Methods of preparing reticuline analogs

Abstract

The present invention provides methods of making reticuline analogs. In particular, the present invention relates to a method for making a 4-substituted reticuline analog of Formula (I) or a pharmaceutically acceptable salt, solvate, and / or ester thereof, the method comprising: i) providing a compound of Formula IIa, ii) generating a compound of Formula IIb by contacting the compound of Formula IIa with a boronating agent, iii) substituting BComp with R 1 to produce the compound of Formula I.

Description

[0001] This application is a divisional application of the invention patent application No. 201780062052.3 entitled "Compound", filed on August 17, 2017. Technical Field

[0002] This invention relates to novel analogues of indigofera and their uses in medicine, such as in the treatment of addiction. The invention also provides improved synthetic routes for the preparation of analogues of indigofera. Background Technology

[0003] Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels expressed in various parts of the human brain and elsewhere in the central nervous system. nAChRs are involved in a range of physiological functions, such as cognitive function, learning and memory, sleep, anxiety, arousal, reward, motor control, and other neurological functions. nAChRs are also associated with a variety of pathological conditions, such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and schizophrenia. nAChRs are also associated with addiction and dependence on a range of substances, such as nicotine addiction (Schalling and Waller, Acta Physiologica Scandinavica. Supplementum, 1980, volume 479, pages 53-56), alcohol addiction (Holgate et al., BrainScience, 2015, September 5(3), pages 258-274), and drug dependence (Rahman et al., Frontiers in Neuroscience, 2014, volume 8, article 426).

[0004] Many nAChR subtypes are known to exist. The muscular nicotinic receptor (located at the neuromuscular junction) is known to be formed by five different substructures, called α, ... β γ, δ, and the recently discovered subunit ε.

[0005] Neuronal nAChRs (located in the CNS, peripheral ganglia, and adrenal medulla) exhibit only two types of subunits, referred to as α2-α9 and... β2-β 4. It can assemble into homopolymers or heteropolymers. Although a large number of neuronal subtypes have been identified, heteropolymers (α4)3 ( β 2)2、a3 β α4 and homopolymer α7 appear to play significant roles in the brain. Heteropolymer α4, in particular, binds to... βα2 is the dominant isoform in the CNS, accounting for approximately 90% of the receptors, and binds to ACh with high affinity. α7 homopolymer binding is another major isoform, binding to ACh with low affinity.

[0006] Heterogeneous binding α4 β 2 can be assembled into two different stoichiometry: (α4)2( β 2)3 and (α4)3 β 2)2, usually referred to as A2B3 and A3B2 respectively. The main α4 is proposed. β Subtype 2 has a structure A2B3, consisting of two α4 and three β 2. Subunit formation; and it is the main subtype involved in addiction.

[0007] It is believed that nicotine can activate this α4 β 2 receptor subtypes, thereby increasing dopamine release in the nucleus accumbens and prefrontal cortex, which are specific areas of the human brain associated with drug dependence.

[0008] In addition, α4 β The 2 receptor subtype is also associated with alcohol dependence (Mitchell et al., Pyschopharmacology, October 2012, 223, 3, pages 299 to 306) and drug addiction (Crunelle et al., European Neuropsychopharmacology, February 2010, 20, 2, pages 69 to 79).

[0009] Compounds with the ability to modulate nAChR have been found to be effective in treating conditions associated with these receptors. For example, studies have shown that transdermal administration of nicotine can improve cognitive function in people with age-related memory impairment (see, for example, White et al., Psychopharmacology, February 2004, 171, 4, pages 465 to 471). However, even when administered transdermally, nicotine use has certain drawbacks. For example, nicotine is known to be addictive, and a 2014 report by the U.S. Surgeon General noted its negative effects on pregnancy outcomes and fetal brain development.

[0010] In the field of smoking cessation therapy, nicotine has been used to help smokers quit, and products that deliver nicotine orally (e.g., tablets or chewing gum) or transdermally have been developed and are well-known.

[0011] Alternative compounds that regulate nAChR have also been used in the treatment of addiction. Varenicline is marketed by Pfizer under the brand name Chantix® in the United States and Champix in Europe. ® It is commercialized and approved for use in smoking cessation therapy. Furthermore, the drug has been tested in the treatment of alcohol and drug dependence (Mitchell et al., Pyschopharmacology, October 2012, 223, 3, pages 299 to 306, and Crunelle et al., European Neuropsychopharmacology, February 2010, 20, 2, pages 69 to 79).

[0012] Mihalak et al. (Molecular Pharmacology, 2006, September, 70(3), pages 801 to 805) found that varenicline is a partial agonist of the α4β2 receptor, a low-efficacy agonist of the α3β4 receptor, a partial agonist of the α3β2 and α6 receptors, and a potent agonist of the α7 receptor.

[0013] Another medication used in smoking cessation therapy is indigoline. Indigoline is a naturally occurring alkaloid containing a pyridone and is known to be a partial agonist of nAChR. Pharmacologically, indigoline is highly similar to nicotine and has been successfully used as a smoking cessation aid for many years. The chemical structure of indigoline (or more specifically, its (-) enantiomer) is shown below:

[0014] Although indigo is a safe and effective treatment for smoking cessation, people have been trying to produce functionalized derivatives of this compound.

[0015] Several different numbering systems for indigo alkaloids have been conventionally used. For the purposes of this discussion and the disclosure of this invention, the following numbering system will be used:

[0016] In two papers (Journal of Medicinal Chemistry, 2006, 49, pages 2673 to 2676 and ChemMedChem, 2007, 2, pages 1157 to 1161), Kozikowski et al. summarized previous work on introducing substituents (mainly at the 3- and 5-positions) into the structure of indigo, and disclosed the reported synthesis of novel racemic analogs including substituents at the 3-, 4-, or 7-positions.

[0017] In a 2006 paper by Kozikowski et al., racemic 4-substituted compounds were reported to exhibit no agonist activity against the α4β2 receptor subtype, despite its high selectivity. The results presented in the 2006 paper indicated that 4-substituted analogues of indigoferazone are weak antagonists of the α4β2 receptor subtype.

[0018] Therefore, the work done by Kozikowski et al. shows that the activity of 4-substituted indigo analogs is significantly different from that of the known addiction therapies indigo and varenicline.

[0019] Recently, other research groups have focused on substitutions at other positions in the structure of indigomine. For example, in International Patent Publication No. WO2014 / 001348, analogs of indigomine having the following general structure were synthesized:

[0020] Furthermore, in Chinese Patent Publication No. 103509021, indigo analogs include substituents at the nitrogen atom and / or the 5-position on the piperidine ring.

[0021] Rouden et al. (Chemical Reviews, 2014, 114, pages 712 to 778) drafted a review of all the different studies on functionalized derivatives of indigo.

[0022] Despite extensive research on indigo analogs, and their potential to provide pharmaceutical formulations with improved performance compared to indigo and / or other nAChR-binding drugs, to the inventors' knowledge, no such compound has entered clinical trials, let alone been approved as a pharmaceutical product. Therefore, there remains a need for pharmaceutical agents with improved performance compared to indigo, such as improved safety and / or efficacy, as agents, for example, in the treatment of addiction. Summary of the Invention

[0023] Therefore, according to a first aspect of the invention, a compound of formula (I) is provided:

[0024] (I) Or its pharmaceutically acceptable salts, solvates and / or esters, wherein R 1 To R 4 As defined below. This invention also provides pharmaceutical compositions comprising such compounds, and the use of these compounds and compositions in medicine.

[0025] Other aspects of the invention described in more detail below are synthetic methods for the convenient preparation of 4-substituted indigo analogs.

[0026] The compounds and compositions of the present invention can be used in medicine. For example, they can be used to prevent, treat, or improve symptoms of CNS disorders, including addictions such as nicotine, alcohol, and drug addiction.

[0027] The compounds of this aspect of the invention have been identified by the inventors as having use in therapeutic applications, particularly in the treatment of drug addiction and / or dependence on alcohol and / or tobacco. While a limited number of 4-substituted indigo analogs have been previously disclosed, the limited binding data associated with these compounds have not demonstrated their suitability for use in medicine, and the authors of these disclosures have concluded that these compounds exhibit weak potency as modulators of receptors associated with neurological conditions including dependence and addiction. For example, Rouden et al., in Chemical Reviews, 2014, 1 14, pages 712 to 778 (page 732 of that document), concluded that the 4-indigo analogs tested 'exhibited no agonist activity and very low potency in the inhibitory channel function of nicotine activation at both α4β2 and α3β4 receptors'. However, surprisingly and unexpectedly, the inventors have found that, based on newly generated data discussed in more detail below, these compounds can exhibit previously unrealized advantages.

[0028] Compounds with extensive substituents at the 4-position of indocyanine have been identified by the inventors as having therapeutic benefits.

[0029] As described herein, the compounds of the present invention may be substituted with one or more substituents, as described herein or illustrated by specific compounds disclosed herein.

[0030] As used herein, the term "aliphatic" includes the terms alkyl, alkenyl, and ynyl, each of which may be optionally substituted as listed below.

[0031] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms. Alkyl groups can be straight-chain or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. The alkyl group may be substituted with one or more substituents (i.e., optionally substituted), such as halogens, phosphine, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocyclic aliphatic [e.g., heterocyclic alkyl or heterocyclic alkenyl], aryl, heteroaryl, alkoxy, arylyl, heteroarylyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocyclic aliphatic)carbonyl], nitro, cyano, amide [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, arylalkylcarbonylamino, (heterocyclic alkyl)carbonylamino, (heterocyclic alkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaryl... Alkylcarbonylaminoalkylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclic alkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl], amino [e.g. aliphatic amino, cycloaliphatic amino or heterocyclic aliphatic amino], sulfonyl [e.g. aliphatic -SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfonamide, thioamide, oxydimethyl, carboxyl, carbamoyl, cycloaliphatic oxy, heterocyclic aliphatic oxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy or hydroxyl.

[0032] As used herein, an "alkenyl" group refers to an aliphatic carbon group comprising 2-12 (e.g., 2-8, 2-6, or 2-4) carbon atoms and at least one double bond. Similar to alkyl groups, alkenyl groups can be straight-chain or branched. Examples of alkenyl groups include, but are not limited to, allyl, vinyl, isoprenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 5-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and 6-hexenyl. The alkenyl group may optionally be substituted with one or more substituents, such as halogens, phosphine, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, arylyl, heteroarylyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amide [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, arylalkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino] Alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclic alkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl], amino [e.g. aliphatic amino, cycloaliphatic amino, heterocyclic aliphatic amino or aliphatic sulfonylamino], sulfonyl [e.g. alkyl-SO2-, cycloaliphatic-SO2- or aryl-SO2-], sulfinyl, thioalkyl, sulfinyloxy, urea, thiourea, sulfonamide, thioamide, oxydimethyl, carboxyl, carbamoyl, cycloaliphatic oxy, heterocyclic aliphatic oxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy or hydroxyl.

[0033] As used herein, an "alkynyl" group refers to an aliphatic carbon group comprising 2-12 (e.g., 2-8, 2-6, or 2-4) carbon atoms and at least one triple bond. Alynyl groups can be straight-chain or branched. Examples of alkynyl groups include, but are not limited to, propynyl, butynyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 6-hexynyl. The alkynyl group may optionally be substituted by one or more substituents, such as aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkoxy, aryloxy, heteroaryloxy, arylalkoxy, nitro, carboxyl, cyano, halogen, hydroxyl, sulfonyl, mercapto, thioalkyl [e.g., aliphatic thioalkyl or cycloaliphatic thioalkyl], sulfinyl [e.g., aliphatic sulfinyl or cycloaliphatic sulfinyl], sulfonyl [e.g., aliphatic -SO2-, aliphatic amino -SO2- or cycloaliphatic -SO2-], amide [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylamino] Carbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocyclic alkyl)carbonylamino, (cycloalkyl alkyl)carbonylamino, heteroarylalkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfonamide, thioamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocyclic aliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl or (heterocyclic aliphatic)carbonyl], amino [e.g., aliphatic amino], sulfinyloxy, oxydimethyl, carboxyl, carbamoyl, (cycloaliphatic)oxy, (heterocyclic aliphatic)oxy or (heteroaryl)alkoxy.

[0034] As used herein, the term "aryl" as used alone or as part of a larger part (such as in "aryl," "arylalkoxy," or "aryloxyalkyl") refers to a monocyclic (e.g., phenyl); a bicyclic (e.g., indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl); and a tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, tetrahydroanthrayl, anthracene) cyclic system, wherein the monocyclic system is aromatic or at least one ring in the bicyclic or tricyclic system is aromatic. Bicyclic and tricyclic groups include benzo[a]fused 2- to 3-membered carbon rings. For example, benzo[a]fused groups include those with two or more C[a] 4-8A phenyl group with partially fused carbocyclic rings. The aryl group is optionally substituted with one or more substituents, including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocyclic aliphatic; (heterocyclic aliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocyclic aliphatic)oxy; aryloxy; heteroaryloxy; (arylaliphatic)oxy; (heteroarylaliphatic)oxy; arylyl; heteroaryloxy; arylyl; heteroarylyl; amino; oxonyl (on the non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl group); nitro; carboxyl; amide; acyl [e.g.] The aryl group can be: (aliphatic)carbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (aromaticaliphatic)carbonyl; (heterocyclic aliphatic)carbonyl; ((heterocyclic aliphatic)aliphatic)carbonyl; or (heteroaromatic aliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO2- or amino-SO2-]; sulfinyl [e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-]; thioalkyl [e.g., aliphatic-S-]; cyano; halogen; hydroxyl; mercapto; sulfinyloxy; urea; thiourea; sulfonamide; thioamide; or carbamoyl. Alternatively, the aryl group may be unsubstituted.

[0035] Non-limiting examples of substituted aryl groups include haloaryl groups [e.g., mono-, di-(such as p,m-dihaloaryl) and (trihalo)aryl]; (carboxyl)aryl groups [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl and (alkoxycarbonyl)aryl]; (acylamino)aryl groups [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl groups [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfonamide)aryl groups [e.g., (amino]...] [Sulfoyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; (alkoxy)alkyl)aryl; (hydroxy)aryl, (carboxyl)alkyl)aryl; ((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; ((alkylsulfonyl)amino)alkyl)aryl; (heterocyclic aliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocyclic aliphatic)-o-(alkyl))aryl.

[0036] As used herein, "aromatic aliphatic" such as "aralkyl" groups refer to aliphatic groups substituted with aryl groups (e.g., C14, C24, C34, C44, C54, C64, C7 ... 1-4Alkyl groups). This article defines "aliphatic", "alkyl", and "aryl". An example of an aryliphatic group such as an aryl group is the benzyl group.

[0037] As used herein, "aralkyl" group refers to an alkyl group substituted with an aryl group (e.g., C10). 1-4 Alkyl groups). Both "alkyl" and "aryl" have been defined above. An example of an aryl alkyl group is benzyl. An aryl alkyl group may optionally be substituted with one or more substituents, such as aliphatic [e.g., alkyl, alkenyl, or ynyl, including carboxylalkyl, hydroxyalkyl, or haloalkyl, such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, arylalkoxy, heteroarylalkoxy, arylylalkoxy, arylylalkoxy, arylylalkoxy, arylylalkoxy, arylylalkoxy, arylylalkoxy, arylylyl, heteroarylyl, nitro, carboxyl Alkoxycarbonyl, alkylcarbonyloxy, acylamino [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocyclic alkyl)carbonylamino, (heterocyclic alkyl)carbonylamino, heteroarylcarbonylamino or heteroarylalkylcarbonylamino], cyano, halogen, hydroxyl, acyl, mercapto, alkylthioalkyl, sulfinyloxy, urea, thiourea, sulfonamide, thioamide, oxydimethyl or carbamoyl.

[0038] As used herein, a “bicyclic system” includes an 8-12 (e.g., 9, 10, or 11)-membered structure forming two rings, wherein the two rings have at least one common atom (e.g., two common atoms). Bicyclic systems include bicyclic aliphatic (e.g., bicyclic alkyl or bicyclic alkenyl), bicyclic heteroaliphatic, bicyclic aryl, and bicyclic heteroaryl.

[0039] As used herein, “carbocyclic” or “cycloaliphatic” groups include “cycloalkyl” and “cycloalkenyl” groups, each of which may optionally be substituted as listed below.

[0040] As used herein, a “cycloalkyl” group refers to a saturated carbon monocyclic or bicyclic (fused or bridged) ring with 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubic, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0041] As used herein, a “cycloalkenyl” group refers to a non-aromatic carbon ring having 3–10 (e.g., 4–8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexyl-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0042] The cycloalkyl or cycloalkenyl group may optionally be substituted with one or more substituents, such as phosphine, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocyclic aliphatic, (heterocyclic aliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocyclic aliphatic)oxy, aryloxy, heteroaryloxy, (arylaliphatic)oxy, (heteroarylaliphatic)oxy, aryl, heteroaryl, amino, amide [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (aryl)carbonylamino, (heterocyclic aliphatic)carbonylamino, ((heterocyclic aliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroarylaliphatic)carbonyl]. Amino, nitro, carboxyl [e.g., HOOC-, alkoxycarbonyl or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (aromaticaliphatic)carbonyl, (heterocyclic aliphatic)carbonyl, ((heterocyclic aliphatic)aliphatic)carbonyl or (heteroaromatic aliphatic)carbonyl], cyano, halogen, hydroxyl, mercapto, sulfonyl [e.g. alkyl-SO2- and aryl-SO2-], sulfinyl [e.g. alkyl-S(O)-], thioalkyl [e.g. alkyl-S-], sulfinyloxy, urea, thiourea, sulfonamide, thioamide, oxydimethyl or carbamoyl.

[0043] As used herein, the term “heterocyclic” or “heterocyclic aliphatic” includes heterocyclic alkyl groups and heterocyclic alkenyl groups, each of which may optionally be substituted as listed below.

[0044] As used herein, a "heterocyclic alkyl" group refers to a 3- to 10-membered mono- or bi-(fused-ring or bridged-ring) (e.g., 5- to 10-membered mono- or bi-) saturated ring structure in which one or more ring atoms are heteroatoms (e.g., N, O, S, or combinations thereof). Examples of heterocyclic alkyl groups include aziridinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, thiocyclic butyl, oxacyclopentyl, dioxacyclohexyl, dioxacyclopentyl, thienyl, dithienyl, trithienyl, thiomorpholinyl, 1,3-dioxacyclopentyl, imidazoalkyl, oxazolyl, ethylene oxide, oxacyclobutyl, isoxazolyl, morpholinyl, pyrrolidinyl, pyrazolyl, tetrahydro... Thiopheneyl, oxothiocyclopentyl, pyranyl, thiomorpholinyl, octahydrobenzofuranyl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyridyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0] 3,7 Nonyl. Monocyclic heterocyclic alkyl groups can be fused with the phenyl moiety to form structures, such as tetrahydroisoquinoline, which can be classified as a heteroaryl group.

[0045] As used herein, a "heterocyclic alkenyl" group refers to a mono- or di- (e.g., 5- to 10-membered mono- or di-) non-aromatic ring structure having one or more double bonds, wherein one or more ring atoms are heteroatoms (e.g., N, O, or S). Monocyclic and bicyclic heterocyclic aliphatic groups are numbered according to standard chemical nomenclature.

[0046] The heterocyclic alkyl or heterocyclic alkenyl group may optionally be substituted with one or more substituents, such as phosphine, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocyclic aliphatic, (heterocyclic aliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocyclic aliphatic)oxy, aryloxy, heteroaryloxy, (arylaliphatic)oxy, (heteroarylaliphatic)oxy, arylyl, heteroarylyl, amino, amide [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)...] Aliphatic carbonylamino, (aryl) carbonylamino, (aromatic aliphatic) carbonylamino, (heterocyclic aliphatic) carbonylamino, ((heterocyclic aliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino or (heteroaromatic aliphatic) carbonylamino], nitro, carboxyl [e.g., HOOC-, alkoxy carbonyl or alkyl carbonyloxy], acyl [e.g., (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic) carbonyl, (aromatic aliphatic) carbonyl, (heterocyclic aliphatic) carbonyl, ((heterocyclic aliphatic) aliphatic) carbonyl or (heteroaromatic aliphatic) carbonyl], nitro, cyano, halogen, hydroxyl, mercapto, sulfonyl [e.g. alkyl sulfonyl and aryl sulfonyl], sulfinyl [e.g. alkyl sulfinyl], thioalkyl [e.g. alkyl thioalkyl], sulfinyloxy, urea, thiourea, sulfonamide, thioamide, oxydimethyl or carbamoyl.

[0047] As used herein, a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic system having 4 to 15 ring atoms, wherein one or more ring atoms are heteroatoms (e.g., N, O, S, or combinations thereof), and wherein the monocyclic system is aromatic or at least one ring in the bicyclic or tricyclic system is aromatic. Heteroaryl groups include benzo[b]-fused ring systems having 2 to 3 rings. For example, benzo[b]-fused groups include benzo[b]-fused groups with one or two 4 to 8-membered heterocyclic aliphatic moieties (e.g., inazinyl, indolyl, isoindolyl, 3H-indolyl, dihydroindolyl, benzo[b]furanyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl groups are azirrobutyl, pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 1H-indazoleyl, furanyl, pyrroleyl, thiopheneyl, thiazolyl, thiopheneyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, thiazolyl, imidazoleyl, diazolyl, triazolyl, tetrazolyl, benzofuranyl, isoquinolinyl, benzene benzo[1,3]m-dioxane, benzo[b]furan, benzo[b]thiophene, indazole, benzimidazolyl, benzothiazolyl, purine, cinolinyl, quinolinyl, quinazolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, 4H-quinolinazinyl, benzo-1,2,5-thiadiazolyl or 1,8-naphthidyl.

[0048] Monocyclic heteroaryl groups include, but are not limited to, furanyl, thiophene, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, or 1,3,5-triazinyl. Monocyclic heteroaryl groups are numbered according to standard chemical nomenclature.

[0049] Bicyclic heteroaryl groups include, but are not limited to, indazinyl, indolyl, isoindolyl, 3H-indolyl, dihydroindolyl, benzo[b]furanyl, benzo[b]thiopheneyl, quinolinyl, isoquinolinyl, indazinyl, isoindolyl, indolyl, benzo[b]furanyl, benzo[b]thiopheneyl, indazoleyl, benzimidazinyl, benzothiazolyl, purineyl, 4H-quinolinazinyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthidyl or pteridyl. Bicyclic heteroaryl groups are numbered according to standard chemical nomenclature.

[0050] The heteroaryl group is optionally substituted by one or more substituents, such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocyclic aliphatic; (heterocyclic aliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocyclic aliphatic)oxy; aryloxy; heteroaryloxy; (arylaliphatic)oxy; (heteroarylaliphatic)oxy; arylyl; heteroarylyl; amino; oxonyl (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl group); carboxyl; amide; acyl The aryl group [e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (aromaticaliphatic)carbonyl; (heterocyclic aliphatic)carbonyl; ((heterocyclic aliphatic)aliphatic)carbonyl; or (heteroaromatic aliphatic)carbonyl]; sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphatic sulfinyl]; thioalkyl [e.g., aliphatic thioalkyl]; nitro; cyano; halogen; hydroxyl; mercapto; sulfinyloxy; urea; thiourea; sulfonamide; thioamide; or carbamoyl. Alternatively, the heteroaryl group may be unsubstituted.

[0051] Non-limiting examples of substituted heteroaryl groups include (halogenated)heteroaryl groups [e.g., mono- and di-(halogenated)heteroaryl groups]; (carboxylated)heteroaryl groups [e.g., (alkoxycarbonyl)heteroaryl groups]; cyanoheteroaryl groups; aminoheteroaryl groups [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl groups]; (acylamino)heteroaryl groups [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocyclic aliphatic)carbonyl)heteroaryl and ((alkylcarbonyl)amino)heteroaryl groups]; (cyanoalkyl)heteroaryl groups; (alkoxy) Heteroaryl; (sulfonamide)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl; ((carboxyl)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl; (heterocyclic aliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

[0052] As used herein, “heteroaryl aliphatic” (such as heteroaryl alkyl groups) refers to aliphatic groups substituted with heteroaryl groups (e.g., C14, C24, C34, C44, C54, C64, C7 ... 1-4 Alkyl groups). "Aliphatic", "alkyl", and "heteroaryl" have been defined above.

[0053] As used herein, "heteroaryl" group refers to an alkyl group substituted with a heteroaryl group (e.g., C10). 1-4 Alkyl groups). Both "alkyl" and "heteroaryl" have been defined above. The heteroaryl group is optionally substituted with one or more substituents, such as alkyl (including carboxylalkyl, hydroxyalkyl, and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, arylalkoxy, arylacyl, heteroarylacyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, arylalkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, cyano, halogen, hydroxyl, acyl, mercapto, alkylthioalkyl, sulfinyloxy, urea, thiourea, sulfonamide, thioamide, oxonyl or carbamoyl.

[0054] As used herein, “cyclic moiety” and “cyclic group” refer to mono-, di-, and tricyclic systems, including cyclic aliphatic, heterocyclic aliphatic, aryl, or heteroaryl systems, each of which has been defined above.

[0055] As used herein, "bridged bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantyl, norbornel, bicyclic [3.2.1]octyl, bicyclic [2.2.2]octyl, bicyclic [3.3.1]nonyl, bicyclic [3.2.3]nonyl, 2-oxabicyclic [2.2.2]octyl, 1-azabicyclic [2.2.2]octyl, 3-azabicyclic [3.2.1]octyl, and 2,6-dioxatricyclic [3.3.1.0] 3,7 Nonyl. The bridged bicyclic ring system may optionally be substituted with one or more substituents, such as alkyl (including carboxylalkyl, hydroxyalkyl, and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, arylyl, heteroarylalkoxy, arylyl, arylyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, arylalkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, cyano, halogen, hydroxyl, acyl, mercapto, alkylthioalkyl, sulfinyloxy, urea, thiourea, sulfonamide, thioamide, oxonyl, or carbamoyl.

[0056] As used herein, "amide" includes both "carbamoyl" and "carbonylamino". These terms refer to the amide group when used alone or in conjunction with other groups, such as -N(R) when used at the end. X )-C(O)-R Y or -C(O)-N(R) X )2, and when used in the middle, it refers to -C(O)-N(R) X - or -N(R) X )-C(O)-, where R X and R Y As defined below, examples of amide groups include alkylamides (such as alkylcarbonylamides or alkylaminocarbonyl), (heterocyclic aliphatic)amides, (heteroaryl)amides, (heteroaryl)amides, (heterocyclic)alkylamides, arylamides, aralkylamides, (cycloalkyl)alkylamides, or cycloalkylamides.

[0057] As used in this article, the "amino" group refers to -NR. XR Y , where R X and R Y Independently, it can be hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, arylaliphatic, heterocyclic aliphatic, (heterocyclic aliphatic)aliphatic, heteroaryl, carboxyl, thioalkyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (arylaliphatic)carbonyl, (heterocyclic aliphatic)carbonyl, ((heterocyclic aliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroarylaliphatic)carbonyl, each of which is defined herein and optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), it is prefixed with -NR. X - indicates. R X It has the same meaning as defined above.

[0058] As used in this article, the "acyl" group refers to a nail acyl group or R. X -C(O)- (such as alkyl-C(O)-, also known as "alkyl carbonyl"), where R X The alkyl group has already been defined above. Acetyl and neopentyl are examples of acyl groups.

[0059] As used herein, “aromatic acyl” or “heteroaromatic acyl” refers to aryl-C(O)- or heteroaromatic-C(O)-. The aryl and heteroaromatic moieties of the aromatic acyl or heteroaromatic acyl may optionally be substituted as defined above.

