formulation into a therapeutic product, as an intermediate for use in the manufacture of a therapeutic compound, as an intermediate that can be isolated or stored, and / or to treat a disease or condition that responds to a therapeutic agent).

[0026] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C ring that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. 3~8 Hydrocarbon, bicyclic or tricyclic C 8~14 " refers to a hydrocarbon, where any individual ring within the bicyclic ring system has 3 to 7 members. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Suitable alicyclic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo-octyl, and bridged tricyclic such as adamantyl.

[0027] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0028] As used herein, the term "alkyl group" refers to a saturated, branched, or unbranched aliphatic hydrocarbon containing carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, etc.). An alkyl group can be substituted or unsubstituted.

[0029] As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms.

[0030] The term "halogen" or "halo" means F, Cl, Br, or I.

[0031] As used herein, "cycloalkyl group" refers to a cyclic non-aromatic hydrocarbon group containing 3 to 12 carbons in the ring (e.g., 3 to 10 carbons, etc.). Cycloalkyl groups include monocyclic, bicyclic, tricyclic, bridged, fused, and spirocyclic rings, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, spiro[2.2]pentane, and dispiro[2.0.2.1]heptane. Cycloalkyl groups can be substituted or unsubstituted.

[0032] As used herein, the term "heteroaliphatic" refers to an aliphatic group in which one or two carbon atoms are independently replaced by one or more heteroatoms, such as oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle," "heterocyclyl," "heterocycloaliphatic," and "heterocyclic" groups.

[0033] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, and a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including in the case of N-substituted pyrrolidinyl) means one or more of:

[0034] As used herein, the terms "heterocycle," "heterocyclyl," "heteroalicyclic," or "heterocyclic" refer to a non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle," "heterocyclyl," "heteroalicyclic," or "heterocyclic" group has 3 to 14 ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and each ring in the system contains 3 to 7 ring members.

[0035] The terms "haloalicyclic" and "haloalkoxy" mean an alicyclic or alkoxy, optionally substituted with one or more halo atoms. Examples of haloalicyclic include -CHF, -CHF, -CF, -CF-, and perhaloalkyl, such as -CFCF.

[0036] As used herein, the term "alkoxy group" refers to an alkyl or cycloalkyl group covalently linked to an oxygen atom. Alkoxy groups can be substituted or unsubstituted, and branched or unbranched substituted.

[0037] The term "aryl," used alone or as part of a larger moiety, such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" also refers to heteroaryl ring systems, as defined herein below.

[0038] The term "heteroaryl," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroarylalkoxy," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members.

[0039] An aryl (including aralkyl, aralkoxy, aryloxyalkyl, etc.) or heteroaryl (including heteroaralkyl and heteroarylalkoxy, etc.) group may be optionally substituted with one or more substituents.

[0040] As used herein, the term "protecting group" refers to any chemical group introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction.

[0041] Methods for adding (a process commonly referred to as "protecting") and removing (a process commonly referred to as "deprotecting") protecting groups are well known in the art and are described, for example, in PJ Kocienski, Protecting Groups, 3 rd edition (Thieme, 2005), and Greene and Wuts, Protective Groups in Organic Synthesis, 4th edition (John Wiley & Sons, New York, 2007), both of which are incorporated herein by reference in their entireties.

[0042] Non-limiting examples of useful protecting groups for amines that can be used in the present disclosure include monovalent protecting groups such as t-butyloxycarbonyl (Boc), benzyl (Bn), β-methoxyethoxytrityl (MEM), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts), and divalent protecting groups such as benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, and 1,3,5-dioxazines.

[0043] Non-limiting examples of useful protecting groups for alcohols that can be used in the present disclosure include, for example, acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS).

[0044] Non-limiting examples of useful protecting groups for carboxylic acids that can be used in the present disclosure include, for example, methyl or ethyl esters, substituted alkyl esters such as 9-fluorenylmethyl, methoxymethyl (MOM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl, β-methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), benzyloxymethyl (BOM), pivaloyloxymethyl (POM), phenylacetoxymethyl, and These include cyanomethyl, acetyl (Ac), phenacyl, substituted phenacyl esters, 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, t-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, cyclopentyl, cyclohexyl, allyl, methallyl, cinnamyl, phenyl (Ph), silyl esters, benzyl, and substituted benzyl, 2,6-dialkylphenyl, and pentafluorophenyl (PFP).

[0045] Non-limiting examples of suitable solvents that can be used in the present disclosure include, for example, water (HO), methanol (MeOH), methylene chloride or dichloromethane (DCM; CHCl), acetonitrile (MeCN; CHCN), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0046] Non-limiting examples of amine bases that can be used in the present disclosure include, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropylethylamine (i-PrEtN; DIPEA), pyridine, 2,2,6,6-tetramethylpiperidine, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and potassium bis(trimethylsilyl)amide (KHMDS). In some embodiments, the amine base is IPA.

[0047] Non-limiting examples of carbonate bases that can be used in the present disclosure include, for example, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), lithium carbonate (Li2CO3), sodium bicarbonate (NaHCO3), and potassium bicarbonate (KHCO3).

[0048] Non-limiting examples of alkoxide bases that can be used in the present disclosure include, for example, t-AmOLi (lithium t-amylate), t-AmONa (sodium t-amylate), t-AmOK (potassium t-amylate), sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and sodium methoxide (NaOMe; NaOCH). In some embodiments, the alkoxide base is in THF. In some embodiments, the alkoxide base is in 2-MeTHF. In some embodiments, the alkoxide base is in IPA.

[0049] Non-limiting examples of hydroxide bases that can be used in the present disclosure include, for example, sodium hydroxide (NaOH), potassium hydroxide (KOH), and lithium hydroxide (LiOH). In some embodiments, the hydroxide base is in THF. In some embodiments, the hydroxide base is in 2-MeTHF. In some embodiments, the hydroxide base is in IPA.

[0050] Non-limiting examples of phosphate groups that can be used in the present disclosure include, for example, tribasic sodium phosphate (NaPO), tribasic potassium phosphate (KPO), dibasic potassium phosphate (KHPO), and monobasic potassium phosphate (KHPO).

[0051] Non-limiting examples of suitable sulfonate esters -OSO2R that can be used in the present disclosure include, for example, methanesulfonyl (R=Me), p-toluenesulfonyl (R=4-MeC6H4-), and 4-nitrobenzylsulfonyl (R=4-NO2C6H4-).

[0052] Unless otherwise specified, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds of the present disclosure are within the scope of the present disclosure.

[0053] Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0054] "Stereoisomer" refers to both enantiomers and diastereomers.

[0055] "Tert" and "t-" are used interchangeably and refer to the tertiary level.

[0056] The present disclosure also provides processes for preparing salts of the compounds of the present disclosure.

[0057] A salt of a compound of the present disclosure is formed between an acidic group of the compound and a basic group, such as an amino functional group, or between a basic group of the compound and an acidic group, such as a carboxyl functional group. In some embodiments, the salt is a pharmaceutically acceptable salt.

[0058] As used herein, the term "pharmaceutically acceptable" refers to a material that is suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0059] "Pharmaceutically acceptable salt" refers to any non-toxic salt that can directly or indirectly provide the compound of the present disclosure upon administration to a recipient. A "pharmaceutically acceptable counterion" is an ionic portion of the salt that is non-toxic when released from the salt upon administration to a recipient. Those skilled in the art will recognize that when the amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. It should be noted that the disclosed amounts of compounds or their pharmaceutically acceptable salts herein are based on their free base form. For example, "at least one compound selected from 10 mg of Compound I and a pharmaceutically acceptable salt thereof" includes 10 mg of Compound I and a concentration of a pharmaceutically acceptable salt of Compound I equivalent to 10 mg of Compound I.

[0060] Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharm. Sci., 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts: [Table 1]

[0061] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids; salts formed with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids; and salts formed using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and the like. Non-limiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4Examples of suitable pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0062] In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition.

[0063] As used herein, the term "derivative" refers to a collection of molecules that have the same chemical structure as the disclosed compounds, except that one or more atoms of the molecule may be replaced with another atom.In addition, unless otherwise specified, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having the structures of the present invention, except for the replacement of a carbon by C, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with improved therapeutic profiles.

[0064] In some embodiments, derivative is silicon derivative, and at least one carbon atom in the disclosed compound is replaced by silicon.In some embodiments, at least one carbon atom that is replaced by silicon can be non-aromatic carbon.In some embodiments, at least one carbon atom that is replaced by silicon can be aromatic carbon.In certain embodiments, the silicon derivative of the present invention can also have one or more hydrogen atoms that are replaced by deuterium and / or germanium.

[0065] In other embodiments, the derivative is a germanium derivative, in which at least one carbon atom in the disclosed compound is replaced by germanium. In certain embodiments, the germanium derivative of the present invention can also have one or more hydrogen atoms replaced by deuterium and / or silicon.

[0066] Because the general properties of silicon and germanium are similar to those of carbon, the replacement of carbon with silicon or germanium can result in compounds with similar biological activity as the original carbon-containing compound.

[0067] The present disclosure provides compound I, [ka] or a pharmaceutically acceptable salt thereof, comprising a compound of formula (I): [ka] or a salt thereof to Compound I or a pharmaceutically acceptable salt thereof, During the ceremony, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10selected from aryl optionally substituted with haloalkyl, halo, or nitro; X c is selected from F, Cl, Br, and I.

[0068] In some embodiments, X a is Br and X c is F.

[0069] In some embodiments, the conversion of a compound of formula (I) or a salt thereof to compound I or a pharmaceutically acceptable salt thereof is 1) combining a compound of formula (I) or a salt thereof with at least one first base to form a compound of formula (II): [ka] or a salt thereof; 2) A compound of formula (II) or a salt thereof is reacted with Compound 1, [ka] or a salt thereof, and at least one second base to form compound I or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) or a salt thereof is X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 It is selected from aryl optionally substituted with haloalkyl, halo, or nitro.

[0070] In some embodiments, in the compound of formula (II) or salt thereof, X a is Br.

[0071] In some embodiments, the at least one first base is selected from a carbonate base, a hydroxide base, an alkoxide base, an acetate base, an amine base, a phosphate base, and a sulfate base. In some embodiments, the at least one first base is selected from sodium carbonate (Na2CO3), potassium carbonate (K2CO3), 2,2,6,6-tetramethylpiperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, potassium bicarbonate (KHCO3), and tribasic potassium phosphate (K3PO4).

[0072] In some embodiments, the combination of the compound of Formula (II) or a salt thereof and Compound 1 or a salt thereof comprises at least one metal catalyst. In some embodiments, the at least one metal catalyst is selected from a palladium catalyst and a copper catalyst.

[0073] In some embodiments, the palladium catalyst is [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) / 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd2dba3 / N-phenyl-2-(di-tert-butylphosphino)pyrrole, Pd2dba3 / 2-di-tert-butylphosphino-2′ -methylbiphenyl, Pd2dba3 / 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, Pd2dba3 / 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole, Pd2dba3 / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Pd2dba3 / 2-(dicyclohexylphosphino)3,6-di Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl (Pd2dba3 / BrettPhos), Pd2dba3 / di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine, Pd2dba3 / 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane, dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-yl] dene](3-chloropyridyl)palladium(II), Pd2dba3 / 1,1′-bis(diphenylphosphino)ferrocene, dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), dichloro[2,2′-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) (Pd(BINAP)Cl2), Pd2dba3 / bis[(2-diphenylphosphino)phenyl]ether (Pd2dba3 / DPEPhos), Pd2dba3 / 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Pd2dba3 / 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, Pd2dba3 / 2-dicyclohexylphosphino-2'-(N,N-di methylamino)biphenyl, Pd2dba3 / 1,1′-bis(di-tert-butylphosphino)ferrocene, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl / Pd2dba3 (tert-butylXPhos / Pd2dba3), [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride (tBuXPhos-Pd-G1), allyl(2-di-tert-butyl Phosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos-Pd-G3), 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl / Pd2db a3 (t-BuBrettPhos / Pd2dba3), trifluoromethanesulfonate allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate / Pd2dba3 (SPhos / Pd2dba3), [1,[1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (PEPSIIpent), di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine / Pddba3 (cBRIDP / Pddba3), and 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane / Pddba3 (Cy-cBRIDP / Pddba3). The active catalyst, palladium(0) 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos), can be generated using a palladium(II) tBuXPhos precatalyst (G1-G3), or a palladium(0) source, such as Pd(dba) or Pd(PPh) in combination with di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos), and finally, by using a palladium(II) source, such as Pd(OAc) or Pd(Cl), in the presence of a reducing agent and di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos).

[0074] In some embodiments, the copper catalyst is selected from copper(II) fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper(I) thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluene complex; N,N′-dimethylethylenediamine, N,N′-dimethylcyclohexane-1,2-diamine, 1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine, cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid, Optionally substituted with ligands such as 2,2'-bipyridine, 2-acetylcyclohexanone, 1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane, 2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol, (1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime, glycolic acid, L-proline, 2,2'-dipyridyl, and N-cyclohexyl-2,6-bis(1-methylethyl)benzenamine. In some embodiments, the copper catalyst is N,N-diisopropyl-1,3-propanediamine. [ka] trans-1,2-diaminocyclohexane [ka] N,N'-Dimethyl-1,3-propanediamine [ka] N,N'-Diethylethane-1,2-diamine [ka] 3-(Dimethylamino)-propylamine [ka] 1,4-Diaminocyclohexane [ka] N,N'-dimethylethane-1,2-diamine [ka] Diethylenetriamine [ka] and trans-N,N-dimethylcyclohexane-1,2-diamine [ka] is optionally substituted with a ligand selected from

[0075] In some embodiments, the at least one metal catalyst is [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0) (Pd2dba3), copper iodide (CuI), or a combination thereof.

[0076] In some embodiments, step 2) further comprises an excess of 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3). In some embodiments, the at least one second base is a carbonate base, such as potassium carbonate (K2CO3) or cesium carbonate (Cs2CO3).

[0077] In some embodiments, the conversion of a compound of Formula (I) or a salt thereof to compound I or a pharmaceutically acceptable salt thereof is achieved by reacting a compound of Formula (I) or a salt thereof with compound 1, [ka] or a salt thereof, and at least one third base to produce Compound I or a pharmaceutically acceptable salt thereof; In the compound of formula (I) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X c is selected from F, Cl, Br, and I.

[0078] In some embodiments, in the compound of formula (I) or salt thereof, X a is Br and X c is F.

[0079] In some embodiments, the at least one third base is selected from a carbonate base, a hydroxide base, an alkoxide base, an acetate base, an amine base, a phosphate base, and a sulfate base. In some embodiments, the at least one third base is selected from sodium carbonate (Na2CO3), potassium carbonate (K2CO3), 2,2,6,6-tetramethylpiperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, potassium bicarbonate (KHCO3), and potassium phosphate (K3PO4).

[0080] In some embodiments, the combination of the compound of Formula (II) or a salt thereof and Compound 1 or a salt thereof further comprises at least one metal catalyst. In some embodiments, the at least one metal catalyst is selected from a palladium catalyst and a copper catalyst.

[0081] In some embodiments, the palladium catalyst is [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) / 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd2dba3 / N-phenyl-2-(di-tert-butylphosphino)pyrrole, Pd2dba3 / 2-di-tert-butylphosphino-2′ -methylbiphenyl, Pd2dba3 / 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, Pd2dba3 / 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole, Pd2dba3 / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Pd2dba3 / 2-(dicyclohexylphosphino)3,6-di Methoxy-2',4',6'-triisopropyl-1,1'-biphenyl (Pd2dba3 / BrettPhos), Pd2dba3 / di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine, Pd2dba3 / 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane, dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-yl] dene](3-chloropyridyl)palladium(II), Pd2dba3 / 1,1′-bis(diphenylphosphino)ferrocene, dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), dichloro[2,2′-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) (Pd(BINAP)Cl2), Pd2dba3 / bis[(2-diphenylphosphino)phenyl]ether (Pd2dba3 / DPEPhos), Pd2dba3 / 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Pd2dba3 / 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, Pd2dba3 / 2-dicyclohexylphosphino-2'-(N,N-di methylamino)biphenyl, Pd2dba3 / 1,1′-bis(di-tert-butylphosphino)ferrocene, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl / Pd2dba3 (tert-butylXPhos / Pd2dba3), [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride (tBuXPhos-Pd-G1), allyl(2-di-tert-butyl Phosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos-Pd-G3), 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl / Pd2db a3 (t-BuBrettPhos / Pd2dba3), trifluoromethanesulfonate allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate / Pd2dba3 (SPhos / Pd2dba3), [1,The active catalysts are selected from [1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (PEPSIIpent), di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine / Pd2dba3 (cBRIDP / Pd2dba3), and 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane / Pd2dba3 (Cy-cBRIDP / Pd2dba3). Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos) can be produced using a palladium(II) tBuXPhos precatalyst (G1-G3), or a palladium(0) source, such as Pd(dba) or Pd(PPh) in combination with di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos), and finally, by using a palladium(II) source, such as Pd(OAc) or Pd(Cl) in the presence of a reducing agent and di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos).

[0082] In some embodiments, the copper catalyst is selected from copper(II) fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper(I) thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluene complex; N,N′-dimethylethylenediamine, N,N′-dimethylcyclohexane-1,2-diamine, 1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine, cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid, Optionally substituted with ligands such as 2,2′-bipyridine, 2-acetylcyclohexanone, 1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane, 2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol, (1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime, glycolic acid, L-proline, 2,2′-dipyridyl, and N-cyclohexyl-2,6-bis(1-methylethyl)benzenamine. In some embodiments, the copper catalyst is optionally substituted with a ligand selected from N,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane, N,N′-dimethyl-1,3-propanediamine, N,N′-diethylethane-1,2-diamine, 3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane, N,N′-dimethylethane-1,2-diamine, diethylenetriamine, and trans-N,N-dimethylcyclohexane-1,2-diamine.

[0083] In some embodiments, the at least one metal catalyst is [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0) (Pd2dba3), copper iodide (CuI), or a combination thereof.

[0084] In some embodiments, the compound of formula (I): [ka] or a salt thereof, a compound of formula (III): [ka] or a salt thereof, is prepared by converting a compound of formula (I) or a salt thereof, In the compound of formula (III) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X c is selected from F, Cl, Br, and I; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group.

[0085] In some embodiments, each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 1 and R 2together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetrachlorophthalimide, N-tri ... Form a nitrogen protecting group selected from trimethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0086] In some embodiments, in the compound of formula (III) or salt thereof, X a is Br and X c is F and R 1 and R 2 together with the atom to which they are attached form N-phthalimide.

[0087] In some embodiments, the conversion of a compound of formula (III) or a salt thereof to a compound of formula (I) or a salt thereof is 1) combining a compound of formula (III) or a salt thereof in the presence of water and a base selected from lithium hydroxide (LiOH), hydrazine, ethanolamine, and N-methylamine; 2) optionally combining the product of step 1) with an acid selected from oxalic acid, hydrochloric acid (HCl), phosphoric acid (H3PO4), and citric acid, and then treating the reaction mixture with water and a base selected from potassium carbonate (K2CO3) and cesium carbonate (Cs2CO3) to produce a compound of formula (I) or a salt thereof.

[0088] In some embodiments, a compound of formula (III): [ka] or a salt thereof, a compound of formula (IV): [ka] or a salt thereof, with a compound of formula (V): [ka] or a salt thereof to form a compound of formula (III) or a salt thereof, During the ceremony, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X b But Cl, F, -OC6F5, [ka] is selected from X c is selected from F, Cl, Br, and I; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group.

[0089] In some embodiments, R 1 and R 2together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetrachlorophthalimide, N-tri ... Form a nitrogen protecting group selected from trimethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0090] In some embodiments, in the compound of formula (IV) or salt thereof, X a is Br and R 1 and R 2 together with the atom to which they are attached form an N-phthalimide. In some embodiments, in the compound of formula (IV) or a salt thereof, X a is Br and R 1 is hydrogen and R 2 is benzyloxycarbonyl (Cbz).

[0091] In some embodiments, in the compound of formula (V) or salt thereof, X b is -OC6F5, and X c is F. In some embodiments, the amide of the compound of Formula (IV) or salt thereof is protected with a nitrogen protecting group.

[0092] In some embodiments, the combination of the compound of Formula (IV) or a salt thereof with the compound of Formula (V) or a salt thereof is carried out in the presence of at least one fourth base. In some embodiments, the at least one fourth base is an alkoxy base. In some embodiments, the alkoxy base is selected from lithium t-amylate (t-AmOLi), sodium t-amylate (t-AmONa), potassium t-amylate (t-AmOK), and lithium t-butoxide (LiOt-Bu).

[0093] In some embodiments, a compound of formula (IV): [ka] or a salt thereof, a compound of formula (VI): [ka] or a salt thereof, into a compound of formula (IV) or a salt thereof, In the compound of formula (VI) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 It is selected from aryl optionally substituted with haloalkyl, halo, or nitro.

[0094] In some embodiments, the amide of the compound of Formula (IV) or salt thereof is protected with a nitrogen protecting group.

[0095] In some embodiments, in the compound of formula (VI) or salt thereof, X a is Br.

[0096] In some embodiments, the conversion of a compound of formula (VI) or a salt thereof to a compound of formula (IV) or a salt thereof is 1) converting the hydroxy group of a compound of formula (VI) or a salt thereof to a sulfonate ester (—OSOR) or Cl; 2) combining the sulfonate ester or Cl of step 1) with an amine and at least one fifth base to produce a compound of formula (IV) or a salt thereof.

[0097] In some embodiments, the R group of the sulfonate ester (—OSOR) is —C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 In some embodiments, the conversion of the hydroxy group to a sulfonate ester in step 1) is carried out in the presence of methanesulfonyl chloride (MsCl) and triethylamine (TEA). In some embodiments, the amine in step 2) is N-phthalimide, and the at least one fifth base in step 2) is a carbonate base, such as potassium carbonate (KCO) or cesium carbonate (CsCO).

[0098] In some embodiments, a compound of formula (VI): [ka] or a salt thereof, [ka] or a salt thereof, by reacting a compound of formula (VII): [ka] or a salt thereof to form a compound of formula (VI) or a salt thereof, In the compound of formula (VII) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X d is selected from F, Cl, Br, and I.

[0099] In some embodiments, in the compound of formula (VII) or salt thereof, X a is Br and X d is F.

[0100] In some embodiments, combining Compound 2, or a salt thereof, with the compound of Formula (VII), or a salt thereof, is carried out in the presence of at least one sixth base. In some embodiments, the at least one sixth base is selected from potassium t-butoxide (KOt-Bu), lithium hydroxide (LiOH), tribasic potassium phosphate (KPO), dibasic potassium phosphate (KHPO), cesium carbonate (CsCO), 2,2,6,6-tetramethylpiperidine, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (TEA), tributylamine (BuN), sodium bicarbonate (NaHCO), potassium bicarbonate (KHCO), sodium carbonate (NaCO), and potassium carbonate (KCO). In some embodiments, the combination of compound 2, or a salt thereof, with the compound of formula (VII), or a salt thereof, is carried out in the presence of potassium carbonate (K2CO3) in an aqueous solution of the substrate in 2-MeTHF.

[0101] In some embodiments, Compound 2, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting Compound 2 or a salt thereof into Compound 2.

[0102] In some embodiments, the conversion of compound 3 or a salt thereof to compound 2 or a salt thereof is carried out in the presence of a reducing agent, in some embodiments, the reducing agent is selected from lithium aluminum hydride (LiAlH), sodium bis(2-methoxyethoxy)aluminum hydride, borane (BH), and borane-tetrahydrofuran (BH-THF).

[0103] In some embodiments, compound 3, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 3 or a salt thereof into compound 3.

[0104] In some embodiments, the conversion of compound 4, or a salt thereof, to compound 3, or a salt thereof, is carried out in the presence of reduction reaction conditions. In some embodiments, the reduction reaction conditions include hydrogen gas (H) and at least one metal catalyst selected from Raney nickel (Ra-Ni), palladium on carbon (Pd / C), palladium on alumina (Pd / AlO), palladium(II) chloride (PdCl), platinum oxide (PtO), palladium on platinum on carbon (Pd / Pt / C), platinum on carbon (Pt / C), and nickel(II) chloride / sodium borohydride (NiCl / NaBH).

[0105] In some embodiments, compound 4, [ka] or a salt thereof, compound (±)-4, [ka] or by chiral resolution of a salt thereof.

[0106] In some embodiments, chiral resolution of compound (±)-4 or a salt thereof is carried out using a method selected from chiral column chromatography, chiral simulated moving bed (SMB), biological resolution, enzymatic resolution, liquid chromatography, salt decomposition, and asymmetric hydrogenation.

[0107] The present disclosure provides compound I, [ka] or a pharmaceutically acceptable salt thereof, comprising a compound of formula (VIII): [ka] or a salt thereof to Compound I or a pharmaceutically acceptable salt thereof, In the compound of formula (VIII) or a salt thereof, X c is selected from F, Cl, Br, and I.

[0108] In some embodiments, the conversion of the compound of Formula (VIII) or its salt to Compound I or a pharmaceutical salt thereof is carried out in the presence of at least one seventh base. In some embodiments, the at least one seventh base is selected from potassium carbonate (KCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,1,3,3-tetramethylguanidine, potassium hydroxide (KOH), potassium hydroxide / Triton B (KOH / Triton B), potassium hydroxide / tetra-n-butylammonium iodide (KOH / nBuNHI), potassium hydroxide / tetra-n-octylammonium bromide (KOH / n-OctNHBr), lithium hydroxide (LiOH), and lithium carbonate (LiCO). In some embodiments, the conversion of the compound of Formula (VIII) or a salt thereof to Compound I or a pharmaceutical salt thereof further comprises magnesium chloride (MgCl 2 ).

[0109] In some embodiments, a compound of formula (VIII): [ka] or a salt thereof, a compound of formula (IX): [ka] or a salt thereof to a compound of formula (VIII) or a salt thereof, In the compound of formula (IX) or a salt thereof, X c is selected from F, Cl, Br, and I; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2together with the atom to which they are attached form a nitrogen protecting group.

[0110] In some embodiments, each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetrachlorophthalimide, N-tri ... Form a nitrogen protecting group selected from trimethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0111] In some embodiments, in the compound of formula (IX) or salt thereof, X c is F and R 1 is hydrogen and R 2 is benzyloxycarbonyl (Cbz).

[0112] In some embodiments, the conversion of a compound of Formula (IX) or a salt thereof to a compound of Formula (VIII) or a salt thereof is carried out in the presence of reduction reaction conditions. In some embodiments, the reduction reaction conditions are selected from hydrogen gas (H) and palladium on carbon (Pd / C), HCOH / EtN / Pd(C), NHHCO / KCO and palladium on carbon, KHPO and Pd / C, KPO and Pd / C, NHNH / Pd(C), and 1,4-cyclohexadiene / Pd(C).

[0113] In some embodiments, a compound of formula (IX): [ka] or a salt thereof, a compound of formula (X): [ka] or a salt thereof, with a compound of formula (V): [ka] or a salt thereof to form a compound of formula (IX) or a salt thereof, In the compound of formula (X) or a salt thereof, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group, In the compound of formula (V) or a salt thereof, X b But Cl, F, -OC6F5, [ka] is selected from X cis selected from F, Cl, Br, and I.

[0114] In some embodiments of the compound of Formula (V) or salt thereof, X b teeth, [ka] and salt is - It is an OTf salt.

[0115] In some embodiments, each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetrachlorophthalimide, N-tri ... Form a nitrogen protecting group selected from trimethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0116] In some embodiments, in the compound of formula (X) or salt thereof, R 1 is hydrogen and R2 is Cbz or R 1 and R 2 together with the atom to which they are attached form N-phthalimide.

[0117] In some embodiments, in the compound of formula (V) or salt thereof, X b teeth, -OC6F5, X c is F.

[0118] In some embodiments, the combination of the compound of Formula (X) or salt thereof with the compound of Formula (V) or salt thereof is carried out in the presence of at least one eighth base. In some embodiments, the at least one eighth base is an alkoxy base. In some embodiments, the alkoxy base is selected from lithium t-amylate (t-AmOLi), sodium t-amylate (t-AmONa), potassium t-amylate (t-AmOK), and lithium t-butoxide (LiOt-Bu).

[0119] In some embodiments, a compound of formula (X): [ka] or a salt thereof, a compound of formula (IV): [ka] or a salt thereof, [ka] or a salt thereof to form a compound of formula (X) or a salt thereof: In the compound of formula (IV) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group.

[0120] In some embodiments, each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetrachlorophthalimide, N-tri ... Form a nitrogen protecting group selected from trimethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0121] In some embodiments, in the compound of formula (IV) or salt thereof, X a is Br and R 1 and R 2 together with the atom to which they are attached form an N-phthalimide. In some embodiments, in the compound of formula (IV) or a salt thereof, X a is Br and R 1 is hydrogen and R 2 is benzyloxycarbonyl (Cbz).

[0122] In some embodiments, the amide of the compound of Formula (IV) or salt thereof is protected with a nitrogen protecting group.

[0123] In some embodiments, the combination of the compound of Formula (IV) or salt thereof with Compound 1 or salt thereof is carried out in the presence of at least one ninth base. In some embodiments, the at least one ninth base is selected from a carbonate base, a hydroxide base, an alkoxide base, an acetate base, an amine base, a phosphate base, and a sulfate base. In some embodiments, the at least one ninth base is selected from sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), lithium carbonate (Li2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium tert-butoxide (NaOt-Bu), potassium tert-butoxide (KOt-Bu), pyridine, 2,2,6,6-tetramethylpiperidine, 1,8-diazabicyclo[5.4.0]undecanoate ... In some embodiments, the at least one ninth base is selected from dec-7-ene (DBU), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, N,N-diisopropylethylamine (DIPEA), potassium bis(trimethylsilyl)amide (KHMDS), pyridine, sodium bicarbonate (NaHCO), potassium bicarbonate (KHCO), tribasic sodium phosphate (NaPO), and tribasic potassium phosphate (KPO). In some embodiments, the at least one ninth base is in THF. In some embodiments, the at least one ninth base is in 2-MeTHF. In some embodiments, the at least one ninth base is in IPA.

[0124] In some embodiments, the combination of the compound of Formula (II) or a salt thereof and Compound 1 or a salt thereof further comprises at least one metal catalyst. In some embodiments, the at least one metal catalyst is selected from a palladium catalyst and a copper catalyst. In some embodiments, the palladium catalyst is [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) / 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd2dba3 / N-phenyl-2-(di-tert-butylphosphino)pyrrole, Pd2dba3 / 2-di-tert-butyl Phosphino-2'-methylbiphenyl, Pd2dba3 / 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, Pd2dba3 / 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole, Pd2dba3 / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Pd2dba3 / 2-(dicyclohexylphosphino) Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (Pd2dba3 / BrettPhos), Pd2dba3 / di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine, Pd2dba3 / 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane, dichloro[1,3-bis(2, 6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II), Pd2dba3 / 1,1′-bis(diphenylphosphino)ferrocene, dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II) (Pd(BINAP)Cl2), Pd2dba3 / bis[(2-diphenylphosphino)phenyl]ether (Pd2dba3 / DPEPhos), Pd2dba3 / 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene, Pd2dba3 / 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl Pd2dba3 / 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, Pd2dba3 / 1,1'-bis(di-tert-butylphosphino)ferrocene, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl / Pd2dba3 (tert-butylXPhos / Pd2dba3), [2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]paradiphenyl Allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) chloride (tBuXPhos-Pd-G1), allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos-Pd-G3), 2-(di-tert-butylphosphino phosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl / Pd2dba3 (t-BuBrettPhos / Pd2dba3), trifluoromethanesulfonate allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate / Pd2dba3 (SPhos / Pd2dba3), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), [1,1′-b(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2), dichloro[1,3-bis(2,6-di-3-pentyl [phenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (PEPSIIpent), di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine / Pd2dba3 (cBRIDP / Pd2dba3), and 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane / Pd2dba3 (Cy-cBRIDP / Pd2db The active catalyst, palladium(0) 2-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos), can be generated using a palladium(II) tBuXPhos precatalyst (G1-G3), or a palladium(0) source, such as Pd2(dba)3 or Pd(PPh3)4, in combination with di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos), and finally, by using a palladium(II) source, such as Pd(OAc)2 or Pd(Cl)2, in the presence of a reducing agent and di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos).