[0060] As used in this article, the "alkoxy" group refers to the alkyl-O- group, where "alkyl" has already been defined above.

[0061] As used in this article, the "carbamoyl" group refers to a group with the structure -O-CO-NR. X R Y or -NR X -CO-OR Z The group, wherein R X and R Y As already defined above, and R Z It can be aliphatic, aryl, aromatic aliphatic, heterocyclic aliphatic, heteroaryl, or heteroaromatic aliphatic.

[0062] As used in this article, the "carboxyl" group, when used as a terminal group, refers to -COOH, -COOR, etc. X -OC(O)H, -OC(O)R X Or, when used as an intermediate group, it refers to -OC(O)- or -C(O)O-.

[0063] As used herein, a “halogenated aliphatic” group refers to an aliphatic group substituted with 1 to 3 halogen atoms. For example, the term halogenated alkyl includes the group -CF3.

[0064] As used in this article, the "thiol" group refers to -SH.

[0065] As used in this article, the "sulfonyl" group, when used at the end, refers to -SO3H or -SO3R. X , or when used in the middle, it refers to -S(O)3-.

[0066] As used in this article, the "thioamide" group, when used at the end, refers to the structure -NR. X -S(O)2-NR Y R Z And when used in the middle, it refers to -NR X -S(O)2-NR Y -, where R X R Y and R Z As defined above.

[0067] As used in this article, the "sulfonamide" group, when used at the end, refers to the structure -S(O)2-NR. X R Y or -NR X -S(O)2-R Z Or, when used in the middle, it refers to -S(O)2-NR X -or-NR X -S(O)2-, where R X R Y and R Z As defined above.

[0068] As used in this article, the "thioalkyl" group, when used at the end, refers to -SR. X And when used in the middle, it refers to -S-, where R X As defined above. Examples of sulfonyl groups include aliphatic -S-, cycloaliphatic -S-, aryl -S-, etc.

[0069] As used in this article, the "sulfinyl" group, when used at the end, refers to -S(O)-R. X And when used in the middle, it refers to -S(O)-, where R X As defined above. Exemplary sulfinyl groups include aliphatic -S(O)-, aryl -S(O)-, (cycloaliphatic (aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocyclic aliphatic -S(O)-, heteroaryl-S(O)-, etc.

[0070] As used in this article, the "sulfonyl" group, when used at the end, refers to -S(O)2-R X And when used in the middle, it refers to -S(O)2-, where R X As defined above. Exemplary sulfonyl groups include aliphatic -S(O)2-, aryl -S(O)2-, (cycloaliphatic (aliphatic))-S(O)2-, cycloaliphatic -S(O)2-, heterocyclic aliphatic -S(O)2-, heteroaryl -S(O)2-, (cycloaliphatic (acylamino (aliphatic)))-S(O)2-, etc.

[0071] As used in this article, the "sulfinyloxy" group, when used at the end, refers to -O-SO-R. X or -SO-OR X And when used in the middle, it refers to -OS(O)- or -S(O)-O-, where R X As defined above.

[0072] As used in this article, "halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine.

[0073] As used herein, “alkoxycarbonyl” included in the term carboxyl group refers to a group such as alkyl-OC(O)- when used alone or in conjunction with other groups.

[0074] As used in this article, “alkoxyalkyl” refers to an alkyl group such as alkyl-O-alkyl-, where alkyl has already been defined above.

[0075] As used in this article, "carbonyl" refers to -C(O)-.

[0076] As used in this article, "oxy subunit" refers to =O.

[0077] As used herein, the term "phosphonium" refers to phosphonite / salt and phosphonate / salt. Examples of phosphonite and phosphonate include -P(O)(R P )2, where R P It is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocyclic aliphatic)oxy, aryl, heteroaryl, cycloaliphatic or amino.

[0078] As used in this article, "aminoalkyl" refers to the structure (R... X )2N-alkyl-.

[0079] As used in this article, “cyanoalkyl” refers to the structure (NC)-alkyl-.

[0080] As used in this article, the "urea" group refers to the structure -NR. X -CO-NR Y R ZFurthermore, when the "thiourea" group is used at the end, it refers to the structure -NR. X -CS-NR Y R Z And when used in the middle, it refers to -NR X - CO-NR Y -or-NR X -CS-NR Y -, where R X R Y and R Z As defined above.

[0081] As used herein, "aliphatic chain" refers to a branched or straight-chain aliphatic group (e.g., alkyl, alkenyl, or alkynyl groups). Straight-chain aliphatic chains have the structure -[CH2]. V - where v is 1-12. Branched aliphatic compounds are straight-chain aliphatic compounds substituted with one or more aliphatic groups. Branched aliphatic compounds have the structure -[CQQ]. V - Wherein, each Q is independently a hydrogen or aliphatic group; however, Q shall be an aliphatic group in at least one case. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, wherein alkyl, alkenyl, and alkynyl are defined above.

[0082] The phrase “optionally substituted” and the phrase “substituted or unsubstituted” are used interchangeably. As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those generally described above, or specific classes, subclasses, and substances as illustrated herein. As described herein, the variable R included in the chemical formulas described herein... 1 R 2 R 3 and R 4 Other variables include specific groups, such as alkyl and aryl groups. Unless otherwise stated, the variable R is included. 1 R 2 R 3 and R 4 Each of the specific groups in the other variables may optionally be substituted by one or more substituents as described herein.

[0083] Each substituent of a particular group may be optionally substituted with one to three of the following: halogen, cyano, oxonyl, alkoxy, hydroxyl, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For example, an alkyl group may be substituted with an alkylthioalkyl group, and the alkylthioalkyl group may be optionally substituted with one to three of the following: halogen, cyano, oxonyl, alkoxy, hydroxyl, amino, nitro, aryl, haloalkyl, and alkyl. Another example is that the cycloalkyl moiety of a (cycloalkyl)carbonylamino group may be optionally substituted with one to three of the following: halogen, cyano, alkoxy, hydroxyl, nitro, haloalkyl, and alkyl. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups may form a ring with one or more of the atoms to which they are bonded.

[0084] The compounds of the present invention are useful nAChRs and can be used in the pharmaceutical field, including for the treatment of CNS disorders such as addiction.

[0085] compound According to the present invention, a compound of formula (I) is provided:

[0086] (I) Or its pharmaceutically acceptable salts, solvates and / or esters, wherein: R 1 yes ·Hydroxy group; ·halogen; • Optional substitution of aliphatic compounds; • Optionally substituted cycloaliphatic compounds; • Optionally substituted heterocyclic aliphatic compounds; • Optionally substituted aryl groups; • Optionally substituted heteroaryl groups; ·-(CH2) m- NR 6 R 7 R 8 ,in oR 6 and R 7Each is independently selected from the group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, or oR 6 Or R 7 One of them is -CO-R 9 And R 6 Or R 7 Another one, as defined above, oR 8 The group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, or none of these groups exist. oR 9 The group selected from the group consisting of hydrogen, halogen, hydroxyl, oxyalkyl group, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl o and m is 0, 1, 2, 3, 4 or 5, ·-(CH2) m -O-(CH2) n -R 10 ,in oR 10 The group selected from the group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl, or optionally substituted heterocyclic alkenyl, and om and n are each independently 0, 1, 2, 3, 4, or 5. ·-CN -COOR 12 ,in oR 12 The group selected from the group consisting of hydrogen, halogen, hydroxyl, oxyalkyl group, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl ·-(CH2) o -CO-(CH2) p -R 13 ,in oR 13The group selected from the group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl, or optionally substituted heterocyclic alkenyl, and oo and p are independently 0, 1, 2, 3, 4 or 5. • Amino acids or their esters, Acyl chloride, • Protecting group, or Indigoferazone R 2 R 3 and R 4 Each is independently selected from the group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, amino acid or indigo base, or R 4 It can be a protecting group or a group having the structure –(CH2)v-Formula 1, where v is 0, 1, 2, 3, 4, 5 or 6, and Formula 1 is a compound of Formula (I) as described herein.

[0087] The condition is that when R 2 R 3 and R 4 When it is hydrogen, R 1 Not methyl, ethyl, vinyl, hydroxymethyl, fluoromethyl, -CH2-O-cyclohexylmethyl, -CH2-O-benzyl, -CH2-O-CH2-C6H4-CF3, -CH2-C6H4-F, -CH2-O-CH 2-CH2-CH3, -COOMe, -CONH2, -NH2 or -NH-CO-CH3, or when the compound is used in medicine and R 2 R 3 and R 4 When it is hydrogen, R 1 Not methyl, hydroxymethyl, fluoromethyl, bromine, fluorine, chlorine, tolyl, -CH2-O-cyclohexylmethyl, -CH2-O-benzyl, -CH2-O-CH2-C6H4-CF3, -CH2-C6H4-F, -CH2-O-CH 2- CH2-CH3, -COOMe, -CONH2, -NH2 or -NH-CO-CH3.

[0088] As mentioned above, R 1 The substituent at the position can be an optionally substituted aliphatic group; an optionally substituted cyclic aliphatic group; an optionally substituted heterocyclic aliphatic group; an optionally substituted aryl group; or an optionally substituted heteroaryl group.

[0089] In an embodiment of the present invention, R 1 The substituent at position C can be 1-8 C 1-4 Or C 3-8 The alkyl group may be substituted or unsubstituted, such as propyl, isopropyl, butyl, or tert-butyl. In some embodiments of the invention, R 1 The substituent at the position can be a substituted C 1-2 alkyl group or C 3-8 Optional substituted alkyl groups. In such an embodiment, C 1-2 The alkyl group can be a substituent other than hydroxymethyl or fluoromethyl.

[0090] Imagine R in the compound of this invention 1 Examples of substituted alkyl groups used at the substituent position include substituted methyl groups, such as aminomethyl, halomethyl, such as chloromethyl, dichloromethyl, trichloromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, or tribromomethyl; substituted ethyl groups, such as 1- or 2-aminoethyl, hydroxyethyl, haloethyl, such as 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, or 2,2,2-trifluoroethyl; substituted propyl groups, such as 1-, 2-, or 3-aminomethyl; hydroxypropyl; or halopropyl.

[0091] In an embodiment of the present invention, R 1The substituent at the position can be an unsubstituted or substituted aryl group. For example, the substituent can be a phenyl group, or a substituted phenyl group, such as a halophenyl group, such as chlorophenyl, bromophenyl, fluorophenyl, perchlorophenyl, perbromophenyl, perfluorophenyl; or a toluene, aniline, phenol, styrene, benzonitrile, anisole, acetophenone, benzaldehyde, or benzoic acid group.

[0092] In alternative implementations, R 1 The substituent at the position can be an optionally substituted heteroaryl group, such as benzyloxypyridine, pyridinone (e.g., 2-pyridinone), pyridine (e.g., 2-pyridine, 3-pyridine, or 4-pyridine), phenyltriazole, optionally substituted triazole, and methyl triazole neopentanoate group.

[0093] R 1 The substituents may alternatively be optionally substituted cycloalkyl or heterocycloalkyl groups, such as cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, piperazine, tetrahydrofuranyl, oxacyclopentyl, or dioxalkyl.

[0094] It can be included in R 1 Examples of optionally substituted alkenyl groups include C 2-8 Alkenyl groups, such as vinyl, acrylate, or -C=C-C6H5 groups.

[0095] It can exist in R 1 The optionally substituted alkynyl group at the C position includes C 2-8 Alkyne group: -CΞC-C6H5 or –CΞC-trimethylsilyl group.

[0096] Furthermore, R can be used in the compounds of this invention. 1 Other substituents include the following groups: -(CH2) m- NR 6 R 7 R 8 , where R 6 R 7 and R 8 As defined above. In such embodiments, the compounds of the present invention may include amines, N-alkylamines, N,N-dialkylamines, and amide groups as R. 1 Substituents at the position. Examples of such groups envisioned to include amines, methylamine, ethylamine, propylamine, isopropylamine, benzylamine, dimethylamine, trimethylammonium methyl, dimethylamine methyl, benzamide, and acetamide groups. In embodiments of the invention, when m is zero and R 8 If it does not exist, then R 6 and R 7 Not simultaneously hydrogen and / or R 6 and R 7 Neither of them are oxygen subunits.

[0097] -(CH2) n -O-(CH2) o -R 10 , where R 10 As defined above. In such embodiments, the compounds of the present invention may include those containing R 1 A group at the ether bond position. Examples of such a group contemplated to include methoxy, ethoxy, propoxy, benzyloxy, or trifluoromethylbenzyloxy groups. In embodiments of the invention, limiting conditions apply to R. 1 The substituent at the position is not a propoxymethyl group (i.e., –CH2-O-CH2-CH2CH3), an alkoxymethyl group, or a group having the following structure: -CH2-O-CH2-C6H4-R 12 or -CH2-O-CH2-C6H 10 -R 12 , where R 12 It can be hydrogen, trifluoromethyl, substituted phenyl, halogen, or fluorine.

[0098] -CN -COOR 12 , where R 12 As defined above. In such embodiments, the compounds of the present invention may include R. 1 A carboxylic acid group or ester, such as ethyl ester, propyl ester, isopropyl ester, butyl ester, or phenyl ester. In embodiments of the invention, R 1 The substituent at the position can be any of the following except C: 1-3 Substituents other than alkyl ester groups or methyl ester groups.

[0099] -(CH2) p -CO-(CH2) q -R 13 , where R 13 As defined above. In such an embodiment, the compounds of the present invention can be used in R 1 The position includes a ketone or aldehyde group, such as acetophenone. In some embodiments, R 1 The substituents at that position are substituents other than -CO-NH2.

[0100] - Amino acids, such as naturally occurring amino acids or their esters, such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or their methyl, ethyl, propyl, or isopropyl esters.

[0101] In which the compound of the present invention is in R 1In embodiments of the invention that include an amino acid or an ester thereof, the amino acid (or ester) may be bonded to the pyridine ring on the basic structure of indigo alkaloid by any atom (e.g., by oxygen, carbon, sulfur, or nitrogen atom), for example, by the oxygen atom in the acid unit, thus forming an amide of amino indigo alkaloid, or by the nitrogen atom in the amine unit.

[0102] -Acyl chloride.

[0103] - Protecting groups, such as tert-butoxycarbonyl (Boc), formyl, acetyl (Ac), succinoyl (Suc), methoxysuccinoyl (MeOSuc), benzyloxycarbonyl (Cbz), or fluorenemethoxycarbonyl (Fmoc), or protected borane protecting groups, optionally having the structure (RO)2B-, such as (pinacol)borane (BPin) and (catechol)borane (BCat). In embodiments of the invention, any protecting group commonly used in organic synthesis may be used, such as those outlined in Gross and Mienhoffer, eds., The Peptides, Vol. 3, Academic Press, New York, 1981, pp. 3-88; Greenand Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc., New York, 1999, the contents of which are incorporated herein by reference.

[0104] - Cytisinyl. In embodiments, the compounds of the present invention can be cytisinyl-cytisinyl dimers. Cytisinyl compounds can be directly coupled to each other, for example, through the carbon atom at the 3-, 4-, or 5-position of each respective compound. Alternatively, two cytisinyl structures can be coupled via a linker, for example, through a carbon, oxygen, or nitrogen atom. When a linker is used, it may itself contain a functional group, such as C. 1-6 alkyl.

[0105] In R 2 To R 4 The substituents at the position are as defined above. In embodiments of the present invention, R 2 and R 3 Or R 2 R 3 and R 4 Each of these can be hydrogen. Alternatively, R 2 It can be halogen, and R 3 and R 4 It is hydrogen. In some embodiments of the present invention, R 4 The substituent at the position can be any of the following except C:2-6 Substituents other than alkyl groups.

[0106] In an embodiment of the present invention, R 4 The substituent at the position can be a protecting group, such as tert-butoxycarbonyl (Boc), formyl, acetyl (Ac), succinoyl (Suc), methoxysuccinoyl (MeOSuc), benzyloxycarbonyl (Cbz), or fluorenemethoxycarbonyl (Fmoc), or a boronized protecting group, optionally having the structure B(OR)2, such as (pinacol)borane (BPin) and (catechol)borane (BCat). In embodiments of the invention, any protecting group commonly used in organic synthesis may be used, such as those outlined in Gross and Mienhoffer, eds., The Peptides, Vol. 3, Academic Press, New York, 1981, pp. 3-88; Green and Wuts, Protective Groups in OrganicSynthesis, 3rd edition, John Wiley and Sons, Inc., New York, 1999, the contents of which are incorporated herein by reference.

[0107] Unless otherwise stated, the structures described herein are also intended to include all isomers of the structure (e.g., enantiomers, diastereomers, and geometric (or conformational) forms; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomers, diastereomers, and mixtures of geometric (or conformations), are within the scope of the present invention. Unless otherwise stated, all tautomer forms of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having a structure identical to this structure except for the substitution of hydrogen with deuterium or tritium or the substitution of carbon with 13C- or 14C-enriched carbon are within the scope of the present invention.

[0108] Exemplary compounds of the present invention include, but are not limited to, the following compounds: 4-Bpin indigo alkaloid 4-Hydroxynodine (+)4-hydroxyindigoline (-)4-Methoxynoindine 4-Methoxynoindine 4-(N-Benzylamino)noindine (+)4-(N-benzylamino)noindine (-)4-(2,2,2-trifluoroethyl)indigoline 4-(2,2,2-trifluoroethyl)indigoline (-)4-(perfluorophenyl)indigoline 4-(perfluorophenyl)noindole (-)4-(2-pyridyl)noindine 4-(2-pyridyl)noindine (-)4-(3-pyridyl)noindine 4-(3-pyridyl)noindine (-)4-(4-pyridyl)noindine 4-(4-pyridyl)noindine 4-(4-(2-benzyloxy)pyridine)noindine 4-(4-(2-pyridone))noindine (+)4-(4-(2-pyridone))noindine (-)4-chloroindole (-)4-Iodonoindine (+)4-Iodonoindine (-)4-Trifluoromethylindigoline 4-Trifluoromethylnoindole (-)4-bromoindole (+)4-Aminoindigoline (-)4-Fluoroindole 4-( N -Methylamino)indigoline (+)4-( N -Methamido)noindine 4-( N, N '-Dimethylamino)indigoline (+)4-( N, N '-Dimethylamino)indigoline 4-( N -benzoylamino)indigoline (+)4-( N -benzoylamino)indigoline (+)4-( N -Acetamido)Indigoline 4-( N -morpholine) indigoline (+)4-( N -morpholine) indigoline 4-( N -( L -proline methyl ester) indigoline (+)4-( N -(L -proline methyl ester) indigoline (-)4-( N -( L -proline) indigoline 4-( N -( L -proline) indigoline (-)4-(carboxymethyl)indigoline (-)4-carboxylic acid indigo base 4-Carboxylic acid indigo base (-)4-(hydroxymethyl)noindine (-)4-((trifluoromethyl)benzyl)oxyindole (-)4-Methylindole (-)4-Vinyl indigo (+)4-Vinyl indigo (-)4-Ethylindoline (+)4-p-Tolylinoindole (-)4-( N -2-pyridinone) indigoline 4-( N -2-pyridinone) indigoline 4-(trimethylsilylacetylene)indigo (-)4-(ethynyl)indigoline 4-(ethynyl)indigoline 4-(Phenylacetylene)indigoline (+)4-(phenylacetylene)indigoline 4-( E Methyl 2-acrylate) Indigoferazone (+)4-( E Methyl 2-acrylate) Indigoferazone 4-( E -(2-Styrene)indigoline (+)4-( E -(2-Styrene)indigoline 4-(1-(4-phenyl)- N H-1,2,3,triazolyl)indigoline (+)4-(1-(4-phenyl)- N H-1,2,3,triazolyl)indigoline (-)4-(1,2,3-triazol-1-yl)neopentate methyl ester) indigo (+)4-(1,2,3-triazol-1-yl)neopentyl methyl ester) indigo 4-( N H-1,2,3-triazolyl)indigoline (+)4-( N H-1,2,3-triazolyl)indigoline 4-( N -Ethylamino)indigoline (+)4-( N -Ethylamino)indigoline 4-( N -Isopropylamino)indigoline (+)4-( N -Isopropylamino)indigoline (-)4-Cyanoindigoline 4-Cyanoindoline (-)4-(carboxyacylamino)noindine (-)4-Aminomethylindigoline 4-Aminomethylindocyanine (-)4-( N -Methyl-aminomethyl)indigoline 4-( N -Methyl-aminomethyl)indigoline (1 R 5 S 10 S ,11a R )-10-(aminomethyl)decahydro-8 H -1,5-Methylenepyrido[1,2-a][1,5]diazo-octano-8-one Aminobis(indigo) derivatives Methamidobis(indigo) derivatives (-)4-Tetrazolyl indigoline 4-Tetraazolylnoindine (-)4-(trimethylammonium)methylindigoline 4-(trimethylammonium)methylindigoline (-)4-(N-acetyl)aminomethylindigoline 4-(N-acetyl)aminomethylindigoline 4-( N -piperazine) indigo alkaloids (+)4-( N -piperazine) indigo alkaloids (-)3-(trifluoromethyl)-4-bromoindole 3-(trifluoromethyl)-4-bromonoindine 3-Bromo-4-iodonoindole (+)3-bromo-4-iodonoindine 3-Bromo-4-N-methylaminoindigoline (+)3-bromo-4-N-methylaminoindigoline synthesis While there are limited disclosures of 4-substituted indigomine compounds in the prior art, a simplified synthetic method for such compounds has never been proposed before. To the inventor's knowledge, no synthetic route for obtaining 4-substituted analogs of indigomine from indigomine has been previously disclosed. Instead, such compounds must be produced through total synthesis starting with monocyclic compounds. See, for example, Kozikowski. et al., ChemMedChem, 2007, 2, pages 1157 to 1161 and Gallagher et al. Scheme 1, Synlett, 2010, pages 2798-2791.

[0109] According to another aspect of the invention, a method for producing 4-substituted indigo alkaloid analogs is provided, comprising: i) Provide compounds of formula IIa

[0110] Among them, R 2 R 3 and R 4 Each is independently selected from the group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, amino acid or indigo base, or R 4 It may be a protecting group or a group having the structure –(CH2)v-Formula 1, wherein v is 0, 1, 2, 3, 4, 5 or 6, and Formula 1 is a compound of Formula (I) as described herein; ii) To produce compounds of formula IIb by contacting compounds of formula IIa with a boriding agent.

[0111] Among them, R 2 R 3 and R 4 As defined above, and BComp is a boride complex; iii) Using R 1 Replacing BComp with compounds of formula I:

[0112] Among them, R 1 yes ·Hydroxy group; ·halogen; • Optional substitution of aliphatic compounds; • Optionally substituted cycloaliphatic compounds; • Optionally substituted heterocyclic aliphatic compounds; • Optionally substituted aryl groups; • Optionally substituted heteroaryl groups; ·-(CH2) m- NR 6 R 7 R 8 ,in oR 6 and R 7 Each is independently selected from the group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, or oR 6 Or R 7 One of them is -CO-R 9 And R 6 Or R 7 Another one, as defined above, oR 8The group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, or none of these groups exist. oR 9 The group selected from the group consisting of hydrogen, halogen, hydroxyl, oxyalkyl group, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl o and m is 0, 1, 2, 3, 4 or 5.

[0113] ·-(CH2) m -O-(CH2) n -R 10 ,in oR 10 The group selected from the group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl, or optionally substituted heterocyclic alkenyl, and om and n are each independently 0, 1, 2, 3, 4, or 5. ·-CN -COOR 12 , where R 12 The group selected from the group consisting of hydrogen, halogen, hydroxyl, oxyalkyl group, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl ·-(CH2) o -CO-(CH2) p -R 13 ,in oR 13 The group selected from the group consisting of hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl, or optionally substituted heterocyclic alkenyl, and oo and p are independently 0, 1, 2, 3, 4 or 5. • Amino acids or their esters, Acyl chloride, • Protecting group, or ·Indigo base.

[0114] The starting material can be any compound included in Formula IIa as outlined above. However, an advantage of the invention is that the method can advantageously be operated using indigo as a starting material. Therefore, in embodiments, all R 2 R 3 and R 4 Both can be hydrogen. Alternatively, position R4 The substituents at the position can be protecting groups or groups having the structure –(CH2)v-Formula 1, where v is 0, 1, 2, 3, 4, 5 or 6, and Formula 1 is a compound of Formula (I) as described herein.

[0115] Therefore, in embodiments, compounds of formula IIa may be included in R 4 The method of the present invention may include the step of adding a protecting group to a compound of formula IIa (which includes indigofera oleifera). Those skilled in the art are familiar with techniques for adding protecting groups to secondary amines, and any method steps used to do so are included within the scope of the present invention. For example, in an embodiment, when the protecting group to be added to R... 4 When the protecting group at the position is Boc (tert-butoxycarbonyl), the method includes the step of providing a reagent containing Boc (e.g., (Boc)₂O) and contacting it with indigo in a suitable solvent (e.g., a solvent containing tetrahydrofuran and sodium tricarbonate).

[0116] Therefore, in the embodiments of the present invention, R 4 The protecting group present at the site can be Boc. Alternative protecting groups that can be used include formyl, acetyl (Ac), succinyl (Suc), methoxysuccinyl (MeOSuc), benzyloxycarbonyl (Cbz), or fluorenemethoxycarbonyl (Fmoc), or borylated protecting groups, optionally having the structure (RO)2B-B(OR)2, such as bis(pinacol)diborane (B2Pin2) and bis(catechol)diborane (B2Cat2). In embodiments of the invention, any protecting group commonly used in organic synthesis may be used, such as those outlined in Gross and Mienhoffer, eds., The Peptides, Vol. 3, Academic Press, New York, 1981, pp. 3-88; Green and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc., New York, 1999, the contents of which are incorporated herein by reference.

[0117] The borizing agent used in step ii) of the method of the present invention may be any borizing agent known to those skilled in the art of bor chemistry. For example, the borizing agent may be a dialkoxyborane or an alkylborane. Examples of dialkoxyboranes include bis(pinacol)diborane (B2Pin2) and bis(catechol)diborane (B2Cat2), as well as any other borizing agent having the general formula (RO)2-BB-(OR)2 or HB(OR)2, such as the borizing agents disclosed in Hartwig et al, Chemical Reviews, 2010, 110, pages 890-931, the contents of which are incorporated herein by reference. Examples of alkylborane borizing agents include 9-boronbicyclo(3.3.1)nonane (9-BBN), B- Alkyl-9-oxa-10-boron bicyclo[3.3.2]decane (OBBD), diisopentylborane, tert-hexylborane and HB(cHex)2.

[0118] In embodiments of the present invention, the molar ratio of borizing agent to starting material of formula IIa can range from about 10 or less: about 1, about 7 or less: about 1, or about 5 or less: about 1. Alternatively, the molar ratio of borizing agent to starting material of formula IIa can range from about 0.1 or more: about 1, about 0.2 or more: about 1, about 0.3 or more: about 1, about 0.4 or more: about 1, or about 0.5 or more: about 1.

[0119] In some embodiments of the invention, the borizing agent may be molar excess compared to the starting material of formula IIa. This may be preferred in some embodiments where indigo is used as the starting material of formula IIa.

[0120] In alternative embodiments of the invention, the starting material of formula IIa may be molar excess compared to the borizing agent. This may be preferred in some embodiments where certain analogs of indigo (e.g., N-boc indigo) are used as the starting material of formula IIa.

[0121] The reaction in step ii) of the method of the present invention can be catalyzed using catalysts known to those skilled in the art. In embodiments of the present invention, step ii) is catalyzed, for example, using a transition metal catalyst. In a preferred embodiment, the catalyst used comprises iridium, palladium, zinc, nickel, and / or rhodium atoms, which may be provided in the form of an organic coordination complex. Specific examples of catalysts that can be used in the method of the present invention include Ir[(COD)(OMe)]2, PdCl2, Pd / P(t-bu)3, Pd(dba)2, NiCl2, [RhCl(cod)]2, or Et2Zn. Iodine can also or alternatively be used as a catalyst.

[0122] Step ii) of the method of the present invention can be carried out in a solvent. Any solvent capable of allowing the borylation process can be used in the method of the present invention. Examples of solvents that can be used include esters (e.g., ethyl acetate), ethers (e.g., dioxane, tetrahydrofuran), ketones (e.g., 2-butanone), sulfoxides (e.g., DMSO), aromatics (e.g., toluene), fluorinated aromatics (e.g., trifluorotoluene), and alkanes (e.g., cyclohexane, n-pentane, n-hexane).

[0123] In the method of the present invention, a ligand may be used in step ii).

[0124] Examples of usable ligands include aromatic or heteroaromatic compounds that can be monocyclic or polycyclic, such as phenanthroline compounds, including but not limited to phenanthroline (phen), dimethylphenanthroline (me2phen), tetramethyl-1,10-phenanthroline (me4phen), and / or bathophen; and bipyridine compounds, such as bipyridine (bpy), di-tert-butyl-2,2'-bipyridine (dtbpy), and 2,2'-bipyridine. (bpy), dimethoxy-2,2'-bipyridine (MeO-bpy); and / or other compounds, such as 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), new cuprous reagents, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Other examples include 1,2-bis(dimethylphosphino)ethane (dmpe) and those disclosed in Hartwig et al, Chemical Reviews, 2010, 110, pages 890-931, the contents of which are incorporated herein by reference, as well as the compounds listed below:

[0125] Alternatively, examples of ligands that may be used include aromatic or heteroaromatic compounds that may be polycyclic, such as tetramethyl-1,10-phenanthroline (Me4phen), di-tert-butyl-2,2'-bipyridine (dtbpy), 2,2'-bipyridine (bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Other examples include 1,2-bis(dimethylphosphino)ethane (dmpe) and those disclosed in Hartwig et al, Chemical Reviews, 2010, 110, pages 890-931, the contents of which are incorporated herein by reference.

[0126] The inventors of this invention have discovered that the molar ratio of the ligand (in use) to the starting material of formula IIa can affect the conversion rate of the boride compound of formula IIb. In embodiments of this invention, the molar ratio of ligand to starting material of formula IIa is less than about 2:1, less than about 1.5:1, less than about 1:1, less than about 0.75:1, less than about 0.5:1, less than about 0.1:1, less than about 0.05:1 to at least about 0.001:1.

[0127] Boration step ii) can be carried out at any temperature, provided that boration can be carried out at an acceptable rate. In embodiments of the invention, the reaction can be carried out at temperatures of about 0°C, about 10°C, about 20°C, about 30°C, about 40°C, or about 50°C to about 100°C, about 120°C, or about 150°C.

[0128] The inventors of the present invention have discovered that the molar ratio of the borizing agent to the starting material of formula IIa can affect the conversion rate of the borinated compound of formula IIb. In embodiments of the present invention, the molar ratio of the borizing agent to the starting material of formula IIa is at least about 0.5:1, at least about 0.75:1, at least about 1:1, at least about 1.5:1, at least about 2:1, at least 2.5:1, or at least 3:1, optionally about 5:1 or about 10:1.

[0129] Regardless of the order in which the starting materials, solvents, catalysts, ligands, and / or borates are added, 4-substituted indigo analogs can be synthesized selectively and efficiently.

[0130] In some embodiments of the invention, the borizing agent and the starting material of formula IIa are added simultaneously or substantially simultaneously to the reaction zone. In such embodiments, the reaction zone may or may not be pre-loaded with solvent, catalyst, and / or ligand.

[0131] In an alternative embodiment of the invention, the borizing agent may be added to the reaction zone (optionally pre-loaded with solvent, catalyst, and / or ligand) prior to the addition of the starting material of Formula IIa. In such an embodiment, the borizing agent may be present in the reaction zone (optionally together with solvent, catalyst, and / or ligand) for a period of time, such as about 1 or more, about 2 or more, or about 5 or more minutes, prior to the addition of the starting material of Formula IIa.

[0132] One advantage of the method of the present invention is that the crude product obtained in step ii) does not require purification before the start of step iii). Therefore, in embodiments of the present invention, no purification step is performed between steps ii) and iii).

[0133] This advantage of the method of the present invention is that steps ii) and at least iii) are initiated in the same reaction region, i.e., as a "one-pot" synthesis. Therefore, in such an embodiment, step iii) can be initiated in the same reaction region as the reaction region for preparing the boride compound of formula IIb.

[0134] In step iii), BComp is removed from position 4 of the indigo ring and replaced by a substituent R as defined above. 1 Replace. To avoid any ambiguity, use R. 1 Replacing BComp does not necessarily have to be done in a single replacement step, although this may be desirable and can be implemented as described in the embodiments below.

[0135] In an embodiment of the present invention, BComp can be in the final R during step iii). 1 The substituent is located before the 4th position on the indigo alkaloid ring, and is first replaced by one or more intermediate Rs. 1 Substituent substitution. In embodiments of the present invention, intermediate R... 1 The substituents can be halogens (e.g., bromine, chlorine, or iodine), benzyloxypyridine, alkyl esters (e.g., methyl esters), alkenyl (e.g., vinyl), alkynyl (acetylene), trimethylsilylacetylene, methyl 1,2,3-triazol-1-yl)neopentate, cyano, aminomethyl, N-Boc-aminomethyl, or (benzyloxy)carbonyl)piperazin-1-yl.

[0136] For simplicity, how the borides of formula IIb are optionally processed via one or more intermediate Rs is not provided here. 1 The complete details of the substituent transformation into each compound of formula I are provided, as those skilled in the art will recognize and understand how such substitutions are carried out. Further details of the reaction conditions that can be used in this regard are provided in the examples below.

[0137] In embodiments, the method of the present invention may include R on the indigo ring. 2 R 3 and / or R 4 Additional steps involving substitution at the 3- or 5-position of the indigo ring may be performed. This step can be carried out, for example, when a 3- or 5-position substitution is required on the indigo ring. Such a step can be achieved using any techniques and reagents known to those skilled in the art. If guidance on how to perform such substitution is required, reference can be made to the following examples which exemplify such steps. Alternatively or additionally, reference can be made to the article by Rouden et al. (Chemical Reviews, 2014, 114, pages 712 to 778), including the articles cited therein, which provide additional guidance in this regard.

[0138] Alternatively, the protecting group may be located at R 4 In one embodiment, the method of the present invention may include the step of deprotecting the nitrogen atom at position 13 of the indigo ring. This deprotection step may be performed after step ii) is completed, before step iii) begins, during step iii) or after step iii) is completed. Those skilled in the art are familiar with deprotection techniques. However, if any guidance is needed in this regard, reference may be made to the following embodiments.

[0139] As can be seen from the above, the method of the present invention advantageously and for the first time allows for the convenient preparation of 4-substituted indigo analogs from indigo itself, without the need for a lengthy total synthesis of such compounds.

[0140] Another advantage of this invention is that steps ii) and iii) do not involve any chiral rearrangement of the molecule, thus the method is stereoselective. This provides another advantage over the prior art, which leads to the formation of racemic analogs of indigo.

[0141] Formulation, administration and use Therefore, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds described herein and optionally include a pharmaceutically acceptable carrier, adjuvant, or solvent. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0142] It should be recognized that certain compounds of the present invention can exist in free form for therapeutic purposes, or, where appropriate, as pharmaceutically acceptable derivatives or prodrugs. According to the present invention, pharmaceutically acceptable derivatives or prodrugs include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adducts or derivatives that, upon administration to a patient in need, can directly or indirectly provide the compound as otherwise described herein, or its metabolites or residues.

[0143] As used herein, the term "pharmaceutically acceptable salt" means, to the extent of reliable medical judgment, that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and in accordance with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any salt or ester salt of the compounds of the present invention that, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention or their inhibitory active metabolites or residues.

[0144] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by reacting an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods employed in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. The invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-soluble, oil-soluble, or dispersible products can be obtained through such quaternization. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0145] As described above, the pharmaceutically acceptable compositions of the present invention additionally include pharmaceutically acceptable carriers, adjuvants, or solvents, which, as used herein, include any and all solvents, diluents or other liquid solvents, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., to suit the desired specific dosage form. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutically acceptable compositions and in known techniques for preparing such compositions. Use of any conventional carrier medium is considered within the scope of the present invention, except that it is incompatible with the compounds of the present invention (e.g., by producing any undesirable biological effects or reacting in a harmful manner with any other component(s) of the pharmaceutically acceptable composition). Examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid or potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates / esters, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose Vitamins and cellulose acetate; yarrow powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; ethylene glycol; propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer, and other non-toxic and compatible lubricants such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavor and aroma agents, preservatives and antioxidants may also be present in the composition, at the discretion of the formulator.

[0146] The pharmaceutically acceptable compositions of the present invention may be administered to humans or other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), orally, as oral or nasal sprays, depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention may be administered orally or parenterally once or more daily at dose levels of about 0.01 mg / kg to about 50 mg / kg of the subject's body weight, and preferably from about 1 mg / kg to about 25 mg / kg, to achieve the desired therapeutic effect.

[0147] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters and mixtures thereof. Besides inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aroma agents.

[0148] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Water, Ringer's solution, USP, and isotonic sodium chloride solutions can be used among acceptable solvents and media. Furthermore, sterile, non-volatile oils are typically used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids (such as oleic acid) are used in the preparation of injectable formulations.

[0149] Injectable formulations can be sterile, for example, by filtration via a bacterial retention filter or by incorporation of a sterilizing agent, in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection media prior to use.

[0150] To prolong the effect of the compounds of the present invention, it is generally necessary to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystals or amorphous substances. The absorption rate of the compound then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of the parenteral administration of the compound can be achieved by dissolving or suspending the compound in an oil solvent. Injectable reservoir forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer such as polylactic acid-polyglycolic acid. The rate of compound release can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir injectable formulations can also be prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0151] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol, or suppository wax), which is solid at ambient temperature but liquid at body temperature, thus melting and releasing the active compound in the rectal or vaginal cavity.

[0152] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium hydrogen phosphate, and / or a) fillers or fillers, such as starch, lactose, sucrose, glucose, mannitol, and silicate; b) binders, such as, for example, carboxymethyl cellulose, alginate / esters, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato and cassava starch, alginate, certain silicates / esters, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0153] Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may optionally contain light-blocking agents and may also be compositions that optionally release one or more active ingredients only in or preferably in a portion of the intestine in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0154] As described above, the active compound can also be present in a microencapsulated form with one or more excipients. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound can be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Conventionally, such dosage forms may also include additional substances besides inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also include buffers. They may optionally contain light-blocking agents and may also be compositions that optionally release the active ingredient (one or more) only in, or preferably in, a portion of the intestine in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes.

[0155] Dosage forms of the compounds of the present invention for topical or transdermal administration include ointments, pastes, emulsions, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the invention. Furthermore, the invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the transdermal flux of the compound. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0156] It should also be recognized that the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e., the compounds and pharmaceutically acceptable compositions can be used simultaneously, before, or after one or more other desired therapies or medical procedures. The specific combination therapy (therapy or procedure) used in a combination regimen will take into account the compatibility of the desired therapy and / or procedure and the desired therapeutic effect. It should also be recognized that the therapies employed may achieve the desired effect on the same condition (e.g., the compounds of the present invention may be administered simultaneously with other agents used to treat the same condition), or they may achieve different effects (e.g., controlling any side effects). As used herein, additional therapeutic agents that are typically administered to treat or prevent a specific disease or condition are referred to as “suitable for the disease or condition being treated.”

[0157] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount normally administered in a composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein ranges from about 50% to 100% of the amount normally present in a composition comprising the pharmaceutical agent as the sole active agent.

[0158] The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Therefore, in another aspect, the present invention includes compositions for coating implantable devices, comprising the compounds of the present invention as generally described above and the classes and subclasses herein, and a carrier suitable for coating said implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising the compounds of the present invention as generally described above and the classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings (paints) and general methods for preparing coated implantable devices are described in U.S. Patents 6,099,562; 5,886,026; and 5,304,121. Coatings are typically biocompatible polymeric materials, such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be additionally covered with a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart controlled-release properties in the composition. Detailed Implementation

[0159] Preparation and Examples From the golden chain flower ( Laburnum anagyroides (-)-Indigo alkaloid extracted from seeds As described above, the method of the present invention advantageously begins with indigofera tinctoria—a naturally occurring compound that can be isolated from the golden chain tree. Although indigofera tinctoria is commercially available, and methods for extracting indigofera tinctoria from natural resources will be familiar to those skilled in the art, the following method is provided for completeness.

[0160] Powdered golden chain flower seeds (332 g), DCM (465 mL), MeOH (135 mL), and NH4OH (50 mL, 35% aqueous solution) were vigorously stirred at room temperature for 3 days using a mechanical stirrer (400 rpm). The mixture was filtered and the solid was washed with DCM (4 × 200 mL) until the filtrate was colorless. The filtrate was acidified to pH 1 with 3M HCl (330 mL) and the mixture was stirred for 2 h (350 rpm). The two layers were separated, and the aqueous phase was slowly alkalized to pH 9-10 with NH4OH (70 mL, 35% aqueous solution). The mixture was stirred for 2 h and extracted with DCM (10 × 70 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give indomethacin (4.76 g) as a brownish-yellow solid. Recrystallization from toluene (5 mL) gave (-)-indomethacin (4.27 g, 1.3%) as a solid.

[0161] Add protecting groups — N -Boc indigo (56)

[0162] An aqueous solution of Na₂CO₃ (4.28 g, 40.4 mmol, 1 M) was added to a solution of (-)-indocyanine (6.41 g, 33.7 mmol) and (Boc)₂O (9.3 mL, 40.4 mmol) in THF (135 mL) and water (70 mL). The mixture was stirred for 3 days and then diluted with EtOAc (200 mL) and brine (70 mL). The aqueous phase was extracted with EtOAc (3 × 150 mL), and the combined organic layers were washed with brine (150 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (3% MeOH)] to give 56 (9.10 g, 93%) as a colorless solid.

[0163] R f: 0.28 [DCM / MeOH (5% MeOH)];mp: 154-155 ℃ (lit: 156-157 ℃); 1 H NMR (400 MHz, CDCl3, δ) H :7.26 (dd, 1H, J= 9.0, 7.0 Hz, C4-H), 6.41 (d, 1H, J = 9.0Hz, C3-H), 6.04 (br s, 1H, C5-H), 4.40-4.08 (m, 3H, C7-H a , C11-H, C12-H), 3.81 (dd, 1H, J = 15.5, 6.5 Hz, C7-H b ), 3.12-2.91 (m, 3H, C11-H, C12-H, C10-H), 2.40 (br s, 1H, C8-H), 2.00-1.90 (m, 2H, C9-H), 1.31-1.20 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ) C The spectral properties of this compound are 163.3 (CO), 154.4 / 154.3 (C6, rotational isomer), 149.3 / 148.7 (COBoc, rotational isomer), 138.9 / 138.4 (C4, rotational isomer), 117.0 (C3), 105.6 / 104.9 (C5, rotational isomer), 80.2 / 79.6 (q Boc, rotational isomer), 51.5 / 50.5 / 49.2 (C11, C12, rotational isomers), 48.8 (C7), 34.8 (C10), 28.0 (3C, Boc), 27.5 (C8), 26.1 (C9). The spectroscopic properties of this compound are consistent with data available in the literature.

[0164] Remove protecting groups As exemplified below, various 4-substituted indigo alkaloid derivatives can be prepared according to the method of the present invention. For such compounds, it is desirable to remove the Boc protecting group. In the examples below, the Boc protecting group present on the 4-substituted indigo alkaloid analogues is removed by one of the following two methods.

[0165] General Process A The indigo derivative was dissolved in a solution of 0.5 M HCl in MeOH (substrate concentration 0.1 M), and the reaction mixture was stirred at room temperature for 72 h. The solvent was then removed under vacuum. The residue was dissolved in a minimal amount of MeOH, and 10 times the volume of MeOH in acetone was slowly added. The solution was stirred for 2 h. The precipitate was then collected by filtration and washed with cold acetone.

[0166] General Process B The indigo derivative was dissolved in a solution of 4.0 M HCl in dioxane (substrate concentration 0.1 M), and the reaction mixture was stirred at room temperature for 72 h. The solvent was then removed under vacuum. The residue was dissolved in a minimal amount of MeOH, and 10 times the volume of MeOH in acetone was slowly added. The solution was stirred for 2 h. The precipitate was then collected by filtration and washed with cold acetone.

[0167] Example 1—— N -Boc 4-Bpin indigo (58)

[0168] Inject into the Schlenk tube N -Boc-indigo, 56 (290 mg, 1.00 mmol), bis-(iridium-cyclooctadienyl-methyl) (6.6 mg, 0.01 equivalent), 4,4'-2,2'-di-tert-butylbispyridine (5.4 mg, 0.02 equivalent), and bis(pinacol)diborane (177 mg, 0.7 equivalent). Schlenk tubes were placed under vacuum and purged three times with nitrogen. THF (1.4 mL) was added, and the mixture was heated at 80 °C for 24 h. The mixture was cooled to room temperature and concentrated under vacuum. Although purification (see below) is feasible, it is unnecessary; the crude reaction mixture without further purification was used in several subsequent conversion steps.

[0169] The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (5% MeOH)] to give 58 (180 mg, 43%) unstable compounds on silica gel; only the pure fraction was collected. 1 (Completely converted by H-NMR) it turned into light orange foam.

[0170] R f : 0.23 [DCM / MeOH (5% MeOH)];FTIR ν max / cm -1 (Net): 3433, 2977, 1688, 1657, 1563, 1423; 1 H NMR (400 MHz, CDCl3, δ H ):6.85 (s, 1H, C3-H), 6.31 (s, 1H,C5-H), 4.34-4.10 (m, 3H, C7-H a , C12-H, C11-H), 3.80 (dd, 1H, J = 15.5, 6.5 Hz, C7-Hb ), 3.07-2.91 (m, 3H, C10-H, C11-H, C12-H), 2.41 (s, 1H, C10-H), 1.95-1.88 (m, 2H, C9-H), 1.41-1.09 (m, 23H, 12 x Bpin-H, 9 x Boc); 13 C NMR (100 MHz, CDCl3, δ) C ): 162.9 (CO), 154.6 / 154.3 (C6, rotatable isomer), 147.9 / 147.5 (CO Boc, rotatable isomer), 124.4 (C3), 109.3 / 108.8 (C5, rotatable isomer), 84.4 (q Boc), 82.6 / 80.3, 79.7 / 75.0 (2C, q Bpin, rotatable isomer), 51.7 / 50.6 / 50.3 / 49.2 (C11, C12, rotatable isomer), 48.9 (C7), 34.7 (C10), 28.0 (4C, Bpin), 27.5 (C8), 26.1 (C9), 24.8 / 24.6 (3C, Boc, rotatable isomer), C4 not detected; 11 B NMR (96.4 MHz, CDCl 3, δ B ):28.94 (br s);HRMS (ESI + ): Calculated value C 22 H 33 BN2NaO5[M+Na] + : 439.2379, measured value: 439.2373.

[0171] Example 2a—— N -Boc4-hydroxynoindole (66)

[0172] Prepared in a 1.0 mmol scale according to the general process for the borylation of indigo as described in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0173] The boronized reaction mixture was cooled to 0°C and dissolved in THF (8.6 mL). 3 M NaOH (1.0 mL, 3.0 mmol) was added, followed by slow addition of 30% H₂O₂ aqueous solution (1.0 mL) over 5 min. The mixture was stirred at 0°C for 30 min, and then stirred overnight at room temperature. The mixture was diluted with water (3 mL) and the aqueous phase was washed with DCM (3 × 5 mL). The aqueous phase was acidified to pH 4–5 with 3 M HCl and extracted with DCM (5 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (5% MeOH)] to give 66 (240 mg, 79%) as a grayish-white solid.

[0174] R f 0.13 [DCM / MeOH (5% MeOH)]; mp: >200 ℃, colorless powder; FTIR ν max / cm -1 (Net): 2864, 1673, 1652, 1535, 1423; 1 H NMR (400 MHz, DMSO-d6, δ H ):10.27 (s, 1H, OH),5.76 (s, 1H, C3-H), 5.45 (s, 1H, C5-H), 4.12-3.78 (m, 3H, C7-H a , C11-H, C12-H), 3.51 (dd, 1H, J = 15.0, 6.5 Hz, C7-H), 3.16-2.93 (m, 3H, C10-H, C11-H,C12-H), 2.29 (br s, 1H, C8-H), 1.84 (s, 2H, C9-H), 1.23-1.14 (m, 9H, Boc); 13 CNMR (100 MHz, DMSO-d6, δ C):166.0 (C4), 164.2 (CO), 154.1 (C6), 150.4 (CO Boc), 98.8 / 98.7 (C3, rotatimer), 96.3 (C5), 79.3 / 78.8 (q Boc, rotatimer), 51.7 / 50.6 / 50.3 / 49.3 (C11, C12, rotatimer), 48.3 (C7), 34.5 (C10), 28.1 (3C, Boc), 27.4 (C8), 25.9 (C9);HRMS (ESI) + ): Calculated value C 16 H 23 N₂O₄: 307.1652, measured value [M+H] + 307.1650, C 16 H 22 N₂NaO₄: 329.1472, measured value [M+Na] + : 329.1469.

[0175] Example 2b — (+)4-hydroxyindigo dihydrochloride (67)

[0176] Following the general procedure A, alcohol 66 (0.79 mmol) yielded alcohol 67 (184 mg, 96%) as a grayish-white solid.

[0177] mp: >200 ℃, colorless powder; [α] D 25 = +3.0 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 3444, 2934, 2597, 1641, 1589; 1 H NMR (400 MHz, D2O, δ H ):6.33 (d, 1H, C3-H, J = 2.0Hz), 6.02 (d, 1H, C5-H, J = 2.0 Hz), 4.07 (d, 1H, C7-H a , J = 15.5 Hz), 3.93(dd, 1H, J = 15.5, 6.5 Hz, C7-H b), 3.40-3.24 (m, 5H, C10-H, C11-H, C12-H), 2.69 (br s, 1H, C8-H), 2.03-1.93 (m, 2H, C9-H); 13 C NMR (100 MHz, D2O, δ C ):168.4 (C6), 164.2 (C7), 149.3 (C8), 105.3 (C9), 97.2 (C10), 49.1 (C11 or C12), 49.0 (C11), 48.1 (C11 or C12), 31.5 (C10), 24.6 (C8), 22.4 (C9);HRMS (ESI) + ): Calculated value C 11 H 15 N₂O₂: 207.1128, measured value [M+H-HCl] + : 207.1136.

[0178] Example 3a—— N -Boc4-methoxynoindine (68)

[0179] Following the general process for the borylation of indigo as described in Example 1 above, 0.50 mmol was prepared. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0180] The freshly prepared CuSO4·5H2O (37 mg, 0.15 mmol), KOH (84 mg, 1.50 mmol), and molecular sieve 4 were added. A solution of 300 mg in methanol (5 mL) was stirred for 5 h under a nitrogen atmosphere and then transferred to the crude material of the borylation reaction using a syringe. The reaction mixture was refluxed and stirred for 18 h under an oxygen atmosphere. The reactants were diluted with 10 mL of methanol, filtered through a diatomaceous earth (celite) pad, and the solvent was removed under vacuum. The crude material separated into layers between ammonia solution (15 mL, 15% aqueous solution) and DCM (15 mL), and the aqueous phase was extracted with DCM (4 × 15 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by rapid column chromatography [DCM / MeOH (2% MeOH)] to give 69 (130 mg, 81%) as a colorless solid.

[0181] mp: 170-171℃, colorless needle-like substance (toluene); R f: 0.41 [DCM / MeOH (6% MeOH)];FTIRν max / cm -1 (Net): 2971, 1673, 1646, 1427; 1 H NMR (500 MHz, CDCl3, δ H , 52.0℃):5.85(s, 1H, C3-H), 5.79 (s, 1H, C5-H), 4.39-4.07 (m, 3H, C11-H, C12-H, C7-H), 3.82-3.74 (m, 1H, C7-H), 3.73 (s, 3H, OMe), 3.13-2.85 (m, 3H, C11-H, C12-H,C10-H), 2.38 (s, 1H, C8-H), 1.93 (m, 2H, C9-H), 1.41-1.18 (s, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ) C , 52.0℃): 167.4 (C4), 164.9 (CO), 154.4 (C6), 148.7 (COBoc), 99.5 (C5), 94.8 (C3), 80.1 (q Boc), 55.1 (OMe), 50.6 (C11, C12), 48.4(C7), 34.9 (C10), 28.1 (3C, Boc), 27.6 (C8), 26.4 (C9);HRMS (ESI + ): Calculated value C 17 H 25 N₂O₄: 321.1809, measured value [M+H] + 321.1800; Calculated value C 17 H 25 N2O4: C 63.73, H 7.55, N 8.74. Measured values: C 64.15, H 7.49, N 8.77.

[0182] Example 3b — (-)4-methoxynoindine (69)

[0183] TFA (0.3 mL, 10 equivalents) was added once to a solution of ether 68 (130 mg, 0.42 mmol) in DCM (4 mL, 0.1 M), and the reaction mixture was stirred at room temperature for 18 h. Water (10 mL) was added, and the aqueous phase was washed with DCM (3 × 10 mL). The aqueous phase was alkalized with ammonia (10 mL, 15% aqueous solution) and extracted with DCM (3 × 10 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated to give 69 (76 mg, 85%) as a colorless solid.

[0184] mp: >200℃, colorless powder; [α] D 24 = -42 [c 1.0, EtOH];FTIR ν max / cm -1 (Net): 2889, 1645, 1580, 1557, 1158; 1 H NMR (500 MHz, CDCl3, δ H :5.87 (d, J = 3.0 Hz, 1H, C3-H), 5.74 (d, J = 3.0 Hz, 1H, C5-H), 4.10 (d, J = 15.0 Hz, 1H, C7-H), 3.85 (dd, J =15.0, 6.5 Hz, 1H, C7-H), 3.77 (s, 3H, OMe), 3.14-2.98 (m, 4H, C11-H, C12-H), 2.84 (s, 1H, C10-H), 2.30 (s, 1H, C8-H), 1.96 (s, 2H, C9-H), 1.55 (s, 1H,NH); 13 C NMR (125 MHz, CDCl3, δ C ):167.4 (CO), 165.1 (C6), 150.6 (C4), 98.6(C5), 94.5 (C3), 55.2 (OMe), 53.4, 53.0 (C11, C12), 49.2 (C7), 35.7 (C10), 27.7 (C8), 26.4 (C9); HRMS (ESI + ): Calculated value C 12 H 17 N₂O₂: 221.1285, measured value [M+H] + :221.1283.

[0185] Example 4a—— N -Boc4-(N-benzylamino)noindine (70)

[0186] Prepared in a 5.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0187] In a separate container, Cu(OAc)·H₂O (300 mg, 1.5 mmol), KF (320 mg, 5.5 mmol), and molecular sieve 4 were added. (4 g) was stirred in MeCN (20 mL) for 15–20 min. The crude borate was dissolved in MeCN (5 mL), and copper solution was added to the crude reactant via syringe, and the mixture was stirred for 10 min. Freshly distilled BnNH2 (1.1 mL, 10.0 mmol) was added, and the reaction mixture was heated under reflux for 18 h under an oxygen atmosphere. The reaction mixture was cooled and passed through a Celite filter. ® The mixture was filtered and concentrated. The crude reaction mixture separated into layers between ammonia (25 mL, 15% aqueous solution) and DCM (25 mL), and the aqueous phase was extracted with DCM (4 × 25 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by rapid column chromatography [DCM / MeOH (2% MeOH)] to give 70 (1.70 g, 72%) as a colorless solid along with inseparable impurities.