[0125] In some embodiments, the copper catalyst is selected from copper(II) fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper(I) thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluene complex; N,N′-dimethylethylenediamine, N,N′-dimethylcyclohexane-1,2-diamine, 1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine, cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid, Optionally substituted with ligands such as 2,2′-bipyridine, 2-acetylcyclohexanone, 1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane, 2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol, (1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime, glycolic acid, L-proline, 2,2′-dipyridyl, and N-cyclohexyl-2,6-bis(1-methylethyl)benzenamine. In some embodiments, the copper catalyst is optionally substituted with a ligand selected from N,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane, N,N′-dimethyl-1,3-propanediamine, N,N′-diethylethane-1,2-diamine, 3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane, N,N′-dimethylethane-1,2-diamine, diethylenetriamine, and trans-N,N-dimethylcyclohexane-1,2-diamine.

[0126] In some embodiments, the at least one metal catalyst is [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0) (Pd2dba3), copper iodide (CuI), or a combination thereof. In some embodiments, combining the compound of Formula (IV) or a salt thereof with Compound 1 or a salt thereof further comprises copper iodide (CuI).

[0127] In some embodiments, the combination of the compound of Formula (IV) or a salt thereof and Compound 1 or a salt thereof further comprises dicyclohexylamine (DMCHDA). In some embodiments, the at least one ninth base is potassium carbonate (KCO).

[0128] In some embodiments, a compound of formula (IV): [ka] or a salt thereof, a compound of formula (XI): [ka] or a salt thereof, by reacting a compound of formula (VII): [ka] or a salt thereof to form a compound of formula (IV) or a salt thereof, In the compound of formula (XI) or a salt thereof, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group, In the compound of formula (VII) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X d is selected from F, Cl, Br, and I.

[0129] In some embodiments, each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetrachlorophthalimide, N-tri ... Form a nitrogen protecting group selected from trimethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0130] In some embodiments, in the compound of formula (XI) or salt thereof, R 1 is hydrogen and R 2 is benzyloxycarbonyl (Cbz). In some embodiments, in the compound of formula (XI) or a salt thereof, R 1 and R 2 together with the atom to which they are attached form N-phthalimide.

[0131] In some embodiments, in the compound of formula (VII) or salt thereof, X a is Br and X d is F.

[0132] In some embodiments, the amide of the compound of Formula (IV) or salt thereof is protected with a nitrogen protecting group.

[0133] In some embodiments, the combination of a compound of Formula (XI) or a salt thereof with a compound of Formula (VII) or a salt thereof is carried out in the presence of at least one tenth base. In some embodiments, the at least one tenth base is selected from an amine base, a carbonate base, a hydroxide base, and a phosphate base. In some embodiments, the at least one tenth base is potassium carbonate (K2CO3). In some embodiments, the combination of a compound of Formula (XI) or a salt thereof with a compound of Formula (VII) or a salt thereof further comprises zinc chloride (ZnCl2), magnesium chloride (MgCl2), aluminum oxide (Al2O3), cesium fluoride (CsF), indium(III) triflate (In(OTf)3), or indium(III) chloride (InCl3). In some embodiments, the combination of a compound of Formula (XI) or a salt thereof with a compound of Formula (VII) or a salt thereof further comprises zinc chloride (ZnCl2).

[0134] In some embodiments, a compound of formula (XI): [ka] or a salt thereof, a compound of formula (XII): [ka] or a salt thereof into a compound of formula (XI) or a salt thereof, In the compound of formula (XII) or a salt thereof, R 3 is a monovalent nitrogen protecting group. In some embodiments, each monovalent nitrogen protecting group is selected from t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and N-phthalimide. In some embodiments, in the compound of formula (XII) or a salt thereof, R 3 is t-butyloxycarbonyl (Boc).

[0135] In some embodiments, the conversion of a compound of formula (XII) or a salt thereof to a compound of formula (XI) or a salt thereof is 1) The primary amine of the compound of formula (XII) or a salt thereof is reacted with a protected amine -NR 1 R 2 and converting 2)R 3 to produce a compound of formula (XI) or a salt thereof.

[0136] In some embodiments, the conversion in step 1) is carried out in the presence of benzyl chloroformate (Cbz-Cl) and potassium carbonate (KOH). 3 is deprotected with hydrochloric acid (HCl), methanesulfonic acid (MsOH), or trifluoroacetic acid.

[0137] In some embodiments, a compound of formula (XII): [ka] or a salt thereof, a compound of formula (XV): [ka] or a salt thereof, to a compound of formula (XII) or a salt thereof, In the compound of formula (XV) or a salt thereof, R 3 is a monovalent nitrogen protecting group. In some embodiments, each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, in a compound of formula (XV) or a salt thereof, R 3 is t-butyloxycarbonyl (Boc).

[0138] In some embodiments, the conversion of a compound of formula (XV), or a salt thereof, to a compound of formula (XII), or a salt thereof, is 1) a compound of formula (XV), [ka] or a salt thereof, by reacting a compound of formula (XIV): [ka] or a salt thereof; 2) A compound of formula (XIV) or a salt thereof is reacted with a compound of formula (XIII): [ka] or a salt thereof; 3) converting the compound of formula (XIII) or a salt thereof into a compound of formula (XII) or a salt thereof, In the compounds of formulae (XIII) to (XV) or salts thereof, R 3 is a monovalent nitrogen protecting group, In the compound of formula (XIV) or a salt thereof, R 4 is -SO2R, R is -C1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 It is selected from aryl optionally substituted with haloalkyl, halo, or nitro.

[0139] In some embodiments, each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). In some embodiments, in a compound of Formula (XIII)-(XV) or a salt thereof, R 3 is t-butyloxycarbonyl (Boc). In some embodiments, in the compound of formula (XIV) or a salt thereof, R 4 is 4-nitrobenzylsulfonyl (Ns).

[0140] In some embodiments, step 1) of the conversion of a compound of Formula (XV) or a salt thereof to a compound of Formula (XII) or a salt thereof is performed in the presence of 4-nitrobenzylsulfonyl chloride (NsCl) and at least one eleventh base. In some embodiments, the at least one eleventh base is an amine base or a carbonate base. In some embodiments, the at least one eleventh base is triethylamine (EtN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or N,N-diisopropylethylamine ((iPr)NEt). In some embodiments, step 2) of the conversion of a compound of Formula (XV) or a salt thereof to a compound of Formula (XII) or a salt thereof is performed in the presence of an azide source. In some embodiments, the azide source is sodium azide (NaN). In some embodiments, step 3) of converting a compound of Formula (XV) or a salt thereof to a compound of Formula (XII) or a salt thereof is carried out in the presence of reducing reaction conditions. In some embodiments, the reducing reaction conditions include hydrogen gas (H) and platinum dioxide (PtO) or palladium on carbon (Pd / C).

[0141] In some embodiments, a compound of formula (XV): [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting a compound of formula (XV) or a salt thereof into

[0142] In some embodiments, the conversion of compound 2 or a salt thereof to a compound of formula (XV) or a salt thereof is carried out in the presence of di-tert-butyl dicarbonate (BocO). In some embodiments, the compound of formula (XV) or a salt thereof is treated with L-glutamic acid.

[0143] In some embodiments, Compound 2, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting Compound 2 or a salt thereof into Compound 2.

[0144] In some embodiments, the conversion of compound 3 or a salt thereof to compound 2 or a salt thereof is carried out in the presence of a reducing agent. In some embodiments, the reducing agent is selected from lithium aluminum hydride (LiAlH), sodium bis(2-methoxyethoxy)aluminum hydride, borane (BH), and borane-tetrahydrofuran (BH-THF). In some embodiments, the solvent is 2-methyltetrahydrofuran (2-MeTHF) or tetrahydrofuran (THF).

[0145] In some embodiments, compound 3, [ka] or a salt thereof, compound (±)-3, [ka] or by chiral resolution of a salt thereof.

[0146] In some embodiments, chiral resolution of compound (±)-3 or a salt thereof is carried out using a method selected from chiral column chromatography, chiral simulated moving bed (SMB), biological resolution, enzymatic resolution, liquid chromatography, salt decomposition, and asymmetric hydrogenation.

[0147] In some embodiments, compound (±)-3, [ka] or a salt thereof, compound (±)-4, [ka] or a salt thereof, is prepared by converting compound (±)-3 or a salt thereof.

[0148] In some embodiments, the conversion of compound (±)-4, or a salt thereof, to compound (±)-3, or a salt thereof, is carried out in the presence of reducing reaction conditions.

[0149] In some embodiments, the reduction reaction conditions include hydrogen gas (H2) and Raney nickel.

[0150] In some embodiments, compound (±)-4, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by combining (±)-4 with 2-nitropropane to produce compound (±)-4 or a salt thereof.

[0151] In some embodiments, the combination of compound 5, or a salt thereof, with 2-nitropropane is carried out in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0152] In some embodiments, compound 5, [ka] or a salt thereof is prepared by converting δ-valerolactone to compound 5 or a salt thereof.

[0153] In some embodiments, the conversion of δ-valerolactone to compound 5 or a salt thereof is 1) combining δ-valerolactone with an alkyl formate and at least one twelfth base; 2) combining the product of step 1) with paraformaldehyde.

[0154] In some embodiments, the method further includes contacting the product of step 2) with SiO to produce compound 5 or a salt thereof. In some embodiments, the alkyl formate is ethyl formate and the at least one twelfth base is sodium hydride (NaH).

[0155] In some embodiments, Compound 1, [ka] or a salt thereof, [ka] or a salt thereof to compound 1 or a salt thereof. In some embodiments, the conversion of compound 6 or a salt thereof to compound 1 or a salt thereof is carried out in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0156] In some embodiments, compound 6, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 6 or a salt thereof into compound 6.

[0157] In some embodiments, the conversion of compound 7 or a salt thereof to compound 6 or a salt thereof is carried out in the presence of at least one thirteenth base and at least one solvent. In some embodiments, the at least one thirteenth base is potassium hydroxide (KOH). In some embodiments, the at least one solvent is methanol (MeOH).

[0158] In some embodiments, compound 7, [ka] or a salt thereof, [ka] or a salt thereof, [ka] or a salt thereof to form compound 7 or a salt thereof.

[0159] In some embodiments, the combination of compound 8, or a salt thereof, with compound 9, or a salt thereof, is carried out in the presence of a phosphine and an azodicarboxylate. In some embodiments, the phosphine is triphenylphosphine (PPh). In some embodiments, the azodicarboxylate is diisopropyl azocarboxylate (DIAD). In some embodiments, the combination of compound 8, or a salt thereof, with compound 9, or a salt thereof, is carried out in the presence of a sulfonyl chloride and at least one base. In some embodiments, the sulfonyl chloride is methanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl). In some embodiments, the at least one fourteenth base is triethylamine (EtN).

[0160] In some embodiments, compound 8, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 8 or a salt thereof into compound 8 or a salt thereof.

[0161] In some embodiments, the conversion of compound 10, or a salt thereof, to compound 8, or a salt thereof, is carried out in the presence of a reducing agent. In some embodiments, the reducing agent is selected from lithium aluminum hydride (LiAlH), boron trifluoride / sodium borohydride (BF / NaBH), borane (BH), and borane complexes such as borane dimethyl sulfide (BHSMe) and borane tetrahydrofuran (BH-THF), vitride (sodium bis(2-methoxyethoxy)aluminum hydride), zinc borohydride (Zn(BH)), and diisobutylaluminum hydride (DIBAL-H).

[0162] In some embodiments, compound 10, [ka] or a salt thereof, Compound 11, [ka] or a salt thereof is prepared by converting compound 10 or a salt thereof into compound 10.

[0163] In some embodiments, the conversion of compound 11 or a salt thereof to compound 10 or a salt thereof is carried out in the presence of at least one base and at least one solvent. In some embodiments, the at least one base is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), and barium hydroxide (Ba(OH)). In some embodiments, the at least one solvent is selected from ethanol (EtOH), methanol (MeOH), ethylene glycol, diethylene glycol, and water. In alternative embodiments, the conversion of compound 11 or a salt thereof to compound 10 or a salt thereof is carried out under acidic hydrolysis conditions, such as hydrochloric acid (HCl), hydrobromic acid (HBr), sulfuric acid (HSO), phosphoric acid (HPO), and acetic acid (HOAc) in water. In alternative embodiments, the conversion of compound 11 or a salt thereof to compound 10 or a salt thereof is carried out in the presence of a nitrilase enzyme.

[0164] In some embodiments, compound 11, [ka] or a salt thereof, Compound 12, [ka] or a salt thereof is prepared by converting compound 11 or a salt thereof into compound 11.

[0165] In some embodiments, the conversion of compound 12, or a salt thereof, to compound 11, or a salt thereof, is carried out in the presence of a cyanide source. In some embodiments, the cyanide source is sodium cyanide (NaCN).

[0166] In some embodiments, compound 12, [ka] or a salt thereof, Compound 13, [ka] or a salt thereof, is prepared by converting compound 12 or a salt thereof into compound 13.

[0167] In some embodiments, the conversion of compound 13 or a salt thereof to compound 12 or a salt thereof is carried out in the presence of a phosphine, a bromine source, and at least one 16th base. In some embodiments, the phosphine is triphenylphosphine (PPh). In some embodiments, the bromine source is molecular bromine (Br). In some embodiments, the at least one 16th base is pyridine.

[0168] In some embodiments, compound 13, [ka] or a salt thereof, Compound 14, [ka] or a salt thereof, is prepared by converting compound 13 or a salt thereof into compound 13.

[0169] In some embodiments, the conversion of compound 14, or a salt thereof, to compound 13, or a salt thereof, is carried out in the presence of a reducing agent. In some embodiments, the reducing agent is selected from lithium aluminum hydride (LiAlH), boron trifluoride / sodium borohydride (BF / NaBH), borane (BH), and borane complexes such as borane dimethyl sulfide (BHSMe) and borane tetrahydrofuran (BH-THF), vitride (sodium bis(2-methoxyethoxy)aluminum hydride), zinc borohydride (Zn(BH)), and diisobutylaluminum hydride (DIBAL-H).

[0170] In some embodiments, compound 14, [ka] or a salt thereof, Compound 15, [ka] or a salt thereof is prepared by converting compound 14 or a salt thereof into compound 14.

[0171] In some embodiments, the conversion of compound 15, or a salt thereof, to compound 14, or a salt thereof, is carried out in the presence of sodium hydroxide (NaOH) in MeOH.

[0172] In some embodiments, compound 13, [ka] or a salt thereof, Compound 15, [ka] or a salt thereof, is prepared by converting compound 13 or a salt thereof into compound 13.

[0173] In some embodiments, compound 15, [ka] or a salt thereof, [ka] or a salt thereof is prepared by converting compound 15 or a salt thereof into compound 15.

[0174] In some embodiments, the conversion of compound 16, or a salt thereof, to compound 15, or a salt thereof, is carried out in the presence of ethyl 2-diazoacetate and copper triflate (Cu(OTf)). In some embodiments, the metal catalyst is rhodium(II) acetate dimer (Rh(OAc)). In some embodiments, the conversion of compound 16, or a salt thereof, to compound 15, or a salt thereof, is carried out in the presence of an enzyme.

[0175] In some embodiments, compound 16, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 16 or a salt thereof into compound 16.

[0176] In some embodiments, the conversion of compound 17, or a salt thereof, to compound 16, or a salt thereof, is carried out in the presence of at least one 17th base. In some embodiments, the at least one 17th base is potassium t-butoxide (KOt-Bu).

[0177] In some embodiments, compound 17, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 17 or a salt thereof into compound 17.

[0178] In some embodiments, the combination of compound 18, or a salt thereof, with compound 17, or a salt thereof, is carried out in the presence of a phosphine, a bromine source, and at least one 18th base. In some embodiments, the phosphine is triphenylphosphine (PPh). In some embodiments, the bromine source is molecular bromine (Br). In some embodiments, the at least one 18th base is pyridine.

[0179] In some embodiments, compound 18, [ka] or a salt thereof, Compound 19, [ka] or a salt thereof is prepared by converting compound 18 or a salt thereof into compound 18.

[0180] In some embodiments, the conversion of compound 19, or a salt thereof, to compound 18, or a salt thereof, is carried out in the presence of ethylmagnesium bromide (EtMgBr) and titanium(IV) isopropoxide (Ti(Oi-Pr)4).

[0181] In some embodiments, compound 6, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 6 or a salt thereof into compound 6.

[0182] In some embodiments, the conversion of compound 20, or a salt thereof, to compound 6, or a salt thereof, is carried out in the presence of potassium hydroxide (KOH) in methanol (MeOH).

[0183] In some embodiments, compound 20, [ka] or a salt thereof, Compound 21, [ka] or a salt thereof, is prepared by converting compound 20 or a salt thereof into compound 20.

[0184] In some embodiments, the conversion of compound 21 to compound 20 is carried out in the presence of hydrochloric acid (HCl).

[0185] In some embodiments, compound 21, [ka] or a salt thereof, compound 22 can be reacted with [ka] compound 23, [ka] or a salt thereof to form compound 21 or a salt thereof.

[0186] In some embodiments, the combination of compound 22 with compound 23, or a salt thereof, is carried out in the presence of at least one 19th base.

[0187] In some embodiments, compound 23, [ka] or a salt thereof, compound 24, [ka] or a salt thereof, is prepared by converting compound 23 or a salt thereof.

[0188] In some embodiments, the conversion of compound 24, or a salt thereof, to compound 23, or a salt thereof, is carried out in the presence of dihydropyran and p-toluenesulfonic acid (pTsOH).

[0189] In some embodiments, compound 24, [ka] or a salt thereof, compound 25, [ka] It is prepared by converting it into compound 24 or a salt thereof.

[0190] In some embodiments, the conversion of compound 25 to compound 24 or a salt thereof is carried out in the presence of hydrazine.

[0191] In some embodiments, compound 15, [ka] or a salt thereof, compound 26 can be reacted with [ka] It is prepared by converting to compound 15 or a salt thereof.

[0192] In some embodiments, the conversion of compound 26 to compound 15 or a salt thereof is carried out in the presence of cyclopropyl(diphenyl)sulfonium(tetrafluoroborate) and at least one 20th base. In some embodiments, the at least one 20th base is cesium hydroxide hydrate (Cs(OH) xHO).

[0193] In some embodiments, compound 26 is [ka] Compound 27, [ka] It is prepared by converting to compound 26.

[0194] In some embodiments, the conversion of compound 27 to compound 26 is carried out in the presence of ethyl(triphenylphosphoranylidene)acetate.

[0195] In some embodiments, compound 10, [ka] or a salt thereof, Compound 14, [ka] or a salt thereof is prepared by converting compound 10 or a salt thereof into compound 10.

[0196] In some embodiments, the conversion of compound 14, or a salt thereof, to compound 10, or a salt thereof, is carried out in the presence of thionyl chloride followed by diazomethane.

[0197] In some embodiments, compound 10, [ka] or a salt thereof, [ka] or a salt thereof is prepared by converting compound 10 or a salt thereof into compound 10.

[0198] In some embodiments, the conversion of compound 28, or a salt thereof, to compound 10, or a salt thereof, is carried out in the presence of hydrazine.

[0199] In some embodiments, compound 28, [ka] or a salt thereof, compound 16 can be reacted with [ka] It is prepared by converting to compound 28 or a salt thereof.

[0200] In some embodiments, the conversion of compound 16 to compound 28, or a salt thereof, is carried out in the presence of rhodium(II) octoate dimer and compound 28, or a salt thereof.

[0201] In some embodiments, a compound of formula (XI): [ka] or a salt thereof, [ka] or a salt thereof.

[0202] In some embodiments, compound 30 or a salt thereof is compound 31, [ka] or a salt thereof, is prepared by converting compound 30 or a salt thereof into compound 30.

[0203] In some embodiments, the conversion of compound 31 or a salt thereof to compound 30 or a salt thereof is 1) reacting compound 31 or a salt thereof in the presence of trifluoroacetic acid; 2) combining the product of step 1) with phthalic anhydride to produce compound 30 or a salt thereof.

[0204] In some embodiments, compound 31, [ka] or a salt thereof, compound 32, [ka] or a salt thereof, is prepared by converting compound 31 or a salt thereof into compound 31.

[0205] In some embodiments, the conversion of compound 32 or a salt thereof to compound 31 or a salt thereof is carried out in the presence of a hydrogen source, a metal catalyst, and at least one 21st base. In some embodiments, the hydrogen source is hydrogen gas. In some embodiments, the metal catalyst is Raney Ni. In some embodiments, the at least one 21st base is potassium carbonate (KCO).

[0206] In some embodiments, compound 32, [ka] or a salt thereof, compound 33, [ka] or a salt thereof, is prepared by converting compound 32 or a salt thereof into compound 33.

[0207] In some embodiments, the conversion of compound 33 or a salt thereof to compound 32 or a salt thereof is carried out in the presence of a sulfonyl chloride and at least one 22nd base. In some embodiments, the sulfonyl chloride is p-toluenesulfonyl chloride. In some embodiments, the at least one 22nd base is triethylamine (EtN) and trimethylamine hydrochloride.

[0208] In some embodiments, compound 33, [ka] or a salt thereof, compound 34, [ka] or a salt thereof, is prepared by converting compound 33 or a salt thereof into compound 33.

[0209] In some embodiments, the conversion of compound 34, or a salt thereof, to compound 33, or a salt thereof, is 1) reacting compound 34 or a salt thereof with a carboxylic acid activator; 2) reacting the product of step 1) with a reducing agent.

[0210] In some embodiments, the activating agent is carbonyldiimidazole. In some embodiments, the reducing agent is sodium borohydride (NaBH4).

[0211] In some embodiments, compound 34, [ka] or a salt thereof, compound (±)-34, [ka] or a salt thereof, is prepared by converting compound 34 or a salt thereof into compound 34.

[0212] In some embodiments, the conversion of compound (±)-34 or a salt thereof to compound 34 or a salt thereof is 1) reacting compound (±)-34 with a chiral amine; 2) reacting the product of step 1) with an acid.

[0213] In some embodiments, the chiral amine is (R)-(-)-α-methylbenzylamine. In some embodiments, the acid is hydrochloric acid (HCl).

[0214] In some embodiments, compound (±)-34, [ka] or a salt thereof, Compound 35, [ka] or a salt thereof, is prepared by converting compound (±)-34 or a salt thereof into compound (±)-34 or a salt thereof.

[0215] In some embodiments, the conversion of compound 35, or a salt thereof, to compound (±)-34, or a salt thereof, is carried out in the presence of a hydroxide base. In some embodiments, the hydroxide base is sodium hydroxide (NaOH).

[0216] In some embodiments, compound 35, [ka] or a salt thereof, compound 36, [ka] or a salt thereof, is prepared by converting compound 35 or a salt thereof into compound 35.

[0217] In some embodiments, compound 36, [ka] or a salt thereof, compound 37, [ka] or a salt thereof, is prepared by converting compound 36 or a salt thereof into compound 36.

[0218] In some embodiments, compound 37, [ka] or a salt thereof, compound 38, [ka] or a salt thereof, is prepared by converting compound 37 or a salt thereof into compound 37.

[0219] In some embodiments, the conversion of compound 38, or a salt thereof, to compound 37, or a salt thereof, is 1) reacting compound 38 or a salt thereof with 3-tert-butoxycarbonylamino-propionic acid and a coupling reagent; 2) reacting the product of step 1) with a reducing agent.

[0220] In some embodiments, the coupling agent is DCC. In some embodiments, step 1) further comprises DMAP. In some embodiments, the reducing agent is sodium borohydride. In some embodiments, step 2) further comprises adding acetic acid.

[0221] In some embodiments, compound 3, [ka] or a salt thereof, compound 39, [ka] or a salt thereof, is prepared by converting compound 3 or a salt thereof into compound 3.

[0222] In some embodiments, the conversion of compound 39, or a salt thereof, to compound 3, or a salt thereof, is carried out in the presence of reduction reaction conditions. In some embodiments, the reduction reaction conditions are a hydrogen source and a metal catalyst. In some embodiments, the hydrogen source is hydrogen gas. In some embodiments, the metal catalyst is Raney Ni.

[0223] In some embodiments, compound 39, [ka] or a salt thereof, compound (±)-39, [ka] or a salt thereof, is prepared by converting compound 39 or a salt thereof into compound 39.

[0224] In some embodiments, the conversion of compound (±)-39 or a salt thereof to compound 39 or a salt thereof is carried out in the presence of an enzyme. In some embodiments, the enzyme is a paratase enzyme.

[0225] In some embodiments, compound (±)-39, [ka] or a salt thereof, compound (±)-4, [ka] or a salt thereof, is prepared by converting compound (±)-39 or a salt thereof into compound (±)-39 or a salt thereof.

[0226] In some embodiments, compounds useful in the synthesis of Compound I are compounds selected from: [Table 2-1] [Table 2-2] and salts thereof, During the ceremony, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X b But Cl, F, -OC6F5, [ka] is selected from X cis selected from F, Cl, Br, and I; X d is selected from F, Cl, Br, and I; R 3 is a monovalent nitrogen protecting group, R 4 is -SO2R, R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group, The compound is [Table 3] Or its salts.

[0227] In some embodiments, R is independently selected from methyl and p-tolyl.