[0188] 1 H NMR (500 MHz, CDCl3, δ H ): 7.35-7.19 (m, 5H, Ar), 5.52 (s, 1H, C3-H), 5.46 (s, 1H, C5-H), 4.66 (s, 1H, NH), 4.38-4.11 (m, 3H, C13-H, C11-H or C12-H); 4.05 (d, J= 15.5 Hz, 1H, C7-H), 3.71 (m, 1H, C7-H), 3.17-2.78 (m, 3H, 2x C11-H or C12-H, 1H x C11-H or C12-H), 2.74 (s, 1H, C10-H), 2.31 (s, 1H, C8-H), 1.96-1.80 (m, 2H, C9-H), 1.28 (s, 9H, Boc).

[0189] Example 4b — (+)4-(N-benzylamino)noindole (71)

[0190] TFA (0.4 mL, 10 equivalents) was added to a solution of secondary amine 70 (1.70 g, 4.30 mmol) in DCM (43 mL, 0.1 M), and the solution was stirred at room temperature for 16 h. Water (20 mL) was added, and the aqueous phase was washed with DCM (3 × 30 mL). The aqueous phase was then alkalized with ammonia (15 mL, 15% aqueous solution) and extracted with DCM (4 × 30 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to give 71 (970 mg, 76%) as a colorless solid.

[0191] R f : 0.39 [DCM / MeOH (8% MeOH)]; mp: 208-211 ℃, (toluene); [α] D 25 = +58 [c 0.5,EtOH];FTIR ν max / cm -1 (Net): 3266, 2919, 1637, 1559, 1533; 1 H NMR (500 MHz, CDCl3, δ) H ):7.35-7.23 (m, 5H, Ar), 5.52 (s, 1H, C3-H), 5.48 (s, 1H, C5-H), 4.58 (s,1H, NHPh), 4.26 (s, 1H, CH2Ph), 4.25 (s, 1H, CH2Ph), 4.03 (d, J = 14.5 Hz, 1H,C7-H), 3.77 (dd, J= 6.5, 14.5 Hz, 1H, C7-H), 3.09-2.93 (m, 4H, C11-H C12-H), 2.71 (s, 1H, C10-H), 2.21 (s, 1H, C8-H), 1.90 (s, 2H, C9-H), 2.07-1.71 (s,1H,NH); 13 C NMR (125 MHz, CDCl3, δ C ):164.6 (CO), 154.9 (C4), 149.7 (C6), 137.8(Ar), 128.7 (Ar, 2C), 127.5 (Ar), 127.4 (Ar, 2C), 97.2 (C5), 91.2 (C3), 53.8(C11), 52.8 (C12), 48.7 (C7), 47.0 (CH2-Ph), 35.5 (C10), 27.7 (C8), 26.5(C9);HRMS (ESI + ): Calculated value C 18 H 22 N3O: 296.1757, measured value [M+H] + : 296.1766; Calculated value C 18 H 21 N3O: C: 73.19, H: 7.17, N: 14.23; Measured values: C: 73.24, H: 7.18, N: 14.35.

[0192] Example 5 – (-)4-(2,2,2-trifluoroethyl)indigo base hydrochloride (79)

[0193] Prepared in a 1.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0194] To the crude borylation reaction mixture, [Pd2(dba)3] (23 mg, 1 mmol%), Xphos (47 mg, 2.5 mmol%), cesium fluoride (450 mg, 3.0 equivalents), and anhydrous cuprous chloride (I) (99 mg, 1.0 equivalents) were added, and the Schlenk tube was placed under vacuum and purged three times with nitrogen. The reaction mixture was dissolved in DMF (4.0 mL, 0.25 M), and 2-iodo-1,1,1-trifluoroethane (0.19 mL, 2.0 equivalents) and water (0.14 mL, 8.0 equivalents) were added. The reaction mixture was stirred at 65 °C for 18 h. The solvent was removed under vacuum, and the crude reaction mixture separated into layers between EtOAc (15 mL) and water (15 mL). The aqueous phase was extracted with EtOAc (3 × 15 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by rapid column chromatography [DCM / MeOH(2%MeOH)] to obtain N -Boc-4-(2,2,2-trifluoroethyl)-noindigo (190 mg, 50%) was a colorless solid. The obtained trifluoro-noindigo derivative was deprotected and converted to its HCl salt according to general procedure A, yielding ligand 79 (93 mg, 34%) as a colorless solid.

[0195] mp: >200 ℃, colorless powder; [α] D 26 = -42 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2723, 1640, 1563, 1467, 1458; 1 H NMR (500 MHz, D2O, δ H ):6.61-6.55 (m, 2H, C3-H, C5-H), 4.14-3.88 (m, 2H, C7-H), 3.5-3.26 (m, 7H, C10-H, C11-H, C12-H, CH2-CF3), 2.75 (s, 1H, C8-H), 2.15-1.95 (m, 2H, C9-H); 13 C NMR (125 MHz, D2O, δ C ):164.5(CO), 147.0 (C6), 145.3 (C4), 125.0 (d, J = 276 Hz, CF3), 118.4, 111.4 (C3,C5), 49.4, 48.2 (C11, C12), 48.6 (C7), 38.3 (q,J = 30.0 Hz, C14), 31.4 (C10), 24.7 (C8), 22.5 (C9); 19 F NMR (376 MHz, D2O, δ F ):-64.5 (t, 11.0 Hz);HRMS (ESI + ): Calculated value C 13 H 16 F3N2O: 273.1209, measured value [M+H-HCl] + :273.1220.

[0196] Example 6 – (-)4-(perfluorophenyl)noindole hydrochloride (75)

[0197] Prepared in a 1.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0198] Bromopentafluorobenzene (0.15 mL, 1.2 equivalents), PdCl2(PPh3)2 (35 mg, 0.05 equivalents), and Cs2CO3 (410 mg, 2.5 equivalents) were added to the crude material from the borylation reaction. The reaction mixture was dissolved in THF (5 mL, 0.2 M) and stirred at 80 °C for 18 h. The reaction mixture was diluted with ammonia (25 mL, 15% aqueous solution), and the aqueous phase was extracted with EtOAc (4 × 25 mL). The combined organic phases were dried over MgSO4, the solids were filtered off, and the solvent was evaporated under vacuum. The crude reaction mixture was purified by rapid column chromatography [DCM / MeOH (1.5% MeOH)] to give 74 (509 mg, 99%) as a colorless solid (contaminated with [PdCl2(PPh3)2]).

[0199] 1 H NMR (500 MHz, CDCl3, δ H ):6.53 (s, 1H, C3-H), 6.09 (s, 1H, C5-H), 4.49-4.12 (m, 3H, C11-H C12-H C7-H), 3.88 (dd, J= 16.5, 6.5 Hz, 1H, C7-H), 3.18-2.96 (m, 3H, C11-H C12-H C8-H), 2.47 (s, 1H, C10-H), 2.02 (m, 2H, C9-H), 1.29 (s, 9H, Boc).

[0200] Following the general procedure A, N-Boc protected indigo derivative 74 (1.1 mmol) yielded 4-(perfluorophenyl)-indigo hydrochloride 75 (160 g, 43%) as a colorless solid.

[0201] mp: >200℃, colorless powder; [α] D 26 = -16 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2977, 2869, 1658, 1536; 1 HNMR (500 MHz, MeOH, δ H ):6.58 (s, 1H, C3-H), 6.43 (s, 1H,C5-H), 4.13 (d, J = 15.5 Hz, 1H, C7-H), 4.00 (dd, J = 6.0, 15.0 Hz, 1H, C7-H), 3.14-2.99 (m, 5H, C11-H C12-H C10-H), 2.43 (s, 1H, C8-H), 2.07 (m, 2H, C9-H); 13 C NMR (125 MHz, MeOH, δ C ):163.7 (CO), 152.4 (C4), 144.9 (m), 143.1 (m),142.2 (m), 140.2 (m), 138.8 (m), 136.7 (m) (6C, Ar), 138.5 (C6), 117.0 (C3),107.4 (C5), 52.6, 51.6 (C11, C12), 49.8 (C7), 35.2 (C10), 27.4 (C8), 25.2(C9); 19 F NMR (376 MHz, D2O, δ F ):-140.7, -141.3, -152.9, -160.8, -161.1;HRMS(ESI + ): Calculated value C17 H 14 F5N2O: 357.1021, measured value [M+H] + -HCl] + :357.1017.

[0202] Example 7a—— N -Boc4-(2-pyridyl)noindine (100)

[0203] Prepared in a 1.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0204] Anhydrous Cs₂CO₃ (814 mg, 2.5 mmol) and PdCl₂(PPh₃)₂ (35 mg, 5 mol%) were added to the crude mixture for the borylation reaction. Anhydrous THF (10 mL) was added, followed by 2-bromopyridine (115 μL, 1.2 mmol). The mixture was stirred at 80 °C for 48 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and passed through Celite. ® Filtration. The organic layer was washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH (4% MeOH) + 0.1% ammonia (15% aqueous solution)] to give 100 (205 mg, 56%) as a yellow oil. This product was used in the next step without any further purification.

[0205] R f : 0.17 [DCM / MeOH (5% MeOH)]; 1 H NMR (400 MHz, CDCl3, δ H ):8.65 (d, 1H, J = 2.0 Hz, C15-H), 7.75-7.68 (m, 2H, C17-H, C18-H), 7.29-7.26 (m, 1H, C16-H), 6.92 (s, 1H, C3-H), 6.86 (s, 1H, C5-H), 4.37-4.17 (m, 3H, C7-H a , C11-H, C12-H), 3.84 (dd, 1H, J= 6.5, 15.5 Hz, C7-H b ), 3.11-2.96 (m, 3H, C10-H, C11-H, C12-H), 2.42 (s, 1H, C8-H), 2.01-1.92 (m, 2H, C9-H), 1.30-1.13 (m, 9H,Boc); 13 C NMR (100 MHz, CDCl3, δ C ):163.7 (CO), 154.5 (CO Boc), 154.2 (C6), 149.6 (C4), 148.8 (C13), 145.4 (C16), 136.9 (C17), 123.8 (C16), 121.1 (C18), 113.8 (C3), 104.4 / 103.9 (C5, rotatimer), 80.3 / 79.8 (q Boc, rotatimer), 51.6 / 50.6 / 50.3 / 49.3 (C11, C12, rotatimer), 48.9 (C7), 35.1 (C10), 27.5 (C8), 26.2 (C9), 24.8 (3C, Boc);HRMS (ESI) + ): Calculated value C 21 H 26 N3O3[M+H] + 368.1969, Measured value: 368.1965; Calculated value C 21 H 25 N3NaO3: 390.1788, measured value [M+Na] + : 390.1784.

[0206] Example 7b — (-)4-(2-pyridyl)noindole dihydrochloride (101)

[0207] Following the general procedure A for deprotection of indigofera tinctoria, N -Boc-4-(2-pyridyl)-indigo 100 (0.55 mmol) yielded 101 (99.2 mg, 63%) as a colorless solid.

[0208] mp: >200℃, colorless powder; [α] D 24 = -12 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 3471, 2750, 1658, 1572;1 H NMR (400 MHz, D2O, δ H ):8.71-8.70 (m, 1H, C16-H), 8.53-8.49(m, 1H, C18-H), 8.16 (d, 1H, J = 8.0 Hz, C19-H), 7.97-7.94 (m, 1H, C17-H), 6.89 (d, 1H, J = 2.0 Hz, C3-H), 6.84 (s, 1H, J = 2.0 Hz, C5-H), 4.11 (d, 1H, J =16.0 Hz, C7-H a ), 3.98 (dd, 1H, J = 6.5, 16.0 Hz, C7-H b ), 3.52 (br s, 1H, C10-H), 3.45-3.30 (m, 4H, C11-H, C12-H), 2.77 (br s, 1H, C10-H), 2.10-2.00 (m,2H, C9-H); 13 C NMR (100 MHz, D2O, δ C ):164.3 (CO), 149.3 (C6), 148.7 (C4), 146.9(Ar py), 143.3 (Ar py), 142.7 (Ar py), 127.3 (Ar py), 126.2 (Ar py), 116.4(C3), 107.0 (C5), 49.3, 49.0 (C11, C12), 48.2 (C7), 31.8 (C8), 24.7 (C10),22.4 (C9);HRMS (ESI + ): Calculated value C 16 H 18 N3O: 268.1444, measured value [M+H + -2HCl] + : 268.1444.

[0209] Example 8 – (-)4-(3-pyridyl)noindole dihydrochloride (104)

[0210] Inject into the Schlenk tube N-Boc-4-bromo-indigo 61 (370 mg, 1.0 mmol), [Pd2(dba)3] (9.0 mg, 1 mmol%), tricyclohexylphosphine (7.0 mg, 2.4 mmol%), and 3-pyridylboronic acid (140 mg, 1.1 equivalents) were placed under vacuum and purged three times with nitrogen. The mixture was dissolved in dioxane (2.6 mL, 0.4 M), and a solution of tripotassium phosphate in water (360 g, 1.7 equivalents, 1.3 M) was added dropwise over 10 min using a syringe. The reaction mixture was heated at 100 °C for 18 h. The solution was filtered through diatomaceous earth and the solvent was removed under vacuum. Ammonia solution (5 mL, 15% aqueous solution) was added, and the aqueous phase was extracted with DCM (4 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The obtained solution was then processed according to general procedure A. N The -Boc-4-(3-pyridyl)-noindigo derivative was deprotected and converted to an HCl salt, yielding 104 (210 mg, 78%) as a colorless solid.

[0211] mp: >200 ℃, colorless powder; [α] D 24 = -11 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 2926, 2528, 2072, 1650, 1539; 1 H NMR (500 MHz, MeOD, δ H ):9.39 (s, 1H, Ar Py), 9.07 (s, 1H, Ar Py), 9.01 (s, 1H, Ar Py), 8.27 (s, 1H, Ar Py), 7.10 (s, 1H, C3-H), 7.06 (s, 1H, C5-H), 4.35 (d, 1H, J = 15.5 Hz, C7-H), 4.14 (dd, 1H, J = 15.5, 6.0Hz, C7-H), 3.69-3.53 (m, 5H, C11-H C12-H C10-H), 2.89 (s, 1H, C8-H), 2.28 (d, J = 13.5 Hz, 1H, C9-H), 2.17 (d, 1H, J = 13.5 Hz, C9-H); 13 C NMR (125 MHz, MeOD, δ) C):163.6 (CO), 148.9 (C6), 145.3 (q Py), 144.9 (Py), 141.7 (Py), 140.2 (Py), 136.7 (C4), 127.7 (Py), 115.0 (C5), 107.1 (C3), 49.1, 48.5 (C11, C12), 48.9(C7), 32.0 (C10), 25.2 (C8), 22.7 (C9);HRMS (ESI + ): Calculated value C 16 H 18 N3O: 268.1444, measured value [M+H-2HCl] + : 268.1444.

[0212] Example 9a — (-)N-Boc4-(4-pyridyl)noindole (102)

[0213] Prepared in a 1.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0214] Anhydrous Cs₂CO₃ (814 mg, 2.5 mmol) and PdCl₂(PPh₃)₂ (35 mg, 5 mol%) were added to the crude borylation reaction mixture. Anhydrous THF (10 mL) was added, followed by 4-iodopyridine (246 mg, 1.2 mmol). The mixture was stirred at 80 °C for 48 h. The mixture was cooled to room temperature, diluted with EtOAC (50 mL), and passed through Celite. ® Filtration. The organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (5% MeOH) + 0.1% ammonia (15% aqueous solution)] to give 102 (312 mg, 85%) as an orange oil. This product was used in the next step without any further purification.

[0215] R f : 0.39 [DCM / MeOH (10% MeOH)]; 1 H NMR (400 MHz, CDCl3, δ H ):8.63 (d,2H, J= 6.0 Hz, C15-H, C17-H), 7.41 (d, 2H, J = 6.0 Hz, C14-H, C18-H), 6.66 (s,1H, C3-H), 6.28 (s, 1H, C5-H), 4.38-4.15 (m, 3H, C7-H a , C11-H, C12-H), 3.82(dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.06 (br s, 3H, C10-H, C11-H, C12-H), 2.42 (br s, 1H, C8-H), 2.02-1.93 (m, 2H, C9-H), 1.30-1.13 (m, 9H, Boc); 13 C NMR (100MHz, CDCl3, δ C ):163.3 (CO), 154.5 / 154.2 (CO Boc, rotatimer), 150.4 (C15, C17), 149.6 (C6), 148.0 / 147.8 (C4, rotatimer), 145.2 (C13), 121.1 (C14, C18), 114.4 (C3), 104.3 / 103.5 (C5, rotatimer), 80.5 / 79.8 (q Boc, rotatimer), 51.7 / 50.6 / 50.3 / 49.3 (C11, C12, rotatimer), 49.0 (C7), 35.1 (C10), 27.4 (C8), 26.1 (C9), 24.8 (3C, Boc);HRMS (ESI + ): Calculated value C 21 H 26 N3O3: 368.1969, measured value [M+H] + 368.1970, calculated value C 21 H 25 N3NaO3: 390.1788, measured value [M+Na] + : 390.1791.

[0216] Example 9b — (-)4-(4-pyridyl)noindole dihydrochloride (103)

[0217] Following the general procedure A, N-Boc4-(4-pyridyl)indole 102 (0.85 mmol) yielded 103 (122 mg, 48%) as a light orange solid.

[0218] mp: >200℃, colorless powder; [α] D 24 = -12 [c 0.5, water];FTIR ν max / cm -1 (Net): 2590, 1653 (w), 1631, 1579, 1545; 1 H NMR (400 MHz, D2O, δ H ):8.75 (d, 2H, J = 6.5 Hz, C14-H, C18-H), 8.20 (d, 2H, J = 6.5 Hz, C15-H, C17-H), 6.90 (d, 1H, J = 2.0 Hz, C3-H), 6.86 (s, 1H, J = 2.0 Hz, C5-H), 4.10 (d, 1H, J = 16.0 Hz, C7-H a ), 3.97(dd, 1H, J = 6.5, 16.0 Hz, C7-H b ), 3.51 (s, 1H, C10-H), 3.45-3.28 (m, 4H, C11-H, C12-H), 2.76 (br s, 1H, C8-H), 2.09-1.99 (m, 2H, C9-H); 13 C NMR (100 MHz, D2O, δ) C ):164.5 (C0), 154.3 (C4), 148.7 (C6), 146.7 (C13), 141.6 (2C, C15, C17), 125.2 (2C, C14, C17), 116.3 (C3), 107.4 (C5), 49.4 (C11 or C12), 48.9 (C7), 48.2 (C11 or C12), 31.8 (C10), 24.7 (C8), 22.5 (C9);HRMS (ESI) + ): Calculated value C 16 H 18 N3O: 268.1444, measured value [M+H] +: 268.1453.

[0219] Example 10a—— N -Boc4-(4-(2-benzyloxy)pyridine)indigoline 105

[0220] Prepared in a 1.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0221] Anhydrous Cs₂CO₃ (814 mg, 2.5 mmol) and PdCl₂(PPh₃)₂ (35 mg, 5 mol%) were added to the crude borate reaction mixture. Anhydrous THF (5.0 mL) was added, followed by a solution of 4-bromo-2-benzyloxypyridine (316 mg, 1.2 mmol) in anhydrous THF (5.0 mL). The mixture was stirred at 80 °C for 48 h. The solution was cooled to room temperature, diluted with EtOAc (50 mL), and passed through Celite. ® Filtration. The organic layer was washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (4% MeOH) + 0.1% ammonia (15% aqueous solution)] to give 10⁵ (485 mg, 99%) as a pale yellow oil with very minor impurities. This product was used in the next step without any further purification.

[0222] R f : 0.23 [DCM / MeOH (5% MeOH)]; 1 H NMR (400 MHz, CDCl3, δ H ):8.22 (d, 1H, J = 5.0 Hz, C16-H), 7.46 (d, 2H, J = 7.0 Hz, C20-H, C24-H), 7.39-7.29 (m, 3H,C21-H, C22-H, C23-H), 7.04 (d, 1H, J= 5.0 Hz, C17-H), 6.96 (s, 1H, C14-H), 6.67 (s, 1H, C3-H), 6.27 (s, 1H, C5-H), 5.41 (s, 2H, C18-H), 4.40-4.18 (m,3H, C7-H a , C11-H, C12-H), 3.84 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.05 (s, 3H,C10-H, C11-H, C12-H), 2.44 (s, 1H, C8-H), 2.03-1.94 (m, 2H, C9-H), 1.33-1.17(m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ C ):164.4 (C15), 163.4 (CO), 154.7 / 154.4 (CO Boc, rotatimer), 150.0, 149.5 (C6, C4), 148.3, 147.7 (C13, C16), 137.2 (C19), 128.6, 128.1, 128.0 (5C, C20, C21, C22, C23, C24), 114.9, 114.5 (C3, C17), 108.9 / 108.7 (C14, rotatimer), 104.4 / 103.7 (C5, rotatimer), 80.5 / 79.9 (q Boc, rotatimer), 68.0 (C18). 51.8 / 50.7 / 50.5 / 49.4 (C11, C12, rotatimers), 49.0 (C7), 35.3 (C10), 28.2 (3C, Boc), 27.6 (C8), 26.3 (C9); HRMS (ESI) + ): Calculated value C 28 H 32 N3O4: 474.2387, measured value [M+H] + 474.2383, calculated value C 28 H 31 N3NaO4: 496.2207, measured value [M+Na] + : 496.2198.

[0223] Example 10b — (+)4-(4-(2-pyridone))noindole hydrochloride (106)

[0224] Towards N -Boc 4-(4-(2-benzyloxy)pyridine)indigo 105 (448 mg, 0.95 mmol) was dissolved in MeOH (5.7 mL) with HCl (2.9 mL, concentrated aqueous solution). The mixture was heated under reflux for 24 h. After cooling to room temperature, the solvent was removed under vacuum. The crude substance was dissolved in MeOH (55 mL) and acetone (550 mL) was added. The mixture was stirred for 2 h. The solid was filtered, washed with acetone, and dried to give 106 (254 mg, 84%) as a pale yellow solid.

[0225] mp: >200 ℃, colorless powder; [α] D 23 = +26 [c 0.5, water];FTIR ν max / cm -1 (Net): 2946, 2732, 2582, 1638, 1567; 1 H NMR (400 MHz, D2O, δ H ):7.56 (d, 1H, J = 6.5 Hz, C18-H), 6.77-6.64 (m, 4H, C3-H, C5-H, C15-H, C19-H), 4.19 (d, 1H, J = 15.5 Hz, C7-H a ), 4.00 (dd, 1H, J = 5.5, 15.5 Hz, C7-H b ), 3.56-3.34 (m, 5H, C10-H, C11-H, C12-H), 2.89 (s, 1H, C8-H), 2.23-2.09 (m, 2H, C9-H); 13 C NMR (100 MHz, D2O, δ) C ):164.3 (C16), 164.0 (C0), 150.4 (C14), 148.4 (C4), 147.8 (C6), 135.4 (C18), 116.3, 114.3 (C15, C19), 107.2 (C3), 106.9 (C5), 49.3 (C11 or C12), 48.7 (C7), 48.2 (C11 or C12), 31.6 (C10), 24.7 (C8), 22.5 (C9);HRMS (ESI)+ ): Calculated value C 16 H 17 N3O2: 284.1394, measured value [M+H-HCl] + : 284.1386.

[0226] Example 11——(-) N -Boc 4-chloronoinine (59)

[0227] The preparation was carried out on a 1.00 mmol scale following the general process for the borylation of indigo as outlined in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0228] The crude mixture from the borylation reaction was dissolved in MeOH (2.5 mL). A solution of CuCl2 (470 mg, 3.5 mmol) in H2O (2.5 mL) was added, and the mixture was stirred in air at room temperature for 4 days. The mixture was diluted with NH4OH (10 mL, 15% aqueous solution), and the aqueous phase was extracted with DCM (3 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by rapid column chromatography on silica gel [EtOAc] to give 59 (247 mg, 76%) as a grayish-white solid.

[0229] R f : 0.21 [EtOAc];mp: 148-149 ℃ (toluene);FTIR ν max / cm -1 (Net): 2976, 2925, 1678, 1639, 1539; 1 H NMR (400 MHz, CDCl3, δ H ):6.43 (s, 1H, C3-H), 6.08 (s, 1H,C5-H), 4.34-4.07 (m, 3H, C7-H a , C11-H, C12-H), 3.74 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.12-2.94 (m, 3H, C10-H, C11-H, C12-H), 2.40 (s, 1H, C8-H), 1.90 (s,2H, C9-H), 1.31-1.22 (m, 9H, Boc); 13C NMR (100 Hz, CDCl3, δ C ):162.5 (CO),154.5 / 154.2 (CO Boc, rotifer), 149.9 / 149.4 (C4, rotifer), 146.1 / 145.8 (C6, rotifer), 115.7 (C3), 107.1 / 106.4 (C5, rotifer), 80.5 / 80.0 (q Boc, rotifer), 51.5 / 50.5 / 50.1 / 49.2 (C11, C12, rotifer), 48.9 (C7), 34.8 (C10), 28.0 (3C, Boc), 27.4 (C8), 26.0 (C9);HRMS (ESI) + ): Calculated value C 16 H 22 ClN2O3: 325.1313, Measured value [M+H]+: 325.1301, Calculated value C 16 H 21 ClN2NaO3: 347.1133, measured value [M+Na]+: 347.1121.

[0230] Example 12 – (-)4-chloroindole (60)

[0231] The preparation was carried out on a 1.00 mmol scale following the general process for the borylation of indigo as outlined in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0232] In a sealed tube, the crude mixture of borylation reaction was dissolved in MeOH (2.5 mL), and an aqueous solution of CuCl2 (470 mg, 3.5 mmol, 1.4 M) was added. The reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was cooled, diluted with NH4OH (5 mL, 15% aqueous solution), and the aqueous phase was extracted with DCM (5 × 5 mL). The combined organic layers were concentrated under vacuum. The residue separated into layers between 3 M HCl (5 mL) and DCM (5 mL). The aqueous phase was washed with DCM (2 × 5 mL), alkalized to pH 10 with concentrated NH4OH, and extracted with DCM (5 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH / ammonia (89:10:1)] to give 60 (179 mg, 80%) as a grayish-white solid. A high-purity sample was obtained by recrystallization in toluene.

[0233] R f : 0.22 [DCM / MeOH (10% MeOH)]; mp: 167-168℃, colorless solid (toluene); [α] D 25 = -32 [c 1.0, EtOH];FTIR ν max / cm -1 (Net): 3330, 3064, 2930, 2793, 1634, 1538; 1 H NMR (400 MHz, CDCl3, δ) H ):6.45 (d, 1H, J = 2.0 Hz, C3-H), 6.02 (d, 1H, J = 2.0 Hz, C5-H), 4.03 (d, 1H, J = 15.5 Hz, C7-H a ), 3.82 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ),3.07-2.85 (m, 4H, C11-H, C12-H), 2.85 (s, 1H, C10-H), 2.31 (s, 1H, C8-H), 1.92 (s, 2H, C9-H), 1.36 (s, 1H, NH); 13 C NMR (100 MHz, CDCl3, δ C):162.7 (CO),151.8 (C4), 146.0 (C6), 115.2 (C3), 106.3 (C5), 53.7, 52.9 (C11, C12), 49.8(C7), 35.6 (C10), 27.5 (C8), 26.2 (C9);HRMS (ESI + ): Calculated value C 11 H 14 ClN2O: 225.0789, measured value [M+H] + 225.0791. Calculated value C. 11 H 13 ClN2O: Theoretical values ​​C = 58.80, H = 5.83, N = 12.47, measured values ​​C = 58.40, H = 5.86, N = 12.32.

[0234] Example 13a——(-) N -Boc 4-iodonoindole(64)

[0235] Prepared in a 5.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0236] Cu(NO3)2·3H2O (2.42 g, 10.0 mmol), NH4I (1.45 g, 10.0 mmol), and molecular sieve 4 (500 mg) was added to the crude borate reaction mixture, and the Schlenk flask was placed under nitrogen and purged three times with oxygen. The reaction mixture was dissolved in DMF (25 mL) and heated at 80 °C for 24 h. The solvent was removed under vacuum, and the residue was dissolved in DCM. The mixture was poured into ammonia (30 mL, 15% aqueous solution), and the aqueous phase was extracted with DCM (4 × 25 mL). The combined organic layers were dried over MgSO4, filtered, concentrated, and the crude substance was purified by rapid column chromatography [DCM / MeOH (2% MeOH)] to give iodide 64 (1.99 g, 95%) as a grayish-yellow solid.

[0237] R f : 0.21 [DCM:MeOH (3% MeOH)]; mp: 139 - 140 ℃, needles (toluene); FTIRν max / cm -1(Net): 2920, 1679, 1632, 1523; 1 H NMR (500 MHz, CDCl3, δ H , 52.0℃):6.90(d, J = 2.0 Hz, 1H, C3-H), 6.37 (d, J = 2.0 Hz, 1H, C5-H), 4.39-4.04 (m, 3H, C11-H, C12-H, C7-H), 3.72 (dd, J = 16.0, 7.0 Hz, 1H, C7-H), 3.09-2.93 (m, 2H, C11-H, C12-H), 2.89 (s, 1H, C10-H), 2.39 (s, 1H, C8-H), 1.99-1.87 (m, 2H, C9-H),1.26 (s, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C , 52.0℃):161.6 (CO), 154.3 (COBoc), 148.8 (C6), 126.3 (C3), 114.3 (C5), 108.2 (C4), 80.1 (q Boc), 50.4,49.3 (C11, C12), 48.8 (C7), 34.5 (C10), 28.1 (3C, Boc), 27.5 (C8), 26.1 (C9);HRMS (ESI + ): Calculated value C 16 H 22 IN₂O₃: 417.0670, measured value [M+H] + : 417.0672; Calculated value C 16 H 21 IN₂NaO₃: 439.0489, measured value [M+Na] + : 439.0491.

[0238] Example 13b — (+)4-iodonoindole hydrochloride (65)

[0239] Following the general process A, N -Boc 4-iodonoindole 64 (0.68 mmol) yielded 65 (0.18 g, 86%) as a colorless solid.

[0240] mp: >200℃, colorless powder; [α]D 21 = +12 [c 1.0, water];FTIR ν max / cm -1 (Net): 2714, 1615, 1551, 1455; 1 H NMR (500 MHz, D2O, δ H ):7.07 (s, 1H, C3-H), 6.89 (s, 1H,C5-H), 4.03 (d, J = 15.5 Hz, 1H, C7-H), 3.88 (dd, J = 15.5, 6.0 Hz, 1H, C7-H),3.44 (s, 1H, C10-H), 3.41-3.29 (m, 4H, C11-H C12-H), 2.76 (s, 1H, C8-H),2.08-1.98 (m, 2H, C9-H); 13 C NMR (125 MHz, D2O, δ C ):163.3 (CO), 146.8 (C6),126.4 (C3), 118.9 (C5), 110.7 (C4), 49.3, 48.2 (C11, C12), 48.7 (C7), 31.0(C10), 24.7 (C8), 22.4 (C9);HRMS (ESI + ): Calculated value C 11 H 14 IN2O: 317.0145, measured value [M+H] + -HCl] + : 317.0141.

[0241] Example 14a——(-) N -Boc 4-trifluoromethylnoindine (76)

[0242] Pour into the Schlenk flask N-Boc 4-iodoindoline 64 (2.08 g, 5 mmol), cuprous iodide (4.52 g, 23.7 mmol), anhydrous potassium fluoride (1.38 g, 23.7 mmol), and trimethyl(trifluoromethyl)silane (3.5 mL, 23.7 mmol) were added, and the reaction mixture was placed under nitrogen. DMF (24 mL, 0.2 M) was added, and the reaction mixture was stirred at 50 °C for 16 h. The solvent was removed under vacuum, and the residue separated into layers between DCM (20 mL) and ammonia (20 mL, 15% aqueous solution). The aqueous phase was extracted with DCM (3 × 20 mL), and the combined organic phases were dried over MgSO4. The solids were filtered off, and the solvent was evaporated under vacuum. The crude reactant was purified by rapid column chromatography [EtOAc / n-hexane (4:1)] to give 76 (1.52 g, 85%) as a colorless solid.

[0243] mp: 150-151℃, colorless solid (toluene); FTIR ν max / cm -1 (Net): 2981, 1680, 1664, 1547; 1 H NMR (500 MHz, CDCl3, δ H ):6.73 (s, 1H, C3-H), 6.22 (s, 1H, C3-H), 4.48-4.15(m, 3H, C11-H C12-H C7-H), 3.85 (dd, 1H, J = 16.0, 6.5 Hz, C7-H), 3.22-2.95 (m,3H, C11-H, C12-H, C8-H), 2.49 (s, 1H, C10-H), 2.02 (m, 2H, C7-H), 1.43-1.15(m, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C ):162.2 (CO), 153.6 (d, J = 43.0 Hz, COBoc), 151.0 (d, J = 53.0 Hz, C6), 140.5 (C4), 122.3 (d, J = 273 Hz, C13), 114.1(C3), 100.1 (d, J = 83.0 Hz, C5), 80.0 (d, J= 62.0 Hz, q Boc), 51.1, 50.3 (C11,C12), 49.3 (C7), 35.3 (C10), 28.0 (3C, Boc), 27.4 (C8), 26.0 (C9); 19 F NMR (470MHz, CDCl3, δ F ):-66.5 (d, J = 102 Hz); HRMS (ESI) + ): Calculated value C 17 H 22 F3N2O3: 359.1577, measured value [M+H] + 359.1584, Calculated value C 17 H 21 F3N2NaO3: 381.1396, measured value [M+Na] + : 381.1406; Analysis and calculation: Calculated value C 56.9 H 5.91 N 7.82, measured value: C 56.6, H 5.5 N 8.1.

[0244] Example 14b — (-)4-trifluoromethylindigo base hydrochloride (77)

[0245] Following the general process A, N -Boc 4-trifluoromethylindocyanine 76 (0.28 mmol) yielded 77 (55 mg, 77%) as a colorless solid.

[0246] mp:>200℃; colorless powder; [α] D 26 = -66 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 1658, 1551, 1278, 1166, 857; 1 H NMR (500 MHz, D2O, δ H ):6.82 (s, 1H, C3-H), 6.70 (s,1H, C5-H), 4.11 (d, 1H, J = 15.5 Hz, C7-H), 3.97 (d, 1H, J= 15.5, 6.5 Hz, C7-H), 3.53-3.30 (m, 5H, C11-H C12-H C10-H), 2.78 (s, 1H, C8-H), 2.05 (m, 2H, C9-H); 13 C NMR (125 MHz, D2O, δ C ):164.3 (CO), 149.3 (C6), 141.5 (q, J = 34.0 Hz, C4), 122.2 (q, J = 273.0 Hz, CF3), 114.5 (C3), 104.4 (C5), 49.2, 48.9 (C11, C12), 48.2 (C7), 31.8 (C10), 24.7 (C8), 22.3 (C9); 19 F NMR (376 MHz, D2O, δC, ppm): -66.2 (s); HRMS (ESI + ): Calculated value C 12 H 14 F3N2O; 259.1053, measured value [M+H-HCl] + :259.1060.

[0247] Example 15a—— N -Boc4-bromonoindole (61)

[0248] Prepared in a 5.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0249] The crude mixture from the borylation reaction was dissolved in MeOH (12.5 mL) and cooled to 0 °C. A solution of CuBr2 (3.35 g, 15.0 mmol) in H2O (12.5 mL) was added over 5 min. After 30 min, the ice bath was removed, and the reaction mixture was stirred in an open flask at room temperature for two days. The mixture was diluted with NH4OH (25 mL, 15% aqueous solution), and the aqueous phase was extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [EtOAc] to give 61 (1.54 g, 83%) as a grayish-white solid.

[0250] Rf 0.25 [EtOAc]; mp: 163-164℃, grayish-white solid (toluene); FTIR ν max / cm -1 (Net): 2976, 2924, 1679, 1635, 1531; 1 H NMR (500 MHz, D2O, δ H ):6.66 (s, 1H, C3-H),6.21 (s, 1H, C5-H), 4.35-4.06 (m, 3H, C7-H a , C11-H, C12-H), 3.73 (dd, 1H, J =6.5, 15.5 Hz, C7-H b ), 3.10-2.93 (m, 3H, C10-H, C11-H, C12-H), 2.40 (s, 1H,C8-H), 1.94 (s, 2H, C9-H), 1.31-1.23 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ) C ): 162.2 (CO), 154.4 / 154.2 (CO Boc, rotifer), 149.6 / 149.1 (C6, rotifer), 135.1 / 134.6 (C4, rotifer), 119.2 (C3), 109.6 / 109.0 (C5, rotifer), 80.5 / 80.0 (q Boc, rotifer), 51.5 / 50.5 / 50.1 / 49.2 (C11, C12, rotifer), 48.9 (C7), 34.7 (C10), 28.0 (3C, Boc), 27.3 (C8), 26.0 (C9); HRMS (ESI) + ): Calculated value C 16 H 22 BrN2O3: 369.0808, measured value [M+H] + 369.0797, calculated value C 16 H 21 BrN₂NaO₃: 391.0628, measured value [M+Na] + : 391.0620.

[0251] Example 15b — (-)4-bromonoindole (62)

[0252] Prepared in a 1.00 mmol scale according to the general process for the borylation of indigo as detailed in Example 1 above. N -Boc-4-(4,4,5,5-tetramethyl-1,3,2,-dioxapentoborane-2-yl)-indigo 58.

[0253] The crude mixture from the borylation reaction was dissolved in MeOH (2.5 mL) in a sealed tube, and a solution of CuBr2 (670 mg, 3.0 mmol) in H2O (2.5 mL) was added. The mixture was heated at 80 °C overnight. The mixture was cooled, diluted with NH4OH (5 mL, 15% aqueous solution), and extracted with DCM (5 × 5 mL). The combined organic layers were concentrated under vacuum. The crude material was separated into layers between 3M HCl (5 mL) and DCM (5 mL). The aqueous layer was washed with DCM (2 × 5 mL), alkalized to pH 10 with concentrated NH4OH, and extracted with DCM (5 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH:(89:10:1)] to give bromide 62 (228 mg, 85%) as a grayish-white solid. A high-purity sample was obtained by recrystallization in toluene.

[0254] R f : 0.21 [DCM / MeOH (10% MeOH)];mp: 169-170℃, grayish-white solid (toluene); [α] D 25 =-32 [c 1.0, EtOH];FTIR ν max / cm -1 (Net): 3335, 3061, 2934, 2791, 2741, 1622, 1531; 1 H NMR (400 MHz, CDCl3, δ H ):6.67 (d, 1H, J = 2.0 Hz, C3-H), 6.17 (d, 1H, J = 2.0Hz, C5-H), 4.04 (d, 1H, J = 15.5 Hz, C7-H a ), 3.83 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b), 3.10-2.97 (m, 4H, C11-H, C12-H), 2.87-2.86 (m, 1H, C10-H), 2.35-2.32(m, 1H, C8-H), 1.94 (s, 2H, C9-H), 1.46 (s, 1H, NH); 13 C NMR (100 MHz, CDCl3, δ) C ):162.5 (CO), 151.6 (C4), 135.0 (C6), 118.7 (C3), 108.8 (C5), 53.7, 52.9(C11, C12), 49.8 (C7), 35.5 (C10), 27.6 (C8), 26.2 (C19);HRMS (ESI + ): Calculated value C 11 H 14 BrN2O: 269.0284, measured value [M+H] + : 269.0289.

[0255] Example 16a—— N -Boc 4-aminonoindoline (80)

[0256] Method A: In the Schlenk tube, N -Boc-4-bromo-indigoline 61 (184 mg, 0.5 mmol), NaN3 (65 mg, 1.0 mmol), CuI (9 mg, 10 mol%), L A mixture of proline (17 mg, 30 mol%) and NaOH (6 mg, 30 mol%) in EtOH / H2O (7:3) (5 mL) was heated overnight at 95 °C. The mixture was cooled and separated into layers between H2O and DCM. The aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH:(89:10:1)] to give amine 80 (116 mg, 76%) as a grayish-white solid.

[0257] Method B: Will NA mixture of 61-Boc-4-bromo-indigo alkaloid (92 mg, 0.25 mmol) and copper (2 mg, 10 mol%) in NH4OH (0.5 mL, concentrated aqueous solution) was stirred in a sealed tube at 100 °C for 24 h. The mixture was cooled and extracted with DCM (5 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH:(89:10:1)] to give 80 (64 mg, 85%) as a grayish-white solid.

[0258] R f : 0.28 [DCM / MeOH (10% MeOH)];mp:>200℃;FTIR ν max / cm -1 (Net): 3414, 3302, 3211, 2905, 1679, 1642, 1551; 1 H NMR (400 MHz, MeOD, δ H ):5.83 (s, 1H, C3-H),5.51 (s, 1H, C5-H), 4.29-4.02 (m, 3H, C7-H a , C11-H, C12-H), 3.68 (dd, 1H, J =6.5, 14.5 Hz, C7-H b ), 3.34-2.93 (m, 3H, C10-H, C11-H, C12-H), 2.36 (s, 1H,C8-H), 1.98 (s, 2H, C9-H), 1.34-1.24 (m, 9H, Boc); 13 C NMR (100 MHz, MeOD, δ C ):165.2 (CO), 157.7 (CO Boc), 154.7 (C6), 149.0 / 148.8 (C4, rotifer), 99.6 / 99.3 (C3, rotifer), 91.9 (C5), 80.1 / 79.6 (q Boc, rotifer), 51.4 / 50.2 / 50.1 (C11, C12, rotifer), 49.0 (C7), 34.9 (C10), 27.9 / 27.7 (C8, rotifer), 27.0 (3C, Boc), 25.7 (C9);HRMS (ESI) + ): Calculated value C 16 H 24N3O3: 306.1812, measured value [M+H] + : 306.1809.

[0259] Example 16b — (+)4-aminonoindole dihydrochloride (81)

[0260] Following the general process A, N -Boc 4-amino-indigo 80 (1.0 mmol) yielded amine 81 (273 mg, 98%) as a grayish-white solid.

[0261] mp:>200℃;[α] D 25 = +77 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 2929, 2790, 1649, 1533; 1 H NMR (400 MHz, D2O, δH): 6.26 (s, 1H, C3-H), 4.09 (d, 1H, J = 15.0 Hz, C7-H a ), 3.95 (dd, 1H, J = 6.5, 15.0 Hz, C7-H b ), 3.41-3.26 (m, 5H, C10-H, C11-H, C12-H), 2.68 (s, 1H, C8-H), 2.07-1.94 (m, 2H, C9-H), C5-H was not detected due to deuterium exchange; 13 C NMR (100 MHz, D2O, δ C ):160.9 (CO), 159.1 (C4), 148.1 (C6),104.5 (d, J =7.2 Hz, C3), 91.5-91.0 (m, C5), 49.2 (C11 or C12), 48.8 (C7), 48.1 (C11 or C12), 31.2 (C10), 24.5 (C8), 22.5 (C9); HRMS (ESI) + ): Calculated value C 11 H 16 N3O: 206.1288, measured value [M+H] + -2HCl] + : 206.1292.

[0262] Example 17 – (-)4-Fluoronoindole (82)

[0263] At -20°C for 1 minute N -Boc-4-amino-indigo 80 (305 mg, 1.0 mmol) was slowly added to a solution of HF-pyridine complex (70%, 2.0 mL) with tBuONO (0.18 mL, 1.5 mmol). The reaction mixture was stirred at -20 °C for 30 min, then allowed to warm to room temperature for 2 h, and finally heated at 60 °C overnight. The mixture was cooled to 0 °C and quenched to pH 10 with concentrated NH4OH aqueous solution. The mixture was diluted with EtOAC (10 mL) and filtered to remove insoluble salts. The aqueous layer was extracted with EtOAc (4 × 10 mL). The combined organic layers were concentrated under vacuum. The crude material was separated into layers between 3 M HCl (5 mL) and DCM (5 mL). The aqueous layer was washed with DCM (2 × 5 mL), alkalized to pH 10 with concentrated NH4OH, and extracted with DCM (5 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH:(89:10:1)] to give 82 (140 mg, 67%) as a pale yellow solid. Analytical grade sample was obtained by recrystallization in toluene.

[0264] R f : 0.25 [DCM / MeOH (20% MeOH)]; mp: 143-145 ℃ (toluene); [α] D 25 = -92 [c1.0, EtOH];FTIR ν max / cm -1 (Net): 3391, 3289, 3069, 2948, 2898, 2852, 1644, 1552; 1 HNMR (400 MHz, CDCl3, δ H ):6.06 (dd, 1H, J = 2.5, 11.0 Hz, C3-H), 5.87 (dd, 1H, J =2.5, 7.0 Hz, C5-H), 4.04 (d, 1H, J = 15.5 Hz, C7-H a ), 3.83 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b), 3.08-2.95 (m, 4H, C11-H, C12-H), 2.89-2.86 (m, 1H, C10-H), 2.34-2.29 (m, 1H, C8-H), 1.93 (t, 2H, J = 3.0 Hz, C9-H), 1.56 (br s, 1H, NH); 13 C NMR (100 MHz, CDCl3, δ C ):169.9 (d, J = 264.0 Hz, C4), 164.8 (d, J = 19.0 Hz, CO), 153.5 (d, J = 13.5 Hz, C6), 99.6 (d, J = 16.5 Hz, C3), 96.5 (d, J = 26.0Hz, C5), 53.7, 52.9 (C11, C12), 49.8 (C7), 36.0 (d, J = 2.0 Hz, C10), 27.5(C8), 26.2 (C9); 19 F NMR (376 MHz, CDCl3, δ F ): - 99.6 (m); HRMS (ESI) + ): Calculated value C 11 H 14 FN2O: 209.1090, measured value [M+H] + 209.1095. Analysis and calculation of C. 11 H 13 FN2O: Theoretical values ​​C = 63.45, H = 6.29, N = 13.45, measured values ​​C = 63.05, H = 6.33, N = 13.20.

[0265] Example 18a—— N -Boc 4-( N -Methamido)noindine (83)

[0266] Will NA mixture of 369 mg (1.0 mmol) of 4-bromo-indigo 61 and copper (7 mg, 10 mol%) in 40% MeNH2 aqueous solution (2.0 mL) was stirred in a sealed tube at 100 °C for 24 h. The mixture was cooled to room temperature and extracted with DCM (5 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by rapid chromatography on silica gel [DCM / MeOH (94:6)] to give 83 (274 mg, 86%) as a grayish-white solid.

[0267] R f : 0.58 [DCM / MeOH (10% MeOH)]; mp: 198-200 ℃ (toluene); FTIR ν max / cm -1 (Net): 3266, 2928, 1684, 1641, 1571; 1 H NMR (400 MHz, CDCl3, δ H ):5.49 (s, 1H, C3-H),5.37 (s, 1H, C5-H), 4.53 (s, 1H, NH), 4.28-4.03 (m, 3H, C7-H a , C10-H, C12-H), 3.72 (dd, 1H, J = 6.5, 15.0 Hz, C7-H b ), 3.02-2.70 (m, 6H, C10-H, C11-H, C12-H,C14-H), 2.31 (s, 1H, C8-H), 1.93-1.81 (m, 2H, C9-H), 1.32-1.22 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ C):164.7 (CO), 156.0 (CO Boc), 154.8 / 154.5 (C6, rotatable isomer), 147.9 / 147.3 (C4, rotatable isomer), 98.0 / 97.2 (C3, rotatable isomer), 90.4 / 90.1 (C5, rotatable isomer), 80.2 / 79.6 (q Boc, rotatable isomer), 51.7 / 50.7 / 50.4 / 49.4 (C11, C12, rotatable isomer), 47.9 (C7), 34.8 (C10), 29.4 (C14), 28.1 (3C, Boc), 27.6 (C8), 26.4 (C9);HRMS (ESI) + ): Calculated value C 17 H 26 N3O3: 320.1969, measured value [M+H] + : 320.1974.

[0268] Example 18b——(+)4-( N -Methylamino)indigo dihydrochloride (84)

[0269] Following the general process A, 4- N -methylamino- N -Boc-indigo 83 (0.77 mmol) yielded amine 84 (190 mg, 85%) as a colorless solid.

[0270] mp: >200℃, colorless powder; [α] D 25 = +66 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 3240, 2939, 2714, 2583, 1644, 1557; 1 H NMR (400 MHz, D2O, δ H ):6.25 (s, 1H, C3-H),4.09 (d, 1H, J = 15.0 Hz, C7-H a ,), 3.95 (dd, 1H, J = 6.5, 15.0 Hz, C7-H b), 3.42-3.26 (m, 5H, C10-H, C11-H, C12-H), 2.71 (s, 4H, C8-H, C14-H), 2.05-1.94 (m, 2H, H9), C5-H was not detected due to deuterium exchange; 13 C NMR (100 MHz, D2O, δ C ):160.7 (C0),158.7 (C4), 147.1 (C6),103.6 (C3), 88.4-87.9 (C5), 49.3 (C11 or C12), 48.7 (C7), 48.1 (C11 or C12), 31.3 (C10), 28.5 (C14), 24.5 (C8), 22.6 (C9);HRMS (ESI) + ): Calculated value C 12 H 18 N3O: 220.1444, measured value [M+H-2HCl] + :220.1441.

[0271] Example 19a—— N -Boc 4-( N , N’ -Dimethylamino)indigoline (85)

[0272] Will N A mixture of 4-Boc-4-bromo-indigo 61 (369 mg, 1.0 mmol) and copper (6 mg, 10 mol%) in 40% Me₂NH aqueous solution (2.0 mL) was stirred in a sealed tube at 100 °C for 24 h. The mixture was cooled, diluted with 35% ammonia (2 mL), and the aqueous phase was extracted with DCM (5 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH / NH₄OH:(94.5:5:0.5)] to give 85 (212 mg, 64%) as a white foam.

[0273] R f : 0.19 [DCM / MeOH (10% MeOH)];FTIR ν max / cm -1 (Net): 2972, 2928, 2863, 1687, 1645, 1578; 1 H NMR (400 MHz, CDCl3, δ H):5.64 (d, 1H, J = 2.5 Hz, C3-H),5.42 (s, 1H, C5-H), 4.31-4.04 (m, 3H, C7-H a , C11-H, C12-H), 3.73 (dd, 1H, J =6.5, 15.0 Hz, C7-H b ), 3.04-2.81 (m, 9H, C10-H, C11-H, C12-H, 2 x C14-H), 2.31(s, 1H, C8-H), 1.94-1.83 (m, 2H, C9-H), 1.32-1.19 (m, 9H, Boc); 13 C NMR (100MHz, CDCl3, δ C ):164.2 (CO), 156.0 (CO Boc), 154.8 / 154.4 (C4, rotifer), 147.9 / 147.5 (C6, rotifer), 95.6 / 95.1 (C3, rotifer), 91.9 / 91.5 (C5, rotifer), 80.2 / 79.5 (q Boc, rotifer), 51.8 / 50.7 / 50.4 / 49.3 (C11, C12, rotifer), 47.8 (C7), 39.3 (2C, C14), 35.2 (C10), 28.1 (3C, Boc), 27.5 (C8), 26.5 (C9);HRMS (ESI) + ): Calculated value C 18 H 28 N3O3: 334.2125, measured value [M+H] + :334.2113.

[0274] Example 19b——(+)4-( N, N '-Dimethylamino)indole dihydrochloride (86)

[0275] Following the general process A, N -Boc-4-N,N'-dimethylamino)indole 85 (202 mg, 0.61 mmol) yielded amino 86 (174 mg, 93%) as a colorless solid.

[0276] mp: >200℃, colorless powder; [α] D 25= +84 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 3202, 2960, 2753, 1644, 1551; 1 H NMR (400 MHz, D2O, δ H ):6.41 (s, 1H, C3-H), 4.12 (d,1H, J = 15.0 Hz, C7-H a ), 3.98 (dd, 1H, J = 6.5, 15.0 Hz, C7-H b ), 3.42-3.27 (m, 5H, C10-H, C11-H, C12-H), 2.96 (s, 6H, C14-H), 2.68 (s, 1H, C8-H), 2.07-1.96 (m, 2H, C9H), H5 was not detected due to deuterium exchange; 13 C NMR (100 MHz, D2O, δ C ):159.8 (CO),157.4 (C4), 147.1 (C6),102.5 (d, J = 5.0 Hz, C3), 89.0-88.5 (m, C5), 49.3 (C11 or C12), 48.7 (C7), 48.1 (C11 or C12), 39.1 (2C, C14), 31.5 (C10), 24.5 (C8), 22.6 (C9); HRMS (ESI) + ): Calculated value C 13 H 20 N3O[M+H-2HCl] + : 234.1601, measured value: 234.1606.

[0277] Example 20a—— N -Boc 4-( N -benzoylamino)indigoline (95)

[0278] Towards N -Boc-4-bromo-indigo 61 (369 mg, 1.0 mmol), CuI (19 mg, 10 mol%), benzamide (145 mg, 1.2 mmol) and K2CO3 (276 mg, 2.0 mmol) were added to a mixture in anhydrous toluene (5.0 mL).N, N '-Dimethylethylenediamine (11 μL, 10 mol%). The mixture was heated at 110 °C for three days. After cooling, the mixture was diluted with H2O (10 mL), and the aqueous phase was extracted with DCM (5 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH:(95:5:0.1)] to give 95 (425 mg) as a yellow solid. The obtained solid was washed overnight in boiling toluene (10 mL) to give 95 (372 mg, 91%) as a colorless solid.

[0279] R f : 0.49 [DCM / MeOH (10% MeOH)];mp:>200℃, colorless powder;FTIR ν max / cm -1 (Net): 3067, 2972, 2864, 1648, 1626, 1548, 1483; 1 H NMR (400 MHz, CDCl3, δ H :7.74-7.72 (m, 2H, C17-H), 7.40-7.28 (m, 3H, C18-H, C19-H), 7.06 / 6.75 (2 br s, 2 x 0.5H, C3-H, rotatimer), 6.62 / 6.33 (2 br s, 2 x 0.5H, C5-H, rotatimer), 4.08-3.94 (m, 4H, NH, C7-H) a , C11-H, C12-H), 3.61 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.16-2.91 (m, 3H, C10-H, C11-H, C12-H), 2.27 (s, 1H, C8-H), 1.83 (s, 2H, C9-H), 1.16-1.05 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ C): 167.5 (C14), 164.5 (CO), 154.5 (CO Boc), 149.5, 148.8 (C6, C4), 133.9 (C16), 131.9 (C19), 128.2 (C17, C21), 127.4 (C18, C20), 102.2 / 101.9 (C3, rotatimer), 101.2 (C5), 80.5 / 79.9 (q Boc, rotatimer), 51.3 / 50.3 / 50.1 / 49.1 / 48.9 / 48.7 / 48.5 / 48.4 / 48.2 / 48.0 / 47.8 (C7, C11, C12, rotatimer), 34.8 (C10), 27.5 (3C, Boc), 27.2 (C8), 25.7 (C9);HRMS (ESI + ): Calculated value C 23 H 28 N3O4: 410.2074, measured value [M+H] + 410.2064, calculated value C 23 H 27 N3NaO4: 432.1894, measured value [M+Na] + : 432.1884.