[0228] In some embodiments, each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 1 and R 2together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetrachlorophthalimide, N-tri ... Form a nitrogen protecting group selected from trimethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0229] List of exemplary embodiments: 1. Compound I, [ka] or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (I): [ka] or a salt thereof to Compound I or a pharmaceutically acceptable salt thereof, During the ceremony, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X c is selected from F, Cl, Br, and I. 2.Xa But Br and X c 2. The method of embodiment 1, wherein 3. The conversion of a compound of formula (I) or a salt thereof to compound I or a pharmaceutically acceptable salt thereof is 1) combining a compound of formula (I) or a salt thereof with at least one first base to form a compound of formula (II): [ka] or a salt thereof; 2) A compound of formula (II) or a salt thereof is reacted with Compound 1, [ka] or a salt thereof, and at least one second base to produce Compound I or a pharmaceutically acceptable salt thereof; In the compound of formula (II) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 2. The method of embodiment 1, wherein the alkyl group is selected from aryl optionally substituted with haloalkyl, halo, or nitro. 4. In the compound of formula (II) or a salt thereof, X a 4. The method of embodiment 3, wherein is Br. 5. The method of embodiment 3 or 4, wherein the at least one first base is selected from a carbonate base, a hydroxide base, an alkoxide base, an acetate base, an amine base, a phosphate base, and a sulfate base. 6. The method of any one of embodiments 3-5, wherein the at least one first base is selected from sodium carbonate (Na2CO3), potassium carbonate (K2CO3), 2,2,6,6-tetramethylpiperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, potassium bicarbonate (KHCO3), and tribasic potassium phosphate (K3PO4). 7. The method of any one of embodiments 3-6, wherein the at least one second base is potassium carbonate (K2CO3). 8. The method of any one of embodiments 3 to 7, wherein the combination of the compound of formula (II) or a salt thereof and compound 1 or a salt thereof further comprises at least one metal catalyst. 9. The method of embodiment 8, wherein the at least one metal catalyst is selected from a palladium catalyst and a copper catalyst. 10. Palladium catalysts include [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) / 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd2dba3 / N-phenyl-2-(di-tert-butylphosphino)pyrrole, and Pd2dba3 / 2-di-tert-butylphosphino-2′-methylbiphenyl. Pd2dba3 / 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, Pd2dba3 / 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole, Pd2dba3 / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Pd2dba3 / 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6 '-Triisopropyl-1,1'-biphenyl (Pd2dba3 / BrettPhos), Pd2dba3 / di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine, Pd2dba3 / 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane, dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium Palladium(II), Pd2dba3 / 1,1′-bis(diphenylphosphino)ferrocene, dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, dichloro[2,2′-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) (Pd(BINAP)Cl2), Pd2dba3 / bis[(2-diphenylphosphino)phenyl]ether (Pd2dba3 / DPEPhos), Pd2dba3 / 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Pd2dba3 / 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, Pd2dba3 / 2-dicyclohexylphosphino-2'-(N,N-di methylamino)biphenyl, Pd2dba3 / 1,1′-bis(di-tert-butylphosphino)ferrocene, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl / Pd2dba3 (tert-butylXPhos / Pd2dba3), [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride (tBuXPhos-Pd-G1), allyl(2-di-tert-butyl Phosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos-Pd-G3), 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl / Pd2db a3 (t-BuBrettPhos / Pd2dba3), trifluoromethanesulfonate allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate / Pd2dba3 (SPhos / Pd2dba3), [1,10. The method of embodiment 9, wherein the catalyst is selected from [1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (PEPSIIpent), di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine / Pd2dba3 (cBRIDP / Pd2dba3), and 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane / Pd2dba3 (Cy-cBRIDP / Pd2dba3). 11. The copper catalyst is selected from copper(II) fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper(I) thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluene complex, and is selected from N,N′-dimethylethylenediamine, N,N′-dimethylcyclohexane-1,2-diamine, 1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine, cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid, 2,2′-bipyridine, 2-acetylcyclohexanone, 1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane, 2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinone, and 2-amino-4,6-pyrimidinone. 10. The method of embodiment 9, wherein the cyclohexane-1,2,3,4,5-pentol is optionally substituted with ligands such as cyclohexane, (1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime, glycolic acid, L-proline, 2,2′-dipyridyl, and N-cyclohexyl-2,6-bis(1-methylethyl)benzenamine, N,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane, N,N′-dimethyl-1,3-propanediamine, N,N′-diethylethane-1,2-diamine, 3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane, N,N′-dimethylethane-1,2-diamine, diethylenetriamine, and trans-N,N-dimethylcyclohexane-1,2-diamine. 12. The method of any one of embodiments 8-11, wherein the at least one metal catalyst is [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0) (Pd2dba3), copper iodide (CuI), or a combination thereof. 13. The method of any one of embodiments 8 to 12, wherein the combination of the compound of formula (II) or a salt thereof and compound 1 or a salt thereof further comprises an excess of 2-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3). 14. Conversion of a compound of formula (I) or a salt thereof to compound I or a pharmaceutically acceptable salt thereof can be achieved by reacting a compound of formula (I) or a salt thereof with compound 1, [ka] or a salt thereof, and at least one third base to produce Compound I or a pharmaceutically acceptable salt thereof; In the compound of formula (I) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X c is selected from F, Cl, Br, and I. 15. In the compound of formula (I) or a salt thereof, X a But Br and X c 15. The method of embodiment 14, wherein 16. The method of embodiment 14 or 15, wherein the at least one third base is selected from a carbonate base, a hydroxide base, an alkoxide base, an acetate base, an amine base, a phosphate base, and a sulfate base. 17. The method of any one of embodiments 14-16, wherein the at least one third base is selected from sodium carbonate (Na2CO3), potassium carbonate (K2CO3), 2,2,6,6-tetramethylpiperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, potassium bicarbonate (KHCO3), and tribasic potassium phosphate (K3PO4). 18. The method of any one of embodiments 14-17, wherein the at least one third base is potassium carbonate (K2CO3). 19. The method of any one of embodiments 14 to 18, wherein the combination of the compound of formula (I) or a salt thereof and compound 1 or a salt thereof further comprises at least one metal catalyst. 20. The method of embodiment 19, wherein the at least one metal catalyst is selected from a palladium catalyst and a copper catalyst. 21. Palladium catalysts include [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) / 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd2dba3 / N-phenyl-2-(di-tert-butylphosphino)pyrrole, and Pd2dba3 / 2-di-tert-butylphosphino-2′-methylbiphenyl. Pd2dba3 / 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, Pd2dba3 / 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole, Pd2dba3 / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Pd2dba3 / 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6 '-Triisopropyl-1,1'-biphenyl (Pd2dba3 / BrettPhos), Pd2dba3 / di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine, Pd2dba3 / 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane, dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium Palladium(II), Pd2dba3 / 1,1′-bis(diphenylphosphino)ferrocene, dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, dichloro[2,2′-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) (Pd(BINAP)Cl2), Pd2dba3 / bis[(2-diphenylphosphino)phenyl]ether (Pd2dba3 / DPEPhos), Pd2dba3 / 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Pd2dba3 / 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, Pd2dba3 / 2-dicyclohexylphosphino-2'-(N,N-di methylamino)biphenyl, Pd2dba3 / 1,1′-bis(di-tert-butylphosphino)ferrocene, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl / Pd2dba3 (tert-butylXPhos / Pd2dba3), [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride (tBuXPhos-Pd-G1), allyl(2-di-tert-butyl Phosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos-Pd-G3), 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl / Pd2db a3 (t-BuBrettPhos / Pd2dba3), trifluoromethanesulfonate allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate / Pd2dba3 (SPhos / Pd2dba3), [1,21. The method of embodiment 20, wherein the catalyst is selected from [1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (PEPSIIpent), di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine / Pd2dba3 (cBRIDP / Pd2dba3), and 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane / Pd2dba3 (Cy-cBRIDP / Pd2dba3). 22. The copper catalyst is selected from copper(II) fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper(I) thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluene complex, and is selected from N,N'-dimethylethylenediamine, N,N'-dimethylcyclohexane-1,2-diamine, 1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine, cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid, 2,2'-bipyridine, 2-acetylcyclohexanone, 1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane, 2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinediol, and 2-amino-4,6-pyrimidinediol. 21. The method of embodiment 20, wherein the compound is optionally substituted with ligands such as N-cyclohexyl-2,6-bis(1-methylethyl)benzenamine, N,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane, N,N'-dimethyl-1,3-propanediamine, N,N'-diethylethane-1,2-diamine, 3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane, N,N'-dimethylethane-1,2-diamine, diethylenetriamine, and trans-N,N-dimethylcyclohexane-1,2-diamine. 23. The method of any one of embodiments 19-22, wherein the at least one metal catalyst is [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0) (Pd2dba3), copper iodide (CuI), or a combination thereof. 24. The method of any one of embodiments 19 to 23, wherein the combination of the compound of formula (I) or a salt thereof and compound 1 or a salt thereof further comprises an excess of 2-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3). 25. A compound of formula (I), [ka] or a salt thereof, wherein the compound is a compound of formula (III): [ka] or a salt thereof, is prepared by converting a compound of formula (I) or a salt thereof, In the compound of formula (III) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X c is selected from F, Cl, Br, and I; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group. 26. The method of embodiment 25, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 27.R 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilyl 26. The method of embodiment 25, wherein a nitrogen protecting group is formed selected from tetrahydrostanzyl azacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, and 1,3,5-dioxazines. 28. In the compound of formula (III) or a salt thereof, X a But Br and X c is F and R 1 and R 2 28. The method of embodiment 25 or 27, wherein, together with the atom to which they are attached, form an N-phthalimide. 29. The conversion of a compound of formula (III) or a salt thereof into a compound of formula (I) or a salt thereof is carried out by 1) combining a compound of formula (III) or a salt thereof in the presence of water and a base selected from lithium hydroxide (LiOH), hydrazine, ethanolamine, and N-methylamine; 29. The method of embodiment 28, comprising: 2) optionally combining the product of step 1) with an acid selected from oxalic acid, hydrochloric acid (HCl), phosphoric acid (H3PO4), and citric acid, and then treating the reaction mixture with water and a base selected from potassium carbonate (K2CO3) and cesium carbonate (Cs2CO3) to produce the compound of formula (I) or a salt thereof. 30. A compound of formula (III), [ka] or a salt thereof, wherein the compound is a compound of formula (IV): [ka] or a salt thereof, with a compound of formula (V): [ka] or a salt thereof to form a compound of formula (III) or a salt thereof, During the ceremony, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X b But Cl, F, -OC6F5, [ka] is selected from X c is selected from F, Cl, Br, and I; During the ceremony, R 1is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group. 31. The method of embodiment 30, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 32.R 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilyl 31. The method of embodiment 30, wherein a nitrogen protecting group is formed selected from tetrahydrostanzyl azacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, and 1,3,5-dioxazines. 33. In the compound of formula (IV) or a salt thereof, X a is Br and R 1 and R 233. The method of embodiment 30 or 32, wherein, together with the atom to which they are attached, form an N-phthalimide. 34. In the compound of formula (IV) or a salt thereof, X a is Br and R 1 is hydrogen and R 2 32. The method of embodiment 30 or 31, wherein is benzyloxycarbonyl (Cbz). 35. In the compound of formula (V) or a salt thereof, X b is -OC6F5, and X c The method of any one of embodiments 30 to 34, wherein is F. 36. The method of any one of embodiments 30-35, wherein combining the compound of formula (IV) or a salt thereof with the compound of formula (V) or a salt thereof is carried out in the presence of at least one fourth base. 37. The method of embodiment 36, wherein at least one fourth base is an alkoxy base. 38. The method of embodiment 37, wherein the alkoxy base is selected from lithium t-amylate (t-AmOLi), sodium t-amylate (t-AmONa), potassium t-amylate (t-AmOK), and lithium t-butoxide (LiOt-Bu). 39. A compound of formula (IV), [ka] or a salt thereof, wherein the compound is a compound of formula (VI): [ka] or a salt thereof, into a compound of formula (IV) or a salt thereof, In the compound of formula (VI) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10The method of any one of embodiments 30-32 and 35-38, wherein the alkyl group is selected from aryl optionally substituted with haloalkyl, halo, or nitro. 40. In the compound of formula (VI) or a salt thereof, X a 40. The method of embodiment 39, wherein is Br. 41. The conversion of a compound of formula (VI) or a salt thereof into a compound of formula (IV) or a salt thereof is carried out by 1) converting the hydroxy group of a compound of formula (VI) or a salt thereof to a sulfonate ester (—OSOR) or Cl; 2) combining the sulfonate ester or Cl of step 1) with an amine and at least one fifth base to produce a compound of formula (IV) or a salt thereof. 42. The R group of the sulfonate ester (-OSO2R) is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 42. The method of embodiment 41, wherein the alkyl group is selected from aryl optionally substituted with haloalkyl, halo, or nitro. 43. The method of embodiment 41, wherein the conversion of the hydroxy group to a sulfonate ester in step 1) is carried out in the presence of methanesulfonyl chloride (MsCl) and triethylamine (Et3N). 44. The method of embodiment 41 or 42, wherein the amine in step 2) is N-phthalimide and the at least one fifth base is potassium carbonate (K2CO3). 45. A compound of formula (VI), [ka] or a salt thereof, [ka] or a salt thereof, by reacting a compound of formula (VII): [ka] or a salt thereof to form a compound of formula (VI) or a salt thereof, In the compound of formula (VII) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X d The method of any one of embodiments 39 and 41-44, wherein is selected from F, Cl, Br, and I. 46. ​​In the compound of formula (VII) or a salt thereof, X a But Br and X d 46. ​​The method of embodiment 45, wherein 47. The method of any one of embodiments 45 or 46, wherein combining compound 2, or a salt thereof, with the compound of formula (VII), or a salt thereof, is carried out in the presence of at least one sixth base. 48. The method of embodiment 47, wherein the at least one sixth base is selected from potassium t-butoxide (KOt-Bu), lithium hydroxide (LiOH), tribasic potassium phosphate (K3PO4), dibasic potassium phosphate (K2HPO4), cesium carbonate (Cs2CO3), 2,2,6,6-tetramethylpiperidine, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (Et3N), tributylamine (Bu3N), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), sodium carbonate (Na2CO3), and potassium carbonate (K2CO3). 49. The method of any one of embodiments 45-48, wherein combining compound 2 or a salt thereof with the compound of formula (VII) or a salt thereof is carried out in the presence of potassium carbonate (K2CO3), water, and 2-methyltetrahydrofuran (2-MeTHF). 50. Compound 2, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 2 or a salt thereof. 51. The method of embodiment 50, wherein the conversion of compound 3 or a salt thereof to compound 2 or a salt thereof is carried out in the presence of a reducing agent or reducing reaction conditions. 52. The method of embodiment 51, wherein the reducing agent is lithium aluminum hydride (LiAlH4). 53. Compound 3, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 3 or a salt thereof into compound 4. 54. The method of embodiment 53, wherein the conversion of compound 4 or a salt thereof to compound 3 or a salt thereof is carried out in the presence of reduction reaction conditions. 55. The method of embodiment 54, wherein the reduction reaction conditions comprise hydrogen gas (H2) and at least one metal catalyst selected from Raney nickel (Ra-Ni), palladium on carbon (Pd / C), palladium on alumina (Pd / Al2O3), palladium(II) chloride (PdCl2), platinum oxide (PtO2), palladium / platinum on carbon (Pd / Pt / C), platinum on carbon (Pt / C), and nickel(II) chloride / sodium borohydride (NiCl2 / NaBH4). 56. Compound 4, [ka] or a salt thereof, [ka] 56. The method of any one of embodiments 53-55, wherein the compound is prepared by chiral resolution of CI 14749, or a salt thereof. 57. The method of embodiment 56, wherein the chiral resolution of compound (±)-4 or a salt thereof is carried out using a method selected from chiral column chromatography, chiral simulated moving bed (SMB) chromatography, biological resolution, enzymatic resolution, liquid chromatography, salt decomposition, and asymmetric hydrogenation. 58. Compound I, [ka] or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (VIII): [ka] or a salt thereof to Compound I or a pharmaceutically acceptable salt thereof, In the compound of formula (VIII) or a salt thereof, X c is selected from F, Cl, Br, and I. 59. The method according to embodiment 58, wherein the conversion of the compound of formula (VIII) or a salt thereof to compound I or a pharmaceutical salt thereof is carried out in the presence of at least one seventh base. 60. The method of embodiment 59, wherein the at least one seventh base is selected from potassium carbonate (K2CO3), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,1,3,3-tetramethylguanidine, potassium hydroxide (KOH), potassium hydroxide / Triton B (KOH / Triton B), potassium hydroxide / tetra-n-butylammonium iodide (KOH / nBu4NH4I), potassium hydroxide / tetra-n-octylammonium bromide (KOH / n-Oct4NH4Br), lithium hydroxide (LiOH), and lithium carbonate (Li2CO3). 61. The method of embodiment 59 or 60, wherein at least one seventh base is potassium carbonate (K2CO3). 62. The method of embodiment 61, wherein the conversion of the compound of formula (VIII) or a salt thereof to compound I or a pharmaceutically acceptable salt thereof further comprises magnesium chloride (MgCl2). 63. A compound of formula (VIII), [ka] or a salt thereof, wherein the compound is a compound of formula (IX): [ka] or a salt thereof to a compound of formula (VIII) or a salt thereof, In the compound of formula (IX) or a salt thereof, X c is selected from F, Cl, Br, and I; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2together with the atom to which they are attached form a nitrogen protecting group. 64. The method of embodiment 63, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 65.R 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilyl 64. The method of embodiment 63, wherein a nitrogen protecting group is formed selected from tetrahydrostanzyl azacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, and 1,3,5-dioxazines. 66. In the compound of formula (IX) or a salt thereof, X c is F and R 1 is hydrogen and R 2 65. The method of embodiment 63 or 64, wherein is benzyloxycarbonyl (Cbz). 67. The method of any one of embodiments 63-66, wherein the conversion of the compound of formula (IX) or a salt thereof to the compound of formula (VIII) or a salt thereof is carried out in the presence of reduction reaction conditions. 68. The method of embodiment 67, wherein the reduction reaction conditions are selected from hydrogen gas (H2) and palladium on carbon (Pd / C), formic acid / triethylamine / palladium on carbon (HC02H / Et3N / (Pd / C)), ammonium formate / potassium carbonate and palladium on carbon (NH4HCO2 / K2CO3 and Pd / C), dibasic potassium phosphate and palladium on carbon (K2HPO4 and Pd / C), potassium phosphate and palladium on carbon (K3PO4 and Pd / C), hydrazine and palladium on carbon (NH2NH2 / (Pd / C)), and 1,4-cyclohexadiene and palladium on carbon. 69. A compound of formula (IX), [ka] or a salt thereof, wherein the compound is a compound of formula (X): [ka] or a salt thereof, with a compound of formula (V): [ka] or a salt thereof to form a compound of formula (IX) or a salt thereof, In the compound of formula (X) or a salt thereof, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group, In the compound of formula (V) or a salt thereof, X b But Cl, F, -OC6F5, [ka] is selected from X cThe method of any one of embodiments 63-65, 67, and 68, wherein is selected from F, Cl, Br, and I. 70. The method of embodiment 69, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 71.R 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilyl 70. The method of embodiment 69, wherein a nitrogen protecting group is formed selected from tetrahydrostanzyl azacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, and 1,3,5-dioxazines. 72. In the compound of formula (X) or a salt thereof, R 1 is hydrogen and R 2 is Cbz or R 1 and R 2 together with the atom to which they are attached form an N-phthalimide. 73. In the compound of formula (V) or a salt thereof, X b is -OC6F5, and X cThe method of any one of embodiments 69 to 72, wherein is F. 74. The method of any one of embodiments 69-73, wherein combining the compound of formula (X) or salt thereof with the compound of formula (V) or salt thereof is carried out in the presence of at least one eighth base. 75. The method of embodiment 74, wherein at least one eighth base is an alkoxy base. 76. The method of embodiment 75, wherein the alkoxy base is selected from lithium t-amylate (t-AmOLi), sodium t-amylate (t-AmONa), potassium t-amylate (t-AmOK), and lithium t-butoxide (LiOt-Bu). 77. A compound of formula (X): [ka] or a salt thereof, wherein the compound is a compound of formula (IV): [ka] or a salt thereof, [ka] or a salt thereof to form a compound of formula (X) or a salt thereof: In the compound of formula (IV) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group. 78. The method of embodiment 77, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 79.R 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilyl 78. The method of embodiment 77, wherein a nitrogen protecting group is formed selected from tetrahydrostanzyl azacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, and 1,3,5-dioxazines. 80. In the compound of formula (IV) or a salt thereof, X a is Br and R 1 and R 2 80. The method of embodiment 77 or 79, wherein, together with the atom to which they are attached, form an N-phthalimide. 81. In the compound of formula (IV) or a salt thereof, X a is Br and R1 is hydrogen and R 2 79. The method of embodiment 77 or 78, wherein is benzyloxycarbonyl (Cbz). 82. The method of any one of embodiments 77-81, wherein combining the compound of formula (IV) or a salt thereof with the compound or a salt thereof is carried out in the presence of at least one ninth base. 83. The method of embodiment 82, wherein the at least one ninth base is selected from a carbonate base, a hydroxide base, an alkoxide base, an acetate base, an amine base, a phosphate base, and a sulfate base. 84. At least one ninth base is selected from the group consisting of sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), lithium carbonate (Li2CO3), sodium hydroxide (NaOH), optionally in THF, MeTHF, or IPA, potassium hydroxide (KOH), sodium tert-butoxide (NaOt-Bu), optionally in THF, MeTHF, or IPA, potassium tert-butoxide (NaOt-Bu), pyridine, 2,2,6,6-tetramethylpiperidine, 1,8-diazabicyclo[5.4. 84. The method of embodiment 82 or 83, wherein the active ingredient is selected from: 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, N,N-diisopropylethylamine (DIPEA), potassium bis(trimethylsilyl)amide (KHMDS), pyridine, sodium bicarbonate (NaHCO), potassium bicarbonate (KHCO), tribasic sodium phosphate (NaPO), and tribasic potassium phosphate (KPO). 85. The method of any one of embodiments 82-84, wherein the at least one ninth base is potassium carbonate (K2CO3). 86. The method of any one of embodiments 77-85, wherein the combination of the compound of formula (IV) or a salt thereof and compound 1 or a salt thereof further comprises at least one metal catalyst. 87. The method of embodiment 86, wherein the at least one metal catalyst is selected from a palladium catalyst and a copper catalyst.88a. Palladium catalysts include [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) / 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl)Pd2dba3 / N-phenyl-2-(di-tert-butylphosphino)pyrrole, and Pd2dba3 / 2-di-tert-butylphosphino-2′- Methylbiphenyl, Pd2dba3 / 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, Pd2dba3 / 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole, Pd2dba3 / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Pd2dba3 / 2-(dicyclohexylphosphino)3,6-dimeth- Pd2dba3 / di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine, Pd2dba3 / 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane, dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-yl] dene](3-chloropyridyl)palladium(II), Pd2dba3 / 1,1′-bis(diphenylphosphino)ferrocene, dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), dichloro[2,2′-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) (Pd(BINAP)Cl2), Pd2dba3 / bis[(2-diphenylphosphino)phenyl]ether (Pd2dba3 / DPEPhos), Pd2dba3 / 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Pd2dba3 / 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, Pd2dba3 / 2-dicyclohexylphosphino-2'-(N,N-di methylamino)biphenyl, Pd2dba3 / 1,1′-bis(di-tert-butylphosphino)ferrocene, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl / Pd2dba3 (tert-butylXPhos / Pd2dba3), [2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride (tBuXPhos-Pd-G1), allyl(2-di-tert-butyl Phosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrettPhos-Pd-G3), 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl / Pd2db a3 (t-BuBrettPhos / Pd2dba3), trifluoromethanesulfonate allyl [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate / Pd2dba3 (SPhos / Pd2dba3), [1,88. The method of embodiment 87, wherein the catalyst is selected from [1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (PEPSIIpent), di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine / Pd2dba3 (cBRIDP / Pd2dba3), and 1-(dicyclohexylphosphino)-2,2-diphenyl-1-methylcyclopropane / Pd2dba3 (Cy-cBRIDP / Pd2dba3). 88b. The method of embodiment 87, wherein the active catalyst, palladium(0) 2-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos), is produced using a palladium(II) tBuXPhos precatalyst (G1-G3), or a combination of a palladium(0) source, such as Pd2(dba)3 or Pd(PPh3)4, and di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos), and finally, a palladium(II) source, such as Pd(OAc)2 or Pd(Cl)2, in the presence of a reducing agent and di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, tert-ButylXPhos). 89. The copper catalyst is selected from copper(II) fluoride, copper(I) bromide (CuBr), copper(I) iodide (CuI), copper(I) thiophene-2-carboxylate, and copper(I) trifluoromethanesulfonate toluene complex, and is selected from N,N′-dimethylethylenediamine, N,N′-dimethylcyclohexane-1,2-diamine, 1,10-phenanthroline, 8-hydroxyquinoline, trans-cyclohexane-1,2-diamine, cis-cyclohexane-1,2-diamine, N,N-dimethylglycine, 2-picolinic acid, 2,2′-bipyridine, 2-acetylcyclohexanone, 1,3-di-tert-butyl-1,3-propanedione, rac-BINOL, dipivaloylmethane, 2-isobutyrylcyclohexanone, 2-amino-4,6-pyrimidinedione, 88. The method of embodiment 87, wherein the compound is optionally substituted with a ligand such as cyclohexane-1,4-diol, (1R,2S,4S,5R)-6-methoxycyclohexane-1,2,3,4,5-pentol, salicylaldoxime, glycolic acid, L-proline, 2,2′-dipyridyl, N-cyclohexyl-2,6-bis(1-methylethyl)benzenamine, N,N-diisopropyl-1,3-propanediamine, trans-1,2-diaminocyclohexane, N,N′-dimethyl-1,3-propanediamine, N,N′-diethylethane-1,2-diamine, 3-(dimethylamino)-propylamine, 1,4-diaminocyclohexane, N,N′-dimethylethane-1,2-diamine, diethylenetriamine, and trans-N,N-dimethylcyclohexane-1,2-diamine. 90. The method of any one of embodiments 86-89, wherein the at least one metal catalyst is [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuXPhos Pd G3), bis(dibenzylideneacetone)palladium(0) (Pd2dba3), copper iodide (CuI), or a combination thereof. 91. The method of any one of embodiments 77-88, wherein the combination of the compound of formula (IV) or a salt thereof and compound 1 or a salt thereof further comprises copper iodide (CuI). 92. The method of embodiment 91, wherein the combination of the compound of formula (IV) or a salt thereof and compound 1 or a salt thereof further comprises dicyclohexylamine (DMCHDA). 93. A compound of formula (IV), [ka] or a salt thereof, wherein the compound is a compound of formula (XI): [ka] or a salt thereof, by reacting a compound of formula (VII): [ka] or a salt thereof to form a compound of formula (IV) or a salt thereof, In the compound of formula (XI) or a salt thereof, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group, In the compound of formula (VII) or a salt thereof, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X d The method of any one of embodiments 77-79 and 82-92, wherein is selected from F, Cl, Br, and I. 94. The method of embodiment 93, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 95.R 1 and R 2 together with the atoms to which they are attached, include benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilyl 94. The method of embodiment 93, wherein a nitrogen protecting group is formed selected from tetrahydrostanzyl azacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, and 1,3,5-dioxazines. 96. In the compound of formula (XI) or a salt thereof, R 1 is hydrogen and R 2 95. The method of embodiment 93 or 94, wherein is benzyloxycarbonyl (Cbz). 97. In the compound of formula (XI) or a salt thereof, R 1 and R 2 96. The method of embodiment 93 or 95, wherein, together with the atom to which they are attached, form an N-phthalimide. 98. In the compound of formula (VII) or a salt thereof, X a But Br and X dThe method of any one of embodiments 93-97, wherein is F. 99. The method of any one of embodiments 93-98, wherein combining the compound of formula (XI) or a salt thereof with the compound of formula (VII) or a salt thereof is carried out in the presence of at least one tenth base. 100. The method of embodiment 99, wherein at least one tenth base is a carbonate base. 101. The method of embodiment 99 or 100, wherein the at least one tenth base is potassium carbonate (K2CO3). 102. The method of embodiment 101, wherein the combination of the compound of formula (XI) or a salt thereof and the compound of formula (VII) or a salt thereof further comprises zinc chloride (ZnCl2). 103. A compound of formula (XI), [ka] or a salt thereof, wherein the compound is a compound of formula (XII): [ka] or a salt thereof into a compound of formula (XI) or a salt thereof, In the compound of formula (XII) or a salt thereof, R 3 The method of any one of embodiments 93-102, wherein is a monovalent nitrogen protecting group. 104. The method of embodiment 103, wherein each monovalent nitrogen protecting group is selected from t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and N-phthalimide. 105. In the compound of formula (XII) or a salt thereof, R 3 The method of embodiment 103 or 104, wherein is t-butyloxycarbonyl (Boc). 106. The conversion of a compound of formula (XII) or a salt thereof into a compound of formula (XI) or a salt thereof is carried out by 1) The primary amine of compound (XII) or a salt thereof is reacted with a protected amine -NR 1 R 2 and converting 2)R 3 to form a compound of formula (XI) or a salt thereof. 107. The method of embodiment 106, wherein the conversion in step 1) is carried out in the presence of benzyl chloroformate (Cbz-Cl) and potassium carbonate (KOH). 108. R in Step 2) 3 108. The method of embodiment 106 or 107, wherein is deprotected with hydrochloric acid (HCl), methanesulfonic acid (MsOH), or trifluoroacetic acid. 109. A compound of formula (XII), [ka] or a salt thereof, wherein the compound is a compound of formula (XV): [ka] or a salt thereof, to a compound of formula (XII) or a salt thereof, In the compound of formula (XV) or a salt thereof, R 3 109. The method of any one of embodiments 103-108, wherein is a monovalent nitrogen protecting group. 110. The method of embodiment 109, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 111. In the compound of formula (XV) or a salt thereof, R 3 111. The method of embodiment 109 or 110, wherein is t-butyloxycarbonyl (Boc). 112. The conversion of a compound of formula (XV) or a salt thereof into a compound of formula (XII) or a salt thereof is carried out by 1) a compound of formula (XV), [ka] or a salt thereof, by reacting a compound of formula (XIV): [ka] or a salt thereof; 2) A compound of formula (XIV) or a salt thereof is reacted with a compound of formula (XIII): [ka] or a salt thereof; 3) converting the compound of formula (XIII) or a salt thereof into a compound of formula (XII) or a salt thereof, In the compounds of formulae (XIII) to (XV) or salts thereof, R 3 is a monovalent nitrogen protecting group, and in the compound of formula (XIV) or a salt thereof, R 4 is -SO2R, R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 The method of any one of embodiments 109-111, wherein the alkyl group is selected from aryl optionally substituted with haloalkyl, halo, or nitro. 113. The method of embodiment 112, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 114. In the compounds of formulae (XIII) to (XV) or salts thereof, R 3 114. The method of embodiment 112 or 113, wherein is t-butyloxycarbonyl (Boc). 115. In the compound of formula (XIV) or a salt thereof, R 4The method of any one of embodiments 112-114, wherein is 4-nitrobenzylsulfonyl chloride (NsCl). 116. The method according to any one of embodiments 112 to 115, wherein the conversion of the compound of formula (XV) or its salt to the compound of formula (XIV) or its salt is carried out in the presence of 4-nitrobenzylsulfonyl chloride (NsCl) and at least one eleventh base. 117. The method of embodiment 116, wherein at least one eleventh base is an amine base or a carbonate base. 118. The method according to any one of embodiments 112-117, wherein the conversion of the compound of formula (XIV) or a salt thereof to the compound of formula (XIII) or a salt thereof is carried out in the presence of an azide source. 119. The method of embodiment 118, wherein the azide source is sodium azide (NaN3). 120. The method of any one of embodiments 112-119, wherein the conversion of the compound of formula (XIII) or a salt thereof to the compound of formula (XII) or a salt thereof is carried out in the presence of reduction reaction conditions. 121. The method of embodiment 120, wherein the reduction reaction conditions comprise hydrogen gas (H2) and a metal catalyst selected from platinum dioxide (PtO2) and palladium on carbon (Pd / C). 122. A compound of formula (XV), [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting a compound of formula (XV) or a salt thereof into a compound of formula (XV) or a salt thereof. 123. The method of embodiment 122, wherein the conversion of compound 2 or a salt thereof to a compound of formula (XV) or a salt thereof is carried out in the presence of di-tert-butyl dicarbonate (Boc2O). 124. The method of embodiment 123, further comprising combining the compound of formula (XV) or a salt thereof with L-glutamic acid. 125. Compound 2, [ka] or a salt thereof, [ka] 125. The method of embodiment 122 or 124, wherein the compound is prepared by converting compound 2, or a salt thereof, to compound 3, or a salt thereof. 126. The method according to embodiment 125, wherein the conversion of compound 3 or a salt thereof to compound 2 or a salt thereof is carried out in the presence of a reducing agent or at least one solvent. 127. The method of embodiment 126, wherein the reducing agent is lithium aluminum hydride (LiAlH4). 128. The method of embodiment 127, wherein at least one solvent is 2-methyltetrahydrofuran (2-MeTHF). 129. Compound 3, [ka] or a salt thereof, [ka] 129. The method of any one of embodiments 125-128, wherein the compound is prepared by chiral resolution of CI 126, CI 127, CI 128, or a salt thereof. 130. The method of embodiment 129, wherein the chiral resolution of compound (±)-3 is carried out using a method selected from chiral column chromatography, chiral simulated moving bed (SMB) chromatography, biological resolution, enzymatic resolution, liquid chromatography, salt decomposition, and asymmetric hydrogenation. 131. Compound (±)-3, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting (±)-3 or a salt thereof to compound (±)-3. 132. The method of embodiment 131, wherein the conversion of compound (±)-4 or a salt thereof to compound (±)-3 or a salt thereof is carried out in the presence of reduction reaction conditions. 133. The method of embodiment 132, wherein the reduction reaction conditions comprise hydrogen gas (H2) and Raney nickel. 134. Compound (±)-4, [ka] or a salt thereof, [ka] or a salt thereof, in combination with 2-nitropropane to produce the compound (±)-4 or a salt thereof. 135. The method of embodiment 134, wherein the combination of compound 5 or a salt thereof with 2-nitropropane is carried out in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). 136. Compound 5, [ka] 136. The method of embodiment 134 or 135, wherein the compound 5, or a salt thereof, is prepared by converting δ-valerolactone to compound 5, or a salt thereof. 137. The conversion of δ-valerolactone to compound 5 or a salt thereof is carried out by 1) combining δ-valerolactone with an alkyl formate and at least one twelfth base; 2) combining the product of step 1) with paraformaldehyde. 138. The method of embodiment 137, wherein the method further comprises contacting the product of step 2) with SiO2 to produce compound 5 or a salt thereof. 139. The method of embodiment 137 or 138, wherein the alkyl formate is ethyl formate and the at least one twelfth base is sodium hydride (NaH). 140. Compound 1, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting Compound 1 or a salt thereof. 141. The method of embodiment 140, wherein the conversion of compound 6 or a salt thereof to compound 1 or a salt thereof is carried out in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). 142. Compound 6, [ka] or a salt thereof, [ka] 142. The method of embodiment 140 or 141, wherein the compound is prepared by converting compound 6, or a salt thereof, to compound 6. 143. The method according to embodiment 142, wherein the conversion of compound 7 or a salt thereof to compound 6 or a salt thereof is carried out in the presence of at least one 13th base and at least one solvent. 144. The method of embodiment 143, wherein the at least one thirteenth base is potassium hydroxide (KOH). 145. The method of embodiment 143 or 144, wherein at least one solvent is methanol (MeOH). 146. Compound 7, [ka] or a salt thereof, [ka] or a salt thereof, [ka] or a salt thereof to form compound 7 or a salt thereof. 147. The method of embodiment 146, wherein the combination of compound 8 or a salt thereof with compound 9 or a salt thereof is carried out in the presence of a phosphine and an azodicarboxylate. 148. The method of embodiment 147, wherein the phosphine is triphenylphosphine (PPh3). 149. The method of embodiment 147 or 148, wherein the azodicarboxylate is diisopropyl azocarboxylate (DIAD). 150. The method of any one of embodiments 146-149, wherein the combination of compound 8 or a salt thereof with compound 9 or a salt thereof is carried out in the presence of a sulfonyl chloride and at least one 14th base. 151. The method of embodiment 150, wherein the sulfonyl chloride is methanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl). 152. The method of embodiment 150 or 151, wherein at least one fourteenth base is triethylamine (Et3N). 153. Compound 8, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 8 or a salt thereof into compound 9. 154. The method of embodiment 153, wherein the conversion of compound 10 or a salt thereof to compound 8 or a salt thereof is carried out in the presence of a reducing agent. 155. The method of embodiment 154, wherein the reducing agent is selected from lithium aluminum hydride (LiAlH4), boron trifluoride / sodium borohydride (BF3 / NaBH4), borane (BH3), and borane complexes such as borane dimethyl sulfide (BH3SMe2) and borane tetrahydrofuran (BH3-THF), vitride (sodium bis(2-methoxyethoxy)aluminum hydride), zinc borohydride (Zn(BH4)2), and diisobutylaluminum hydride (DIBAL-H). 156. Compound 10, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 10 or a salt thereof into compound 11. 157. The method according to embodiment 156, wherein the conversion of compound 11 or a salt thereof to compound 10 or a salt thereof is carried out in the presence of at least one 15th base and at least one solvent. 158. The method of embodiment 157, wherein the at least one fifteenth base is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), and barium hydroxide (Ba(OH)2). 159. The method of embodiment 157 or 158, wherein at least one solvent is selected from ethanol (EtOH), methanol (MeOH), ethylene glycol, diethylene glycol, and water. 160. Compound 11, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 11 or a salt thereof into compound 12. 161. The method according to embodiment 160, wherein the conversion of compound 12 or a salt thereof to compound 11 or a salt thereof is carried out in the presence of a cyanide source. 162. The method of embodiment 161, wherein the cyanide source is sodium cyanide (NaCN). 163. Compound 12, [ka] or a salt thereof, [ka] 163. The method of any one of embodiments 160 or 162, wherein the compound is prepared by converting compound 12, or a salt thereof, to compound 13, or a salt thereof. 164. The method of embodiment 163, wherein the conversion of compound 13 or a salt thereof to compound 12 or a salt thereof is carried out in the presence of a phosphine, a bromine source, and at least one 16th base. 165. The method of embodiment 164, wherein the phosphine is triphenylphosphine (PPh3). 166. The method of embodiment 164 or 165, wherein the bromine source is molecular bromine (Br2). 167. The method of any one of embodiments 164-166, wherein at least one 16th base is pyridine. 168. Compound 13, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 13 or a salt thereof into compound 14. 169. The method of embodiment 168, wherein the conversion of compound 14 or a salt thereof to compound 13 or a salt thereof is carried out in the presence of a reducing agent. 170. The method of embodiment 169, wherein the reducing agent is selected from lithium aluminum hydride (LiAlH4), boron trifluoride / sodium borohydride (BF3 / NaBH4), borane (BH3), and borane complexes such as borane dimethyl sulfide (BH3SMe2) and borane tetrahydrofuran (BH3-THF), vitride (bis(2-methoxyethoxy)sodium aluminum hydride), zinc borohydride (Zn(BH4)2), and diisobutylaluminum hydride (DIBAL-H). 171. Compound 14, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 14 or a salt thereof. 172. The method of embodiment 171, wherein the conversion of compound 15 or a salt thereof to compound 14 or a salt thereof is carried out in the presence of sodium hydroxide (NaOH) in methanol (MeOH). 173. Compound 15, [ka] or a salt thereof, [ka] 173. The method of embodiment 171 or 172, wherein the compound is prepared by converting compound 15, or a salt thereof, to compound 15. 174. The method of embodiment 173, wherein the conversion of compound 16 or a salt thereof to compound 15 or a salt thereof is carried out in the presence of ethyl 2-diazoacetate and a metal catalyst. 175. The method of embodiment 174, wherein the metal catalyst is rhodium(II) acetate dimer (Rh2(OAc)4) or copper triflate (Cu(OTf)2). 176. Compound 16, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 16 or a salt thereof. 177. The method according to embodiment 176, wherein the conversion of compound 17 or a salt thereof to compound 16 or a salt thereof is carried out in the presence of at least one 17th base. 178. The method of embodiment 177, wherein at least one 17th base is potassium t-butoxide (KOt-Bu). 179. Compound 17, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 17 or a salt thereof into compound 17. 180. The method of embodiment 179, wherein the combination of compound 18 or a salt thereof with compound 17 or a salt thereof is carried out in the presence of a phosphine, a bromine source, and at least one 18 base. 181. The method of embodiment 180, wherein the phosphine is triphenylphosphine (PPh3). 182. The method of embodiment 180 or 181, wherein the bromine source is molecular bromine (Br2). 183. The method of any one of embodiments 180-182, wherein at least one 18th base is pyridine. 184. Compound 18, [ka] or a salt thereof, [ka] or a salt thereof, is prepared by converting compound 18 or a salt thereof into compound 19. 185. The method of embodiment 184, wherein the conversion of compound 19 or a salt thereof to compound 18 or a salt thereof is carried out in the presence of ethylmagnesium bromide (EtMgBr) and titanium(IV) isopropoxide (Ti(Oi-Pr)4). 186. A compound selected from the following: [Table 4-1] [Table 4-2] and salts thereof, During the ceremony, X a is selected from F, Cl, Br, I, and -OSOR; R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; X b But Cl, F, -OC6F5, [ka] is selected from X c is selected from F, Cl, Br, and I; X d is selected from F, Cl, Br, and I; R 3 is a monovalent nitrogen protecting group, R 4 is -SO2R, R is -C 1-10 Alkyl, -C 1-10 Haloalkyl, and -C 1-10 Alkyl, -C 1-10 selected from aryl optionally substituted with haloalkyl, halo, or nitro; During the ceremony, R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group, R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or R 1 and R 2 together with the atom to which they are attached form a nitrogen protecting group, The compound is [Table 5] or a salt thereof, as well as a compound thereof. 187. The compound of embodiment 186, wherein each monovalent nitrogen protecting group is independently selected from t-butyloxycarbonyl (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts). 188.R 1 and R 2together with the atoms to which they are attached, benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilyl The compound of embodiment 186, wherein the nitrogen protecting group is selected from azacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilaisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, and 1,3,5-dioxazines.