[0280] Example 20b——(+)4-( N -benzoylamino)indigo hydrochloride (96)

[0281] Following the general process B, N -Boc-4-( N ⁻benzamide)-indigo 95 (363 mg, 0.89 mmol) yielded benzamide 96 (290 mg, 80%) as a colorless solid.

[0282] mp: >200℃, colorless powder; [α] D 26 = +30 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2937, 2798, 1677, 1633, 1599; 1 H NMR (400 MHz, D2O, δ H ):7.55 (d, 2H, J= 7.5 Hz, C17-H, C21-H), 7.45-7.42 (m, 1H, C19-H), 7.32-7.28 (m, 2H, C18-H, C20-H), 6.76(d, 1H, J = 2.0 Hz, C3-H), 6.62 (d, 1H, J = 2.0 Hz, C5-H), 3.96 (d, 1H, J = 15.5Hz, C7-H a ), 3.70 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.39-3.23 (m, 5H, C10-H,C11-H, C12-H), 2.64 (s, 1H, C8-H), 1.96 (d, 1H, J = 13.5 Hz, C9-H), 1.76 (d, 1H, J = 13.5 Hz, C9-H); 13 C NMR (100 MHz, D2O, δ C ):169.1 (C14), 164.6 (C0),149.2 (C4), 147.6 (C6), 133.0 (C19), 132.6 (C16), 128.7 (C18, C20), 127.5 (C17, C21), 104.1 (C5), 102.8 (C3), 49.2 (C11 or C12), 48.6 (C7), 48.2 (C11 or C12), 31.5 (C10), 24.6 (C8), 22.5 (C9);HRMS (ESI) + ): Calculated value C 18 H 20 N3O2: 310.1550, measured value [M+H-HCl] + : 310.1549.

[0283] Example 21a—— N -Boc 4-( N -Acetamido)Indigoline (93)

[0284] Towards N-Boc-4-bromo-indigo 61 (369 mg, 1.0 mmol), CuI (19 mg, 10 mol%), acetamide (70 mg, 1.2 mmol), and K2CO3 (276 mg, 2.0 mmol) were added to a mixture in anhydrous toluene (5.0 mL). N,N '-Dimethylethylenediamine (11 μL, 10 mol%). The mixture was heated at 110 °C for 24 h. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and then extracted with DCM (5 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH:(95:5:0.1)] to give 93 (340 mg, 98%) as a pale yellow foam with very minor impurities. This product was used in the next step without further purification.

[0285] R f : 0.49 [DCM / MeOH (10% MeOH)];FTIR ν max / cm -1 (Net): 2971, 2929, 1688, 1644, 1556, 1422; 1 H NMR (400 MHz, CDCl3, δ H :7.11 / 6.74 (2x s, 1H, C3-H, rotiferous isomer), 6.58 / 6.23 (2 xs, 1H, H5, rotiferous isomer), 4.34-4.12 (m, 3H, C7-H) a , C11-H, C12-H), 3.77 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.04-2.97 (m, 3H, C10-H, C11-H, C12-H), 2.51 (s, 1H, C8-H), 2.09 (s, 3H, C16-H), 2.01-1.89 (m, 2H, C9-H), 1.33-1.21 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ C):170.2 (C15), 164.4 (CO), 154.8 / 154.5 (CO Boc, rotatimer), 148.5, 148.3 (C6, C4), 101.9 (C3), 100.4 (C5), 80.7 / 79.6 (q Boc, rotatimer), 51.6 / 50.7 / 50.5 / 49.3 (C11, C12, rotatimer), 48.6 (C7), 35.0 (C10), 28.1 (3C, Boc), 27.5 (C8), 26.2 (C9), 24.6 (C16);HRMS (ESI) + ): Calculated value C 18 H 26 N3O4: 348.1918, measured value [M+H] + : 348.1916, C 18 H 25 N3NaO4: 370.1737, measured value [M+Na] + : 370.1737.

[0286] Example 21b——(+)4-( N -Acetamido)Indigoline (94)

[0287] Following the general process B, N -Boc-4-( N 93 (306 mg, 0.88 mmol) of acetamide-indigo alkaloid yielded 94 (250 mg, quantified) as a pale yellow solid.

[0288] mp: >200℃, colorless powder; [α] D 25 = +30 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2457, 2374, 1612, 1530, 1506; 1 H NMR (400 MHz, D2O, δ H ):6.79 (d, 1H, J = 2.0 Hz, C3-H), 6.64 (d, 1H, J = 2.0 Hz, C5-H), 4.04 (d, 1H, J = 15.5 Hz, C7-H a ), 3.88 (dd,1H, J= 6.5, 15.5 Hz, C7-H b ), 3.40-3.25 (m, 5H, C10-H, C11-H, C12-H), 2.70 (s,1H, C8-H), 2.05-1.91 (m, 5H, C9-H, C16-H); 13 C NMR (100 MHz, D2O, δ C ):173.6 (C15), 164.5 (C0), 149.4 (C4), 148.1 (C6), 104.4 (C5), 101.7 (C3), 49.2 (C11 or C12), 48.8 (C7), 48.1 (C11 or C12), 31.5 (C10), 24.6 (C8), 23.6 (C16), 22.5 (C9);HRMS (ESI) + ): Calculated value C 13 H 18 N3O2: 248.1394, measured value [M+H-HCl] + : 248.1394.

[0289] Example 22——(+)4- N - Morpholinoindocyanine dihydrochloride (92)

[0290] Inject into the sealed tube N -Boc-4-bromo-indigo 61 (370 mg, 1.0 mmol), copper(II) (15 mg, 0.1 equivalent), and morpholine (0.4 mL, 5 equivalent) were added, and the reaction mixture was dissolved in water (2.0 mL, 0.5 M) and heated in air at 100 °C for 18 h. The reaction mixture was cooled to room temperature, and the aqueous phase was extracted with DCM (4 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The obtained solution was processed using general procedure A. N -Boc-protected indigo derivatives were deprotected and converted to HCl salts, yielding 92 (180 mg, 85%) as a colorless solid.

[0291] mp: >200℃, colorless powder; [α] D 25 = +61 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 2560, 1641, 1541; 1 H NMR (500 MHz, D2O, δH ):6.48 (s, 1H, C3-H), 4.09 (d, 1H, J = 16.0Hz, C7-H), 3.96 (dd, 1H, J = 16.0, 5.5 Hz, C7-H), 3.74 (s, 4H, C11-H, C12-H), 3.39 (m, 9H, CH2morpholine, C10-H), 2.71 (s, 1H, C8-H), 2.04 (m, 2H, C9-H); C5-H is invisible due to H-solvent exchange; 13 C NMR (125 MHz, D2O, δ C ):162.5 (CO), 157.9 (C6), 147.4(C4), 101.6 (C3), 91.7 (C5), 65.8 (2C, C15), 49.4, 48.2 (C11, C12), 48.4(C7), 45.7 (2C, C16), 31.7 (C10), 24.6 (C8), 22.7 (C9);HRMS (ESI + ): Calculated value C 15 H 22 N3O2: 276.1707, measured value [M+H-HCl] + :276.1718.

[0292] Example 23a—— N -Boc 4-( N -( L -proline methyl ester) indigoline (136)

[0293] Will N A mixture of -Boc 4-bromoindocyanine 61 (369 mg, 1.0 mmol), L-proline methyl ester hydrochloride (198 mg, 1.2 mmol), Cs₂CO₃ (814 mg, 2.5 mmol), Pd(OAc)₂ (11 mg, 5 mol%), and (±)-BINAP (44 mg, 7 mol%) in anhydrous toluene (5.0 mL) was stirred at 100 °C for 48 h. The mixture was cooled to room temperature and analyzed by Celite. ®The crude material was filtered through a short slab, washed with EtOAc, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH:(95:5:0.1)] to give 136 (371 mg, 89%) as a grayish-white foam with very few impurities.

[0294] R f : 0.11 [DCM / MeOH (5% MeOH)]; 1 H NMR (400 MHz, CDCl3, δ H ):5.55 (s, 1H, C3-H), 5.28 (s, 1H, C5-H), 4.27-4.02 (m, 4H, C7-H a , C11-H, C12-H, C15-H),3.73-3.67 (m, 4H, C7-H b , C20-H), 3.48 (s, 1H, C18-H), 3.36 (s, 1H, C18-H), 3.00-2.85 (m, 3H, C10-H, C11-H, C12-H), 2.31-2.16 (m, 2H, C18-H, C16H), 2.08-1.99 (m, 3H, C16-H, C17-H), 1.91-1.81 (m, 2H, C9-H), 1.31-1.18 (m, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C ): 173.3 (C19), 164.0 (CO), 154.7 / 154.4 (CO Boc, rotatable isomer), 153.0 (C4), 148.6 / 148.2 (C6, rotatable isomer), 96.2 / 95.5 (C3, rotatable isomer), 92.3 (C5), 80.2 / 79.6 (q Boc, rotatable isomer), 60.0 (C15), 52.3 (C20), 50.7 / 50.6 / 50.4 / 49.4 (C11, C12, rotatable isomer), 47.9 (C18), 47.8 (C7), 35.1 (C10), 30.6 (C16), 28.1 (3C, Boc), 27.5 (C8), 26.3 (C9), 23.5 (C17);HRMS (ESI + ): Calculated value C 22 H 32 N3O5: 418.2336, measured value [M+H]+ 418.2340, calculated value C 22 H 31 N3NaO5: 440.2156, measured value [M+Na] + : 440.2161.

[0295] Example 23b——(+)4-( N -( L 137) Proline methyl ester) Indigo dihydrochloride

[0296] Following the general process B, N -Boc-4-( N -( L 136 (0.88 mmol) of indigo ester (proline methyl ester) yielded 137 (304 mg, 89%) as a colorless solid.

[0297] mp: >200 ℃, colorless powder; [α] D 26 = +2 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2951, 2714, 2385, 1740, 1637, 1538, 1484; 1 H NMR (400 MHz, D2O, δ H ):6.38 (s, 1H, C3-H), 4.62 (s, 1H, C15-H), 4.25 (d, 1H, J = 15.0 Hz, C7-H a ), 4.12 (dd, 1H, J =6.5, 15.5 Hz, C7-H b ), 3.79 (s, 3H, C20-H), 3.60-3.40 (m, 7H, C10-H, C11-H, C12-H, C18-H), 2.82 (s, 1H, C8-H), 2.43-2.26 (m, 2H, C16-H), 2.18-1.99 (m, 4H, C14-H, C17-H), H3 was not detected due to deuterium exchange; 13 C NMR (100 MHz, D2O, δ C): 174.6 (C19), 160.9 (C6), 155.2 (C4), 147.8 (C6), 102.9 (C3), 60.5 (C15), 53.2 (C20), 49.3, 48.7, 48.6, 48.0 (C7, C11, C12, C18), 31.4 (C10), 30.1 (C16), 24.5 (C8), 23.0 (C17), 22.5 (C20), C3 not detected due to deuterium exchange; HRMS (ESI) + ): Calculated value C 17 H 24 N3O3: 318.1812, measured value [M+H-2HCl] + : 318.1802.

[0298] Example 24——(-)4-( N -( L 138) Proline indigo dihydrochloride

[0299] Will N A mixture of 138 (341 mg, 0.82 mmol) in HCl (37% in water, 8.2 mL) was heated under reflux for 48 h. The mixture was cooled to room temperature and concentrated under vacuum. The crude material was dissolved in MeOH (4 mL) and then acetone (40 mL) was slowly added. The resulting suspension was stirred for 1 h. The solid was filtered off, washed with acetone, and dried under vacuum to give 138 (261 mg, 85%) as a light brown solid.

[0300] mp: >200℃, colorless powder; [α] D 26 = -32 [c 0.5, water];FTIR ν max / cm -1 (Net): 2908, 2754, 2583, 1719, 1640, 1546; 1 H NMR (400 MHz, D2O, δ H ):6.28 (s, 1H, C3-H), 4.51 (s, 1H, C15-H), 4.21 (d, 1H, J = 15.0 Hz, C7-H a ,), 4.07 (dd, 1H, J = 6.5, 15.0 Hz, C7-Hb ), 3.59-3.39 (m, 7H, C10-H, C11-H, C12-H, C18-H), 2.81 (s, 1H, C8-H), 2.46-2.36 (m, 1H, C16-H), 2.28-2.22 (m, 1H, C16-H), 2.17-2.01 (m, 4H, C14-H, C17-H), H5 was not detected due to deuterium exchange; 13 C NMR (100 MHz, D2O, δ C ):176.1 (C19),160.8 (CO), 155.2 (C4), 147.8 (C6), 102.8 (C3), 60.6 (C15), 49.3, 48.8, 48.6,48.0 (C7, C11, C12, C18), 31.4 (C10), 30.3 (C16), 24.5 (C8), 23.0 (C17), 22.5 (C9), C3 not detected; HRMS (ESI) + ): Calculated value C 16 H 22 N3O3[M+H-2HCl] + : 304.1656, measured value: 304.1651.

[0301] Example 25a—— N -Boc 4-(carboxymethyl)indigoline (119)

[0302] Will N A solution of Boc-4-bromo-indigo 61 (369 mg, 1.0 mmol), Et3N (0.4 mL, 2.5 mmol), dppp (82 mg, 0.2 mmol), and Pd(OAc)2 (45 mg, 0.2 mmol) in DMF / MeOH (1:1) (5 mL) was stirred at 80 °C under 1 atm CO for 24 h. The mixture was cooled to room temperature and analyzed by Celite. ® The mixture was filtered and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [EtOAc] to give 119 (300 mg, 86%) as a yellow foam.

[0303] R f : 0.25 [EtOAc];FTIR ν max / cm -1(Net): 2931, 1683, 1657, 1575, 1547; 1 HNMR (400 MHz, CDCl3, δ H ):7.00 (s, 1H, C3-H), 6.54 (s, 1H, C5-H), 4.31-4.06 (m,3H, C7-H a , C11-H, C12-H), 3.85 (s, 3H, Me), 3.79 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.14-2.88 (m, 3H, C10-H, C11-H, C12-H), 2.41 (s, 1H, C8-H), 1.98-1.91(m, 2H, C9-H), 1.28-1.15 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ C ): 165.4 (C14), 163.2 (CO), 154.32 (CO Boc), 150.0 / 149.5 (C4, rotatimer) 139.5 (C6), 118.4 (C3), 104.1 / 103.5 (C5, rotatimer), 80.4 / 79.9 (q Boc, rotatimer), 52.7 (C7), 51.5 / 50.5 / 50.3 (C11, C12, rotatimer), 49.2 (Me), 35.0 (C10), 28.0 (3C, Boc), 27.4 (C8), 26.0 (C9); HRMS (ESI) + ): Calculated value C 18 H 25 N₂O₅: 349.1758, measured value [M+H] + : 349.1750.

[0304] Example 25b — (-)4-carboxymethyl indigo (120)

[0305] Towards N-Boc-4-methyl-ester-indigo 119 (95 mg, 0.27 mmol) was added to a solution of TFA (0.21 mL, 2.7 mmol) in DCM (1.3 mL). The mixture was stirred for 24 h and then concentrated under vacuum. The crude material separated into layers between HCl 3M (5 mL) and DCM (5 mL). The aqueous layer was washed with DCM (2 × 5 mL), alkalized to pH 9 with Na₂CO₃, and then extracted with DCM (5 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to give 120 (55 mg, 81%) as a grayish-white solid. Analytical grade sample was obtained by recrystallization in toluene.

[0306] R f : 0.23 [DCM / MeOH (10% MeOH)]; mp: 141-142℃, (toluene); [α] D 25 = -96 [c 0.3, water]; FTIR ν max / cm -1 (Net): 3300, 2926, 2893, 2847, 1719 (w), 1648, 1571; 1 H NMR (400MHz, CDCl3, δ H ):7.02 (d, 1H, J = 1.5 Hz, C3-H), 6.49 (d, 1H, J = 1.5 Hz, C5-H), 4.08 (d, 1H, J = 15.5 Hz, C7-H a ), 3.88 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.87(s, 3H, Me), 3.08-2.95 (m, 5H, C10-H, C11-H, C12-H), 2.33 (s, 1H, C8-H), 1.97-1.90 (m, 2H, C9-H), 1.50 (s, 1H, NH); 13 C NMR (100 MHz, CDCl3, δ C):165.6(COOMe), 163.4 (CO), 151.9 (C6), 139.4 (C4), 118.0 (C3), 103.3 (C5), 53.8,52.9 (C12, C11), 52.7 (Me), 50.2 (C7), 35.8 (C10), 27.7 (C8), 26.2 (C9);HRMS(ESI + ): Calculated value C 13 H 17 N₂O₃: 249.1234, measured value [M+H] + :249.1245.

[0307] Example 26 – (-)4-carboxylic acid indigo base hydrochloride (229)

[0308] Will N A solution of 119 (263 mg, 0.75 mmol) of 4-methyl-ester-indigo 119 in HCl (37% aqueous solution, 7.5 mL) was heated under reflux for 24 h. The mixture was cooled to room temperature and then concentrated under vacuum. The crude reaction mixture was dissolved in MeOH (30 mL) and then acetone (300 mL) was slowly added. The resulting suspension was stirred for 1 h. The solid was filtered off, washed with acetone, and dried under vacuum to give 229 (164 mg, 81%) as a colorless solid.

[0309] mp: >200℃, colorless powder; [α] D 22 = -33 [c 0.3, water];FTIR ν max / cm -1 (Net): 1698, 1648, 1543, 1471; 1 H NMR (400 MHz, D2O, δ H ):6.88 (s, 1H, C3-H), 6.79 (s, 1H,C5-H), 4.06 (d, 1H, J = 15.5 Hz, C7-H a ), 3.91 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ),3.44-3.27 (m, 5H, C10-H, C11-H, C12-H), 2.75 (s, 1H, C8-H), 2.08-1.96 (m, 2H,C9-H);13 C NMR (100 MHz, D2O, δ C ):167.7 (COOH), 164.8 (CO), 148.0 (C6), 142.1 (C4), 118.1 (C3), 107.8 (C5), 49.4 (C11 or C12), 49.0 (C7), 48.2 (C11 or C12), 31.7 (C10), 24.7 (C8), 22.5 (C9);HRMS (ESI) + ): Calculated value C 12 H 15 N₂O₃: 235.1077, measured value [M+H-HCl] + :235.1078.

[0310] Example 27a—— N -Boc 4-(hydroxymethyl)noindole (121)

[0311] During a 5-minute period at -78°C, N Boc-4-methyl ester-indigo 119 (350 mg, 1.00 mmol) was added dropwise to a solution of Boc-4-methyl ester-indigo 119 in THF (4 mL) with LiAlH4 (1.0 M in Et2O) and the reaction mixture was stirred for 3.5 h. EtOAc (2 mL) was added dropwise, followed by a saturated Rochelle salt solution (10 mL). The reaction mixture was stirred for 30 min, and the aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated. Purification by rapid column chromatography [DCM / MeOH (2% MeOH to 5% MeOH)] yielded 121 (194 mg, 62%) as a colorless foam.

[0312] mp: 201-203 ℃, colorless solid (toluene); 1 H NMR (500 MHz, CDCl3, δ H ):6.49 (s, 1H,C3-H), 6.16 (s, 1H, C5-H), 4.55 (s, 2H, C14-H), 4.28-4.16 (m, 3H, C7-H, C11-H, C12-H), 3.86 (dd, 1H, J= 6.5, 16.0 Hz, C7-H), 3.19-2.92 (m, 3H, C11-H, C12-H, C10-H), 2.45 (s, 1H, C8-H), 1.99 (m, 2H, C9-H), 1.41-1.18 (m, 9H, Boc). 13 CNMR (125 MHz, CDCl3, δ C ): 163.5 (CO), 154.6 (C6), 153.5 (C4), 112.7 (C3), 104.5 (C5), 80.6, 80.5 (C11, C12), 63.2 (C13), 48.8 (C7), 34.9 (C8), 28.0 (3C,Boc), 27.6 (C10), 26.2 (C9). No quaternary carbon atoms of the boc group were found.

[0313] Example 27b — (-)4-(hydroxymethyl)noindole hydrochloride (122)

[0314] Following the general process A, N -Boc 4-hydroxymethylindocyanine 121 (0.60 mmol) yields alcohol 122 (120 mg, 90%) as a colorless solid.

[0315] mp: >200℃, colorless solid; [α] D 23 = -24 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 3292,2726, 2323, 1643, 1571; 1 H NMR (500 MHz, D2O, δ H ):6.50 (s, 1H, C3-H), 6.47 (s,1H, C5-H), 4.50 (s, 2H, C14-H), 4.10 (d, 1H, J = 15.0 Hz, C7-H), 3.96 (dd, 1H, J = 15.0, 6.0 Hz, C7-H), 3.48-3.31 (m, 5H, C11-H C12-H C10-H), 2.77 (s, 1H, C8-H), 2.11-1.99 (m, 2H, C9-H); 13 C NMR (125 MHz, D2O, δC ):164.8 (CO), 156.1 (C4),147.0 (C6), 112.5 (C3), 108.4 (C5), 61.5 (C13), 49.6 (C7), 48.5, 48.3 (C11,C12), 31.5 (C10), 24.7 (C8), 22.6 (C9) ;m / z (ESI + ):224 [M+H-HCl] + HRMS (ESI) + ): Calculated value C 12 H 16 N₂O₂: 224.1757, measured value [M+H-HCl] + : 224.1758.

[0316] Example 28a—— N -Boc 4-(4-(trifluoromethyl)benzyl)oxynodine (123)

[0317] NaH (33 mg, 1.1 equivalents, 60% dispersion in mineral oil) was added to a solution of ethanol 121 (240 mg, 0.75 mmol) in anhydrous THF (7.5 mL), and the mixture was stirred at 0 °C. After 30 min, TBAI (14 mg, 0.05 equivalents) and 4-(trifluoromethyl)benzyl bromide (358 mg, 2 equivalents) were added. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched with water (10 mL) and the aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (1% MeOH)] to give 123 (250 mg, 71%) as a colorless solid, which was used in the next step without further purification.

[0318] FTIR ν max / cm -1 (Net): 2975, 2931, 2864, 1686, 1660, 1545; 1 H NMR (500 MHz, CDCl3, δ) H ):7.60 (d, 2H, J = 8.5 Hz, C18-H), 7.46 (d, 2H, J = 8.5 Hz, C17-H), 6.42(s, 1H, C3-H), 6.06 (d, 1H,J = 1.5 Hz, C5-H), 4.58 (s, 2H, CH2), 4.37 (s, 2H,CH2), 4.26-4.08 (m, 3H, C7-H, C11-H, C12-H), 3.80 (dd, 1H, J = 15.0, 6.5 Hz,C7-H), 3.13-2.89 (m, 3H, C10-H, C11-H, C12-H), 2.40 (s, 1H, C8-H), 1.95 (m,2H, C9-H), 1.39-1.12 (s, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C ):163.4 (CO),154.6 (CO), 149.9 (C4), 148.5 (C6), 141.7 (CF3), 129.3 (q, J = 33.8 Hz (Ar), 127.7 (2C, Ar), 125.4 (2C, Ar), 123.3 (Ar), 114.2 (C3), 104.5 / 103.7 (C5 rotomer), 80.4 / 79.4 (q Boc rotomer), 71.5 (CH2), 70.5 (CH2), 51.6 / 50.6 / 50.5 / 49.3 (C11, C12 rotomer), 48.8 (C7), 34.9 (C10), 28.1 (3C, Boc), 27.5 (C8), 26.2 (C9); HRMS (ESI) + ): Measured value [M+H] + 479.2142, calculated value C 25 H 30 F3N2O4: 479.2152.

[0319] Example 28b — (-)4-(4-(trifluoromethyl)benzyl)oxynodine (124)

[0320] Ester 123 (0.25 g, 0.52 mmol) was converted to HCl salt using general process A to give 124 (110 mg, 60%) as a colorless solid.

[0321] mp: >200℃, colorless solid; [α] D 25 = -18 [c 1.0, MeOH];FTIR νmax / cm -1 (Net): 2974, 2930, 1687, 1658, 1545, 1421; 1 H NMR (500 MHz, D2O, δ H ):7.65 (d, 2H, J = 9.0 Hz, Ar), 7.50 (d, 2H, J = 9.0, Ar), 6.47 (s, 1H, C3-H), 6.45 (s, 1H, C5-H), 4.64(s, 2H, CH2), 4.48 (s, 2H, CH2), 4.07 (d, 1H, J =15.0 Hz, C7-H), 3.92 (dd, 1H, J =15.0, 6.0 Hz, C7-H), 3.47-3.28 (m, 5H, C10-H, C11-H, C12-H), 2.76 (s, 1H, C8-H), 2.07 (d, 1H, J = 13.5 Hz, C9-H), 1.99 (d, 1H, J = 13.5 Hz, C9-H); 13 C NMR (125MHz, D2O, δ C ):164.8 (CO), 152.4 (C4), 146.9 (C6), 141.2 (CF3), 129.6 (q, J = 30Hz, C-CF3), 128.7 (2C, Ar), 125.4 (2C, Ar), 123.4 (Ar), 114.4 (C3), 108.7(C5), 72.1 (CH2), 70.0 (CH2), 49.5, 48.3 (C11, C12), 48.6 (C7), 31.5 (C10), 24.8 (C8), 22.6 (C9); 19 F NMR (376 MHz, D2O, δ F ):-63.2(s);HRMS (ESI + ): Calculated value C 20 H 22 F3N2O2: 379.1628, measured value [M+H + -HCl] + : 379.1623.

[0322] Example 29a—— N -Boc 4-methylnoindoline (109)

[0323] Towards N Me4Sn (0.35 mL, 2.5 mmol) was added to a mixture of Boc-4-bromo-indigo 61 (369 mg, 1.0 mmol) and PdCl2(PPh3)2 (35 mg, 5 mol%) in anhydrous toluene (5.0 mL). The mixture was stirred at 100 °C under N2 for 24 h. The mixture was cooled to room temperature and analyzed by Celite. ® The mixture was filtered, washed with EtOAc (50 mL), and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH (97:3)] to give 109 (308 mg, quantified) of a pale yellow solid with very few impurities.

[0324] R f : 0.26 [DCM / MeOH (5% MeOH)]; 1 H NMR (400 MHz, CDCl3, δ H ):6.19 (s, 1H, C3-H), 5.87 (s, 1H, C5-H), 4.30-4.06 (m, 3H, C7-H a , C11-H, C12-H), 3.74 (dd, 1H, J = 6.5, 15.5 Hz, C 7 - H b ), 3.06-2.90 (m, 3H, C10-H, C11-H, C12-H), 2.35 (s,1H, C8-H), 2.09 (s, 3H, Me), 1.94-1.85 (m, 2H, C9-H), 1.29-1.16 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ C):163.5 (CO), 154.7 / 154.3 (CO Boc, rotifer), 150.4 / 149.8 (C4, rotifer), 148.0 / 147.5 (C6, rotifer), 116.0 (C3), 108.3 / 107.6 (C5, rotifer), 80.4 / 79.7 (q Boc, rotifer), 51.8 / 50.7 / 50.5 / 49.4 (C11, C12, rotifer), 48.6 (C7), 34.8 (C10), 28.1 (3C, Boc), 27.6 (C8), 26.3 (C9), 21.2 (Me);HRMS (ESI) + ): Calculated value C 17 H 25 N₂O₃: 305.1860, measured value [M+H] + 305.1864, Calculated value C 17 H 24 N₂NaO₃: 327.1679, measured value [M+Na] + : 327.1684.