[0230] General Synthesis Compound I can be synthesized according to Scheme 1. [ka]

[0231] In some embodiments, the present disclosure provides: 1) combining compound 45 with compound 46 to form compound 47; 2) converting compound 47 to compound 48; 3) converting compound 48 to compound 40, and 4) combining compound 40 with compound 1 to produce compound I.

[0232] In some embodiments, compound 45 is combined with compound 46 in the presence of an alkoxide base to produce compound 47.

[0233] In some embodiments, compound 47 is converted to compound 48 in the presence of an acid.

[0234] In some embodiments, compound 48 is converted to compound 40 in the presence of a base.

[0235] In some embodiments, compound 40 is combined with compound 1 in the presence of a base and, optionally, a metal catalyst to produce compound I.

[0236] In some embodiments, compound 40 is combined with compound 1 in the presence of a copper catalyst to produce compound I.

[0237] Compound I can also be synthesized according to Scheme 2. [ka]

[0238] In some embodiments, the present disclosure provides: 1) combining compound 49 with compound 46 in the presence of an alkoxide base to form compound 50; 2) converting compound 50 to compound 48; 3) converting compound 48 to compound 40, and 4) combining compound 40 with compound 1 to produce compound I.

[0239] In some embodiments, compound 49 is combined with compound 46 in the presence of an alkoxide base to produce compound 50.

[0240] In some embodiments, compound 50 is converted to compound 48 in the presence of aqueous base.

[0241] In some embodiments, compound 48 is converted to compound 40 in the presence of a base.

[0242] In some embodiments, compound 40 is combined with compound 1 in the presence of a base and, optionally, at least one metal catalyst to produce compound I.

[0243] Compound I can also be synthesized according to Scheme 3. [ka]

[0244] In some embodiments, the present disclosure provides: 1) combining compound 45 with compound 1 to form compound 51; 2) combining compound 51 with compound 46 to form compound 52; 3) converting compound 52 to compound 53; and 4) converting compound 53 to compound I.

[0245] In some embodiments, compound 45 is combined with compound 1 in the presence of a base and optionally at least one metal catalyst to produce compound 51.

[0246] In some embodiments, compound 51 is combined with compound 46 in the presence of an alkoxide base to produce compound 52.

[0247] In some embodiments, compound 52 is converted to compound 53 in the presence of an acid.

[0248] In some embodiments, compound 52 is converted to compound 53 in the presence of palladium on carbon.

[0249] In some embodiments, compound 53 is converted to compound 1 in the presence of a base and optionally a metal catalyst.

[0250] Compound I was prepared according to the general synthesis and synthetic examples disclosed herein.

[0251] In order that the disclosure described herein may be more fully understood, the following general experimental procedures and examples are set forth. It should be understood that these procedures and examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner. [Example]

[0252] General experimental procedure Definitions of certain abbreviations in the following examples are summarized below. [Table 6-1] [Table 6-2] [Table 6-3]

[0253] Reagents and starting materials were obtained from commercial sources and used without purification unless otherwise noted.

[0254] Synthesis Examples If the name of a compound conflicts with the structure of the compound anywhere in this application, the structure is intended to take precedence over the name and control.

[0255] Example 1: 3-(2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (6) [ka] Step 1: Synthesis of [1,1'-bi(cyclopropane)]-1-ol (18) [ka] A solution of methylcyclopropanecarboxylate (109 g, 1.09 mol) in 2-MeTHF (1.31 L) and titanium(IV) isopropoxide (71 mL, 240.6 mmol) was stirred in a Morton flask and then cooled to 18 °C. Ethyl magnesium bromide (753 mL of 3 M, 2.259 mol) was added dropwise over 2 h to control the temperature between 15 and 20 °C. The mixture was stirred for an additional 2 h, then cooled to 5 °C and quenched (slowly) by the dropwise addition of cold (approximately 5-10 °C) NaHSO (1.31 L of 20 w / v%, 2.182 mol), maintaining the temperature below 10 °C. The organic phase was isolated, and the aqueous phase was re-extracted with hexane (500 mL). The aqueous phase was discarded. The organic phases were combined, added to saturated aqueous NaHCO3 (200 mL of 10 w / v%, 238 mmol), dried over Na2SO4, and concentrated (30 °C / ca. 40 Torr) to give 108.6 g of [1,1'-bi(cyclopropane)]-1-ol as a pale yellow liquid. The sample contained ca. 8 wt. % 2-MeTHF and 2 wt. % iPrOH. 1 The corrected yield of the desired product as determined by 1 H NMR was 91%.

[0256] 1 H NMR (400 MHz, chloroform-d) δ 1.99 (s, 1H), 1.35 (tt, J = 8.2, 5.1 Hz, 1H), 1.22 (dd, J = 9.0, 6.1 Hz, 1H), 0.70-0.65 (m, 2H), 0.52-0.45 (m, 2H), 0.43-0.38 (m, 2H), 0.21-0.15 (m, 2H).

[0257] Step 2: Synthesis of 1-bromo-1,1'-bi(cyclopropane) (17) [ka] A solution of PhP (216 g, 824 mmol) in CHCl (770 mL) was cooled to −10°C. A solution of Br (132 g, 42.6 mL, 824 mmol) in CHCl (154 mL) was added over 15 min. The mixture was stirred for an additional 15 min and then further cooled to −20°C when pyridine (6.21 g, 6.35 mL, 78.5 mmol) was added. A solution of [1,1'-bi(cyclopropane)]-1-ol (77.0 g, 785 mmol), pyridine (65.2 g, 66.7 mL, 824 mmol), and DCM (385 mL) was added dropwise, maintaining the temperature at approximately −15 to −20°C. The mixture was stirred at −20 to −10°C for 45 min and then heated to reflux (42°C) until the reaction was complete (approximately 1 h). The mixture was cooled to ambient temperature and concentrated to remove most of the solvent. The mixture was slurried in hexane (1 L), allowed to stand overnight, and then filtered. The filter cake was washed with hexane (2 × 500 mL). The combined filtrate and washings were then washed with aqueous HCl (392 mL of 1 M, 392 mmol), then with water (200 mL), then dried over NaSO and concentrated to give 82.2 g (65% yield) of 1-bromo-1,1'-bi(cyclopropane) as a yellow liquid.

[0258] 1 H NMR (400 MHz, chloroform-d) δ 5.30 (s, 1H), 1.61 (tt, J = 8.2, 5.0 Hz, 1H), 1.07-1.02 (m, 2H), 0.78-0.66 (m, 2H), 0.67-0.51 (m, 2H), 0.35-0.21 (m, 2H).

[0259] Step 3: Synthesis of 1,1'-bi(cyclopropylidene) (16) [ka] A solution of t-BuOK (62.7 g, 559 mmol) in DMSO (225 mL) was stirred at ambient temperature. Then, a solution of crude 1-bromo-1-cyclopropyl-cyclopropane (75.0 g, 465.7 mmol) in DMSO (150 mL) was added dropwise while maintaining the temperature at 10-25°C with an ice-water bath. After 1 h, the addition was complete and the mixture was allowed to warm to ambient temperature. After 20 min, 1 1 HNMR showed the reaction was fairly clean and nearly complete.

[0260] After stirring overnight, the product was isolated by flask-to-flask vacuum distillation with the receiver in an ice / i-PrOH bath at -5°C with a condenser. Vacuum was slowly applied from 100 torr to 40 torr. The external pot temperature was increased from 70 to 80°C. The distillate was slowly collected in the receiver (head temperature 20-30°C) to yield 40.8 g of a colorless liquid, a mixture of the desired product, t-BuOH, and a small amount of DMSO (molar ratio of 1.0:1.1:0.15).

[0261] The above product was redistilled at atmospheric pressure under a nitrogen blanket using a 14 / 20 6-inch Vigreaux column. The condenser was cooled to 2°C and the receiver was placed in an ice-water bath. The collected distillate (bp 60-62°C) gave 28.7 g as a colorless liquid, which was again the desired product, a mixture of t-BuOH and DMSO (1.0:1.8:0.15 molar ratio). The calculated yield ( 1 1 H NMR) was 10.0 g of 1,1'-bi(cyclopropylidene).

[0262] Distillation continued under reduced pressure (50–30 Torr) while the external pot temperature was increased from ambient to 70° C. Additional distillate was collected in a chilled receiver (ice / i-PrOH) to yield an additional 6.9 g of 1,1′-bi(cyclopropylidene), containing traces of t-BuOH and DMSO, for a total yield of 16.9 g (45%).

[0263] 1 H NMR (400 MHz, chloroform-d) δ 1.19 (s, 8H).

[0264] Step 4: Ethyl dispiro[2.0.2 4 .1 3 Synthesis of ]heptane-7-carboxylate (15) [ka] A nitrogen-purged, 1 L jacketed reaction vessel was charged with Rh(OAc)2 (14.43 g, 32.64 mmol), 1,1'-bi(cyclopropylidene) (170 g, 2.122 mol), and DCM (377.7 mL). The jacket was cooled to 0 °C (internal temperature 0.6 °C). Ethyl 2-diazoacetate (411.6 g, 379.4 mL, 3.607 mol) was added at 0.08 mL / min (4.8 mL / h) using a metering pump. After 68 h (295 mL added), the addition was stopped (total amount of ethyl 2-diazoacetate added was approximately 320 mL or 1.3 equivalents). The dark amber reaction mixture was warmed to 20 °C. Celite was added (29 g; 2 g / g catalyst), and the reaction mixture was allowed to stand overnight.

[0265] A portion of the reaction mixture was filtered using a packed bed of Celite. A bed of SiO2 (80 g) packed with DCM was prepared. The remaining unfiltered suspension was slurried with SiO2 (40 g) and filtered under vacuum using a bed of SiO2. The flask / bed was washed with DCM (3 x 400 mL). The Celite filtrate and SiO2 filtrate / washings were combined and concentrated to give 409 g (116%) of a dark brown liquid.

[0266] A bed of SiO2 (300 g) was packed with hexane. The concentrate obtained above was dissolved in heptane / hexane (approximately 300 mL). The resulting solution was loaded onto the packed SiO2 bed using hexane (400 mL). The column was eluted with 10% EtOAc / hexane, collecting approximately 400 mL fractions. The elution solvent turned orange (a brown band remained on the SiO2 bed). Fraction 1 was orange, Fraction 2 was yellow, Fraction 3 was pale yellow, and Fraction 4 was yellowish. Fractions 1-3 were combined and concentrated to give 341.6 g of ethyl dispiro[2.0.2] as an orange liquid.4 .1 3 ]heptane-7-carboxylate (yield 97%) was obtained.

[0267] 1 H NMR (400 MHz, chloroform-d) δ 4.13 (q, J = 7.2 Hz, 2H), 2.24 (s, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.08-0.94 (m, 4H), 0.90-0.82 (m, 2H), 0.78 (ddd, J = 8.3, 5.1, 3.6 Hz, 2H).

[0268] Step 5: Dispiro 2.0.2 4 .1 3 ]Synthesis of heptan-7-ylmethanol (13) [ka] To a slurry of LiAlH4 (24 g, 616.0 mmol) in THF (750 mL) was added ethyl dispiro[2.0.2 4 .1 3 A solution of 2.0.2 heptane-7-carboxylate (100 g, 601.6 mmol) was slowly added and the mixture brought to a gentle reflux. The reaction temperature was controlled with an ice bath and the rate of addition. The addition took 90 minutes, and the mixture was stirred at ambient temperature for 16 hours. The mixture was cooled in an ice bath, and the reaction was quenched by the addition of water (24 mL, 1.332 mol), followed by NaOH (24 mL of 2 M, 48.00 mmol), and then water (72 mL, 3.997 mol). The slurry was filtered over Celite, and the filtrate was concentrated in vacuo. The oil was diluted with 300 mL of DCM, dried over MgSO4, filtered, and concentrated in vacuo to give dispiro[2.0.2] as a pale yellow oil. 4 .1 3 ]Heptan-7-ylmethanol (58.5 g, 78%) was obtained.

[0269] 1H NMR (400 MHz, chloroform-d) δ 3.71 (d, J = 6.7 Hz, 2H), 1.71 (t, J = 6.7 Hz, 1H), 1.51-1.39 (m, 1H), 0.93-0.81 (m, 4H), 0.71-0.61 (m, 2H), 0.61-0.49 (m, 2H).

[0270] Step 6: 7-(bromomethyl)dispiro[2.0.2 4 .1 3 Synthesis of ]heptane (12) [ka] To a solution of Ph3P (98.5 g, 375.5 mmol) in DCM (600 mL) was added dropwise a solution of Br2 (59.6 g, 372.9 mmol) in DCM (100 mL) at -15 °C. The reaction mixture was stirred at -15 °C for 15 min and then cooled to -30 °C. The mixture was added with dispiro[2.0.2] in DCM (100 mL). 4 .1 3 ] A solution of heptan-7-ylmethanol (43.2 g, 347.9 mmol) and pyridine (30 mL, 370.9 mmol) was added dropwise over 20 minutes. After the addition, the reaction was stirred at -5°C for 1 hour, at which time 1 Analysis by H NMR indicated complete reaction. The reaction mixture was concentrated in vacuo (35 °C / 200 Torr) until approximately 100 mL of slurry remained. The slurry was diluted with approximately 500 mL of 10% EtO / hexanes and the solid was filtered. The filtrate was concentrated in vacuo to give more precipitate, which was removed by filtration. The filtrate was concentrated again and the slurry was diluted with 250 mL of 10% EtO / hexanes. The precipitate was removed by filtration and washed with 50 mL of EtO. The filtrate was concentrated in vacuo to give 7-(bromomethyl)dispiro[2.0.2]. 4 .1 3 ]Heptane (65 g, 100%) was obtained.

[0271] 1H NMR(400MHz,chloroform-d)δ 3.49(d,J=7.5Hz,2H),1.90(t,J=7.5Hz,1H),1.02-0.91(m,5H),0.70(ddd,J=9.2,5.1,4.0Hz,2H),0.54(dddd,J=8.6,4.8,3.7,1.0Hz,2H).

[0272] The product was used in the next step without further purification.

[0273] Step 7: 2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)acetonitrile (11) [ka] 7-(Bromomethyl)dispiro[2.0.2] in DMSO (400 mL) 4 .1 3 To a solution of 2-(dispiro[2.0.2]heptane (65 g, 347.5 mmol) was added NaCN (17.5 g, 357.1 mmol). The red mixture was stirred at ambient temperature for 16 h. The reaction was poured into Na2CO3 (1,000 mL) and extracted three times with Et2O (500 mL). The combined organic phases were washed with water (500 mL), brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 2-(dispiro[2.0.2]heptane) as a dark red oil containing residual Et2O and PPh3O. 4 .1 3 ]heptan-7-yl)acetonitrile (45.9 g, 99%) was obtained.

[0274] 1 H NMR (400 MHz, chloroform-d) δ 2.42 (d, J = 6.6 Hz, 2H), 1.69 (t, J = 6.6 Hz, 1H), 1.03-0.88 (m, 4H), 0.78-0.68 (m, 2H), 0.64-0.55 (m, 2H).

[0275] Step 8: 2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)acetic acid (10) [ka] 2-(dispiro[2.0.2])-2-(2-methyl-2-propanol)-2-one in ethanol (300 mL) and water (100 mL) 4 .1 3 To a solution of 2-(dispiro[2.0.2]heptan-7-yl)acetonitrile (45 g, 337.9 mmol) was added NaOH (100 g of 50 w / w%, 1.250 mol). The mixture was stirred at 70 °C for 16 h. The ethanol was removed under vacuum, and the remaining aqueous phase was diluted with water (200 mL) and extracted twice with MTBE (400 mL). The aqueous phase was acidified with 6 M HCl (220 mL, 1.320 mol), and the dark mixture was extracted twice with MTBE (400 mL). The organic phase was washed with brine (400 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 2-(dispiro[2.0.2]heptan-7-yl)acetonitrile (45 g, 337.9 mmol) as a dark yellow solid containing MTBE and traces of PPh3O. 4 .1 3 ]heptan-7-yl)acetic acid (31.8 g, 62%) was obtained.

[0276] 1 H NMR(400MHz,chloroform-d)δ 2.44(d,J=6.9Hz,2H),1.67(t,J=6.9Hz,1H),0.91(ddd,J=9.0,5.2,3.9Hz,2H),0.81(d ddd,J=8.9,5.2,4.0,0.6Hz,2H),0.68(ddd,J=8.9,5.2,3.8Hz,2H),0.55-0.45(m,2H).

[0277] Step 9: 2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethan-1-ol (8) [ka] 2-(dispiro[2.0.2]) in THF (320 mL) 4 .1 3To a solution of 28.4 g (186.6 mmol) of 1,2-hexanediol (heptan-7-yl)acetic acid was added 8.2 g (210.5 mmol) (pellets). The mixture was stirred at ambient temperature for 16 hours. 1 H NMR indicated complete reaction). The reaction was quenched by careful sequential addition of water (8.2 mL, 455.2 mmol), NaOH (8.2 mL of 15 w / w%), and then water (24.6 mL, 1.366 mol). To the slurry was added MgSO4, and the slurry was stirred at ambient temperature for 30 min. The pale yellow precipitate was filtered using Celite and washed with MTBE. The filtrate was concentrated in vacuo (35 °C, 150 Torr) to give 2-(dispiro[2.0.2]) as a yellow oil containing approximately 9% MTBE. 4 .1 3 ]heptan-7-yl)ethan-1-ol (24.3 g, yield 94%) was obtained.

[0278] 1 H NMR(400MHz,chloroform-d)δ 3.62(t,J=6.9Hz,2H),1.68(q,J=6.8Hz,2H),1.39(t,J=6.6Hz,1H),0.89-0.74(m,4H),0.65(ddd,J=8.0,4.7,3.5Hz,2H),0.53-0.44(m,2H).

[0279] Step 10: 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2])-2-methyl-2-propanol) 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (7) [ka] DIAD (490 mL, 2.49 mol, 1.15 equiv.) in toluene (3 L) 4 .1 3To a suspension of 1-(tert-butyl)4-ethyl 3-(2-(dispiro[2.0.2-heptan-7-yl]ethan-1-ol) (85 wt%, 345 g, 2.17 mol, 1 eq.), 1-tert-butyl 4-ethyl 3-hydroxy-1H-pyrazole-1,4-dicarboxylate (555.6 g, 2.17 mol, 1 eq.), and triphenylphosphine (654.6 g, 2.49 mol, 1.15 eq.) was added. After stirring overnight at 40 °C, the reaction was diluted with heptane (1.2 L) and cooled to 20 °C over 60 min, allowing the majority of the triphenylphosphine oxide-DIAD complex to crystallize. At ambient temperature, the mixture was filtered, whereupon the cake was washed with heptane (1.5 L) and suction dried. The filtrate was concentrated under reduced pressure to give crude 1-(tert-butyl)4-ethyl 3-(2-(dispiro[2.0.2-heptan-7-yl]ethan-1-ol) as a viscous yellow oil. 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (1.2 kg). The residue was purified by flash column chromatography eluting with 20% ethyl acetate in hexane. The colorless oil was diluted with heptane (200 mL) and stirred at 0° C. for approximately 30 minutes. The resulting white solid was filtered to give 1-(tert-butyl)4-ethyl 3-(2-(dispiro[2.0.2]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (1.2 kg). 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (603.7 g, 74% yield, >95% purity).

[0280] 1 H NMR(300MHz,CDCl3)δ8.31(s,1H),4.37-4.26(m,4H),1.92(d,J=6.9Hz,2H),1 .64(s,9H),1.36(t,1H),1.32(t,J=4.2Hz,3H),0.86-0.82(m,4H),0.64-0.60 (m,2H),0.49-0.46(m,2H).

[0281] Mass spectrum (positive mode): m / z = 377.3 [M+H] + .

[0282] Step 11: 3-(2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (6) [ka] A 45% solution of potassium hydroxide in water (760 mL, 8.8 mol, 10.0 equiv.) was added to 1-(tert-butyl)4-ethyl 3-(2-(dispiro[2.0.2])-2-methyl-2-propanol in methanol (1 L) while maintaining the internal temperature below 50 °C. 4 .1 3 To a heated (40 °C) solution of [Heptan-7-yl]ethoxy)-1H-pyrazole-1,4-dicarboxylate (330 g, 877 mmol, 1.0 equiv.) was added portionwise. The reaction was stirred at 50 °C overnight, at which point LCMS indicated the reaction was complete. The reaction was partially concentrated under reduced pressure to remove most of the methanol. The resulting solution was diluted with water (1.65 L) and 2-MeTHF (1 L). The layers were shaken vigorously and separated. The aqueous layer was washed again with 2-MeTHF (660 mL). The aqueous layer was cooled to 5 °C and partially adjusted to pH 1 with 6 M aqueous HCl (2.24 L), maintaining the internal temperature between 10 and 30 °C. The product began to crystallize at approximately pH 7, accompanied by strong off-gassing. The resulting suspension was diluted with 2-MeTHF (2.7 L), and the product dissolved in the organic layer. Stirring was stopped and the layers were separated. The aqueous layer was re-extracted with 2-MeTHF (660 mL). The combined organic layers were washed with saturated brine (660 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50° C. Heptane (2 L) was added and the mixture was partially concentrated under reduced pressure to remove most of the 2-MeTHF. The mixture was stirred and cooled to room temperature. The resulting solid was filtered and washed with heptane (660 mL). The product was dried under vacuum at 35° C. overnight to give 3-(2-(dispiro[2.0.2])-2-methyl-2-propanol) as a white solid. 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (200.2 g, 92% yield, >99% purity).

[0283] 1 H NMR(300MHz,CDCl3)δ 7.96(s,1H),4.13(t,J=13.0Hz,2H),1.74(t,J=6.9Hz,2H),1.41(t,1H),0.83-0.77(m,4H),0.62-0.57(m,2H),0.45-0.41(m,2H).

[0284] Mass spectrum (positive mode): m / z = 497.2 [2M+H] + .

[0285] Example 2: 3-(2-(dispiro[2.0.2 4 .1 3 Alternative synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (6) [ka] Step 1: Synthesis of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (24) [ka] 55% w / w hydrazine hydrate (29 mL, 515 mmol, 1.03 equiv.) was added dropwise to a solution of diethyl 2-(ethoxymethylene)propanedioate (108 g, 500 mmol, 1 equiv.) in ethanol (0.45 L). The resulting mixture was heated to reflux for 20 h, after which HPLC indicated complete reaction. The mixture was a slurry when cooled to ambient temperature. The solid was collected by filtration, washed with EtOH (2 × 100 mL), and dried in a vacuum oven at 40 °C to give 46 g (60%) of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate as an off-white solid.

[0286] Step 2: Synthesis of ethyl 3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (23) [ka] 2,3-Dihydropyran (18 mL, 197.2 mmol, 1.03 equiv.) was added to a solution of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (30 g, 192 mmol, 1 equiv.) in acetonitrile (180 mL), and the resulting mixture was cooled to 0° C. p-Toluenesulfonic acid hydrate (1.26 g, 6.6 mmol, 0.035 equiv.) was added in one portion as a solid. After 2 h, the mixture was warmed to 10° C. After 2 h, HPLC showed complete conversion. The solid was collected by filtration, washed with acetonitrile (2×35 mL), and dried in a vacuum oven at 40° C. to give ethyl 3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (39.2 g, 85%) as an off-white solid.

[0287] Step 3: Ethyl 3-(2-(dispiro[2.0.2])-2.0.2) 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (21) [ka] 2-(dispiro[2.0.2]) in DMF (50 mL) 4 .1 3 A mixture of ethyl 3-(2-(dispiro[2.0.2-heptan-7-yl]heptan-7-yl)ethyl methanesulfonate (9.2 g, 43.2 mmol, 1.04 equiv.) and ethyl 3-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (10 g, 41.6 mmol, 1 equiv.) was stirred at room temperature. 1,1,3,3-tetramethylguanidine (5.7 mL, 45.7 mmol, 1.1 equiv.) was then added, and the mixture was heated to 60°C. After heating for 12 hours, HPLC indicated a complete reaction. 100 mL of water was added, followed by 75 mL of ethyl acetate. The phases were separated, and the organic layer was washed with 25 mL of water. The organic layer was filtered, concentrated, and dried in a vacuum oven at 40°C to give ethyl 3-(2-(dispiro[2.0.2-heptan-7-yl]heptan-7-yl)ethyl methanesulfonate as a pale yellow solid. 4 .1 3]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (14.3 g) which was used without further purification.

[0288] Step 4: 3-(2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (20) [ka] Ethyl 3-(2-(dispiro[2.0.2])-2-methyl-2,4-dimethyl ... 4 .1 3 A solution of ethyl 3-(2-(dispiro[2.0.2]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (7.15 g, 19.7 mmol, 1 equiv.) was stirred at room temperature. A precipitate began to form after approximately 30 minutes of stirring. After 1 hour, heptane (75 mL) was added, and the solid was collected by filtration, washed with heptane (2 x 10 mL), and dried in a vacuum oven at 40 °C to give ethyl 3-(2-(dispiro[2.0.2]heptan-7-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (7.15 g, 19.7 mmol, 1 equiv.). 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (4.03 g) was obtained, which was used further.

[0289] Step 5: 3-(2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (6) [ka] 45% aqueous potassium hydroxide (6 g, 106 mmol, 10 equiv.) was dissolved in ethyl 3-(2-(dispiro[2.0.2])-2-methyl-2-propanol) in methanol (12 mL). 4 .1 3To a solution of 3-(2-(dispiro[2.0.2-heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (4.03 g, 14.5 mmol, 1.0 equiv.) was added, and the mixture was stirred at 45° C. for 20 hours. Water (20 mL) and 2-methyltetrahydrofuran (18 mL) were added, and the layers were separated. The aqueous layer was washed with 2-methyltetrahydrofuran (8 mL) and adjusted to pH 1 with 6 N HCl. 2-Methyltetrahydrofuran (35 mL) was added, and the layers were separated. The aqueous phase was washed with 2-methyltetrahydrofuran (20 mL). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 3-(2-(dispiro[2.0.2-heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (4.03 g, 14.5 mmol, 1.0 equiv.))-1H-pyrazole-4-carboxylate (4.03 g, 14.5 mmol, 1.0 equiv.)-1H-pyrazole-4-carboxylate (2.0.2-heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (2.0.2-heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylate (2.0.2 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazole-4-carboxylic acid (2.73 g, purity 95.3%, 2-(dispiro[2.0.2 4 .1 3 ]heptan-7-yl)ethyl methanesulfonate in a 48% yield over three steps.

[0290] Example 3: Dispiro[2.0.2 4 .1 3 ] Alternative synthesis of heptane-7-carboxylic acid (14) [ka] Step 1: Synthesis of ethyl 2-cyclopropylideneacetate (26) [ka] To a 3000 mL round-bottom flask equipped with a magnetic stir bar was added (1-ethoxycyclopropoxy)trimethylsilane (200 g, 1147 mmol, 1.1 equiv.). Methanol (600 mL) was then added, and the resulting solution was stirred overnight at room temperature. The solvent was evaporated under reduced pressure (25°C water bath). The residual oil was dissolved in tetraethylene glycol dimethyl ether (700 mL) using a magnetic stir bar. Benzoic acid (28 g, 229 mmol, 0.22 equiv.) was then added, and the resulting mixture was heated to 100°C (heat block). Ethyl (triphenylphosphoranylidene)acetate (360 g, 1033 mmol, 1.0 equiv.) was dissolved in dichloromethane (550 mL) in a 1000 mL addition funnel and added dropwise to the above cyclopropanone solution over 2 h. After the addition, the addition funnel was closed to collect the condensed dichloromethane. The resulting mixture was heated at 100 °C for an additional hour and then cooled to room temperature. The reaction mixture was then purified by fractional distillation at 0.54 Torr from 83 to 100 °C (the cooling temperature of the fluid in the condenser was -6 °C, and all distillates under these conditions were identified as product). A total of 164.19 g of crude ethyl 2-cyclopropylideneacetate (61% purity by Q-NMR) was obtained. The crude ethyl 2-cyclopropylideneacetate was dissolved in pentane (400 mL), washed with ice-cold saturated sodium carbonate solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure (25 °C water bath) to give ethyl 2-cyclopropylideneacetate (92.52 g, 80% purity by Q-NMR, 57% yield) as a colorless liquid.

[0291] 1 H NMR (300MHz, CDCl3) δ 6.23(t,J=1.8Hz,1H),4.22(q,J=7.2Hz,2H),1.49-1.42(m,2H),1.33-1.20(m,5H).

[0292] Mass spectrum (positive mode): m / z = 125.8 [M] + .

[0293] Step 2: Ethyl dispiro[2.0.24 .1 3 Synthesis of ]heptane-7-carboxylate (15) [ka] Cyclopropyl(diphenyl)sulfonium(tetrafluoroborate) (95%, 265 g, 800 mmol, 1.01 equiv.) was dissolved in non-anhydrous dimethyl sulfoxide (4000 mL) in a 22 L round-bottom flask equipped with an overhead stirrer. Room temperature water was added to the secondary vessel. Ethyl 2-cyclopropylideneacetate (79% pure by Q-NMR, 33.75 g; 80% pure by Q-NMR, 92.52 g, 793 mmol, 1.0 equiv.) was added, followed by cesium hydroxide hydrate (containing approximately 10% HO, 133 g, 800 mmol, 1.01 equiv.) in one portion. At 120 min, ice was added to the secondary vessel, and the reaction was diluted with ice-cold methyl tert-butyl ether (8 L). Ice-cold saturated ammonium chloride solution (6 L) was added slowly, maintaining the temperature below 25 °C. The aqueous layer was extracted with methyl tert-butyl ether (4 L x 3) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure (25 °C water bath) to give a total of crude ethyl dispiro[2.0.2] as a pale yellow liquid. 4 .1 3 ]heptane-7-carboxylate (316.67 g) was obtained.

[0294] The crude ethyl dispiro[2.0.2] with approximately 17% ethyl 2-cyclopropylideneacetate (68.17 g, approximately 170.7 mmol, 1.0 equiv.) 4 .1 3]heptane-7-carboxylate was dissolved in non-anhydrous dimethyl sulfoxide (300 mL) at room temperature. Cyclopropyl(diphenyl)sulfonium(tetrafluoroborate) (95%, 19.2 g, 58 mmol, 0.34 equiv.) was added, followed by the addition of cesium hydroxide hydrate (containing approximately 10% HO, 9.7 g, 58 mmol, 0.34 equiv.) in one portion. At 120 min, the reaction was diluted with methyl tert-butyl ether (800 mL). The DMSO layer was separated and cooled to 0 °C in an ice bath. The MTBE layer was washed with saturated ammonium chloride solution (650 mL). This aqueous layer was separated and slowly added to the above DMSO mixture. The resulting aqueous layer was extracted with methyl tert-butyl ether (800 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure (25 °C water bath) to give crude ethyl dispiro[2.0.2 4 .1 3 ]heptane-7-carboxylate. Another batch of this reaction (approximately 17% ethyl 2-cyclopropylideneacetate) was used to obtain 204.51 g of crude ethyl dispiro[2.0.2]heptane-7-carboxylate. 4 .1 3 ]heptane-7-carboxylate) was treated in the same manner, and both batches were combined and purified. This combined mixture was then purified by fractional distillation at 0.68 Torr from 68 to 120 °C (the cooling temperature of the fluid in the condenser was -6 °C, and all distillates under these conditions were identified as product) to give crude ethyl dispiro[2.0.2]heptane-7-carboxylate as a colorless liquid. 4 .1 3 ]heptane-7-carboxylate (83.32 g, 65% purity by Q-NMR, 47% yield).

[0295] 1 H NMR(300MHz,CDCl3)δ6.23(t,J=1.8Hz,1H),4.22(q,J=7.2Hz,2H), 1.49-1.42(m,2H),1.33-1.20(m,5H).

[0296] Mass spectrum (positive mode): m / z = 165.1 [MH] + .

[0297] Step 3: Dispiro 2.0.2 4 .1 3 Synthesis of ]heptane-7-carboxylic acid (14) [ka] Ethyl dispiro[2.0.2] in methanol / THF (8:1, 126 mL) 4 .1 3 To a crude mixture of 2.0.2 heptane-7-carboxylate (5.0 g, 30.0 mmol, 1.0 equiv.) and diphenyl sulfide (6.24 g) was added lithium hydroxide (0.72 g, 30.0 mmol, 1.0 equiv.) and aqueous sodium hydroxide (21.0 g, 525.0 mmol, 17.5 equiv.) in water (30 mL). The resulting mixture was stirred at 40° C. overnight. The solvent was removed under reduced pressure, and the residue was then dissolved in water (80 mL) and washed with methyl tert-butyl ether (80 mL). The pH of the aqueous layer was adjusted to 2 using 5 N HCl (approximately 110 mL). The precipitate was collected by suction filtration, dried to constant weight, and purified as a white solid to give dispiro[2.0.2]. 4 .1 3 ]Heptane-7-carboxylic acid (2.98 g, 72% yield, >95% purity) was obtained.

[0298] 1 H NMR (300MHz, CDCl3) δ2.26 (s, 1H), 1.11-1.02 (m, 4H), 0.90-0.80 (m, 4H).

[0299] Mass spectrum (positive mode): m / z = 137.0 [MH] + .

[0300] Example 4: 2-(dispiro[2.0.2 4 .1 3 Alternative synthesis of ]heptan-7-yl)acetic acid (10) [ka] Step 1: Dispiro 2.0.2 4.1 3 Synthesis of ]heptane-7-carboxylic acid (14) [ka] Sodium hydroxide (21.5 g, 542 mmol, 2.0 equiv.) was dissolved in ethyl dispiro[2.0.2] in a 4:1 mixture of methanol and water (500 mL). 4 .1 3 ]heptane-7-carboxylate (45.0 g, 271 mmol, 1 equiv.) and stirred at 55 °C for 4 h. LC-MS showed the reaction was complete. Most of the solvent was removed under reduced pressure, and the residue was then suspended in water (100 mL) and the pH was adjusted to 2 using 5 N HCl. The precipitate that formed was collected by suction filtration and dried to constant weight to give dispiro[2.0.2] as an off-white solid. 4 .1 3 ]Heptane-7-carboxylic acid (31 g, 85% yield, >95% purity) was obtained.

[0301] 1 H NMR (300MHz, CDCl3) δ2.25 (s, 1H), 1.05 (m, 4H), 0.88-0.96 (m, 4H).

[0302] Mass spectrum (positive mode): m / z = 136.9 [MH] + .

[0303] Step 2: 2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)acetic acid (10) [ka] Thionyl chloride (176 mL, 2.4 mol, 9.6 equiv.) was added to dispiro[2.0.2 4 .1 3]heptane-7-carboxylic acid (35 g, 251 mmol, 1.0 equiv.) was added, and the resulting solution was heated at 60 °C for 2 h. The reaction was cooled to room temperature, concentrated under reduced pressure, and then azeotroped with toluene (2 × 50 mL) until all thionyl chloride was removed. The residue was diluted with anhydrous acetonitrile (3 L). Trimethylsilyldiazomethane (2 M in hexanes, 190 mL, 380 mmol, 1.5 equiv.) was added over 5 min. After stirring for 2 h, silver acetate (64 g, 380 mmol, 1.5 equiv.), triethylamine (70 mL, 502 mmol, 2.0 equiv.), and water (200 mL) were added sequentially. After stirring overnight, the reaction was filtered through a 2-inch pad of Celite, which was rinsed with acetonitrile (100 mL). The combined filtrates were concentrated under reduced pressure to remove most of the acetonitrile. The resulting semi-solid was diluted with 1N HCl (300 mL) and dichloromethane (300 mL). The mixture was filtered again through a 1-inch pad of Celite, which was washed with additional dichloromethane (100 mL). The layers were separated, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a yellow solid (approximately 2.3% of dispiro[2.0.2]). 4 .1 3 ]heptane-7-carboxylic acid) as 2-(dispiro[2.0.2 4 .1 3 ]heptan-7-yl)acetic acid (28 g, 78% yield, approximately 85% purity by GC-MS).

[0304] 1 H NMR(400MHz,chloroform-d)δ 2.44(d,J=6.9Hz,2H),1.67(t,J=6.9Hz,1H),0.91(ddd,J=9.0,5.2,3.9Hz,2H),0.81(d ddd,J=8.9,5.2,4.0,0.6Hz,2H),0.68(ddd,J=8.9,5.2,3.8Hz,2H),0.55-0.45(m,2H).

[0305] Example 5: 2-(dispiro[2.0.2 4 .1 3 Alternative synthesis of ]heptan-7-yl)acetic acid (10) [ka] Step 1: Ethyl 2-(dispiro[2.0.2] 4 .1 3 Synthesis of ]heptan-7-yl)-2-oxoacetate (28) [ka] A solution of ethyl 3-diazo-2-oxopropionate (16.2 g, 125 mmol, 2.0 equiv.) in dichloromethane (approximately 48 mL, total volume of the solution was 60 mL) was added over 24 h to a suspension of rhodium octanoate dimer (0.78 g, 1 mmol, 0.016 equiv.) and 1,1'-bi(cyclopropylidene) (5 g, 62.5 mmol, 1 equiv.) in dichloromethane (10 mL) at 0 °C via a syringe pump at 0.04 mL / min, keeping the needle tip below the solvent surface. 1 H-NMR analysis indicated 80% conversion of the starting material (including approximately 10% of a homocoupling by-product). The reaction mixture was warmed to room temperature and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (RediSep 2 x 220 g) eluting with a gradient of 0 to 30% ethyl acetate in heptane to give ethyl 2-(dispiro[2.0.2]) as a pale yellow liquid. 4 .1 3 ]heptan-7-yl)-2-oxoacetate (7.1 g, 58% yield, 1 The purity was over 95% by HNMR.

[0306] 1 H NMR(300MHz, CDCl3)δ 4.28(q,J=7.2Hz,2H),3.24(s,1H),1.35(t,J=7.2Hz,3H),1.15-1.09(m,2H),1.01-0.95(m,2H),0.92-0.80(m,4H).

[0307] Mass spectrum (positive mode): m / z = 195.1 [M+H] + .

[0308] Step 2: 2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)acetic acid (10) [ka] Ethyl 2-(dispiro[2.0.2 4 .1 3 [Heptan-7-yl]-2-oxoacetate (5 g, 25.7 mmol, 1.0 equiv.) was added dropwise to a solution of hydrazine hydrate (50-60% in water, 4.95 g, 77 mmol, 3.0 equiv.) and water (5 mL) at -20 °C. The reaction mixture became a loose solid after the addition. The mixture was warmed to room temperature over 30 min and then heated to 80 °C for 5 min. After the reaction mixture was cooled to room temperature, potassium hydroxide (3.6 g, 64.4 mmol, 2.5 equiv.) was added in three portions while the reaction mixture became a solution. The reaction was stirred at 80 °C for 16 h, after which GC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (15 mL), and washed with diethyl ether (30 mL). The aqueous layer was adjusted to pH 1 with concentrated HCl (approximately 6 mL). The aqueous layer was extracted with toluene (4 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2-(dispiro[2.0.2]) as a pale yellow solid. 4 .1 3 ]heptan-7-yl)acetic acid (3.2 g, 82% yield, 1 The purity was about 94% by HNMR and GC-MS.

[0309] 1 H NMR(300MHz, CDCl3)δ 2.44(d,J=6.9Hz,1H),1.63(t,1H),0.91-0.88(m,2H),0.82-0.80(m,2H),0.68(m,2H),0.52(m,2H).

[0310] Mass spectrum (positive mode): m / z = 151.1 [MH] + .

[0311] Example 6: 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2 4 .1 3 Alternative synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (7) [ka] Step 1: 2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethyl methanesulfonate (22) [ka] 2-(dispiro[2.0.2]) in 2-MeTHF (160 mL) 4 .1 3 A mixture of 2-(dispiro[2.0.2]heptan-7-yl)-ethan-1-ol (20 g, 144.6 mmol, 1 equiv.) and triethylamine (26.1 mL, 185.8 mmol, 1.28 equiv.) was cooled to 0 °C. A solution of MsCl (15.1 mL, 193.7 mmol; 1.34 equiv.) in 2-MeTHF (90 mL) was added dropwise over 1 h while maintaining the reaction temperature at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for an additional 1 h. The mixture was allowed to warm to ambient temperature. The reaction mixture was quenched with water (80 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO (80 mL), dried over Na SO, filtered, and concentrated under reduced pressure. The residue was dried in vacuo to give 2-(dispiro[2.0.2]heptan-7-yl)-ethan-1-ol as a brown solid. 4 .1 3 ]heptan-7-yl)ethyl methanesulfonate (33.1 g) was obtained, which was used subsequently.

[0312] Step 2: 1-(tert-butyl) 4-ethyl 3-(2-(dispiro[2.0.2])-2-methyl-2-propanol 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (7) [ka] 1-tert-Butyl 4-ethyl 3-hydroxy-1H-pyrazole-1,4-dicarboxylate (38.7 g, 151.2 mmol, 1 equiv.), 2-(dispiro[2.0.2])-2-hydroxy-1H-pyrazole-1,4-dicarboxylate (38.7 g, 151.2 mmol, 1 equiv.) in DMF (180 mL). 4 .1 3 A mixture of 1-(tert-butyl)-4-ethyl 3-(2-(dispiro[2.0.2]heptan-7-yl)ethyl methanesulfonate (33.1 g, 152.7 mmol, 1.01 equiv.) and CsCO (55.1 g, 169.3 mmol, 1.12 equiv.) was heated at 50 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with water (360 mL) and 2-MeTHF (360 mL), and the phases were separated. The aqueous phase was extracted with 2-MeTHF (2 × 150 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (RediSep 220 g) eluting with a gradient of 0–35% ethyl acetate in heptane to give the compound 1-(tert-butyl)-4-ethyl 3-(2-(dispiro[2.0.2]heptan-7-yl)ethyl methanesulfonate (33.1 g, 152.7 mmol, 1.01 equiv.) and CsCO (55.1 g, 169.3 mmol, 1.12 equiv.). 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazole-1,4-dicarboxylate (34.3 g, 2-(dispiro[2.0.2 4 .1 3 ]heptan-7-yl)-ethan-1-ol in 67% yield and 97% purity over two steps.

[0313] 1 H NMR(400MHz,CDCl3)δ 8.32(s,1H),4.35(t,J=8.0Hz,2H),4.31(q,J=8.0Hz,2H),1.93(q,J=8.0Hz,2H),1.63(s,9H),1.4 8(t,J=6.4Hz,1H),1.35(t,J=8.0Hz,3H),0.90-0.78(m,4H),0.67-0.62(m,2H),0.50-0.47(m,2H).

[0314] Mass spectrum (positive mode): m / z = 377.2 [M+H] + .

[0315] Example 7: Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (49) [ka] Step 1: Preparation of (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (4) [ka] Racemic 3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one was dissolved in 80 g / L + / - 8 g / L in MeOH / ACN 70 / 30 v / v (target 80 + / - 2 g / L) and separated on a Chiralpak AD 20 μm column using MeOH / ACN 70 / 30 v / v as the mobile phase and the stationary phase. (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one is peak 2. Optional recrystallization of (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one: (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (9.5 kg, 1.0 equiv.) was stirred in isopropanol (76 L, 8 vol.) and then heated to above 70°C to dissolve the solids. The mixture was then cooled to 20°C over 4-5 hours, the solids isolated by filtration, and the cake washed with isopropanol (4.75 L, 0.5 vol.) and suction dried. The material was dried under vacuum, resulting in approximately 90% recovery of (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one.

[0316] Step 2: Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3) [ka] A suspension of Raney Nickel 2400 (77 wt%, 2.8 kg) was allowed to settle for 2 days. The standing liquid was decanted and discarded, and the remaining catalyst, along with a water auxiliary (2.6 kg), was charged to a reactor and then degassed with N2. In a second reactor, a mixture of (S)-3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one (13.9 kg) and EtOH (170.8 kg) was heated to 30 °C, degassed with N2, and then transferred to the reactor containing Raney Nickel. The transfer was completed with an EtOH (29.8 kg) rinse. The mixture was purged three times with nitrogen and three times with hydrogen. The reactor contents were heated to 60-65 °C and stirred under H2 (4-8 psi) until the reaction was complete (18 h). The mixture was cooled to 15-20°C, purged with nitrogen three times, and then filtered through a pad of Celite (3.0 kg) wetted with EtOH (3.2 kg). The reactor and Celite cake were washed with EtOH (2 x 14.0 kg). The filtrate was distilled to a final volume of approximately 25 L and then heated to 45°C. MTBE (269.4 kg) was then distilled at ambient pressure from 48-55°C, maintaining a temperature of 48-50°C, to a final volume of approximately 30 L. Two more portions of MTBE (269.4 kg, then 187.4 kg) were added sequentially and then concentrated to a volume of approximately 30 L.

[0317] The reactor contents were seeded with (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (70.1 g) at 40°C. The seeded crystal slurry was cooled to 15°C over 3.5 hours, then stirred at 12-15°C for 16.5 hours, and then filtered. The reactor and filter cake were then washed with chilled (-2 to -10°C) MTBE (2 x 10 kg). The filter cake was dried to constant weight to give (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (10.4 kg, 88%) as a white crystalline solid.

[0318] Recrystallization of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one: A mixture of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (10.3 kg) and DCM (28.2 kg) was stirred and heated to 25°C for 2 hours, then transferred to another reactor through an in-line filter (45 μm). The initial reactor was rinsed with DCM (6.8 kg) at 21°C for 10 minutes, then transferred to the reactor through an in-line filter. MTBE (38.1 kg) was charged to the solution at 25-30°C, and the mixture was distilled at atmospheric pressure from 35-52°C over 2.5 hours to a final volume of approximately 30 L. MTBE (38.2 kg) was charged to the reactor at 45-50°C. The resulting suspension was distilled at 49-55°C over 3.25 hours to a final volume of approximately 30 L. The reactor contents were cooled to 21° C. over 2.5 hours and stirred at 20° C. for 16 hours. The suspension was filtered. The reactor and filter cake were rinsed with MTBE (7.7 kg, 0.0° C.). The filter cake was dried for 2 days. Yield: 9.1 kg (88.3%) of an off-white solid.

[0319] 1 H NMR(400MHz,DMSO-d6)δ 7.63(s,1H),4.38(s,1H),3.38(t,J=6.5Hz,2H),2.37(qd,J=9.5,4.4Hz,1H),2.02(d d,J=12.4,8.6Hz,1H),1.78-1.63(m,1H),1.50-1.33(m,3H),1.16(d,J=17.9Hz,7H).

[0320] ESI-MS m / z calculated 171.12593, observed 172.0 [M+1] + .

[0321] GCMS: 100% (AUC).

[0322] Chiral HPLC: 100% (AUC).

[0323] Step 3: Synthesis of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2) [ka] LiAlH pellets (332.5 g, 8.760 mol, 1.50 equiv.) were slowly added to a reactor containing 2-MeTHF (10.00 L, 10 vol.) at 30–40 °C. The mixture was then heated to 75 °C. A mixture of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (1,000 g, 5.840 mol, 1.00 equiv.) and 2-MeTHF (10.00 L, 10 vol.) was prepared in a separate reactor, heated to 65 °C, and then carefully transferred to the reactor containing the LiAlH mixture over 2 h. The mixture was stirred at 70 °C until the reaction was complete (18–24 h) and then cooled to 0–10 °C. Water (400.0 mL, 1× LiAlH by weight) was then carefully added while maintaining the temperature of the mixture below 30 °C. Then, while maintaining the mixture temperature below 30 °C, 15% aqueous NaOH (400.0 mL, 1 × LiAlH4 by weight) was added, followed by water (400.0 mL, 1 × LiAlH4 by weight). The resulting mixture was then heated to 60 °C and held at that temperature for at least 30 minutes. The mixture was cooled to 20-30 °C, and then Celite (200 g, 20 wt%) was added. The mixture was then filtered through a pad of Celite. The reactor and filter cake were rinsed with 2-MeTHF (4.0 L, 4.0 vol). The filtrate was concentrated under vacuum to give the pyrrolidine compound (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (872 g; 94.95% yield) as a clear oil.

[0324] 1 H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 3.36 (t, J = 6.3 Hz, 3H), 2.95 (dd, J = 10.6, 7.6 Hz, 1H), 2.40 (dd, J = 10.6, 7.7 Hz, 1H), 2.12-1.97 (m, 1H), 1.69 (dd, J = 12.1, 8.2 Hz, 1H), 1.47-1.25 (m, 5H), 1.08 (s, 3H), 1.02 (s, 3H).

[0325] Step 4: Synthesis of (S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide [ka] A mixture of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2325 g, 14.8 mol) and 6-bromo-2-fluoropyridine-3-carboxamide (3400 g, 15.5 mol) in 2-methyltetrahydrofuran (23 L) was stirred, and then potassium carbonate (2650 g, 19.2 mol) and deionized water (7 L) were added. The mixture was stirred at less than 25° C. until the reaction was complete (16 hours or more).

[0326] The aqueous phase was removed, and the upper organic phase was washed with water (7 L) and 2% aqueous sodium chloride solution (7 L). The organic layer was concentrated under reduced pressure to approximately 19 L. 2-Methyltetrahydrofuran was chased from the mixture by two sequential additions and concentrations of acetonitrile (2 × 20 L), followed by distillation. To the remaining solution, acetonitrile (20 L) was added, and the reaction was warmed to 85 °C for 2 hours, then cooled to 25 °C at 10 °C / hour. The slurry was cooled to 10 °C, stirred for 4 hours, and then filtered. The cake was rinsed twice with acetonitrile (2 × 3 L), and the solid was dried under vacuum to give (S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (3850 g, 73% yield) as a crystalline white solid.

[0327] 1 H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.39(s,1H),7.34(dd,J=7.7,1.0Hz,1H),6.67(d,J=7.6Hz,1H),4.42(t,J=5.1Hz,1H),3.39(q,J= 5.7Hz,2H),3.29-3.12(m,2H),2.19(dt,J=10.9,5.8Hz,1H),1.92(dd,J=11.9,5.7Hz,1H),1.53(s,3H),1.50(s,3H),1.48-1.29(m,5H).

[0328] Step 5: Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (49) [ka] A mixture of (S)-6-bromo-2-(4-(3-hydroxypropyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (2.65 kg, 7.4 mol), 2-methyltetrahydrofuran (16 L), and triethylamine (900 g, 8.88 mol) was stirred at 20° C., and then methanesulfonyl chloride (933 g, 8.14 mol) was added over 2 hours. The mixture was stirred at 20° C. until the reaction was complete (typically 16 hours). The resulting mixture was filtered, and the filter cake was rinsed with tert-butyl methyl ether (2×4 L). The combined filtrate (containing the mesylate intermediate) was transferred to a reactor and diluted with dimethyl sulfoxide (16 L). To the mixture was added phthalimide (1198 g, 8.14 mol). The mixture was stirred until a solution was obtained, and then potassium carbonate (1023 g, 7.4 mol) was added. The mixture was stirred and heated to 70° C. until the reaction was complete (2 h). The mixture was cooled to 20° C. and diluted with 2-methyltetrahydrofuran (16 L), followed by the addition of deionized water (21 L). The phases were separated, and the upper organic phase was washed with deionized water (10 L) and saturated aqueous sodium chloride solution (2 × 1 L). The organic phase was diluted with toluene (16 L) and concentrated under reduced pressure to a volume of approximately 10 L. The solid was isolated by filtration, and the filter cake was rinsed with toluene (2 × 2 L). The resulting solid was dried to give the compound (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (3393 g, 6.99 mol, 94% yield) as an off-white solid.

[0329] 1H NMR(400MHz,DMSO-d6)δ7.91-7.80(m,4H),7.80-7.71(m,1H),7.42-7.36(m,1H),7.34( d,J=7.7Hz,1H),7.29-7.09(m,3H),6.67(d,J=7.7Hz,1H),3.59(t,J=6.9Hz,2H),3.23( t,J=10.4Hz,1H),3.16(dd,J=10.2,7.4Hz,1H),2.30(s,2H),2.28-2.13(m,1H),1.90(d d,J=12.0,5.6Hz,1H),1.71-1.53(m,2H),1.51(s,3H),1.48(s,3H),1.47-1.23(m,3H).

[0330] Example 8: Synthesis of (R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide The reaction in this example uses (S)-(-)-α-methylbenzylamine as a reagent and therefore provides (R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide. (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide can be obtained using the same reactants and (R)-(-)-α-methylbenzylamine as a reagent. [ka]

[0331] Step 1: Synthesis of tert-butyl (3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propyl)carbamate (37) [ka] To a stirred solution of 3-tert-butoxycarbonylamino-propionic acid (30.0 g, 158.6 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (27.4 g, 190.3 mmol), and 4-dimethylaminopyridine (31.03 g, 254.0 mmol) in dichloromethane (600 mL) was added dropwise a solution of N,N'-dicyclohexylcarbodiimide (39.3 g, 190.3 mmol) in dichloromethane (300 mL) at 0 °C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 16 h. The precipitated dicyclohexylurea was filtered, and the filtrate was washed with 5% aqueous potassium hydrogen sulfate (3 × 200 mL), followed by brine (100 mL), and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered, and the filtrate was cooled to 0 °C. Glacial acetic acid (91 mL, 1.59 mol) was added slowly, followed by the portionwise addition of sodium borohydride (15.0 g, 397.0 mmol). After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was recooled to 0° C. and quenched with water (200 mL). The organic layer was separated, washed with water (2×300 mL), followed by brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give crude 2,2-dimethyl-5-(3-tert-butoxycarbonylamino-propyl)-[1,3]dioxane-4,6-dione (49.05 g, 103%, containing approximately 10% unreacted 2,2-dimethyl-[1,3]dioxane-4,6-dione) as an off-white solid. The crude product was carried on to the next step without further purification.

[0332] LCMS Method: Final purity was determined by reverse-phase HPLC using a Kinetex C18 column (50 x 3.0 mm) and a double gradient run of 5 to 100% mobile phase B over 12 min. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H). Flow rate = 1.5 mL / min, injection volume = 10 μL, column temperature = 30 °C.

[0333] 1H NMR(250MHz,CDCl3)δ(ppm):4.62(broad s,1H),3.74-3.72(m,1H),3.22-3.15(m,2H),2.17-2.08(m,2H),1.81(s,3H),1.75(s,3H),1.70-1.66(m,2H),1.43(s,9H).

[0334] ESI-MS m / z calculated 301.3, observed 302.2 [M+1] + . Retention time: 3.87 minutes.

[0335] Step 2: Synthesis of ethyl 5-((tert-butoxycarbonyl)amino)-2-methylenepentanoate (36) [ka] To a stirred solution of 2,2-dimethyl-5-(3-tert-butoxycarbonylamino-propyl)-[1,3]dioxane-4,6-dione (23.7 g, 78.6 mmol) in absolute ethanol (850 mL) was added N,N'-dimethylmethyleneiminium iodide (36.5 g, 197.0 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 65°C for 18 hours. The reaction mixture was concentrated, and the crude product was extracted with ethyl acetate (400 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (400 mL), 10% aqueous potassium hydrogen sulfate solution (400 mL), and brine (100 mL), then dried over anhydrous sodium sulfate and concentrated. The product was purified by silica gel column chromatography using 0-15% hexane-ethyl acetate to give 5-tert-butoxycarbonylamino-2-methylene-pentanoic acid ethyl ester (14.76 g, 73%) as a colorless oil.

[0336] 1H NMR(250MHz,CDCl3)δ(ppm):6.17(s,1H),5.56(s,1H),4.60(broad s,1H),4.24-4.16(q,J=7.1Hz,2H),3.17-3.10(m,2H),2.30-2.36(m,2H),1.72-1.60(m,2H),1.44(s,9H),1.30(t,J=7.1Hz,3H).

[0337] ESI-MS m / z calculated 257.3, observed 258.7 [M+1] + . Retention time: 5.12 minutes.

[0338] Step 3: Synthesis of ethyl 2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoate (35) [ka] To a stirred solution of 5-tert-butoxycarbonylamino-2-methylene-pentanoic acid ethyl ester (16.95 g, 65.87 mmol) and 2-nitropropane (29.4 g, 330.0 mmol) in anhydrous acetonitrile (250 mL) under a nitrogen atmosphere, 1,8-diazabicyclo[5.4.0]undec-7-ene (12.03 g, 79.0 mmol) was added, and the reaction mixture was heated to 90 °C for 2 h. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate (400 mL). The organic layer was washed with 5% aqueous potassium hydrogen sulfate (2 × 300 mL), followed by brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The product was purified by silica gel column chromatography using 0-25% hexane-acetone to give 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid ethyl ester (20.65 g, 90%) as a yellow oil.

[0339] 1H NMR(250MHz,CDCl3)δ(ppm):4.51(broad s,1H),4.17-4.08(q,J=7.1Hz,2H),3.13-3.08(m,2H),2.45-2.29(m,2H),2.1 7-2.04(m,1H),1.73-1.64(m,1H),1.58-1.36(m,18H),1.25(t,J=7.1Hz,3H).

[0340] ESI-MS m / z calculated 346.4, observed 347.3 [M+1]. Retention time: 5.65 min.

[0341] Step 4: Synthesis of 2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoic acid ((±)-34) [ka] To a mixture of 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid ethyl ester (5 g, 14.43 mmol) in ethanol (20 mL) was added 10 w / v% NaOH (7 mL, 17.50 mmol) under a nitrogen atmosphere, and the reaction mixture was heated to 50 °C. After 5 h, an additional 0.7 mL of 10 w / v% NaOH was added. After heating for an additional 2 h, LC indicated a complete reaction. 20 mL of water was added to the reaction mixture, and the mixture was concentrated to remove the EtOH. 15 mL of IPAc was added. After mixing, the layers were separated, and the aqueous layer was acidified with 6 M HCl (pH 2-3). 20 mL of IPAc was added. After mixing, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid.