[0325] Example 29b — (-)4-methylindigo hydrochloride (110)

[0326] Following the general process A, N -Boc 4-methylindocyanine 109 (1.40 mmol) yielded 110 (337 mg, quantified) as a colorless solid.

[0327] mp: >200℃, colorless powder; [α] D 26 = -28 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2714, 2604, 2038, 1727, 1643, 1567; 1 H NMR (400 MHz, D2O, δ H ):6.67 (s, 1H, C3-H),6.59 (s, 1H, C5-H), 4.21 (d, 1H, J = 15.5 Hz, C7-H a ,), 4.07 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b), 3.52-3.37 (m, 5H, C10-H, C11-H, C12-H), 2.83 (s, 1H, C8-H), 2.27 (s, 3H, Me), 2.16-2.13 (m, 2H, C9-H); 13 C NMR (100 MHz, D2O, δ C ): 163.3 (C6), 156.0 (C4), 146.5 (C6), 114.6 (C3), 114.5 (C5), 49.3 (C11 or C12), 49.0 (C7), 48.1 (C11 or C12), 31.2 (C10), 24.7 (C8), 22.4 (C9), 20.4 (Me); HRMS (ESI) + ): Calculated value C 12 H 17 N2O: 205.1335, measured value [M+H + -HCl] + : 205.1336.

[0328] Example 30a——(-) N -Boc 4-vinylindocyanine (115)

[0329] Will N A mixture of -Boc-4-bromo-indigo 61 (369 mg, 1.0 mmol), 2,4,6-trivinylcycloboroxane pyridine complex (194 mg, 1.2 mmol), K₂CO₃ (276 mg, 2.0 mmol), and PdCl₂(PPh₃)₂ (35 mg, 5 mol%) in dioxane / H₂O (8:2) (5.0 mL) was stirred at 90 °C under N₂ for 24 h. The mixture was cooled to room temperature and analyzed by Celite. ® Filter and wash with EtOAc (50 mL). Wash the organic layer with water (10 mL) and brine (10 mL), dry with Na2SO4, filter, and concentrate under vacuum. Purify the crude reaction mixture by rapid column chromatography on silica gel [DCM / MeOH (97:3)] to give 115 (271 mg, 86%) as a pale yellow foam, which is used in the next step without further purification.

[0330] R f : 0.22 [DCM / MeOH (5% MeOH)]; 1 H NMR (400 MHz, CDCl3, δ H):6.44 (s, 1H,C14-H), 6.32 (s, 1H, C3-H), 6.14 (s, 1H, C5-H), 5.77 (d, 1H, J = 17.5 Hz, C15-H A ), 5.39 (d, 1H, J = 11.0 Hz, C15-H B ), 4.33-4.10 (m, 3H, C7-H a , C11-H, C12-H), 3.77 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.09-2.89 (m, 3H, C10-H, C11-H, C12-H), 2.38 (s, 1H, C8-H), 1.97-1.88 (m, 2H, C9-H), 1.30-1.15 (m, 9H, Boc); 13 CNMR (100 MHz, CDCl3, δ C ):163.8 (CO), 154.6 / 154.3 (CO Boc, rotatable isomer), 148.6 / 148.2 (C6, rotatable isomer), 147.1 / 146.9 (C4, rotatable isomer), 134.8 (C14), 118.9 (C15), 114.7 (C3), 102.9 / 102.2 (C5, rotatable isomer), 80.4 / 79.7 (q Boc, rotatable isomer), 51.9 / 50.7 / 50.4 / 49.3 (C11, C12, rotatable isomer), 48.8 (C7), 35.0 (C10), 28.1 (3C, Boc), 27.6 (C8), 26.3 (C9);HRMS (ESI) + ): Calculated value C 18 H 25 N₂O₃: 317.1860, measured value [M+H] + 317.1844, calculated value C 18 H 24 N₂NaO₃: 339.1679, measured value [M+Na] + : 339.1665.

[0331] Example 30b — (+)4-vinyl indigo base hydrochloride (116)

[0332] Following the general process B, N -Boc-4-vinyl-indigo 115 (271 mg, 0.86 mmol) yielded 116 (214 mg, 99%) as a colorless solid.

[0333] mp: >200℃, colorless powder; [α] D 26 = +18 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 3376, 2938, 2717, 2574, 2386, 1643, 1552; 1 H NMR (400 MHz, D2O, δ H ):6.82 (d, 1H, J =1.5 Hz, C3-H), 6.63-6.55 (m, 2H, C5-H, C14-H), 6.03 (d, 1H, J = 17.5 Hz, C15-H A ), 5.60 (d, 1H, J = 11.0 Hz, C15-H B ), 4.16 (d, 1H, J = 15.5 Hz, C7-H a ), 4.00(dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.52-3.37 (m, 5H, C10-H, C11-H, C12-H), 2.83 (s, 1H, C8-H), 2.18-2.04 (m, 2H, C9-H); 13 C NMR (100 MHz, D2O, δ C ):164.5 (C0), 150.3 (C4), 146.8 (C6), 133.2 (C14), 122.0 (C15), 113.2 (C5), 108.0 (C3), 49.4 (C11 or C12), 48.8 (C7), 48.1 (C11 or C12), 31.5 (C10), 24.7 (C8), 22.6 (C9);HRMS (ESI) + ): Calculated value C 13 H 17 N₂O: 217.1335, measured value [M+H-HCl] +: 217.1332.

[0334] Example 31a—— N -Boc 4-ethylindocyanine (117)

[0335] To 4-vinyl- N -Boc-indigo 115 (353 mg, 1.1 mmol) was added to a solution of Pd / C 10% w / w (35 mg) in methanol (22 mL). The reaction vessel was placed under vacuum and purged three times with hydrogen. The mixture was stirred at room temperature under 1 atm H2 for 24 h. The mixture was then passed through a Celite tube. ® Filter, wash with EtOAc (50 mL), and concentrate under vacuum to give 117 (337 mg, 95%) as a grayish-white solid.

[0336] R f : 0.17 [DCM / MeOH (5% MeOH)]; 1 H NMR (400 MHz, CDCl3, δ H ):6.22 (s, 1H,C3-H), 5.88 (s, 1H, C5-H), 4.33-4.30 (m, 3H, C7-H a , C11-H, C12-H), 3.74 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.05-2.91 (m, 3H, C10-H, C11-H, C12-H), 2.41-2.34 (m, 3H, C8-H, C14-H), 1.94-1.85 (m, 2H, C9-H), 1.28-1.14 (m, 12H, C15-H,Boc); 13 C NMR (100 MHz, CDCl3, δ C): 163.8 (CO), 156.0 / 155.5 (CO Boc, rotifer), 154.7 / 154.3 (C4, rotifer), 148.1 / 147.6 (C6, rotifer), 114.5 (C3), 107.3 / 106.4 (C5, rotifer), 80.3 / 79.7 (q Boc, rotifer), 51.7 / 50.7 / 50.5 / 49.3 (C11, C12, rotifer), 48.7 (C7), 34.8 (C10), 28.1 (3C, Boc), 27.6 (C8), 26.5 (C14), 26.3 (C9), 13.7 / 13.3 (C15, rotifer);HRMS (ESI + ): Calculated value C 18 H 27 N₂O₃: 319.2016, measured value [M+H] + 319.2015, calculated value C 18 H 26 N₂NaO₃: 341.1836, measured value [M+Na] + : 341.1840.

[0337] Example 31b—(-)4-ethylindigo base hydrochloride (118)

[0338] Following the general process A, N -Boc-4-ethyl-indigo 117 (0.92 mmol) yielded 118 (227 mg, 97%) as a colorless solid.

[0339] mp: >200℃, colorless powder; [α] D 26 = -16 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2724, 2603, 1716, 1634, 1555; 1 H NMR (400 MHz, D2O, δ H ):6.67 (d, 1H, J = 1.5 Hz, C3-H), 6.57 (s, 1H, C5-H), 4.21 (d, 1H, J = 15.5 Hz, C7-H a ), 4.06 (dd, 1H, J=6.5, 15.5 Hz, C7-H b ), 3.53-3.39 (m, 5H, C10-H, C11-H, C12-H), 2.83 (s, 1H,C8-H), 2.58 (q, 2H, J = 7.5 Hz, C14-H), 2.17-2.06 (m, 2H, H9), 1.16 (t, 3H, J =7.5 Hz, C15-H); 13 C NMR (100 MHz, D2O, δ C ):163.9 (C0), 161.1 (C4), 146.5 (C6), 113.5 (C5), 112.9 (C3), 49.4 (C11 or C12), 48.9 (C7), 48.1 (C11 or C12), 31.3 (C10), 27.7 (C14), 24.7 (C8), 22.5 (C9), 12.6 (C15);HRMS (ESI) + ): Calculated value C 13 H 19 N2O: 219.1492, measured value [M+H + -HCl] + : 219.1494.

[0340] Example 32a—— N -Boc 4-p-Tolyl indigo (72)

[0341] Inject into the Schlenk tube N -Boc-4-bromo-indigo 61 (370 mg, 1.0 mmol), potassium carbonate (250 mg, 1.8 equivalents), tetrakis(triphenylphosphine)palladium (0) (58 mg, 5 mol%), and p-tolylboronic acid (160 mg, 1.2 equivalents) were added to a mixture of DME / water (5:1, 10 mL). The reaction mixture was heated at 80 °C for 18 h. The solution was cooled and the solvent was removed under vacuum. The crude product of the reaction separated into layers between water (15 mL) and DCM (15 mL), and the aqueous phase was extracted with DCM (3 × 15 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by rapid column chromatography [DCM / MeOH (1.5% MeOH)] to give 72 as a colorless solid. The crude product was recrystallized from hot toluene to give 72 (260 mg, 71%) as a colorless foam.

[0342] mp: 194-195℃, colorless foam (toluene); FTIR ν max / cm -1 (Net): 2922, 1678, 1648, 1431; 1 H NMR (500 MHz, CDCl3, δ H ):7.44 (d, 2H, J = 8.0 Hz, Ar), 7.20 (d, 2H, J = 8.0 Hz,Ar), 6.62 (s, 1H, C3-H), 6.28 (s, 1H, C5-H), 4.41-4.13 (m, 3H, C11-H, C12-H,C7-H), 3.83 (dd, 1H, J = 15.0, 6.5 Hz, C7-H), 3.15-2.91 (m, 3H, C11-H, C12-H,C10-H), 2.39 (s, 1H, C8-H), 2.36 (s, 3H, Me), 1.99 (d, 1H, J = 13.5 Hz, C9-H), 1.93 (d, 1H, J = 13.5 Hz, C9-H), 1.23 (s, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C ):163.5 (CO), 154.3 (CO), 150.5 (C3), 148.6 (C5), 139.2 (Ar), 134.9 (Ar), 129.5(2C, Ar), 126.5 (2C, Ar), 113.2 (C3), 104.6 (C5), 79.8 (q Boc), 51.0, 50.6(C11, C12), 48.6 (C7), 35.0 (C10), 28.0 (3C, Boc), 27.7 (C8), 26.4 (C9), 21.1(Me);HRMS (ESI + ): Calculated value C 23 H 29 N₂O₃: 381.2173, measured value [M+H] + 381.2164; Calculated value C 23 H 28 N₂NaO₃: 403.1992, measured value [M+Na] + :403.1984.

[0343] Example 32b — (+)4-p-Tolyl indigo (73)

[0344] In a Schlenk flask, N -Boc-4-p-Tolyl-Indigofera 72 (270 mg, 0.71 mmol) was dissolved in DCM (7.0 mL), and TFA (0.3 mL, 10 equivalents) was added. The reaction mixture was stirred at room temperature for 18 h. Then, water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with DCM (3 × 15 mL). Then, ammonia solution (20 mL, 15% aqueous solution) was added, and the aqueous phase was extracted with DCM (3 × 15 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated to give 73 (140 mg, 74%) as a colorless solid. The product was recrystallized from hot toluene to give 73 (73 mg, 40%) as a colorless solid.

[0345] mp: >200℃, colorless solid (toluene); [α] D 25 = +44 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 1638, 1552, 1531; 1 H NMR (500 MHz, MeOD, δ H ):7.56 (d, 2H, J = 8.0 Hz, Ar), 7.27(d, 2H, J = 8.0 Hz, Ar), 6.65 (d, 1H, J = 2.0 Hz, C3-H), 6.58 (d, 1H, J = 2.0 Hz, C5-H), 4.10 (d, 1H, J = 15.5 Hz, C7-H), 3.93 (dd, 1H, J = 15.5, 7.0 Hz, C7-H), 3.10-2.97 (m, 5H, C11-H, C12-H, C10-H), 2.38 (s, 3H, Me), 2.34 (s, 1H, C8-H), 2.01 (m, 2H, C9-H); 13 C NMR (125 MHz, MeOD, δ C):164.5 (CO), 152.0 (C4), 151.4(C6), 139.5 (Ar), 134.4 (Ar, 2C), 129.3 (Ar, 2C), 126.2 (Ar), 111.2 (C3),105.6 (C5), 53.0, 51.9 (C11, C12), 49.5 (C7), 35.4 (C10), 27.6 (C8), 25.5(C9), 19.7 (Me);HRMS (ESI + ): Calculated value C 18 H 21 N2O: 281.1648, measured value [M+H] + : 281.1653.

[0346] Example 33a—— N -Boc 4-( N -2-pyridone)indoline (107)

[0347] Towards N A mixture of 4-bromo-indigo 61 (369 mg, 1.0 mmol), CuI (19 mg, 10 mol%), 2-hydroxypyridine (114 mg, 1.2 mmol), and K2CO3 (277 mg, 2.0 mmol) in anhydrous toluene (5.0 mL) was added. N, N '-Dimethylethylenediamine (22 μL, 20 mol%). The mixture was heated at 110 °C for 24 h under nitrogen. Further CuI (19 mg, 10 mol%) was added. N,N '-Dimethylethylenediamine (DMEDA) (22 μL, 20 mol%) was added and stirred for 36 h. After cooling, the mixture was diluted with EtOAc (50 mL) and then passed through Celite. ® Filtration. The organic layer was washed with NH4OH (2 × 10 mL, 15% aqueous solution). The combined aqueous layers were extracted with DCM (5 × 10 mL). The combined organic layers (EtOAc and DCM) were dried over Na2SO4, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (95:5)] to give 107 (336 mg, 88%) as a pale yellow solid, which was used in the next step without further purification.

[0348] R f : 0.17 [DCM / MeOH (5% MeOH)];1 H NMR (400 MHz, CDCl3, δ H ):7.37-7.33(m, 1H, C17-H), 7.22 (d, 1H, J = 6.0 Hz, C19-H), 6.57 (d, 1H, J = 9.0 Hz, C16-H), 6.33-6.32 (m, 2H, C3-H, C5-H), 6.24-6.21 (m, 1H, C18-H), 4.36-4.15 (m,3H, C7-H a , C11-H, C12-H), 3.76 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.04-2.98 (m,3H, C10-H, C11-H, C12-H), 2.41 (s, 1H, C8-H), 2.04-1.90 (m, 2H, C9-H), 1.31-1.24 (m, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C ): 163.6 (CO py), 161.5 (CO), 154.7 / 154.4 (CO Boc, rotatable isomer), 151.1 (C4), 149.7 (C6), 140.4 (C17), 136.7 / 136.2 (C19, rotatable isomer), 122.3 / 122.0 (C16, rotatable isomer), 113.0 / 112.7 (C3, rotatable isomer), 106.7 (C18), 104.9 / 104.3 (C5, rotatable isomer), 80.5 / 80.0 (q Boc, rotatable isomer), 51.4 / 50.6 / 50.5 / 49.3 (C11, C12, rotatable isomer), 49.1 (C7), 35.1 (C10),28.1 (3C, Boc), 27.4 (C8), 26.0 (C9);HRMS (ESI + ): Calculated value C 21 H 26 N3O4: 384.1918, measured value [M+H] + 384.1921, calculated value C 21 H 25 N3NaO4: 406.1737, measured value [M+Na] + : 406.1747.

[0349] Example 33b——(-)4-( N -2-pyridone) indigo base hydrochloride (108)

[0350] Following the general process B, N -Boc4-(N-2-pyridone)-indigo 107 (289 mg, 0.75 mol) yielded 108 (182 mg, 76%) as a pale orange solid.

[0351] mp: >200 ℃, colorless powder (toluene); [α] D 25 = -20 [c 0.5, water];FTIR ν max / cm -1 (Net): 2922, 2710, 2601, 1662, 1638, 1595; 1 H NMR (400 MHz, D2O, δ H ):7.74-7.70 (m, 1H,C17-H), 7.60 (dd, 1H, J = 1.5, 7.0 Hz, C19-H), 6.69-6.62 (m, 4H, C3-H, C5-H,C16-H, C18-H), 4.23 (d, 1H, J = 15.5 Hz, C7-H a ), 4.07 (dd, 1H, J = 6.5, 15.5Hz, C7-H b ), 3.57-3.40 (m, 5H, C10-H, C11-H, C12-H), 2.87 (s, 1H, C8-H), 2.20-2.10 (m, 2H, C9-H); 13 C NMR (100 MHz, D2O, δ C ):165.1 (CO), 163.1 (CO py), 151.4(C4), 148.8 (C6), 143.6 (C17), 137.3 (C19), 119.8 (C16), 114.3 (C3), 109.4(C18), 108.0 (C5), 49.2 (C11 or C12), 48.9 (C7), 48.1 (C11 or C12), 31.7 (C10), 24.7 (C8), 22.4 (C9);HRMS (ESI)+ ): Calculated value C 16 H 18 N3O2: 284.1394, measured value [M+H-HCl] + : 284.1388.

[0352] Example 34a—— N -Boc 4-(trimethylsilylacetylene)indigo (125)

[0353] Towards N The mixture of -Boc-4-bromo-indigo 61 (369 mg, 1.0 mmol), CuI (19 mg, 10 mol%), and PdCl2(PPh3)2 (35 mg, 5 mol%) in anhydrous toluene (10.0 mL) was supplemented with i-Pr2NH (0.42 mL, 3.0 mmol), followed by trimethylsilylacetylene (0.16 mL, 1.1 mmol). The mixture was stirred at room temperature under nitrogen for 24 h. The mixture was diluted with DCM (50 mL). The organic layer was washed with NH4Cl (10 mL saturated solution), brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [EtOAc] to give 125 (406 mg, quantified) with trace impurities (palladium catalyst) as a light brown foam. This product was used in the next step without further purification.

[0354] R f : 0.21 [EtOAc];FTIR ν max / cm -1 (Net): 2972, 2932, 1689, 1651, 1574; 1 H NMR (400 MHz, CDCl3, δ) H ):6.48 (s, 1H, C3-H), 6.05 (s, 1H, C5-H), 4.32-4.09 (m, 3H,C7-H a , C11-H, C12-H), 3.78 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b), 3.08-2.92 (m, 3H,C10-H, C11-H, C12-H), 2.38 (s, 1H, C8-H), 1.96-1.88 (m, 2H, C9-H), 1.30-1.23(m, 9H, Boc), 0.21 (s, 9H, C16-H); 13 C NMR (100 MHz, CDCl3, δ C ):162.7 (CO),154.4 (CO Boc), 148.8, 148.5 (C6, C4), 119.7 (C3), 107.9, 107.3 (C5, rotatimer), 107.9 (C14), 100.2 (C15), 80.4, 79.9 (q Boc, rotatimer), 51.5, 50.5, 50.3, 49.3 (C11, C12, rotatimer), 48.8 (C7), 34.7 (C10), 28.0 (3C, Boc), 27.5 (C8), 26.1 (C9), -0.35 (3C, C16);HRMS (ESI) + ): Calculated value C 21 H 31 N₂O₃Si: 387.2098, measured value [M+H] + 387.2094, calculated value C 21 H 30 N₂NaO₃Si: 409.1918, measured value [M+Na] + :409.1910.

[0355] Example 34b—— N -Boc 4-(acetylene)indigoline 126

[0356] Towards N -Boc-4-(trimethylsilylacetylene)-indigo 125 (379 mg, 0.98 mmol) was added to a solution of MeOH (14 mL) and DCM (7 mL) with K2CO3 (270 mg, 1.96 mmol). The mixture was stirred for 24 h. Water (10 mL) was added and the aqueous phase was extracted with DCM (3 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by rapid column chromatography on silica gel [EtOAc] to give 126 (275 mg, 89%) as a white solid with trace impurities (palladium catalyst). This product was used in the next step without further purification.

[0357] R f : 0.21 [EtOAc];FTIR ν max / cm -1 (Net): 3225, 2915, 2862, 1686, 1654, 1574; 1 H NMR (400 MHz, CDCl3, δ H ):6.52 (s, 1H, C3-H), 6.06 (s, 1H, C5-H), 4.31-4.09(m, 3H, C7-H a , C11-H, C12-H), 3.76 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.23 (s,1H, C15-H), 3.04-2.93 (m, 3H, C10-H, C11-H, C12-H), 2.38 (s, 1H, C8-H), 1.96-1.88 (m, 2H, C9-H), 1.30-1.21 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ C ): 162.5 (CO), 154.4 / 154.3 (CO Boc, rotatimer), 149.3, 148.8 (C6, C4), 120.3 (C3), 107.8 / 107.1 (C5, rotatimer), 82.1 (C15), 80.8 (C14), 80.3 / 79.9 (q Boc, rotatimer), 51.6 / 50.5 / 50.2 / 49.3 (C11, C12, rotatimer), 48.9 (C7), 34.7 (C10), 28.0 (3C, Boc), 27.4 (C8), 26.0 (C9); HRMS (ESI) + ): Calculated value C 18 H 23 N₂O₃: 315.1703, measured value [M+H] + 315.1696, Calculated value C 18 H 22 N₂NaO₃: 337.1523, measured value [M+Na] + : 337.1516.

[0358] Example 34c — (-)4-(ethynyl)indigo base hydrochloride (127)

[0359] Following the general process B, N -Boc4 4-(ethynyl)indole 126 (0.77 mmol) yielded 127 (150 mg, 78%) as a pale yellow solid.

[0360] mp: >200℃, pale yellow solid; [α] D 26 = -32 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2726, 2604, 1631, 1540; 1 H NMR (400 MHz, D2O, δ H ):6.55 (s, 1H, C3-H), 6.48 (s, 1H,C5-H), 4.00 (d, 1H, J = 15.5 Hz, C7-H a ), 3.86 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ),3.74 (s, 1H, C15-H), 3.39-3.23 (m, 5H, C10-H, C11-H, C12-H), 2.70 (s, 1H, C8-H), 2.03-1.91 (m, 2H, C9-H); 13 C NMR (100 MHz, D2O, δ C ):164.0 (C0), 147.4 (C4), 135.0 (C6), 119.8 (C3), 111.9 (C5), 85.2 (C15), 79.7 (C14), 49.3 (C11 or C12), 48.8 (C7), 48.1 (C11 or C12), 31.4 (C10), 24.7 (C8), 22.4 (C9);HRMS (ESI) + ): Calculated value C 13 H 15 N₂O: 215.1179, measured value [M+H-HCl] + : 215.1176.

[0361] Example 35a—— N -Boc 4-(phenylacetylene)indigoline (128)

[0362] Towards N The mixture of -Boc4-bromo-indigo 61 (369 mg, 1.0 mmol), CuI (38 mg, 20 mol%), and PdCl2(PPh3)2 (70 mg, 10 mol%) in anhydrous toluene (5.0 mL) was supplemented with i-Pr2NH (0.42 mL, 3.0 mmol), followed by phenylacetylene (0.22 mL, 2.0 mmol). The mixture was stirred at room temperature under nitrogen for 24 h. The mixture was diluted with EtOAc (50 mL). The organic layer was washed with NH4Cl (10 mL, saturated solution), brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [EtOAc] to give 128 (376 mg, 96%) with trace impurities (palladium catalyst) as a light brown foam. This product was used in the next step without further purification.

[0363] R f : 0.14 [EtOAc]; 1 H NMR (400 MHz, CDCl3, δ H ):7.50-7.48 (m, 2H, C17-H),7.34-7.33 (m, 3H, C18-H, C19-H), 6.56 (s, 1H, C3-H), 6.13 (s, 1H, C5-H),4.34-4.12 (m, 3H, C7-H a , C11-H, C12-H), 3.79 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ),3.05-2.96 (m, 3H, C10-H, C11-H, C12-H), 2.40 (s, 1H, C8-H), 1.98-1.89 (m, 2H,C9-H), 1.32-1.23 (m, 9H, Boc); 13 C NMR (100 MHz, CDCl3, δ C): 162.7 (CO), 154.4 (CO Boc), 148.9 / 148.5 (C6, rotatimer), 134.0 / 133.7 (C4, rotatimer), 131.8 (C17, C21), 129.1 (C19), 128.4 (C18, C20), 122.1 (C16), 119.2 (C3), 107.8 / 107.1 (C5, rotatimer), 94.2 (C15), 86.6 (C14), 80.4 / 79.9 (q Boc, rotatimer), 51.6 / 50.5 / 50.4 / 49.3 (C11, C12, rotatimer), 48.8 (C7), 34.8 (C10). 28.1(3C, Boc), 27.5 (C8), 26.1 (C9);HRMS (ESI + ): Calculated value C 24 H 27 N₂O₃: 391.2016, measured value [M+H] + 391.2024, Calculated value C 24 H 26 N₂NaO₃: 413.1836, measured value [M+Na] + : 413.1876.

[0364] Example 35b — (+)4-(phenylacetylene)indigo hydrochloride (129)

[0365] Following the general process B, N -Boc-4-(phenylacetylene)-indigo 128 (0.88 mmol) yielded 129 (267 mg, 92%) as a pale yellow solid.

[0366] mp: >200℃, pale yellow solid; [α] D 26 = +42 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2925, 2717, 2214, 1630, 1537; 1 H NMR (400 MHz, MeOH, δ H):7.51-7.49 (m, 2H, C17-H), 7.41-7.33 (m, 3H, C18-H, C19-H), 7.00 (s, 1H, C3-H), 6.89 (s, 1H, C5-H), 4.33(d, 1H, J = 15.5 Hz, C7-H a ), 4.17 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.56-3.22(m, 5H, C10-H, C11-H, C12-H), 2.78 (s, 1H, C8-H), 2.17 (d, 1H, J = 13.0 Hz, C9-H a ), 2.07 (d, 1H, J = 13.0 Hz, C9-H b ); 13 C NMR (100 MHz, MeOD, δ C ):163.8 (CO),150.3 (C6), 139.4 (C4), 133.2 (C17, C21), 131.4 (C19), 129.9 (C18, C20),122.4 (C16), 117.5 (C5), 116.6 (C3), 99.4 (C15), 86.3 (C14), 51.4 (C7), 50.3(C11, C12), 33.0 (C10), 26.4 (C8), 23.6 (C9);HRMS (ESI + ): Calculated value C 19 H 19 N₂O: 291.1492, measured value [M+H-HCl] + : 291.1486.