[0342] The crude product from above was dissolved in 30 mL of IPAc. Dicyclohexylamine (2.6 mL, 13.05 mmol) was added dropwise via an addition funnel. Upon stirring, crystallization initiated. After stirring the slurry for several hours, the solid was collected by filtration and washed with IPAc (2 x 7 mL). The salt was dried in a vacuum oven at 50 °C with a N bleed to give 6.37 g of 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid dicyclohexylammonium salt (88% over two steps).

[0343] The salt was then slurried in 40 mL of IPAc. 20 mL of 10 w / v% aqueous citric acid was added. The mixture was stirred vigorously until all solids dissolved. The layers were then separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. 50 mL of heptane was added, and the mixture was concentrated. 40 mL of heptane was added to the solid, and the slurry was stirred at ambient temperature. After stirring the slurry for several hours, the solid was collected by filtration and washed with heptane (2 x 8 mL). The product was dried in a vacuum oven at 50 °C with a N bleed to give 3.27 g of 2-(3-tert-butoxycarbonylamino-propyl)-4-methyl-4-nitro-pentanoic acid (71% overall).

[0344] Step 5: Synthesis of (R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoic acid [ka] Initial crystallization: To a 100 mL flask containing 2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoic acid (5 g, 15.705 mmol, 1 equiv.) in CHCN (25 mL, 0.628 M, 5 vol.) was added (S)-(-)-α-methylbenzylamine (0.952 g, 1.012 mL, 7.852 mmol, 0.5 equiv.). With stirring at ambient temperature, the mixture first became clear and then became a slurry within 5-10 min.

[0345] The mixture was heated to 75°C and held at 71-75°C for 1 hour, then cooled to 60°C and held at 60°C for 1 hour. The mixture was then cooled to 50°C and seeded with approximately 25 mg of (R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentanoic acid. The mixture became cloudy and after 1 hour was cooled to 40°C. The resulting slurry was held at 40°C for 1 hour, then cooled to ambient temperature and stirred overnight. The slurry was collected by filtration, washed with ACN (3 × 3 mL), and dried in a vacuum oven overnight at 40°C with a N bleed. 2.27 g was obtained (TY = 3.45 g, 65%). The enantiomeric ratio was 95:5 [% (AUC)]. The mother liquor ratio was 26:74.

[0346] First recrystallization: (1R)-1-phenylethanaminium 2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoate (2.22 g, 5.051 mmol, 1 equiv.) in CHCN (15.54 mL, 0.325 M, 7 vol.) in a 50 mL RBF. The mixture was heated to 75 °C; the mixture became homogeneous at 66 °C and was held at 71–75 °C for 1 hour. It was then cooled to 60 °C to form a slurry. It was held at 60 °C for 1 hour. It was cooled to 50 °C and held for 1 hour. It was cooled to 40 °C. It was held at 40 °C for 1 hour, and then cooled to ambient temperature with stirring overnight. The solid was collected by filtration and dried overnight in a vacuum oven at 40 °C with a N bleed to give 2.056 g of product (92%) as a white solid. The enantiomer ratio was 97:3 [%(AUC)]. The mother liquor ratio was 25:75.

[0347] Second recrystallization: To a 100 mL round-bottom flask was added (1R)-1-phenylethanaminium 2-{3-[(tert-butoxycarbonyl)amino]propyl}-4-methyl-4-nitropentanoate (2 g, 4.55 mmol, 1 equiv.) in CHCN (16 mL, 0.284 M, 8 volumes). The mixture was heated to 75°C. The mixture became homogeneous above 66°C and was then held at 71-75°C for 1 hour. The mixture was then cooled to 65°C. A slurry formed and was held for 1 hour. The mixture was then cooled to 60°C and held for 1 hour, then cooled to 55°C and held for 1 hour, then cooled to 50°C and held for 1 hour, then cooled to 45°C and held for 1 hour, then cooled to ambient temperature and stirred overnight. The solid was collected by filtration and dried overnight in a vacuum oven at 40 °C with a N bleed to give 1.92 g of product (96%, 57% overall) as a white solid. The enantiomeric ratio was 99:1 [% (AUC)]. The mother liquor ratio was 53:47.

[0348] Step 6: Synthesis of tert-butyl (R)-(4-(hydroxymethyl)-6-methyl-6-nitroheptyl)carbamate [ka] CDI (305.7 mg, 1.885 mmol) was added to a solution of (R)-2-[3-(tert-butoxycarbonylamino)propyl]-4-methyl-4-nitro-pentanoic acid (500 mg, 1.571 mmol) in THF (1.500 mL) at room temperature. The mixture was stirred at ambient temperature. CDI activation of the carboxylic acid was confirmed using n-butylamine in ACN. UPLC was performed at 80 min, 3 h, and 4 h.

[0349] The reaction mixture was then transferred to a solution of NaBH (178.3 mg, 188.7 μL, 4.713 mmol) in a mixture of THF (1.000 mL) and HO (625.0 μL) at 0-5°C over 15 min. The addition was exothermic. The mixture was stirred at ambient temperature for 90 min. UPLC showed that the starting material was completely consumed.

[0350] EtOAc (2.5 mL) and aqueous citric acid (approximately 2.415 g, 1.450 mL, 12.57 mmol) in 2.5 mL of water were added to quench the reaction. The layers were separated. The pH of the aqueous layer was 3. The organic layer was dried over Na2SO4 and concentrated by rotary evaporation (80 mbar, 20 °C bath temperature). MTBE (5 mL) was added to the crude product and washed with 1.5 mL of saturated bicarbonate / water (1:1), at which point the aqueous layer pH was 5. The washes were repeated, at which point the aqueous layer had a pH of 7. The MTBE layer was dried over Na2SO4, concentrated by rotary evaporation (300-150 mbar, 20 °C bath temperature), and used in the next step reaction without further purification.

[0351] Step 7: Synthesis of (R)-2-(3-((tert-butoxycarbonyl)amino)propyl)-4-methyl-4-nitropentyl 4-methylbenzenesulfonate [ka] To a mixture of (R)-tert-butyl N-[5-hydroxy-4-(2-methyl-2-nitropropyl)pentyl]carbamate (480 mg, 1.577 mmol, 1 equiv.), triethylamine (0.319 g, 0.443 mL, 3.154 mmol, 2 equiv.), and trimethylamine hydrochloride (0.154 g, 1.608 mmol, 1.02 equiv.) in 2-MeTHF (3.5 mL, 0.451 M, 7.292 vol.) was added p-toluenesulfonyl chloride (0.451 g, 2.365 mmol, 1.5 equiv.) at 0-5 °C. The reaction was stirred at this temperature for 1 h, then warmed to ambient temperature and stirred at ambient temperature for an additional 3 h. The starting material was completely consumed by UPLC. The reaction mixture was washed with water and brine, dried over Na2SO4, and concentrated. The crude was purified by column chromatography eluting with EtOAc / hexanes.

[0352] Step 8: Synthesis of tert-butyl (R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate [ka] To a solution of (R)-tert-butyl N-(6-methyl-4-{[(4-methylbenzenesulfonyl)oxy]methyl}-6-nitroheptyl)carbamate (0.55 g, 1.103 mmol, 1 equiv.) in MeTHF (9 mL, 0.123 M, 16.364 vol.) was added potassium carbonate (0.153 g, 1.103 mmol, 1 equiv.) and Raney nickel (0.13 g, 1.103 mmol, 1 equiv.). The mixture was degassed (vacuum) and then purged with a hydrogen balloon (three times). The reaction was heated to 78 °C. The reaction mixture was cooled to room temperature and filtered through Celite, and the cake was washed with MeTHF (50 mL). The filtered solution was washed with water to remove some of the product and transfer it to the aqueous layer (pH 5-6), which was then re-extracted with MeTHF. The combined MeTHF layers were dried over NaSO and concentrated on a rotary evaporator. After drying overnight in a housing vacuum, 640 mg of crude product was obtained as an oil, which was used without further purification.

[0353] Step 9: Synthesis of (R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione [ka] A method for preparing (R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione from tert-butyl (R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate is shown in the scheme above.

[0354] Step 10: Synthesis of (R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide [ka] To a 1 L, three-necked round-bottom flask was added (R)-2-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)isoindoline-1,3-dione (38.98 g, 136.1 mmol, 1.03 equiv), 6-bromo-2-fluoronicotinamide (28.91 g, 132.0 mmol, 1 equiv), and MeCN (202 mL, 7 vol) followed by KCO (-325 mesh, 21.16 g, 153.1 mmol, 1.16 equiv). The mixture was heated to 40 °C and the reaction was monitored by LC analysis. The reaction was complete after 17 h. The reaction mixture was cooled to ambient temperature. 300 mL (10.3 vol) of water was added via addition funnel to give a slurry. The resulting solid was collected by filtration. The solid was washed with water / MeCN (½, 2×40 mL, 1.4 vol) and then dried in a vacuum oven at 45° C. to give (R)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (56.5 g, 88%).

[0355] Example 9: Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (50) [ka] Step 1: Synthesis of perfluorophenyl 6-fluoropyridine-2-sulfonate [ka] To a solution of 2,3,4,5,6-pentafluorophenol (33.21 g, 180.4 mmol) in iPrOAc (175 mL) was added aqueous KHCO (approximately 90.30 mL of 20 w / v%, 180.4 mmol). The mixture was stirred at ambient temperature for 10 minutes. Then, a solution of 6-fluoropyridine-2-sulfonyl chloride (35.29 g, 180.4 mmol) in iPrOAc (25 mL) was added while maintaining the temperature below 20 °C. The reaction mixture was stirred at ambient temperature for 1 hour to complete the reaction. The aqueous layer was removed, and the organic layer was washed with water (50 mL), dried over NaSO, and then concentrated by rotary evaporation to remove most of the solvent and precipitate a white solid. Heptane (70 mL) was added, and the slurry was stirred at ambient temperature. The solid was collected by filtration, rinsed with heptane (30 mL), and dried under vacuum to give 58.76 g of perfluorophenyl 6-fluoropyridine-2-sulfonate as a white solid. The mother liquor was concentrated by rotary evaporation, followed by the addition of 1 mL (iPrOAc) / 20 mL (heptane) and stirring at ambient temperature overnight. The resulting solid was collected and dried overnight at ambient temperature in a vacuum oven with a N bleed to give 0.87 g as a second crop. A total of 59.63 g (96% yield) of perfluorophenyl 6-fluoropyridine-2-sulfonate was obtained.

[0356] 1 H NMR (400MHz, DMSO-d6) δ 8.46 (q, J = 7.7 Hz, 1H), 8.20 (dd, J = 7.5, 2.0 Hz, 1H), 7.84 (dd, J = 8.3, 2.2 Hz, 1H).

[0357] 19 F NMR(376MHz,DMSO-d6)δ-64.25(s,1F),-152.20--152.69(m,2F),-154.84(t,J=23.3Hz,2F),-161.00--161.74(m,1F).

[0358] Step 2: Synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (50) [ka] A solution of lithium tert-butoxide (1,905.13 g, 2.20 equiv., 20 w / w % in THF) was added to a mixture of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide (1,050 g, 1.00 equiv.) and perfluorophenyl 6-fluoropyridine-2-sulfonate (890.93 g, 1.20 equiv.) in 2-MeTHF (10.5 L, 10.0 vol.) while maintaining the internal temperature below −2° C. The mixture was stirred at −10° C. until the reaction was complete (typically 0.5 h). Aqueous HCl (5.25 L, 5 vol., 1 N) was added while maintaining the internal temperature below 20° C. 2-MeTHF (5.0 L, 5 volumes) was then added to the reactor at ambient temperature, and the phases were then allowed to separate. The lower aqueous layer was discarded. The organic phase was washed with water (5 volumes) and then concentrated to 5 volumes under vacuum, maintaining the temperature below 50°C. 2-MeTHF (10.0 L, 10 volumes) was added, and the mixture was again concentrated to 5 volumes. 2-MeTHF (5 volumes) was added, and the heterogeneous mixture was heated to 70°C with stirring until complete dissolution occurred. The mixture was then cooled linearly to 45°C over 6 hours, and then held at 45°C for 6 hours. The mixture was then cooled to 25°C over 2 hours, and then heptane (10.0 L, 10 volumes) was added to the mixture over 3 hours. The mixture was discharged from the reactor, and the solid was isolated. The reactor and filter cake were then washed twice with a mixture of 2-MeTHF (2.0 L, 2 volumes) and heptane (2.0 L, 2 volumes). The solid was dried under vacuum at 45° C. to give (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide.

[0359] 1 H NMR(400MHz,DMSO-d6)δ 13.05(s,1H),8.37(q,J=7.8Hz,1H),8.11(dd,J=7.4,1.9Hz,1H),7.95-7.88(m,2H),7.88-7.81(m,2H), 7.59(dd,J=8.1,2.4Hz,2H),6.78(d,J=7.9Hz,1H),3.59(t,J=6.8Hz,2H),2.45(dd,J=8.8,3.9Hz,2H),2 .17(s,1H),1.87(dd,J=11.9,5.5Hz,1H),1.56(dddd,J=22.3,16.7,8.9,4.1Hz,2H),1.47(s,3H),1.44( s,3H),1.35(t,J=12.1Hz,1H),1.21(ddd,J=13.3,10.5,5.4Hz,1H),1.00(dtd,J=14.1,9.4,5.7Hz,1H).

[0360] Example 10: (14S)-8-Bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]Synthesis of tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trionene (40) [ka] Step 1: Alternative synthesis of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (50) [ka] 6-Fluoropyridine-2-sulfonyl chloride (529 g, 340 mL, 2.71 mol) was added to a 2:1 ratio solution of (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide in toluene (1.20 kg, 2.26 mol; 91.2% potency) in 2-MeTHF (6.56 L; 6 volume equivalents) at 0-5 °C, followed by the addition of lithium 2-methylbutan-2-olate (t-OAmLi; 1.22 kg of 40 w / w%, 1.67 L of 40 w / w%, 5.19 mol; 2.3 equivalents), while maintaining the reaction temperature at 5-10 °C. After the addition was complete, the reaction solution was stirred at 0-10 °C until the reaction was complete (HPLC showed less than 1% AUC, (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)nicotinamide remaining). The reaction solution was carried on to the next step without any further treatment.

[0361] Step 2: Synthesis of (S)-2-((3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamoyl)benzoic acid [ka] The reaction solution containing (S)-6-bromo-2-(4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-2,2-dimethylpyrrolidin-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide from the previous step was cooled and maintained below 10 °C when a solution of LiOH·HO (284 g, 6.77 mol; 3 eq) in water (2.19 L; 2 vol eq) was added. The biphasic mixture was stirred at 5-15 °C until the reaction was complete (approximately 2 h). 2 M HCl (5.64 L, 11.3 mol; 5 eq) was added dropwise over approximately 1 h, maintaining the reaction temperature below 10 °C. The pH of the aqueous phase was approximately 2. The phases were then separated, and the organic layer was concentrated to a minimum volume to remove most of the 2-MeTHF (40 °C / 150-70 Torr). The reaction mixture was carried on to the next step without any further treatment.

[0362] Step 3: Synthesis of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (48) [ka] The concentrate containing (S)-2-((3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamoyl)benzoic acid from the previous step was diluted with CHCN (6.56 L; 6 volume equivalents) and water (3.83 L; 2 volume equivalents). Oxalic acid (508 g, 5.64 mol; 2.5 equivalents) was then added, and the resulting solution was heated at 60 °C until the reaction was complete (approximately 4 h). The solution was cooled to 0-10 °C, and then a solution of KCO (2.18 kg, 15.8 mol; 7 equivalents) in water (3.83 L; 3.5 volume equivalents) was added dropwise, maintaining the reaction temperature below 10 °C. The solid was collected by filtration. The wet filter cake was washed successively with water (2 × 2.2 L; 2 volume equivalents), then i-PrOH (2 × 600 mL; 0.5 volume equivalents), air-dried by suction, and dried under vacuum (50 °C / 30 Torr) to give (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (959 g; 83% 3 steps; >98% AUC) as a fine white powder.

[0363] 1 H NMR(400MHz,DMSO-d6)δ 8.09(q,J=7.9Hz,1H),7.83(dd,J=7.5,2.2Hz,1H),7.67(s,3H),7.39(d,J=7.6Hz,1H),7 .23(dd,J=8.2,2.4Hz,1H),6.58(d,J=7.6Hz,1H),3.20-2.99(m,2H),2.81(td,J=7.2,4.7 Hz,2H),2.08(dh,J=15.3,7.0Hz,1H),1.84(dd,J=11.8,5.7Hz,1H),1.54(q,J=7.6Hz,2H ),1.48(s,3H),1.47(s,3H),1.37(t,J=11.9Hz,1H),1.26(ddd,J=29.1,13.8,7.4Hz,2H).

[0364] Step 4: (14S)-8-Bromo-12,12-dimethyl-2λ 6-Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]Synthesis of tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trionene (40) [ka] A mixture of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (950 g, 1.85 mol) and Na2CO3 (392 g, 3.69 mol; 2 eq) in DMSO (7.60 L; 8 vol eq) was heated at 85°C until the reaction was complete (approximately 6 h). The suspension was cooled to below 15°C and diluted with MeTHF (19.0 L; 20 vol eq). Water (13.3 L) was added slowly, maintaining the reaction temperature below 15°C. 2 M HCl (4.62 L, 9.24 mol; 5 eq) was added (pH approx. 2), maintaining the reaction temperature below 15°C. The phases were separated, and the organic phase was washed twice with water (9.50 L, 10 volume equivalents) containing NaCl (190 g, 2 wt%). The organic phase was concentrated to a minimum volume (45 °C / 180 Torr) and chased with i-PrOAc (2-3 × 500 mL) to remove MeTHF. The concentrate was back-charged with i-PrOAc (3.800 L; 4 volume equivalents) and stirred at 45 °C until crystallization occurred. (The mixture was optionally diluted with (14S)-8-bromo-12,12-dimethyl-2λ.) 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (may be seeded with tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione). The suspension was stirred for at least 30 minutes and then cooled to 20 °C. After aging at 20 °C for at least 2 hours, the solid was collected by filtration. The filter cake was washed with 1:1 i-PrOAc / MTBE (500 mL), air-dried under suction, vacuum-dried (40-55 °C / <100 Torr / N bleed), and (14S)-8-bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] Tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione·0.8i-PrOAc (830 g, 78% yield corrected for i-PrOAc solvate) was obtained as a slightly yellowish white powder.

[0365] A second crop was obtained by concentrating the filtrate to a total volume of approximately 400 mL. The mixture was then seeded and aged at 15-20 °C. The solid was collected by filtration. The filter cake was washed with 1:1 i-PrOAc / MTBE (200 mL) and MTBE (100 mL), air-dried under suction, and vacuum-dried (55 °C / <100 Torr / N bleed) to give (14S)-8-bromo-12,12-dimethyl-2λ. 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] Tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione·0.67i-PrOAc (113 g, corrected yield 11%) was obtained as a pale yellow solid.

[0366] 1H NMR(400MHz,chloroform-d)δ 9.13(s,1H),7.66(d,J=7.9Hz,1H),7.54(dd,J=8.4,7.3Hz,1H),7.43(d,J=7.3Hz,1H),6.79(d,J=7 .9Hz,1H),6.56(d,J=8.4Hz,1H),4.99(septet,J=6.3Hz,1H),4.57(d,J=8.8Hz,1H),4.02-3.85(m,1H), 3.27-3.09(m,2H),2.96(t,J=10.2Hz,1H),2.35(p,J=9.5Hz,1H),2.02(s,3H),1.95(dd,J=12.1,6.7 Hz,1H),1.72-1.59(m,6H),1.58(s,3H),1.55(s,3H),1.43(d,J=40.1Hz,1H),1.23(d,J=6.3Hz,5H).

[0367] Example 11: (14S)-8-Bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]Synthesis of tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trionene (40) [ka] A mixture of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (40.2 g, 78.2 mmol) and K2CO3 (-325 mesh, 27.0 g, 195.5 mmol; 2.5 equiv.) in DMSO (0.4 L; 10 volume equiv.) was heated at 70°C until the reaction was complete. The suspension was cooled to below 15°C and diluted with IPAc (0.3 L; 7.5 volume equiv.). 1 M HCl (0.41 L, 406.8 mmol; 4.3 equiv.) was added (pH approx. 2) while maintaining the reaction temperature below 15°C.

[0368] After aging at 20° C. for at least 2 hours, the solid was collected by filtration. The filter cake was washed with water (4×50 mL), followed by IPAc (2×75 mL), air-dried under suction, dried under vacuum (45° C. / <100 Torr / N bleed), and (14S)-8-bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] to give tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione·1 DMSO (29 g, 73% yield corrected for DMSO solvate).

[0369] 1 H NMR (400 MHz, chloroform-d) δ 9.13 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.4, 7.3 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 4.99 (septet, J = 6.3 Hz, 1H), 4.57 (d, J = 8.8 Hz, 1H), 4.02-3.85 (m, 1 H),3.27-3.09(m,2H),2.96(t,J=10.2Hz,1H),2.5(s,6H,DMSO),2.35(p,J=9.5Hz,1H),2.02(s,3H),1.95(dd,J =12.1,6.7Hz,1H),1.72-1.59(m,6H),1.58(s,3H),1.55(s,3H),1.43(d,J=40.1Hz,1H),1.23(d,J=6.3Hz,5H).

[0370] Example 12A: (14S)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10]Synthesis of tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound I) [ka] (14S)-8-Bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (86 w / w%) 120 g IPAc [103.2 g (14S)-8-bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trionene], 0.21 mol, 1 eq), 3-(2-dispiro[2.0.2 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazole (42.6 g, 0.21 mol, 1 equiv.), K2CO3 (325 mesh, 63.4 g, 0.46 mol, 2.2 equiv.), CuI (3.3 g, 17.2 mmol, 0.083 equiv.), and BuOAc (740 mL, activated (14S)-8-bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10A mixture of 7.2 volumes of N,N'-dimethylcyclohexane-1,2-diamine (based on tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione) was stirred at room temperature. DMF (300 mL, 2.9 volumes) and N,N'-dimethylcyclohexane-1,2-diamine (14.6 g or 16.2 mL, 0.1 mol, 0.49 equiv.) were then added, and the reactor contents were purged with N. The mixture was then heated to 120 °C until the reaction was complete (approximately 4 h).

[0371] The mixture was cooled to ambient temperature, and then 10% w / v aqueous oxalic acid (860 mL, 0.96 mol, 4.6 equiv.) was added dropwise. The mixture was stirred for at least 1 hour, and then the solid was removed by filtration. The removed solid was washed with IPAc (2×120 mL). The organic layer was isolated and then washed with 8% w / v aqueous trisodium citrate (600 mL), followed by 1:1 v / v water / brine (400 mL). The organic layer was filtered through a pad of Celite. The filter pad was washed with IPAc (150 mL), and the filtrate was concentrated. 1-PrOH (7.8 volumes of 800 mL) was added, and the mixture was concentrated. This step was repeated once more, and then toluene (800 mL) was added, and the mixture was concentrated. This step was repeated once more to obtain a thick slurry. The crude mixture was concentrated to a volume of 300 mL (2.9 volumes) of toluene. (If the mixture was homogeneous, the mixture was seeded with Compound I Form A.) After stirring the slurry overnight, the solid was collected by filtration and washed with toluene (2×100 mL, 0.97 vol.). The solid was dried under vacuum to give Compound I Form A as a white / off-white solid (107.0 g, 83%, 94.5% (AUC) HPLC purity).

[0372] Compound I Form A [22.2 g, 94.6% (AUC)] was suspended in toluene (440 mL, 20 volumes based on Compound I) and the mixture was heated to reflux for at least 2 hours. The mixture was cooled to ambient temperature over 8 hours and then stirred overnight. The solid was collected by filtration and washed with toluene (40 mL, 1.8 volumes). The solid was dried under vacuum at 50° C. with a nitrogen bleed until the loss on drying was 1.0% NMT to give Compound I Form A (18.8 g, 84%, 96.8% (AUC) HPLC purity) as a white / off-white solid.

[0373] Compound I Form A [17.5 g, 97.0% (AUC)] was suspended in toluene (350 mL, 20 volumes) and the mixture was heated to reflux. After being held at reflux for at least 2 hours, the mixture was cooled to ambient temperature over 8 hours and then stirred at ambient temperature overnight. The solid was collected by filtration, washed with toluene (40 mL, 1.8 volumes), and then dried under vacuum to give Compound I Form A as a white / off-white solid (15.7 g, 89%, 98.4% (AUC) HPLC purity).

[0374] 1 H NMR(500MHz,DMSO-d6)δ 12.52(s,1H),8.21(d,J=2.9Hz,1H),7.83(d,J=8.2Hz,1H),7.59(t,J=7.9Hz,1H),7.12-6.83(m,3H),6.7 2(d,J=8.5Hz,1H),6.09(d,J=2.8Hz,1H),4.22(td,J=6.8,2.3Hz,2H),4.04-3.84(m,1H),3.16(s,1H),2.9 6(d,J=13.1Hz,1H),2.70(d,J=11.3Hz,1H),2.13(s,1H),1.84(dq,J=20.2,6.6,5.9Hz,4H),1.70-1.40(m, 10H), 1.32(q,J=12.2Hz,1H),0.90-0.75(m,4H),0.65(dd,J=8.6,4.2Hz,2H),0.51(dd,J=8.5,4.2Hz,2H).

[0375] Example 12B: (14S)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] Alternative synthesis of tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound I) [ka] Then, (14S)-8-bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (110 g, 182.441 mmol, 1.00 equiv., iPrOAc solvate), 3-(2-(dispiro[2.0.2 4 .1 3 A mixture of ]heptan-7-yl)ethoxy)-1H-pyrazole (48.447 g, 237.174 mmol, 1.3 equiv) and MEK (8 vol) was heated to 40° C. and then degassed with N. tBuXphos Pd G3 (1.922 g, 2.372 mmol, 1.25 mol%) was then added to the mixture. A degassed solution of MTBD (67.034 g, 428.737 mmol, 2.35 equiv) in MEK (2.00 vol) was then added to the reactor over 1 h, maintaining the temperature at 40° C. The reaction was then stirred at 40° C. until complete (approximately 2 h) and then cooled to 20° C. An aqueous workup using 1M HCl was then performed, and the organic layer was then purified with Silia Met S thiol (66 g, 60 w / w%, (14S)-8-bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111 , 14 .0 5 , 10 ]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trionene) and stirred at 50° C. for 6 hours. The mixture was cooled to 20° C., then filtered through Celite, and then concentrated under vacuum. The solvent was replaced with toluene (3 volumes) by vacuum distillation, then cooled to 20° C. and stirred for at least 3 hours. The solid was isolated by filtration and then dried under vacuum to give Compound I Form A (92 g, 81% yield).

[0376] Example 13: Synthesis of benzyl (S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (45) [ka] A stirred suspension of 6-bromo-2-fluoronicotinamide (40.0 g, 183 mmol), benzyl (S)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate·HCl (65.7 g, 201 mmol; 1.1 equiv.), and K2CO3 (30.3 g, 219 mmol) in acetonitrile (260 mL) was warmed to 40 °C until the reaction was complete (approximately 20 h) and then cooled to ambient temperature. Water (480 mL) was added slowly, and the resulting solid was collected by filtration. The filter cake was washed with 2:1 water:CHCN (2 x 120 mL) and then dried to give benzyl (S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (86.8 g; 97%; 99.0% AUC) as an off-white powder.

[0377] 1H NMR(400MHz,DMSO-d6)δ7.80(d,J=2.3Hz,1H),7.40(d,J=2.2Hz,1H),7.39-7.25(m,7H),6.68(d,J=7.7Hz,1H),5.01(s,2H),3. 29-3.10(m,2H),3.00(q,J=6.6Hz,2H),2.19(s,1H),1.90(dd,J=11.8,5.6Hz,1H),1.53(s,3H),1.49(s,3H),1.47-1.24(m,5H).

[0378] UPLC-MS:M+1=489 / 491 (compatible).

[0379] Example 14: (14S)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] Alternative synthesis of tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound I) [ka] Step 1: Benzyl (S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2])) 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (51) [ka] Benzyl (S)-(3-(1-(6-bromo-3-carbamoylpyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (85.0 g, 174 mmol), 3-(2-(dispiro[2.0.2 4.1 3 ]heptan-7-yl)ethoxy)-1H-pyrazole (42.57 g, 208.4 mmol, 1.2 equiv.), K2CO3 (52.8 g, 382 mmol, 2.2 equiv.), and (1R,2R)-N 1 ,N 2 A suspension of 1,2-dimethylcyclohexane-1,2-diamine (19.8 g, 21.9 mL, 139 mmol, 0.8 equiv.) was purged with N2 for 20 minutes. CuI (3.3 g, 17 mmol, 0.1 equiv.) was added, and the mixture was purged for an additional 5 minutes, then heated at 90 °C until the reaction was complete (approximately 3.5 hours). The reaction was then cooled to ambient temperature. 2-MeTHF (850 mL) and 0.5 M NH4OH (452 ​​mL, 226 mmol) were added, and the top organic phase was isolated and washed successively with 0.5 M NH4OH (2 × 174 mL, 86.8 mmol), 0.5 M HCl (347 mL, 174 mmol), water (150 mL) / brine (50 mL), and saturated NaHCO3 (50 mL). The solution was dried (Na2SO4) and then concentrated to an oil. CHCN (255 mL) was added and then removed under vacuum to give a tan solid. The solid was slurried in CHCN (255 mL) at 40° C. for 20 minutes to give a suspension, which was then cooled to room temperature and stirred. The solid was isolated by filtration and then dried to give benzyl(S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2])-2,3-dihydro-1,4-dihydro-2,4-dihydro-2,5-dihydro-2,6 ... 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (70.4 g; 66%; 95.8% AUC).

[0380] 1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.7Hz,1H),7.73(s,1H),7.61(d,J=8.0Hz,1H),7.42-7.20(m,7H),6.8 4(d,J=8.0Hz,1H),6.05(d,J=2.7Hz,1H),5.01(s,2H),4.20(t,J=6.7Hz,2H),3.32(t,J=10.4Hz,1H),3.1 9(t,J=8.8Hz,1H),3.01(q,J=6.5Hz,2H),2.21(s,1H),1.94(dd,J=11.9,5.6Hz,1H),1.81(q,J=6.6Hz,2H ),1.61(s,3H),1.57(s,3H),1.53-1.23(m,6H),0.90-0.77(m,4H),0.67-0.60(m,2H),0.53-0.46(m,2H).

[0381] Step 2: Benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (52) [ka] Benzyl (S)-(3-(1-(3-carbamoyl-6-(3-(2-(dispiro[2.0.2])) in 2-MeTHF (408 mL, 6 volume equivalents) 4 .1 3A solution of (1H-heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (68.0 g, 111 mmol) was cooled to 0-5 °C, and then 6-fluoropyridine-2-sulfonyl chloride (29.2 g of 92.9 w / w%, 139 mmol, 1.25 equiv.) in 2-MeTHF (136 mL, 2 volume equiv.) was added. A 40 w / w% heptane solution of lithium 2-methylbutan-2-olate (82.3, 255 mmol; 2.3 equiv.) was added slowly, maintaining the reaction temperature at 0-5 °C. The solution was stirred until the reaction was complete (30 min), then a solution of EtOAc (408 mL, 6 vol eq) and NaHSO (32.0 g, 266 mmol, 2.4 eq) in water (272 mL; 4 vol eq) was added. The organic phase was isolated, then washed with water (272 mL; 4 vol eq), dried (NaSO), and concentrated to a brown semi-solid. MIBK (238 mL; 3.5 vol eq) was added, and the mixture was heated to 70 °C, followed by precipitation of the crystalline benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2])-2H-pyrrolidine). 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate, then cooled to ambient temperature and stirred for 2 hours. The solid was collected by filtration and then dried to give benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (53.7 g, 63%; 97.5% AUC) as a white powder.

[0382] Further product was obtained as a second crop after SiO plug filtration and crystallization from i-PrOH / MIBK, affording benzyl(S)-(3-(1-(6-(3-(2-(dispiro[2.0.2])-2H-pyridin-1-yl ... 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (14.4 g; 17%; 92.5% AUC) as an off-white powder.

[0383] 1 H NMR(400MHz,DMSO-d6)δ8.34(q,J=7.8Hz,1H),8.13(dd,J=7.4,2.0Hz,1H),7.88(d,J=8.3Hz,1H),7.59(dd,J=8.3,2.3Hz,1H),7.37(d,J=4. 2Hz,4H),7.34-7.21(m,2H),6.94(d,J=8.3Hz,1H),6.10(d,J=2.8Hz,1H),5.05(s,2H),4.22(t,J=6.7Hz,2H),3.01(septet,J=6.7Hz,2H),2.46 (dd,J=10.4,7.0Hz,1H),2.13(s,1H),1.89(dd,J=11.8,5.5Hz,1H),1.81(q,J=6.6Hz,2H),1.54(s,6H),1.47(t,J=6.5Hz,1H),1.34(td,J=1 3.1,12.6,6.7Hz,3H),1.17(dt,J=16.1,5.2Hz,1H),0.97(dt,J=13.4,8.8Hz,1H),0.89-0.75(m,4H),0.71-0.57(m,2H),0.56-0.41(m,2H).

[0384] 19 F NMR(376MHz,DMSO-d6)δ-65.73.

[0385] Step 3: (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2 4 .1 3Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide ((S)-53) [ka] Benzyl (S)-(3-(1-(6-(3-(2-(dispiro[2.0.2 4 .1 3 A suspension of ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (40.0 g, 51.8 mmol), ammonium formate (26.1 g, 415 mmol, 8 equiv.), DABCO (116 mg, 1.03 mmol, 0.02 equiv.), and 10% Pd on carbon (1.0 g, 0.94 mmol, 0.02 equiv.) was stirred at ambient temperature until the reaction was complete (approximately 70 min). The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to an oil. The mixture was slurried in MeTHF (200 mL) and EtOAc (200 mL) at 40° C., and the solid was then removed by filtration. The filter cake was rinsed with 2-MeTHF (3 x 30 mL), then the combined filtrate and washings were concentrated in vacuo to give (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2]-methyl)-2,2-dimethylpyrrolidin-1-yl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2]methyl)-2,2-dimethylpyrrolidin-1-yl ... 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (36.0 g; 102% of the HCOH salt; 96.2% AUC) as a white granular powder, which was used without further purification.

[0386] 1H NMR(500MHz,DMSO-d6)δ 8.15(d,J=2.7Hz,1H),8.11(q,J=7.9Hz,1H),7.86(dd,J=7.4,2.2Hz,1H),7.70(d,J=7.9Hz,1H),7.24(dd,J=8.3,2.4Hz ,1H),6.79(d,J=7.9Hz,1H),6.01(d,J=2.7Hz,1H),4.20(t,J=6.7Hz,2H),3.15(t,J=10.6Hz,1H),3.06(dd,J=10.9,7.3H z,1H),2.82(septet,J=7.2,6.3Hz,2H),2.08(s,1H),1.81(q,J=6.5Hz,2H),1.55(s,5H),1.51(s,3H),1.47(t,J=6.5Hz,1H ),1.42-1.27(m,3H),1.26-1.15(m,1H),0.83(d,J=5.5Hz,4H),0.64(dd,J=8.5,4.2Hz,2H),0.50(dd,J=8.5,4.0Hz,2H).

[0387] Step 4: (14S)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]Synthesis of tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound I) [ka] (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-(3-(2-(dispiro[2.0.2])-2-methylpyrrolidin-1-yl)-2,2-dimethyl ... 4 .1 3A mixture of [(6-fluoropyridin-2-yl)sulfonyl]-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide·HCOH (35.0 g, 51.2 mmol) and KCO (21.2 g, 154 mmol; 3 equiv.) was heated at 90 °C under a N blanket for 6 h and then cooled to room temperature. The suspension was diluted with EtOAc (525 mL, 15 volume equiv.) and water (280 mL, 8 volume equiv.). The phases were separated, and the aqueous phase was extracted with EtOAc (210 mL). The combined organic phases were washed with a solution of 20% w / v citric acid (49.2 mL, 51.2 mmol) diluted in water (280 mL) to an aqueous pH of 3–4. The organic phase was then washed with water (2×280 mL), dried (Na 2 SO 4 ), and concentrated (40° C. / 30 Torr) to give crude Compound I (35.9 g, 114% theoretical yield, 94.9% AUC) as a pale orange foam.

[0388] The crude product was dissolved in hot (105°C) PhMe (210 mL; 6 volume equivalents) to give a yellow solution at approximately 40°C. The solution autofused at approximately 80°C, resulting in gradual crystallization. The reaction mixture remained a suspension at 105°C. The suspension was cooled to 20°C at 10°C / h and stirred overnight. The solid was collected by filtration, and the filter cake was washed with PhMe (2 x 20 mL). The wet solid was air-dried under suction and then vacuum-dried (50°C / 300 Torr / N2 bleed) to give crystalline Compound I (25.3 g; 80%; 98.7% AUC) as a bright white powder.

[0389] 1H NMR(500MHz,DMSO-d6)12.52(s,1H),8.21(d,J=2.9Hz,1H),7.83(d,J=8.2Hz,1H),7.59(t,J=7.9Hz,1H),7.12- 6.83(m,3H),6.72(d,J=8.5Hz,1H),6.09(d,J=2.8Hz,1H),4.22(td,J=6.8,2.3Hz,2H),4.04-3.84(m,1H),3.16( s,1H),2.96(d,J=13.1Hz,1H),2.70(d,J=11.3Hz,1H),2.13(s,1H),1.84(dq,J=20.2,6.6,5.9Hz,4H),1.70-1. 40(m,10H),1.32(q,J=12.2Hz,1H),0.90-0.75(m,4H),0.65(dd,J=8.6,4.2Hz,2H),0.51(dd,J=8.5,4.2Hz,2H).

[0390] UPLC-MS: [M+1]=618.5 (compliant).

[0391] Example 15: (14S)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] Alternative synthesis of tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound I) [ka] Step 1: Synthesis of benzyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (47) [ka] The reaction solution containing 6-fluoropyridine-2-sulfonyl chloride (459.5 mg, 2.349 mmol, 1.15 equiv.) was diluted with 2-MeTHF (10 mL, 10 volume equiv.), and benzyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (1.00 g, 2.043 mmol, 1.0 equiv.) was added via syringe to maintain an internal temperature below 7 ° C. The mixture was then cooled to 5 ° C., and lithium t-amoxide (40 wt.% solution in heptane, 1.20 g, 5.108 mmol, 2.5 equiv.) was added slowly. After the addition was complete, the reaction mixture was stirred, warmed to room temperature, and maintained until the reaction was complete (approximately 1 h). The reaction mixture was cooled to below 10° C., and 1 M aqueous HCl (8.172 mL, 8.172 mmol, 4.0 equiv.) was added to bring the mixture to pH=1. The phases were separated, and the organic phase was washed with water (5.000 mL, 5.0 volume equiv.) and then with brine (3.000 mL, 3.0 volume equiv.). The organic phase was transferred to a flask and concentrated to solid benzyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (1.38 g, 104.2% yield, not corrected for residual solvent).

[0392] 1 H NMR(400MHz,DMSO-d6)δ 13.09(s,1H),8.44-8.31(m,1H),8.12(d,J=7.2Hz,1H),7.59(d,J=8.0Hz,2H),7.41-7.22(m,5H),6.78(d,J=8.0Hz,1H),5.04(s, 2H),3.87-3.71(m,2H),3.52(q,1H),3.09-2.91(m,2H),2.11(s,1H),2.01-1.68(m,1H),1.46(d,J=8.4Hz,6H),1.39-1.24(m,4H).

[0393] Step 2: Alternative synthesis of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (48) [ka] To a stirred reaction vessel at room temperature, water was added, followed by sulfuric acid to prepare a 9 M aqueous solution of H2SO4 (41.14 mL, 9.0 M, 370.2 mmol). To the resulting solution, benzyl (S)-(3-(1-(6-bromo-3-(((6-fluoropyridin-2-yl)sulfonyl)carbamoyl)pyridin-2-yl)-5,5-dimethylpyrrolidin-3-yl)propyl)carbamate (8.0 g, 12.34 mmol, 1.0 equiv.) was added, and the resulting reaction mixture was stirred at 30 °C until the reaction was deemed complete. The reaction mixture was cooled to above 10 °C, basified with aqueous NaOH (4 M aqueous solution, approximately 100 mL, 400 mmol), diluted with 2-MeTHF (160.0 mL, 20.0 volume equiv.), stirred at 20-25 °C, and separated. The aqueous phase was re-extracted with 2-MeTHF (80.0 mL, 10.0 volume equivalents). The organic phases were combined and partially concentrated (4–8 volume equivalents), allowing the product to crystallize from solution. The mixture was then filtered, the solid was rinsed with 2-MeTHF (16.0 mL, 2.0 volume equivalents), and the solid was dried under vacuum to give (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (2.96 g, 45%) as an off-white crystalline solid.

[0394] 1H NMR(400MHz,DMSO-d6)δ 8.08(q,J=8.0Hz,1H),7.83(dd,J=7.3,2.4Hz,1H),7.39(d,J=7.7Hz,1H),7.32(d ,J=5.1Hz,1H),6.56(d,J=7.6Hz,1H),3.86-3.79(m,0H),3.77-3.68(m,0H),3.55 (td,J=8.0,6.4Hz,0H),3.03-2.87(m,2H),1.97-1.89(m,0H),1.86-1.77( m,1H),1.46(s,6H),1.30(ddt,J=12.9,5.3,3.8Hz,2H),1.14-1.07(m,2H).

[0395] Step 3: (14S)-8-Bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] Alternative synthesis of tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trionene (40) [ka] To a stirred mixture of (S)-2-(4-(3-aminopropyl)-2,2-dimethylpyrrolidin-1-yl)-6-bromo-N-((6-fluoropyridin-2-yl)sulfonyl)nicotinamide (2.80 g, 5.443 mmol, 1.0 equiv) in DMSO (28.00 mL, 10.0 volume equiv), MgCl (518.2 mg, 5.443 mmol, 1.0 equiv) was added, followed by KCO (1.881 g, 13.61 mmol, 2.50 equiv, 325 mesh) and stirred at 80 °C until complete (20 h). The mixture was cooled to 10° C., diluted with EtOAc (42.00 mL, 15.0 volume equiv.), acidified with 1 M aqueous HCl (32.66 mL, 32.66 mmol, 6.0 equiv.), the aqueous phase was re-extracted with EtOAc (22.40 mL, 8.0 volume equiv.), the organic phases were combined and washed with water (22.40 mL, 8.0 volume equiv.), and then twice with brine (8.400 mL, 3.0 volume equiv.). The solution was concentrated to give 2.59 g (96% yield) of (14S)-8-bromo-12,12-dimethyl-2λ. 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] Tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione was obtained as an amber foam.

[0396] 1 H NMR(400MHz,DMSO-d6)δ 12.63(s,1H),7.67-7.44(m,2H),7.06(d,J=7.2Hz,1H),6.73(dd,J=17.6,8.2Hz,2H),4.86(p,J=6.3Hz,1H),3.87(s,1H),3.09(s,1H),2.94( d,J=13.5Hz,1H),2.61(d,J=10.6Hz,1H),2.11(s,1H),1.90-1.68(m,1 H),1.55(s,2H),1.42(s,2H),1.36-1.23(m,1H),1.17(d,J=6.3Hz,6H).

[0397] Step 4: (14S)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ] Alternative synthesis of tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound I) [ka] A container was charged with DMF (17,500 mL, 7.0 volume equivalents), butyl acetate (17,500 mL, 7.0 volume equivalents), (14S)-8-bromo-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]tetracosa-1(23),5,7,9,19,21-hexaene-2,2,4-trione (2,500 g, 5,056.58 mmol, 1.00 equiv.), and 3-(2-(dispiro[2.0.2 4 .1 3

[0043] (heptan-7-yl)ethoxy)-1H-pyrazole (1,122.716 g, 5,056.58 mmol, 1.00 equiv.) was charged. The mixture was stirred at room temperature, and then KCO (325 mesh, 1,537.514 g, 11,124.477 mol, 2.2 equiv.), CuI (79.931 g, 419.696 mmol, 0.083 equiv.), and trans-cyclohexane-1,2-diamine (238.794 g, 1,678.785 mmol, 0.332 equiv.) were added. The mixture was heated to 120°C until completion, then the mixture was cooled to above 30°C and aqueous oxalic acid (27.0 L of a 0.8 M aqueous solution prepared by mixing 2,094.236 g of oxalic acid in 25,0000 mL of water) was added to adjust the pH to above 3. The resulting mixture was diluted by the addition of isopropyl acetate (7,500 mL, 3.0 volume equivalents), filtered through Celite, and washed with isopropyl acetate (2,500 mL, 1.0 volume equivalents). The filtrate layers were allowed to separate (slowly). The organic phase was then washed with aqueous sodium citrate (8% solution, made from 1,150.963 g of trisodium citrate, 4,459.904 mmol, 5.0 equivalents dissolved in 15.0 L, 6.0 volume equivalents of water), the organic phase was washed with brine (5.0 L, 2.0 volume equivalents of 10 wt / wt% NaCl in aqueous solution), the organic phase was filtered through Celite, and the Celite cake was rinsed with isopropyl acetate (2.5 L, 1.0 volume equivalents). The organic phase was concentrated to a thick oil, diluted with toluene (50,000 mL, 20.0 volume equivalents), transferred to a reactor (reactor jacket at 60°C), stirred, heated to reflux, held at reflux for 2 hours, cooled to 20°C over 8 hours, and filtered. The filter cake was washed with toluene (5.0 L, 2.0 volume equivalents) and dried in vacuo (50-55 °C, vacuum) to give compound I (1,290 g, 41.296% yield) as a crystalline solid.

[0398] 1H NMR(400MHz,DMSO-d6)δ 12.49(s,1H),8.20(d,J=2.8Hz,1H),7.82(d,J=8.2Hz,1H),7.58(dd,J=8.5,7.2Hz,1H),7.06(d,J=7.1Hz,1H),6.97( d,J=9.2Hz,1H),6.92(d,J=8.2Hz,1H),6.71(d,J=8.5Hz,1H),6.08(d,J=2.7Hz,1H),4.21(td,J=6.6,1.4Hz,2H),3.9 2(d,J=12.0Hz,1H),3.15(d,J=9.1Hz,1H),2.95(d,J=13.4Hz,1H),2.71(t,J=10.5Hz,1H),2.12(s,1H),1.83(tq,J=1 4.8,8.1,6.7Hz,4H),1.66-1.43(m,11H),1.39-1.24(m,1H),0.88-0.79(m,4H),0.69-0.58(m,2H),0.54-0.44(m,2H).

[0399] Example 16: Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3) [ka] Step 1: Synthesis of 3-methylenetetrahydro-2H-pyran-2-one (5) [ka] Step 1a: A 5 L, three-neck round-bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe / controller, and nitrogen inlet / outlet. The vessel was charged under a nitrogen atmosphere with sodium hydride (59.91 g of 60% w / w, 1.498 mol) followed by heptane (1.5 L), resulting in a gray suspension. Stirring was initiated, and the internal temperature was recorded at 19 °C. The vessel was then charged with ethyl alcohol (3.451 g, 74.91 mmol) added via syringe, resulting in gas evolution. The addition funnel was charged with a clear, pale yellow solution of tetrahydropyran-2-one (150 g, 1.498 mol) and ethyl formate (111 g, 1.50 mol). The solution was added dropwise over 1 h, resulting in gas evolution and a gradual exotherm to 45 °C. The resulting thick white suspension was then heated to 65 °C for 2 h and then cooled to room temperature. The mixture was allowed to stir overnight (approximately 10 hours) at room temperature. The reaction mixture was vacuum filtered through a glass-fritted Buchner funnel (medium porosity) under a stream of nitrogen. The filter cake was replaced, washed with heptane (2 x 250 mL), and suctioned for several minutes. The slightly damp heptane cake was transferred to a glass tray and dried in a vacuum oven at 45 °C for 15 hours to give the desired product (E)-(2-oxotetrahydropyran-3-ylidene)methanolate as a white solid (205 g, 1.36 mol, 91% yield).

[0400] 1 H NMR(400MHz,DMSO-d6)δ 8.99(s,1H),3.90-3.83(m,2H),2.09(t,J=6.3Hz,2H),1.57(qd,J=6.4,4.7Hz,2H).

[0401] Step 1b: A 5 L, three-neck round-bottom flask was equipped with a mechanical stirrer, heating mantle, addition funnel, J-Kem temperature probe / controller, and nitrogen inlet / outlet. The vessel was charged with (E)-(2-oxotetrahydropyran-3-ylidene)methanolate-Na salt (205 g, 1.366 mol) and tetrahydrofuran (1640 mL) under a nitrogen atmosphere to provide a white suspension. Stirring was initiated, and the pot temperature was recorded at 19 °C. The vessel was then charged in one portion with paraformaldehyde (136.6 g, 4.549 mol), added as a solid. The resulting suspension was heated to 63 °C, and the conditions were maintained for 15 hours. The resulting white gelatin mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The remaining residue was partitioned in a separatory funnel with ethyl acetate (1000 mL), saturated sodium chloride (500 mL), and saturated sodium bicarbonate (500 mL). The organic phase was removed, and the remaining aqueous phase was extracted with ethyl acetate (5 x 300 ml). The combined organic phases were dried over sodium sulfate (500 g) and then vacuum filtered through a glass-fritted Buchner funnel with a 20 mm layer of Celite. The filter cake was replaced and washed with ethyl acetate (250 ml). The clear filtrate was concentrated under reduced pressure to give a clear, pale yellow oil (135 g) as the desired crude product. The material was purified by flash column chromatography eluting with a gradient of 100% hexane to 60% ethyl acetate in hexane over 1 h, collecting 450 ml fractions. Note: The product was detected by TLC analysis on silica gel eluting with 3:1 Hex / EtOAc and can be visualized under UV light. The product fractions were combined and concentrated under reduced pressure to give a clear, colorless oil (132 g, 1.18 mol, 86% yield) as the desired product, 3-methylenetetrahydropyran-2-one.

[0402] 1H NMR (400 MHz, DMSO-d6) δ 6.18 (q, J = 1.9 Hz, 1H), 5.60 (q, J = 1.9 Hz, 1H), 4.40-4.26 (m, 2H), 2.61 (ddt, J = 7.0, 6.3, 2.0 Hz, 2H), 1.90-1.75 (m, 2H). Proton NMR indicates approximately 16% by weight of residual ethyl acetate. The corrected yield can then be (100 - 16 = 84) 0.84 (132) = 110.9 g (72% yield).

[0403] The preparation of this compound in a one-pot procedure has been reported. See J. Org. Chem. 2016, 81, 11235-11249. The distillation of this compound is reported at 52 °C and 0.2 Torr in Synthesis 1985, (1), 35-38.

[0404] Step 2: Synthesis of 3-(2-methyl-2-nitropropyl)tetrahydro-2H-pyran-2-one ((±)-4) [ka] A 5 L, three-neck round-bottom flask was equipped with a mechanical stirrer, a cooling bath used as secondary containment, a J-Kem temperature probe, an addition funnel, and a nitrogen inlet / outlet. The vessel was charged with 2-nitropropane (104.9 g, 1.177 mol) under a nitrogen atmosphere. Stirring was initiated, and the pot temperature was recorded at 19 °C. The vessel was then charged with 1,8-diazabicyclo[5.4.0]undec-7-ene (22.41 g, 147.2 mmol) neat in one portion, resulting in a clear, pale yellow solution. No exotherm was observed. The addition funnel was charged with a solution of 3-methylenetetrahydropyran-2-one (110 g, 981.0 mmol) in acetonitrile (1100 mL), which was added dropwise over 1 h, resulting in a clear, pale yellow solution and a gradual exotherm to 24 °C. The reaction mixture was continued to stir at room temperature for 3.5 h and then concentrated under reduced pressure. The remaining residue was dissolved in dichloromethane (1000 ml) and partitioned with 500 ml of a 3:2 mixture of 1 M citric acid solution and saturated sodium chloride solution. Note: The resulting organic phase was a clear, pale blue solution, and the aqueous phase was a slightly cloudy, very pale blue solution. The organic phase was removed, and the remaining aqueous solution was extracted with dichloromethane (300 ml). The combined organic phases were washed with saturated sodium chloride solution (300 mml), dried over sodium sulfate (250 g), and then filtered through a glass-fritted Buchner funnel. The filtrate was concentrated under reduced pressure to a volume of approximately 200 ml. The clear, pale blue dichloromethane solution was diluted with methyl tert-butyl ether (1500 ml), and the cloudy solution was concentrated under reduced pressure to a volume of approximately 200 ml, resulting in a suspension. The mixture was diluted with methyl tert-butyl ether (1500 ml) and concentrated under reduced pressure to a volume of approximately 250 ml. The resulting suspension was allowed to stand overnight (approximately 12 hours) at ambient temperature. The solid was collected by vacuum filtration in a glass-fritted Buchner funnel, and the filter cake was displacement washed with cold methyl tert-butyl ether (2 x 150 ml) and then suctioned for 30 minutes. The material was further dried in a vacuum oven at 45 °C for 5 hours to give the desired product, 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (160 g, 0.795 mol, 81% yield), as a white solid.

[0405] 1 H NMR(400MHz,DMSO-d6)δ4.34(ddd,J=11.1,9.3,4.3Hz,1H),4.20(dt,J=11.1,5.1Hz,1H),2.75-2.62(m,1H),2.56(dd,J= 14.9,5.2Hz,1H),2.01-1.89(m,2H),1.89-1.67(m,2H),1.55(d,J=6.0Hz,6H),1.44(dddd,J=12.8,11.5,8.1,6.6Hz,1H). ESI-MS m / z calculated value 201.10011, measured value 202.0[M+1] + .

[0406] Retention time: 0.97 min as an off-white solid.

[0407] Step 3: Synthesis of 3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one ((±)-3) [ka] A solution of 3-(2-methyl-2-nitropropyl)tetrahydropyran-2-one (122 g, 606.3 mmol) in ethanol (2000 mL) was purged with nitrogen, followed by the addition of Raney Ni (40 g, 50 w / w%, 340 mmol) (washed twice with water and once with ethanol by mixing and decantation). The mixture was purged with nitrogen and then with hydrogen. The suspension was vigorously stirred and heated at 60° C. under hydrogen (1 atm) for 20 hours. The reaction was cooled to room temperature, then purged with nitrogen, filtered through Celite, and carefully washed with ethanol to prevent the drying out of residual catalyst. The clear, colorless filtrate was evaporated, and the solid residue (105 g) was suspended in MTBE (approximately 1.5 L) and concentrated to a thick suspension (approximately 200 mL of MTBE) at reflux. The solid was collected by filtration and washed with dry-ice-cooled MTBE. The solid was dissolved in DCM (approximately 300 mL) under warming and slowly diluted with MTBE (approximately 1 L) while seeding to give a colorless suspension. The colorless suspension was concentrated under reduced pressure at 45° C. to approximately 500 mL, and the suspension was stirred at room temperature overnight. The colorless suspension was filtered, washed with dry-ice-cooled MTBE, and dried to give 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (94.1 g, 88%).

[0408] 1 H NMR(400MHz,DMSO-d6)δ 7.63(s,1H),4.38(s,1H),3.38(t,J=6.5Hz,2H),2.37(qd,J=9.5,4.4Hz,1H),2.02(dd,J =12.4,8.6Hz,1H),1.78-1.63(m,1H),1.50-1.33(m,3H),1.16(d,J=17.9Hz,7H).ESI-MS m / z calculated value 171.12593, measured value 172.0[M+1] + .

[0409] Step 4: Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3) [ka] 3-(3-hydroxypropyl)-5,5-dimethyl-pyrrolidin-2-one (1813 g) was separated at ambient temperature using a Chiralpak® AZ column eluted with an isocratic mixture of hexane:ethanol (85:15) to give, after removal of the solvent, (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (810 g) as a colorless solid.

[0410] Enantiomeric excess of 98.6% (Chiralpak® AZ column, 210 nm); (S)-enantiomer elutes at 13.1 min. (R)-enantiomer elutes at 22.5 min.

[0411] Example 17: Alternative synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3) [ka] Step 1: Synthesis of ethyl 2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate ((±)-39) [ka] A 500 mL jacketed reactor equipped with a reflux condenser, nitrogen purge, 450 rpm stirrer, and 20° C. jacket was loaded with 3-(2-methyl-2-nitro-propyl)tetrahydropyran-2-one (55.0 g, 273.3 mmol, 1.0 equiv) and EtOH (440.0 mL, 8.0 vol) and stirred. The starting material did not dissolve. To the reaction mixture was added HCl, 4 M dioxane (13.67 mL of 4 M, 54.66 mmol, 0.20 equiv), allowing the temperature to rise by 2° C., followed by an endotherm and a temperature drop to 19° C. The starting material did not dissolve. The reaction progress was followed by HPLC and was deemed complete after 2 hours (>98.0% conversion). The reaction solution was neutralized with 20% aqueous KHCO3, and the resulting mixture was then partially concentrated to remove bulk EtOH (75-85% of the EtOH was removed). The mixture was diluted with 2-MeTHF (550.0 mL, 10.0 vol) and water (275.0 mL, 5.0 vol), then transferred back to a 500 mL reactor, stirred, then stopped, the layers allowed to separate, and the aqueous layer was drained. The organic layer was washed with brine (165.0 mL, 3.0 vol). The organic layer was dried over Na2SO4, filtered through Celite, and the cake washed with 2-MeTHF (110.0 mL, 2.0 vol). The clear, light amber filtrate was concentrated to give the desired product, ethyl 2-(3-hydroxypropyl)-4-methyl-4-nitro-pentanoate (62.98 g, 93%), as a light amber oil.

[0412] 1 H NMR(400MHz,DMSO-d6)δ 4.43(br s,1H),4.04(q,J=7.1Hz,2H),3.35(t,J=6.3Hz,2H),2.38-2.24(m,2H),2 .07-1.96(m,1H),1.50(m,7H),1.46-1.28(m,1H),1.18(t,J=7.1Hz,3H).

[0413] Step 2: Synthesis of ethyl (S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate (39) [ka] A 500 ml jacketed reactor equipped with a reflux condenser, nitrogen purge, 450 rpm stirrer, and a 35°C jacket was loaded with 0.8 M (250.0 mL) pH 7.93 phosphate buffer and ethyl 2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate (5 g, 20.22 mmol, 1.0 equiv.) and stirred to form a suspension. The enzyme lipase from Rhizomucor miehei (125.0 mL, 25.0 volumes, Palatase® 20,000 L) was added. The resulting reaction mixture was sampled and had a starting pH of 7.63. The reaction was run at 35°C. The reaction progress was followed by chiral GC and was deemed complete after 2 days (>99.0% of the desired ester remained). Upon completion, the reaction was cooled to 20°C and the product was extracted into MTBE (250.0 mL, 50 vol). A large emulsion formed in the organic layer, which was separated from the aqueous layer. The aqueous layer was re-extracted with MTBE (125.0 mL, 25.0 vol). The emulsified organic layers were combined and filtered through Celite to break the emulsion, rinsed back into the reactor, and the aqueous phase was separated from the organic layer. The organic (product) layer was washed with 20% aqueous Na2CO3 (50.00 mL, 10.0 vol), 20% aqueous Na2CO3 (25.00 mL, 5.0 vol), 20% aqueous Na2CO3 (25.00 mL, 5.0 vol), and finally with 20% aqueous Na2CO3 (25.00 mL, 5.0 vol). The organic layer was then washed with water (25.00 mL, 5.0 vol) and then with 10% brine (25.00 mL, 5.0 vol). The washed organic layer was concentrated in a rotary evaporator (45° C., in vacuo) to give 2.01 g of ethyl (S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate as a pale amber oil, concentrated to 99.7% of the desired enantiomer.

[0414] Step 3: Synthesis of (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (3) [ka] Ethyl (S)-2-(3-hydroxypropyl)-4-methyl-4-nitropentanoate (5 g, 20.22 mmol) in ethanol (250 mL) was cycled three times with vacuum / nitrogen, and Raney Ni (2.374 g, 50 w / w%, 20.22 mmol) (washed twice with water and once with ethanol by mixing and decantation) was added. The mixture was cycled three times with vacuum / nitrogen, then three times with vacuum / hydrogen. The suspension was vigorously stirred and heated at 60° C. under hydrogen (2 bar) until the reaction was complete.

[0415] The reaction was cooled to room temperature, cycled vacuum / nitrogen three times, filtered over Celite, and washed with ethanol (50 mL). The solvent was removed from the filtrate, then MeCN (50 mL) was added and the solvent was removed to give (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (2.88 g, 83%) as an off-white solid.

[0416] 1 H NMR(400MHz,DMSO-d6)δ 7.63(s,1H),4.38(s,1H),3.38(t,J=6.5Hz,2H),2.37(qd,J=9.5,4.4Hz,1H),2.02(d d,J=12.4,8.6Hz,1H),1.78-1.63(m,1H),1.50-1.33(m,3H),1.16(d,J=17.9Hz,7H).

[0417] ESI-MS m / z calculated 171.12593, observed 172.0 [M+1] + .

[0418] Example 18: Synthesis of tert-butyl (S)-2,2-dimethyl-4-(3-((6-sulfamoylpyridin-2-yl)amino)propyl)pyrrolidine-1-carboxylate [ka] Step 1: Synthesis of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (2) [ka] To a 50 L reactor equipped with a reflux condenser (10°C) with a jacket set at 40°C and a nitrogen purge, 2-MeTHF (10.00 L, 10 volumes) was added, followed by the portionwise addition of LAH pellets (332.5 g, 8.760 mol, 1.50 equiv.). After the pellet addition, the internal temperature was recorded at 38°C. The stirring speed was then adjusted to 175 rpm, and the mixture was heated to an internal temperature of 75°C. To a 20 L RBF, (S)-3-(3-hydroxypropyl)-5,5-dimethylpyrrolidin-2-one (1,000 g, 5.840 mol, 1.00 equiv.) and 2-MeTHF (10.00 L, 10 volumes) were added. The resulting mixture was stirred and heated in a water bath at 65°C. The resulting mixture was added to the reactor containing the LAH mixture via a heated addition funnel over 2 hours. The mixture was stirred and then quenched using the Fieser method. Water was added dropwise (400.0 mL, 1×LAH wt.) at 3.5°C with the jacket at -2°C, using the reactor temperature control to maintain internal temperature control below 30°C. Sodium hydroxide (aqueous solution, 15%; 400.0 mL, 1×LAH wt.) was added, followed by the portionwise addition of water (400.0 mL, 1×LAH wt.). The resulting mixture was heated to 60°C for at least 30 minutes and then cooled to 25±5°C. Celite (200 g, 20 wt.%) was added and stirred, and the mixture was then filtered from the reactor using a 12-inch diameter QVF filter packed with a half-inch layer of Celite. The reactor was rinsed with 2-MeTHF (4.0 L, 4.0 vol.), and the resulting mixture was filtered. The filtrate (clear, light amber) was concentrated in vacuo (50° C. bath, vacuum) to give a clear oil (872 grams, 94.95% yield).

[0419] Step 2: Synthesis of tert-butyl (S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (42) [ka] To a 50 L glass-jacketed reactor with a N purge, the jacket set at 20 °C, stirring at 175 rpm, and a condenser set at 20 °C, was added water (3.480 L, 4.0 vol) and potassium carbonate (1.914 kg, 13.85 mol, 2.5 eq). To the resulting mixture was then added a solution of (S)-3-(5,5-dimethylpyrrolidin-3-yl)propan-1-ol (870 g, 5.532 mol, 1.0 eq) in 2-MeTHF (3.480 L, 4.0 vol). 2-MeTHF (3.480 L, 4.0 vol) and BocO (1.096 kg, 5.023 mol, 0.90 eq) were mixed in a glass vessel. The reactor temperature was set to maintain 20° C. before the mixture of 2-MeTHF and BocO was added via addition funnel over 35 minutes, and the resulting mixture was stirred for 30 minutes.

[0420] To the resulting emulsion, L-glutamic acid (203.5 g, 1.383 mol, 0.25 equiv.) was added, and the emulsion was stirred overnight at room temperature. The stirrer was stopped, and the layers were allowed to separate. Water (2.610 L, 3.0 vol.) was added, and the mixture was stirred. The organic layer was isolated, and the aqueous layer was extracted with 2-MeTHF (2.610 L, 3.0 vol.). The combined organic layers were washed with aqueous sodium bisulfate (0.5 M, 1.740 L, 2.0 vol.), acidifying the aqueous layer pH, followed by 0.5 M aqueous NaHSO (870.0 mL, 1.0 vol.). The organic layer was then washed with 0.5 M aqueous KCO (1.740 L, 2.0 vol.) (pH 12 with pH strips), and 0.5 M aqueous KCO (1.740 L, 2.0 vol.). The organic layer was then washed with brine (870.0 mL, 1.0 vol), then dried over NaSO and filtered through Celite. The filter cake was rinsed with 2-MeTHF (870.0 mL, 1.0 vol). The filtrate was concentrated in vacuo to give tert-butyl (S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1,336 g, 94%) as a clear, viscous oil.

[0421] Step 3: Synthesis of tert-butyl (S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate [ka] To a 50 L jacketed reactor with the jacket set at 20 °C, stirring at 175 rpm, a reflux condenser (10 °C), and N purging, was added tert-butyl (S)-4-(3-hydroxypropyl)-2,2-dimethylpyrrolidine-1-carboxylate (1,330 g, 5.168 mol, 1.0 equiv.), DCM (7.980 L, 6.0 vol.), and 4-nitrobenzenesulfonyl chloride (1.753 kg, 7.752 mol, 1.50 equiv.). The resulting mixture was stirred at an internal reactor temperature of 5 °C. Triethylamine (1.046 kg, 10.34 mol, 2.0 equiv.) was added via an addition funnel at a rate that maintained the reaction temperature below 15 °C.

[0422] The resulting mixture was stirred for approximately 30 minutes, after which water (3.990 L, 3.0 vol) and saturated aqueous sodium bicarbonate (2.660 L, 2.0 vol) were added. The resulting mixture was stirred and allowed to warm to room temperature. An additional exotherm occurred on the scale from 5°C to 12°C, and the jacket was set to 20°C. The stirring was then stopped, and the organics were isolated and washed with saturated aqueous sodium bicarbonate (3.990 L, 3.0 vol). The amber organic solution was dried over sodium sulfate and filtered through Celite. The filter cake was washed with DCM (1.330 L, 1.0 vol). The filtrate was partially concentrated in vacuo, and then IPA (5.320 L, 4.0 vol) was added. Partially concentrated in vacuo, seed material (tert-butyl (S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate, 250 mg) was added, returned to the rotary evaporator flask, and stirred overnight at room temperature. An ice-water bath was then added, stirring continued, and the mixture cooled for 1-2 hours. The mixture was filtered through a QVF filter (12 inch diameter). The filter cake was washed with cold IPA (1.330 L, 1.0 vol), and the filter cake was scooped into a rotovap flask and dried in vacuo (50 °C, rotary evaporator, vacuum). The solid was dried to 2,091 grams (91.43% yield) as a fine beige solid.

[0423] Step 4: Synthesis of tert-butyl (S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate (44) [ka] Step 4a: To a 50 L jacketed reactor with the jacket set at 20° C., stirring at 175 rpm, a reflux condenser (10° C.), and a nitrogen purge was added tert-butyl (S)-2,2-dimethyl-4-(3-(((4-nitrophenyl)sulfonyl)oxy)propyl)pyrrolidine-1-carboxylate (2090 g, 4.723 mol, 1.00 equiv) and NMP (10.45 L, 5.0 vol). The system was set to maintain an internal temperature of 20° C. with stirring. Sodium azide (307.0 g, 4.723 mol, 1.00 equiv) was added to the reactor in two portions and rinsed in with NMP (2.090 L, 1.0 vol). The resulting mixture was stirred for 1 hour and then diluted with 2-MeTHF (25.08 L). The organic layer was isolated and washed with 1:1 water, saturated NaHCO3 solution (16.72 L, 8.0 vol). Additional water (4.180 L, 2.0 vol) was added, stirred, and then allowed to separate. The aqueous layer was extracted with 2-MeTHF (6.270 L, 3.0 vol). The organic layers were combined and washed with 2:1 water / sodium bicarbonate (6.270 L, 3.0 vol total, 2 vol water: 1 vol bicarbonate), then 2:1 water / brine (6.270 L, 3.0 vol), 1:1 water / brine (4.180 L, 2.0 vol), and brine (4.180 L, 2.0 vol). The organic layer was dried over sodium sulfate and filtered through Celite. The filter cake was washed with 2-MeTHF (2.090 L, 1.0 vol), and the filtrate was partially concentrated to 5 + / - 1 vol in a rotary evaporator. Concentrated to 3.02 kg as a clear amber solution, estimated yield 75% used without further purification.

[0424] Step 4b: A Buchi 1 L pressure system with a jacket at 20 °C was purged with nitrogen and a solution of tert-butyl (4S)-4-(3-azidopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (200 g, 708.3 mmol) in 2-MeTHF (approximately 700 mL) was added, followed by platinum oxide (2.0 g, 8.85 mmol, 1.0 wt%) and a 2-MeTHF (50.00 mL, 0.25 vol) rinse. The resulting mixture was stirred at 400 rpm, and the reaction chamber was degassed with three N / vacuum cycles, followed by three H / vacuum cycles. The H pressure was set to 2.0 bar, the system was set to H autofeed, and stirring was increased to 900 rpm at 21.1 °C. The jacket was then set to 20 °C, and the headspace was evacuated by cycling with nitrogen / vacuum for 1 hour. The reaction mixture was filtered through Celite. The filter cake was rinsed with 2-MeTHF (100.0 mL, 0.5 vol). The filtrate was transferred to a stirred vessel and diluted with 2-MeTHF (2000.0 mL, 10.0 vol). After that, cold 1N HCl (1.062 L of 1M, 1.062 mol, 5.0 vol) was added with stirring. The stirring was stopped, the pH was measured with an indicator strip, and the layers were separated. The organic layer was extracted with cold 1N aqueous HCl (354.1 mL of 1M, 354.2 mmol, 0.5 equiv). The aqueous layers were combined in a reactor and stirred at room temperature. 2-MeTHF (1.600 L, 8.0 vol) was added, and the mixture was basified, if necessary, by adding (4M) aqueous NaOH (approximately 354.2 mL of 4M, 1.417 mol). The layers were separated and then drained into a clean vessel. The aqueous layer was isolated and extracted with 2-MeTHF (400.0 mL, 2.0 vol). The organic layers were combined and added to a reactor, then washed with brine (600.0 mL, 3.0 vol), then dried over sodium sulfate, and then filtered through Celite. The filter cake was rinsed with 2-MeTHF (400.0 mL, 2.0 vol). The filtrate was concentrated in vacuo (50° C., vacuum) to give an oil. The material was used without further purification.

[0425] Step 4c: The crude amine oil (990 g, 3.87 mol) was diluted with 2-MeTHF (25.0 L, 25 vol) and transferred to a 50 L reactor and stirred at 25 °C. The required amount of oxalic acid (208.9 g, 425.0 mmol, 0.60 equiv.) was measured and dispensed into a glass carboy. 2-MeTHF (5.0 L, 5.0 vol.) was then added and stirred to dissolve the acid. Slow addition of the oxalic acid solution to the amine solution was begun. Note that a salt begins to form upon addition; slow addition may be necessary to prevent large solid chunks from forming. The salt appeared to form a slowly changing gel. The mixture was stirred overnight at room temperature. The appearance of the solid changed from a gel to a mixture containing fine solids. The mixture was filtered (slow filtration), and the cake was then washed with 2-MeTHF (4.00 L, 4.0 vol.) and sucked dry in the filter. The cake was skimmed from the filter and dried in vacuo (50°C, vacuum, rotary evaporator). 1,057 g of tert-butyl (S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate hemioxalate salt was obtained as an off-white solid. Crude amine oil (990 g, 3.87 mol) was diluted with 2-MeTHF (25.0 L, 25 vol) and transferred to a 50 L reactor and stirred at 25°C. Oxalic acid (208.9 g, 425.0 mmol, 0.60 equiv) was measured and dispensed into a glass carboy and then dissolved in 2-MeTHF (5.0 L, 5.0 vol) with stirring to dissolve the acid. The oxalic acid solution was added slowly to the amine solution. Note that the salt begins to form upon addition, and slow addition may be necessary to prevent large solid clumps from forming. The salt appeared to form a slowly changing gel. The mixture was stirred at room temperature overnight. The appearance of the solid changed from a gel to a mixture containing fine solids. The mixture was filtered (slow filtration), and the cake was then washed with 2-MeTHF (4.00 L, 4.0 vol) and sucked dry in the filter. The cake was skimmed off the filter and dried in vacuo (50° C., vacuum, rotary evaporator).There was obtained 1,057 g of tert-butyl (S)-4-(3-aminopropyl)-2,2-dimethylpyrrolidine-1-carboxylate hemioxalate salt as an off-white solid.

[0426] Example 19: 2-chloro-6-(3-(2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid [ka] Step 1: Ethyl 2-chloro-6-(3-(2-dispiro[2.0.2]) 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate [ka] 3-(2-(dispiro[2.0.2])-2-(2-(di-spiro[2.0.2])-2-methyl-2-propanol) in DMF (240 mL) 4 .1 3A suspension of [(heptan-7-yl)ethoxy)-1H-pyrazole (40.0 g, 196 mmol), ethyl 2,6-dichloronicotinate (43.1 g, 196 mmol), and K2CO3 (35.2 g, 255 mmol) was stirred at room temperature. Dissolution was endothermic at 22°C to 16°C. DABCO (3.3 g, 29 mmol) was added in one portion. The addition was mildly exothermic, raising the reaction temperature from 17°C to 23°C over 20 minutes. The reaction temperature was maintained at 20°C to 30°C. After approximately 20 hours, HPLC analysis indicated the reaction was complete (no ethyl 2,6-dichloronicotinate remained; approximately 90% AUC). The mixture was diluted by dropwise addition of water (400 mL), forming a white solid and allowing the temperature to gradually rise from 22°C to 32°C. The mixture was recooled to maintain the temperature at 15-25 °C. After an unsuccessful filtration (solids were blocked by the filter), the suspension was diluted with EtOAc (480 mL) and the phases were separated. The organic phase was washed with water (200 mL) / brine (50 mL) (twice), dried (Na2SO4), and concentrated (40 °C / 30 Torr) to give crude ethyl 2-chloro-6-(3-(2-dispiro[2.0.2])-2-methyl-2-propanol). 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate (73.1 g, 96%) was obtained as an amber oil which became crystalline.

[0427] The crude solid was dissolved in warm (80°C) i-PrOH (200 mL) and cooled to room temperature over 2 h. The solution was seeded at 38-40°C for a slow nucleation / crystallization event. Extensive crystallization was observed at 35-34°C. The suspension was allowed to stir at room temperature overnight.

[0428] The resulting suspension was very thick (oatmeal consistency). The solid was collected by filtration (sintered glass / paper), the filter cake was washed with i-PrOH (50 mL), air dried under suction, and then vacuum dried (55 °C / 300 Torr / N bleed) to give ethyl 2-chloro-6-(3-(2-dispiro[2.0.2])-2-methyl-2,4-dihydroxybenzoate) as a white powder. 4 .1 3]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate (60.2 g; 79%; 98.6% AUC). The filtrate was cooled to 3°C and a second crop (5.8 g, 8%) was collected as a white powder of acceptable purity (approximately 98% AUC). Total yield: 60.2 + 5.8 = 66.0 g (87%).

[0429] 1 H NMR(400MHz,DMSO-d6)δ8.45-8.36(m,2H),7.73(d,J=8.3Hz,1H),6.19(d,J=2.8Hz,1H),4.34(q,J=7.1Hz,2H),4.25(t,J=6.7Hz,2H),1. 82(q,J=6.7Hz,2H),1.47(t,J=6.6Hz,1H),1.34(t,J=7.1Hz,4H),0.89-0.77(m,1H),0.83(s,4H),0.71-0.60(m,3H),0.54-0.44(m,2H).

[0430] Step 2: 2-chloro-6-(3-(2-(dispiro[2.0.2])) 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid [ka] Ethyl 2-chloro-6-(3-(2-dispiro[2.0.2])-2-methyl-2,2-dihydro ... 4 .1 3A solution of 2-chloro-6-(3-(2-(dispiro[2.0.2-heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate (62.0 g, 160 mmol) was stirred at ambient temperature (13 °C). 2 M aqueous NaOH (approximately 96 mL; 192 mmol) was added in one portion, and an exotherm from 13 to 20 °C was observed. After 1 h, UPLC-MS analysis indicated the reaction was complete. The reaction solution was concentrated (40 °C / 50 Torr) to remove most of the organic solvent. The concentrate was diluted with water (248 mL) and 2-MeTHF (750 mL), and then 2 M HCl (100 mL, 200 mmol) was added while maintaining the internal temperature below 20 °C. The phases were separated, and the organic phase was washed with water (2 × 200 mL), dried (NaSO), and concentrated to give crude 2-chloro-6-(3-(2-(dispiro[2.0.2-heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinate. 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid (62.4 g (109% of theory) was obtained as a white powder. The product contains some residual solvent(s).

[0431] The crude product was recrystallized from warm (106 °C) PhMe (5 volume equivalents), seeded at approximately 95 °C, cooled to room temperature over 2 hours, and then further cooled to 10 °C. The solid was collected by filtration, washed with cold PhMe (1 volume equivalent), and the filter cake was dried under suction and then in a vacuum oven (40 °C / 100 Torr) to give 2-chloro-6-(3-(2-(dispiro[2.0.2], 2.0.2). 4 .1 3 ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid (88% yield) was obtained as a white powder.

[0432] 1H NMR(400MHz,DMSO-d6)δ13.61(s,1H),8.44-8.36(m,2H),7.72(d,J=8.4Hz,1H),6.17(d,J=2.9Hz,1H),4.24(t,J=6.7Hz,2H),1. 82(q,J=6.7Hz,2H),1.47(t,J=6.5Hz,1H),0.89-0.77(m,2H),0.83(s,2H),0.71-0.60(m,2H),0.50(ddd,J=8.2,4.5,2.2Hz,2H).

[0433] Example 20: (14R)-8-[3-(2-{dispiro[2.0.2 4 .1 3 ]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1 11 , 14 .0 5 , 10 ]Synthesis of tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione [ka] Step 1: Synthesis of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)propyl)-2,2-dimethylpyrrolidine-1-carboxylate [ka] A biphasic mixture of tert-butyl (4R)-4-(3-aminopropyl)-2,2-dimethyl-pyrrolidine-1-carboxylate (22.0 g, 85.8 mmol) and NaOH (86 mL of 2 M, 172 mmol) in PhMe (132 mL) was cooled to 0-10 °C, then a solution of Cbz-Cl (22.0 g, 18.4 mL, 129 mmol) in PhMe (44 mL) was added over 15 min, maintaining the reaction temperature below 10 °C. Upon completion of the reaction, the biphasic mixture was warmed to room temperature and the phases were separated. The aqueous phase was extracted with PhMe (44.00 mL) and the combined organic phases were washed with water (88 mL), dried (Na2SO4) and concentrated to give tert-butyl (4R)-4-[3-(benzyloxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (36.1 g, 108%) as a colorless oil.

[0434] Step 2: Synthesis of benzyl (R)-(3-(5,5-dimethylpyrrolidin-3-yl)propyl)carbamate [ka] A solution of tert-butyl (4R)-4-[3-(benzyloxycarbonylamino)propyl]-2,2-dimethyl-pyrrolidine-1-carboxylate (30.0 g, 76.8 mmol) in DCM (60 mL) was treated with a solution of HCl in dioxane (96 mL of 4 M, 384 mmol) and stirred at room temperature until the reaction was complete, then the solvent was removed under vacuum. The concentrate was partitioned between water (180 mL) and MTBE (120 mL) and the phases were separated. The aqueous layer was washed with MTBE (120 mL). The aqueous phase was diluted with MTBE (180 mL) and basified with NaOH (46 mL of 2 M, 92 mmol) (pH ∼14). The phases were separated and the aqueous phase was extracted with MTBE (120 mL). The combined organic phases were dried (Na2SO4) and concentrated (40 °C / 20 Torr) to give benzyl N-[3-[(3R)-5,5-dimethylpyrrolidin-3-yl]propyl]carbamate (15.2 g, 68%) as a colorless liquid.

[0435] UPLC-MS analysis: tR=0.99 min / M+1=291 (fits structure).

[0436] 1 H NMR(400MHz,chloroform-d)δ7.43-7.23(m,5H),5.09(s,2H),4.79(s,1H),3.26-3.05(m,3H),2.55(dd,J=11.0,8.0Hz,1H),2.13(dq,J= 15.5,7.8Hz,1H),1.79(dd,J=12.5,8.0Hz,2H),1.48(q,J=7.3Hz,2H),1.37(ddd,J=9.8,7.2,3.3Hz,2H),1.18(s,3H),1.12(s,4H).

[0437] Step 3: 2-chloro-6-(3-(2-(dispiro[2.0.2 4 .1 3 Synthesis of ]heptan-7-yl)ethoxy)-1H-pyrazol-1-yl)nicotinic acid [ka] tert-Butyl 2-chloro-6-[3-(2-dispiro[2.0.2 4 .1 3 To a solution of 2-chloro-6-[3-(2-dispiro[2.0.2-heptan-7-ylethoxy)pyrazol-1-yl]pyridine-3-carboxylate (10.0 g, 24.0 mmol) was added trifluoroacetic acid (26 mL, 338 mmol). The reaction was stirred under nitrogen gas at room temperature for 16 ...

Claims

1. Compound I: 【Chemical 347】 or a pharma- ceutically acceptable salt thereof, comprising reacting a compound of formula (I): 【Chemical 348】 or a salt thereof to Compound I or a pharma- ceutically acceptable salt thereof; During the ceremony, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; X ｃ is selected from F, Cl, Br, and I.

2. Said conversion of said compound of formula (I) or a salt thereof to compound I or a pharma- ceutically acceptable salt thereof comprises 1) combining the compound of formula (I) or a salt thereof with at least one first base to form a compound of formula (II): 【Chemical 349】 or a salt thereof; 2) The compound of formula (II) or a salt thereof is reacted with Compound 1: 【Chemistry 350】 or a salt thereof, and at least one second base to produce Compound I, or a pharma- ceutically acceptable salt thereof; In the compound of formula (II) or a salt thereof, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ 2. The method of claim 1, wherein the alkyl group is selected from aryl optionally substituted with haloalkyl, halo, or nitro.

3. The conversion of the compound of formula (I) or a salt thereof to compound I or a pharma- ceutically acceptable salt thereof comprises reacting the compound of formula (I) or a salt thereof with compound 1: 【Chemistry 351】 or a salt thereof, and at least one third base to produce Compound I, or a pharma- ceutically acceptable salt thereof; In the compound of formula (I) or a salt thereof, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; X ｃ 2. The method of claim 1 , wherein is selected from F, Cl, Br, and I.

4. The compound of formula (I): 【Chemistry 352】 or a salt thereof, wherein the compound has the formula (III): 【Chemical 353】 or a salt thereof, is prepared by converting the compound of formula (I) or a salt thereof, In the compound of formula (III) or a salt thereof, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; X ｃ is selected from F, Cl, Br, and I; During the ceremony, R １ is hydrogen, R ２ is a monovalent nitrogen protecting group, R １ and R ２ is independently selected from a monovalent nitrogen protecting group; or R １ and R ２ The method of claim 1 , wherein, together with the atom to which they are attached, form a nitrogen protecting group.

5. The compound of formula (III): 【Chemical 354】 or a salt thereof, wherein the compound has the formula (IV): 【Chemistry 355】 or a salt thereof, 【Chemical 356】 or a salt thereof to produce a compound of formula (III) or a salt thereof, During the ceremony, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; X ｂ Cl, F, -OC ６ F ５ , 【Chemical 357】 is selected from X ｃ is selected from F, Cl, Br, and I; During the ceremony, R １ is hydrogen, R ２ is a monovalent nitrogen protecting group, R １ and R ２ is independently selected from a monovalent nitrogen protecting group; or R １ and R ２ The method of claim 4 , wherein, together with the atom to which they are attached, form a nitrogen protecting group.

6. The compound of formula (IV): 【Chemical 358】 or a salt thereof, 【Chemical 359】 or a salt thereof into a compound of formula (IV) or a salt thereof, In the compound of formula (VI) or a salt thereof, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ 6. The method of claim 5, wherein the alkyl group is selected from aryl optionally substituted with haloalkyl, halo, or nitro.

7. The compound of formula (VI): 【Hua360】 or a salt thereof, 【Chemistry 361】 or a salt thereof, 【Chemical 362】 or a salt thereof to produce a compound of formula (VI) or a salt thereof, In the compound of formula (VII) or a salt thereof, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; X ｄ The method of claim 6 , wherein is selected from F, Cl, Br, and I.

8. Compound 2: 【Chemistry 363】 or a salt thereof, 【Chemistry 364】 8. The method of claim 7, wherein the compound is prepared by converting compound 2, or a salt thereof, into compound 3, or a salt thereof.

9. Compound 3: 【Chemistry 365】 or a salt thereof, 【Chemistry 366】 9. The method of claim 8, wherein the compound is prepared by converting compound 3, or a salt thereof, into compound 4, or a salt thereof.

10. Compound 4: 【Chemical 367】 or a salt thereof, 【Chemistry 368】 10. The method of claim 9, prepared by chiral resolution of 1,2,3,4,5,6,7,8,9,10,11, or a salt thereof.

11. Compound I: 【Chemical 369】 or a pharma- ceutically acceptable salt thereof, comprising reacting a compound of formula (VIII): 【Hua370】 or a salt thereof to Compound I or a pharma- ceutically acceptable salt thereof; In the compound of the formula (VIII) or a salt thereof, X ｃ is selected from F, Cl, Br, and I.

12. The compound of formula (VIII): 【Chemical 371】 or a salt thereof, wherein the compound has the formula (IX): 【Chemical 372】 or a salt thereof, into a compound of formula (VIII) or a salt thereof, In the compound of formula (IX) or a salt thereof, X ｃ is selected from F, Cl, Br, and I; During the ceremony, R １ is hydrogen, R ２ is a monovalent nitrogen protecting group, R １ and R ２ is independently selected from a monovalent nitrogen protecting group; or R １ and R ２ 12. The method of claim 11 , wherein, together with the atom to which they are attached, form a nitrogen protecting group.

13. The compound of formula (IX): 【Chemical 373】 or a salt thereof, 【Chemical 374】 or a salt thereof, 【Chemical 375】 or a salt thereof to produce a compound of formula (IX) or a salt thereof, In the compound of the formula (X) or a salt thereof, R １ is hydrogen, R ２ is a monovalent nitrogen protecting group, R １ and R ２ is independently selected from a monovalent nitrogen protecting group; or R １ and R ２ together with the atom to which they are attached form a nitrogen protecting group, In the compound of formula (V) or a salt thereof, X ｂ Cl, F, -OC ６ F ５ , 【Chemical 376】 is selected from X ｃ The method of claim 12, wherein is selected from F, Cl, Br, and I.

14. The compound of formula (X): 【Chemical 377】 or a salt thereof, wherein the compound has the formula (IV): 【Chemical 378】 or a salt thereof, 【Chemical 379】 or a salt thereof to produce a compound of formula (X) or a salt thereof, In the compound of formula (IV) or a salt thereof, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; During the ceremony, R １ is hydrogen, R ２ is a monovalent nitrogen protecting group, R １ and R ２ is independently selected from a monovalent nitrogen protecting group; or R １ and R ２ 14. The method of claim 13, wherein, together with the atom to which they are attached, form a nitrogen protecting group.

15. The compound of formula (IV): 【Hua380】 or a salt thereof, wherein the compound is of formula (XI): 【Chemistry 381】 or a salt thereof, 【Chemical 382】 or a salt thereof to produce a compound of formula (IV) or a salt thereof, In the compound of formula (XI) or a salt thereof, R １ is hydrogen, R ２ is a monovalent nitrogen protecting group, R １ and R ２ is independently selected from a monovalent nitrogen protecting group; or R １ and R ２ together with the atom to which they are attached form a nitrogen protecting group, In the compound of formula (VII) or a salt thereof, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; X ｄ The method of claim 14, wherein is selected from F, Cl, Br, and I.

16. The compound of formula (XI): 【Chemical 383】 or a salt thereof, wherein the compound is of formula (XII): 【Chemical 384】 or a salt thereof into a compound of formula (XI) or a salt thereof, In the compound of formula (XII) or a salt thereof, R ３ The method of claim 15 , wherein is a monovalent nitrogen protecting group.

17. The compound of formula (XII): 【Chemistry 385】 or a salt thereof, wherein the compound has the formula (XV): 【Chemistry 386】 or a salt thereof into a compound of formula (XII) or a salt thereof, In the compound of formula (XV) or a salt thereof, R ３ The method of claim 16 , wherein is a monovalent nitrogen protecting group.

18. said conversion of said compound of formula (XV) or a salt thereof to said compound of formula (XII) or a salt thereof 1) A compound of formula (XV): 【Chemical 387】 or a salt thereof, 【Chemistry 388】 or a salt thereof; 2) reacting the compound of formula (XIV) or a salt thereof with a compound of formula (XIII): 【Chemical 389】 or a salt thereof; 3) converting said compound of formula (XIII) or a salt thereof into said compound of formula (XII) or a salt thereof, In the compounds of the formulae (XIII) to (XV) or salts thereof, R ３ is a monovalent nitrogen protecting group, and in the compound of formula (XIV) or a salt thereof, R ４ But -SO ２ R, R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ 18. The method of claim 17, wherein the alkyl group is selected from aryl optionally substituted with haloalkyl, halo, or nitro.

19. The compound of formula (XV): 【Chemical 390】 or a salt thereof, 【Chemical 391】 or a salt thereof, is prepared by converting said compound of formula (XV) or a salt thereof into

20. Compound 2: 【Chemical 392】 or a salt thereof, 【Chemical 393】 20. The method of claim 19, wherein the compound is prepared by converting compound 2, or a salt thereof, into compound 3, or a salt thereof.

21. Compound 3: 【Chemical 394】 or a salt thereof, 【Chemical 395】 21. The method of claim 20, prepared by chiral resolution of 1,2,3,4,5,6,7,8,9,10,11, or a salt thereof.

22. Compound (±)-3: 【Chemical Formula 396】 or a salt thereof, 【Chemical 397】 or a salt thereof to the compound (±)-3 or a salt thereof.

23. Compound (±)-4: 【Chemical 398】 or a salt thereof, 【Chemical 399】 23. The method of claim 22, wherein the compound (±)-4 or a salt thereof is prepared by combining (±)-4 or a salt thereof with 2-nitropropane to produce the compound (±)-4 or a salt thereof.

24. Compound 1: 【Chemical 400】 or a salt thereof, 【Chemistry 401】 3. The method of claim 2, wherein the compound is prepared by converting compound 1 or a salt thereof into compound 2.

25. Compound 6: 【Chemistry 402】 or a salt thereof, 【Chemistry 403】 25. The method of claim 24, wherein the compound is prepared by converting compound 6, or a salt thereof, into compound 7, or a salt thereof.

26. Compound 7: 【Chemistry 404】 or a salt thereof, 【Chemistry 405】 or a salt thereof, 【Chemistry 406】 or a salt thereof to produce compound 7, or a salt thereof.

27. Compound 8: 【Chemistry 407】 or a salt thereof, 【Chemistry 408】 27. The method of claim 26, wherein the compound is prepared by converting compound 8, or a salt thereof, into compound 9, or a salt thereof.

28. Compound 10: 【Chemistry 409】 or a salt thereof, 【Chemistry 410】 28. The method of claim 27, wherein the compound is prepared by converting compound 10, or a salt thereof, into compound 11, or a salt thereof.

29. Compound 11: 【Chemistry 411】 or a salt thereof, 【Chemistry 412】 29. The method of claim 28, wherein the compound is prepared by converting compound 11, or a salt thereof, to compound 11, or a salt thereof.

30. Compound 12: 【Chemistry 413】 or a salt thereof, 【Chemistry 414】 30. The method of claim 29, wherein the compound is prepared by converting compound 12, or a salt thereof, into compound 13, or a salt thereof.

31. Compound 13: 【Chemistry 415】 or a salt thereof, 【Chemistry 416】 or a salt thereof is prepared by converting compound 13 or a salt thereof into compound 14.

32. Compound 14: 【Chemistry 417】 or a salt thereof, 【Chemistry 418】 or a salt thereof is prepared by converting compound 14 or a salt thereof.

33. Compound 15: 【Chemistry 419】 or a salt thereof, 【Chemistry 420】 33. The method of claim 32, wherein the compound is prepared by converting compound 15, or a salt thereof, into compound 16, or a salt thereof.

34. Compound 16: 【Chemistry 421】 or a salt thereof, 【Chemistry 422】 or a salt thereof is prepared by converting compound 16 or a salt thereof.

35. Compound 17: 【Chemistry 423】 or a salt thereof, 【Chemistry 424】 35. The method of claim 34, wherein the compound is prepared by converting compound 17, or a salt thereof, to compound 17.

36. Compound 18: 【Chemistry 425】 or a salt thereof, 【Chemistry 426】 36. The method of claim 35, wherein the compound is prepared by converting compound 18, or a salt thereof, to compound 19, or a salt thereof.

37. below: 【Table 9-1】 【Table 9-2】 and salts thereof, During the ceremony, X ａ is F, Cl, Br, I, and -OSO ２ R is selected from R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; X ｃ is selected from F, Cl, Br, and I; X ｄ is selected from F, Cl, Br, and I; R ３ is a monovalent nitrogen protecting group, R ４ But -SO ２ R, R is -C １－１０ Alkyl, -C １－１０ Haloalkyl, and -C １－１０ Alkyl, -C １－１０ aryl optionally substituted with haloalkyl, halo, or nitro; During the ceremony, R １ is hydrogen, R ２ is a monovalent nitrogen protecting group, R １ and R ２ is independently selected from a monovalent nitrogen protecting group; or R １ and R ２ together with the atom to which they are attached form a nitrogen protecting group, The compound is 【Table 8】 or a salt thereof, as well as salts thereof.

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