[0367] Example 36a—— N -Boc 4-( E Methyl 2-acrylate) Indigoferazone (111)

[0368] Towards N -Boc 4-bromoindocyanine 61 (369 mg, 1.0 mmol) and Pd2(dba)3 (12 mg, 2.5 mol%) were added to a mixture in anhydrous dioxane (5.0 mL) with Cy2NMe (0.2 mL, 1.1 mmol) and P(t -Bu)3 (0.1M in dioxane, 0.5 mL, 5 mol%) and ethyl acrylate (0.2 mL, 2.0 mmol). The mixture was stirred at room temperature under nitrogen for 24 h. Pd2(dba)3 (12 mg, 2.5 mol%) and P( t -Bu)3 (0.1 M in dioxane, 0.5 mL, 5 mol%) and ethyl acrylate (0.2 mL, 2.0 mmol), and the mixture was stirred for 24 h. The mixture was then passed through Celite ® The mixture was filtered, washed with EtOAc, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH(97:3)] to give 111 (321 mg, 83%) as a pale yellow solid.

[0369] R f : 0.26 [DCM / MeOH (5% MeOH)];mp:>200℃, colorless powder;FTIR ν max / cm -1 (Net): 2973, 2934, 1723, 1679, 1655, 1640, 1567, 1431; 1 H NMR (400 MHz, CDCl3, δ H ):7.35 (d, 1H, J = 16.0 Hz, C14-H), 6.47 (s, 1H, C3-H), 6.38 (d, 1H, J = 16.0 Hz, C15-H), 6.15 (s, 1H, C5-H), 4.34-4.07 (m, 5H, C7-H a , C11-H, C12-H, C17-H),3.77 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.10-2.90 (m, 3H, C10-H, C11-H, C12-H), 2.39 (s, 1H, C8-H), 1.98-1.90 (m, 2H, C9-H), 1.31-1.14 (m, 12H, Boc, C18-H); 13 C NMR (125 MHz, CDCl3, δ C):165.9 (C16), 163.3 (CO), 154.5 / 154.2 (CO Boc, rotatable isomer), 149.8 / 148.9 (C6, rotatable isomer), 144.1 / 143.8 (C4, rotatable isomer), 141.7 (C14), 123.1 (C15), 117.4 (C3), 102.9 / 102.0 (C5, rotatable isomer), 80.4 / 79.8 (q Boc, rotatable isomer), 60.9 (C17), 51.7 / 50.6 / 50.4 / 49.2 (C11, C12, rotatable isomer), 49.0 (C7), 35.1 (C10), 28.1 (3C, Boc), 27.5 (C8). 26.2 (C9), 14.2 (C18);HRMS(ESI + ): Calculated value C 21 H 29 N₂O₅: 389.2071, measured value [M+H] + 389.2059, Calculated value C 21 H 28 N₂NaO₅: 411.1890, measured value [M+Na] + : 411.1880.

[0370] Example 36b——(+)4-( E Methyl 2-acrylate) Indigo hydrochloride (112)

[0371] Following the general process B, 111 (1.00 mol) yields 112 (300 mg, 92%) as a pale yellow solid.

[0372] mp: >200℃, pale yellow solid; [α] D 26 = +22 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2943, 2751, 1706, 1655, 1637, 1570; 1 H NMR (400 MHz, D2O, δ H ):7.28 (d, 1H, J = 16.0Hz, C14-H), 6.62 (d, 1H, J= 1.5 Hz, C3-H), 6.47-6.43 (m, 2H, C5-H, C15-H), 4.11 (q, 2H, J = 7.0 Hz, C17-H), 4.00 (d, 1H, J = 16.0 Hz, C7-H a ), 3.83 (dd,1H, J = 6.5, 15.5 Hz, C7-H b ), 3.40-3.24 (m, 5H, C10-H, C11-H, C12-H), 2.69 (s,1H, C8-H), 2.05-1.92 (m, 2H, C9-H), 1.16 (t, 3H, J = 7.0 Hz, C18-H); 13 C NMR (100 MHz, D2O, δ) C ):167.9 (C16), 164.7 (C0), 147.2 (C4), 146.2 (C6), 141.1 (C14), 124.0 (C15), 116.9 (C3), 106.9 (C5), 62.1 (C17), 49.4 (C11 or C12), 48.7 (C7), 48.2 (C11 or C12), 31.6 (C10), 24.7 (C8), 22.6 (C9), 13.2 (C18);HRMS (ESI) + ): Calculated value C 16 H 21 N2O3: 289.1547, measured value [M+H + -HCl] + :289.1561.

[0373] Example 37a—N-Boc-4-( E- (2-Styryl)indigo (113)

[0374] Towards N -Boc-4-bromo-indigo 61 (369 mg, 1.0 mmol) and Pd2(dba)3 (12 mg, 2.5 mol%) were added to a mixture in anhydrous dioxane (5.0 mL) with Cy2NMe (0.2 mL, 1.1 mmol) and P( tPd2(dba)3 (0.1 M in dioxane, 0.50 mL, 5 mol%) and styrene (0.2 mL, 2.0 mmol) were added. The mixture was stirred at room temperature under nitrogen for 24 h. Pd2(dba)3 (12 mg, 2.5 mol%), P(t-Bu)3 (0.1 M in dioxane, 0.5 mL, 5 mol%), and styrene (0.2 mL, 2.0 mmol) were added again, and the mixture was stirred for another 24 h. The mixture was then passed through a Celite tube. ® The mixture was filtered, washed with EtOAc, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH(97:3)] to give 113 (373 mg, 95%) as a pale yellow foam. This product was used in the next step without further purification.

[0375] R f : 0.19 [DCM / MeOH (5% MeOH)]; 1 H NMR (400 MHz, CDCl3, δ H ):7.49-7.47(m, 2H, C17-H, C21-H), 7.36-7.25 (m, 3H, C18-H, C19-H, C20-H), 7.11 (d, 1H, J = 16.0 Hz, C15-H), 6.81 (s, 1H, C14-H), 6.43 (s, 1H, C3-H), 6.28 (s, 1H, C5-H), 4.39-4.13 (m, 3H, C7-H a , C11-H, C12-H), 3.80 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.12-2.92 (m, 3H, C10-H, C11-H, C12-H), 2.39 (s, 1H, C8-H), 2.00-1.91(m, 2H, C9-H), 1.37-1.17 (m, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C):163.8 (CO),154.6 / 154.3 (CO Boc, rotational isomer), 148.5 / 148.1 (C6, rotational isomer), 147.0 / 146.7 (C4, rotational isomer), 136.1 (C16), 133.4 / 133.3 (C15, rotational isomer), 128.8 (C18,C20), 128.7 (C19), 127.0 (C17, C21), 126.0 (C14), 114.6 (C3), 103.1 / 102.3 (C5, rotational isomer), 80.3 / 79.7 (q Boc, rotational isomer), 51.8 / 50.6 / 50.5 / 49.3 (C11,C12, Rotational isomers), 48.7 (C7), 35.0 (C10), 28.1 (3C, Boc), 27.5 (C8), 26.3 (C9); HRMS (ESI) + Calculated value C 24 H 29 N₂O₃: 393.2173, measured value [M+H] + 393.2173, Calculated value C 24 H 28 N₂NaO₃: 415.1992, measured value [M+Na] + :415.1991.

[0376] Example 37b——(+)4-( E -(2-Styryl))Indigo Hydrochloride (114)

[0377] Following the general procedure B, 113 (0.88 mmol) yielded 114 (259 mg, 89%) as a grayish-white solid.

[0378] mp: >200℃, grayish-white solid; [α] D 26 = +90 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2925, 2713, 2606, 1629, 1553; 1 H NMR (400 MHz, D2O, δ H ):7.26-7.16 (m, 5H, C17-H, C18-H, C19-H), 6.99 (d, 1H, J= 16.5 Hz, C15-H), 6.59 (d, 1H, J = 16.5 Hz, C14-H), 6.51 (s, 1H, C3-H), 6.23 (s, 1H, C5-H), 3.87 (d, 1H, J = 15.5 Hz, C7-H a ), 3.54(dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.31-3.16 (m, 5H, C10-H, C11-H, C12-H), 2.56 (s, 1H, C8-H), 1.91 (d, 1H, J = 13.5 Hz, C9-H), 1.67 (d, 1H, J = 13.5 Hz, C9-H); 13 C NMR (100 MHz, D2O, δ C ):164.1 (C0), 149.8 (C16), 146.3 (C6), 135.4 (C15), 135.3 (C14), 129.2 (C19), 128.8 (C18, C20), 127.2 (C17, C21), 124.3 (C4), 113.1 (C3), 107.7 (C5), 49.5 (C11 or C12), 48.5 (C7), 48.1 (C11 or C12), 31.4 (C10), 24.6 (C8), 22.5 (C9);HRMS (ESI) + ): Calculated value C 19 H 21 N₂O: 293.1648, measured value [M+H-HCl] + : 293.1655.

[0379] Example 38a—— N -Boc 4-(1-(4-phenyl)- N H-1,2,3-triazolyl)noindine (134)

[0380] Towards NDMEDA (22 μL, 20 mol%) was added to a mixture of Boc-4-bromo-indigo 61 (369 mg, 1.00 mmol), NaN3 (130 mg, 2.0 mmol), sodium ascorbate (20 mg, 10 mol%), and CuI (19 mg, 10 mol%) in EtOH / H2O (7:3) (5.0 mL), followed by phenylacetylene (132 μL, 1.2 mmol). The mixture was stirred at 50 °C for 24 h under nitrogen. The mixture was cooled to room temperature, diluted with NH4OH solution (20 mL, 15% aqueous solution), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude material (based on...) was... 1 (86-93% conversion by ¹H NMR) was purified by rapid column chromatography on silica gel [EtOAc then DCM / MeOH / NH4OH (97:3:0.1)] to give 134 (214 mg, 49%) as a grayish-white solid, which was used in the next step without further purification.

[0381] R f : 0.11 [EtOAc]; 1 H NMR (400 MHz, CDCl3, δ H ):8.22 (s, 1H, C14-H), 7.89(d, 2H, J = 7.0 Hz, C17-H, C21-H), 7.47-7.44 (m, 2H, C18-H, C20-H), 7.39- 7.36(m, 1H, C19-H), 6.91 (s, 1H, C3-H), 6.70 (s, 1H, C5-H), 4.39-4.20 (m, 3H, C7-H a , C11-H, C12-H), 3.87 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.15-3.00 (m, 3H,C10-H, C11-H, C12-H), 2.47 (s, 1H, C8-H), 2.06-1.98 (m, 2H, C9-H), 1.34-1.19(m, 9H,Boc); 13 C NMR (125 MHz, CDCl3, δ C): 163.3 (CO), 154.6 (CO Boc), 152.0 / 151.5 (C6, rotatable isomer), 149.0 (C15), 145.0 (C4), 129.7 (C16), 129.1 (C18,C20), 128.9 (C19), 126.1 (C17, C21), 116.9 (C14), 103.8 (C5), 98.3 / 97.8 (C3, rotatable isomer), 80.7 / 80.1 (q Boc, rotatable isomer), 51.6 / 50.8 / 50.3 / 49.4 (C11, C12, rotatable isomer), 49.3 (C7), 35.5 (C10), 28.2 (3C, Boc), 27.5 (C8), 26.1 (C9);HRMS(ESI + ): Calculated value C 24 H 27 N5NaO3: 456.2006, measured value [M+Na] + :456.1993.

[0382] Example 38b——(+)4-(1-(4-phenyl)- N H-1,2,3-triazolyl)noindole dihydrochloride (135)

[0383] Following the general process B, N -Boc-4-((4-phenyl)-NH-1,2,3,triazole)-indigoline 134 (0.46 mmol) yielded 135 (151 mg, 81%) as a colorless solid.

[0384] mp: >200℃, colorless powder; [α] D 22 = +36 [c 0.5, water];FTIR ν max / cm -1 (Net): 3436, 3034, 2565, 1656, 1563; 1 H NMR (400 MHz, DMSO-d6, δ H ):9.50 (s, 1H, C14-H), 8.58(s, 1H, NH), 7.94 (d, 2H, J = 7.5 Hz, C17-H, C21-H), 7.50 (app t, 2H, J= 7.5Hz, C18-H, C20-H), 7.40 (app t, 1H, J = 7.5 Hz, C19-H), 7.10 (d, 1H, J = 2.5Hz, C3-H), 6.93 (d, 1H, J = 2.5 Hz, C5-H), 4.01 (d, 1H, J = 15.5 Hz, C7-H a ),3.85 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.46 (s, 1H, C10-H), 3.35-3.16 (m, 4H,C11-H, C12-H), 2.67 (s, 1H, C8-H), 2.07 (d, 1H, J = 13.0 Hz, C9-H), 1.94 (d, 1H, J = 13.0 Hz, C9-H); 13 C NMR (100 MHz, DMSO-d6, δ C ):162.7 (C0), 150.2 (C4),147.8 (C15), 144.4 (C6), 129.7 (C19), 129.1 (C18, C20), 128.6 (C16), 125.5 (C17, C21), 119.5 (C14), 103.8 (C5), 97.6 (C3), 48.4 (C11 or C12), 48.1 (C7), 47.4 (C11 or C12), 31.6 (C10), 24.5 (C8), 22.7 (C9);HRMS (ESI) + ): Calculated value C 19 H 20 N5O: 334.1662, measured value [M+H] + -2HCl] + 334.1676; Calculated value C 19 H 19 N5NaO: 356.1482, measured value [M+Na-2HCl] + :356.1503.

[0385] Example 39a—N-Boc 4-(1,2,3-triazol-1-yl)neovalerate methyl ester) indigo (131)

[0386] Towards N A solution of -Boc-4-(acetylene)-indigo 126 (544 mg, 1.73 mmol) in a mixture of tBuOH / H2O (1:1) (8.6 mL) was successively added with methyl azidopentanoate (0.3 mL, 2.08 mmol), CuSO4·5H2O (22 mg, 5 mol%), and sodium ascorbate (102 mg, 30 mol%). The mixture was stirred at room temperature for 48 h. The mixture was diluted with NH4OH (10 mL, 15% aqueous solution) and then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH (95:5:0.1)] to give 131 (722 mg, 89%) as a pale yellow oil with very few impurities, which was used in the next step without further purification.

[0387] R f : 0.08 [DCM / MeOH (5% MeOH)]; 1 H NMR (500 MHz, CDCl3, δ H ):8.07 (s, 1H,C15-H), 6.78-6.72 (m, 2H, C3-H, C5-H), 6.26 (s, 2H, C16-H), 4.37-4.16 (m, 3H,C7-H a , C11-H, C12-H), 3.84 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.08-2.95 (m, 3H,C10-H, C11-H, C12-H), 2.43 (s, 1H, C8-H), 2.02-1.94 (m, 2H, C9-H), 1.32-1.13(m, 18H, Boc, C19-H); 13 C NMR (125 MHz, CDCl3, δ C):178.0 (C17), 163.5 (CO), 154.7 / 154.5 (CO Boc, rotatimer), 150.1 / 149.5 (C4, rotatimer), 145.5 (C14), 140.1 / 139.9 (C6, rotatimer), 123.2 / 123.0 (C15, rotatimer), 112.4 (C3), 103.5 / 102.9 (C5, rotatimer), 80.5 / 79.9 (q Boc, rotatimer), 69.9 (C16), 51.7 / 50.8 / 50.4 / 49.4 (C11, C12, rotatimer), 49.0 (C7), 38.9 (C18), 35.1 (C10). 28.2 (3C, Boc), 27.7 (C8), 26.9 (3C, C19), 26.3 (C9);HRMS (ESI + ): Calculated value C 24 H 34 N5O5: 472.2554, measured value [M+H] + : 472.2551; Calculated value C 24 H 33 N5NaO5: 494.2374, measured value [M+Na] + : 494.2371.

[0388] Example 39b—— N -Boc4-( N H-1,2,3-triazolyl))-nobinine (132)

[0389] Towards N Methyl 1,4-(1,2,3-triazol-1-yl)neovalerate (Boc-4-(1,2,3-triazol-1-yl)neovalerate)-indigoferazone 131 (688 mg, 1.46 mmol) was added to a solution of MeOH (3.2 mL) with NaOH (3.2 mL, 1 M aqueous solution). The mixture was stirred at room temperature for 12 h. The mixture was neutralized with HCl (3.2 mL, 1 M aqueous solution), diluted with water (30 mL), and extracted with EtOAc (5 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by rapid column chromatography on silica gel [DCM / MeOH / NH4OH:(97:3:0.1)] to give 132 (461 mg, 88%) as a grayish-white solid.

[0390] R f: 0.32 [DCM / MeOH (10% MeOH)]; 1 H NMR (500 MHz, CDCl3, δ H ):8.01-7.82(m, 1H, C15-H), 7.03-6.92 (m, 1H, C3-H), 6.77 (s, 1H, C5-H), 4.39-4.15 (m,3H, C7-H a , C11-H, C12-H), 3.91 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.15-2.99 (m,3H, C10-H, C11-H, C12-H), 2.47 (s, 1H, C8-H), 2.06-1.97 (m, 2H, C9-H), 1.36-1.14 (m, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C ):164.0 (CO), 155.0 / 154.7 (COBoc, rotatable isomer), 149.9 / 149.1 (C4, rotatable isomer), 143.6 (C14), 141.2 (C6), 128.7 / 128.3 (C15, rotatable isomer), 112.4 (C3), 104.7 / 104.2 (C5, rotatable isomer), 81.3 / 80.1 (q Boc, rotatable isomer), 51.8 / 50.9 / 50.8 / 49.5 (C11, C12, rotatable isomer), 49.2 (C7), 35.2 (C10), 28.2 (3C, Boc), 27.3 (C8), 26.3 (C9);HRMS (ESI) + ): Calculated value C 18 H 24 N5O3: 358.1874, measured value [M+H] + 358.1874; Calculated value C 18 H 23 N5NaO3: 380.1693, measured value [M+Na] + : 380.1703.

[0391] Example 39c——(+)4-( N H-1,2,3-triazolyl))indigo dihydrochloride 133( A)

[0392] Following the general process A, N -Boc-4-( N H-1,2,3-triazole)-indigo 132 (1.22 mmol) was deprotected and converted to an HCl salt, yielding 133 (352 mg, 87%) as a colorless solid using general process A.

[0393] mp: >200℃, colorless powder; [α] D 22 = +32 [c 0.5, water];FTIR ν max / cm -1 (Net): 3094, 2905, 2723, 2396, 1651, 1552; 1 H NMR (400 MHz, D2O, δ H ):8.19 (s, 1H, C15 H),6.81 (d, 1H, J = 1.5 Hz, C3-H), 6.68 (d, 1H, J = 1.5 Hz, C5-H), 4.13 (d, 1H, J =15.5 Hz, C7-H a ), 3.90 (dd, 1H, J = 6.5, 15.5 Hz, C7-H b ), 3.54-3.38 (m, 5H, C10-H, C11-H, C12-H), 2.83 (s, 1H, C8-H), 2.16 (d, 1H, J = 13.5 Hz, C9-H), 2.05(d, 1H, J = 13.5 Hz, C9-H); 13 C NMR (100 MHz, D2O, δ C ):164.2 (C6), 147.9 (C6), 142.1 (C14), 141.5 (C4), 125.4 (C15), 111.2 (C5), 107.0 (C3), 49.3 (C11 or C12), 48.7 (C7), 48.2 (C11 or C12), 31.6 (C10), 24.7 (C8), 22.5 (C9);HRMS (ESI) + ): Calculated value C 13 H 16 N5O: 258.1349, measured value [M+H]+ -2HCl] + : 258.1342; Calculated value C 13 H 15 N₅NaO: 280.1169, measured value [M + Na⁻ 2HCl] + : 280.1163.

[0394] Example 40——(+)4-( N -Ethylamino)indigo (87)

[0395] In the sealed tube N A mixture of 369 mg (1.0 mmol) of 4-bromo-indigo 61 and copper (7 mg, 10 mol%) in EtNH2 (2.0 mL, 2.0 M in THF) was stirred in water (1 mL) at 100 °C for 24 h. The mixture was cooled and extracted with DCM (5 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH (6% MeOH)] to give 87 (102 mg, 42%) as a grayish-white solid.

[0396] Mp: ≥ 200℃; [α] D 23 = +50 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 3269, 2901, 2868, 1639, 1532; 1 H NMR (500 MHz, D2O, δ H ):5.92 (d, 1H, J = 2.0 Hz, C3-H), 5.54(d, 1H, J = 2.0 Hz, C5-H), 3.92 (d, 1H, J = 15.0 Hz, C7-H), 3.79 (dd, 1H, J = 6.0,15.0 Hz, C7-H), 3.13 (q, 2H, J = 7.5 Hz, CH2), 3.06-2.90 (m, 5H, C10-H, C11-H,C12-H), 2.33 (s, 1H, C8-H), 1.98 (d, 1H, J = 13.5 Hz, C9-H), 1.91 (d, 1H,J =13.5 Hz, C9-H), 1.10 (t, 3H, J = 7.5 Hz, CH3); 13 C NMR (125 MHz, D2O, δ C ):165.3(CO), 157.1 (C4), 150.7 (C6), 99.5 (C3), 89.4 (C5), 52.0, 50.8 (C11, C12),48.9 (C7), 36.8 (CH2), 34.5 (C10), 26.8 (C8), 24.9 (C9), 13.0 (CH3); HRMS (ESI + ): Calculated value C 13 H 20 N3O: 234.1601, measured value [M+H] + : 234.1609.

[0397] Example 41——(+)4-( N -Isopropylamino)Indigoline 88

[0398] Will N A mixture of 61-Boc-4-bromo-indigo alkaloid (369 mg, 1.0 mmol) and copper (7 mg, 10 mol%) in 2.0 mL of 40% iPrH2 aqueous solution was stirred in a sealed tube at 100 °C for 24 h. The mixture was cooled and extracted with DCM (5 × 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude substance was purified by rapid column chromatography on silica gel [DCM / MeOH (6% MeOH)] to give 88 (88 mg, 33%) as a grayish-white solid.

[0399] Mp: ≥ 200℃; [α] D 24 = +50 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2969, 1639, 1535, 1276; 1 H NMR (500 MHz, MeOD, δ H :5.76 (d, J = 2.5 Hz, 1H, C3-H), 5.46 (d, J =2.5 Hz, 1H, C5-H), 3.97 (d, J= 15.0 Hz, 1H, C7-H), 3.79 (dd, J = 15.0, 6.0 Hz,1H, C7-H), 3.57(hept, J = 6.5 Hz, 1H, C13-H), 3.07-2.92 (m, 4H, C11-H C12-H), 2.83 (s, 1H, C10-H), 2.27(s, 1H, C8-H), 1.95 (m, 2H, C9-H), 1.20 (dd, J = 6.5, 2.0 Hz, 6H, C14-H); 13 C NMR (125 MHz, MeOD, δ C ):165.5 (CO), 155.7 (C4), 149.7(C6), 98.7 (C3), 89.1 (C5), 52.7, 51.6 (C11 C12), 48.5 (C7), 43.1 (C13), 35.1(C10), 27.6 (C8), 25.6 (C9), 21.0 (2C, C14); HRMS (ESI + ): Calculated value C 14 H 22 N3O: 248.1757, measured value [M+H + -HCl] + : 248.1766.

[0400] Example 42a—— N -Boc 4-cyanoninoindole (139)

[0401] Inject into the Schlenk tube N -Boc-4-bromo-indigo 61 (1.85 g, 5.00 mmol), Pd((PPh3)4) (230 mg, 0.20 mmol) and zinc cyanide (350 mg, 3.00 mmol) were placed under nitrogen atmosphere. DMF (6.2 mL) was added and the reaction mixture was heated at 80 °C for 18 h. The reaction mixture was cooled and the solvent was removed under vacuum. The crude reaction mixture was purified by rapid column chromatography [DCM:MeOH (1% MeOH)] to give 139 (1.6 g, 99%) as a colorless solid.

[0402] R f0.7 [DCM / MeOH (4% MeOH)]; mp: 153-156℃, colorless powder (toluene); FTIR ν max / cm -1 (Net): 2973, 2233 (weak peaks are conjugate, CN band), 1658, 1572; 1 H NMR (500 MHz, CDCl3, δ H ,52.0℃):6.74 (s, 1H, C3-H), 6.18 (s, 1H, C5-H), 4.42-4.07 (m, 3H, C11-H, C12-H, C7-H), 3.81 (dd, 1H, J = 6.5, 16.0 Hz, C7-H), 3.19-2.91 (m, 3H, C11-H, C12-H, C10-H), 2.48 (s, 1H, C8-H), 1.98 (s, 2H, C9-H), 1.38-1.17 (s, 9H, Boc); 13 CNMR (125 MHz, CDCl3, δ C (52.0℃): 161.3 (CO), 154.1 (C4), 151.7 (C6), 121.9 (C3), 115.9 (CN), 104.3 (C5), 80.5 (q Boc), 50.1, 49.8 (C11, C12), 49.2 (C7), 34.8 (C10), 28.4 (3C, Boc), 27.4 (C8), 25.8 (C9). (No carbonyl carbon of the Boc group was observed); HRMS (ESI) + ): Calculated value C 17 H 21 N3NaO: 338.1475, measured value [M+Na] + : 338.1467.

[0403] Example 43 – (-)4-cyanoindigo (140)

[0404] In a Schlenk flask, N-Boc-4-cyano-indigo 139 (140 mg, 0.46 mmol) was dissolved in DCM (3.0 mL, 0.1 M), and TFA (0.3 mL, 10 equivalents) was added. The solution was stirred at room temperature for 16 h. Water (10 mL) was added, and the aqueous phase was washed with DCM (3 × 20 mL). Ammonia (10 mL, 15% aqueous solution) was added, and the aqueous phase was extracted with DCM (4 × 20 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to give 140 (86 mg, 86%) as a colorless solid.

[0405] mp: 161-163℃, colorless needle-like substance (toluene); [α] D 23 = -53 [c 0.66, MeOH];(FTIR ν max / cm -1 (Net): 2233 (weak peaks are conjugate, CN band), 1649, 1581; 1 H NMR (500 MHz, MeOD, δ H ):6.87(d, 1H, J = 2.0 Hz, C3-H), 6.59 (d, 1H, J = 2.0 Hz, C5-H), 4.19 (d, 1H, J = 16.0Hz, C7-H), 4.01 (dd, 1H, J = 16.0, 7.0 Hz, C7-H), 3.52-3.35 (m, 5H, C10-H, C11-H, C12-H), 2.78 (s, 1H, C8-H), 2.18 (d, 1H, J = 14.0 Hz, C9-H), 2.10 (d, 1H, J =14.0 Hz, C9-H); 13 C NMR (125 MHz, MeOD, δ C ):161.6 (C2), 154.1 (C6), 122.7 (C4),121.4 (C3), 116.4 (C13), 104.1 (C5), 53.7, 52.9 (C11, C12), 50.4 (C7), 35.7(C10), 27.5 (C8), 25.9 (C9);HRMS (ESI + ): Calculated value C 12 H 14 N3O: 216.1131, measured value [M+H]+ :216.1129.

[0406] Example 44a—— N -Boc-4-(carboxyacylamino)noindine (141)

[0407] Towards N -Boc-4-cyano-indigo 139 (320 mg, 1.0 mmol) was added to a solution of NaBH4 (33 mg, 0.75 mmol) in an equimolar mixture of EtOH / water (5 mL), and the reaction mixture was stirred at 75 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with water (5 mL). Ethanol was removed under vacuum. The aqueous phase was then extracted with DCM (3 × 15 mL), and the combined organic phase was dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by rapid column chromatography [DCM / MeOH (from 2% to 4% MeOH)] to give 141 (150 mg, 46%) as a colorless solid, which was recrystallized from toluene.

[0408] R f :0.43 [DCM / MeOH (4% MeOH)] ;mp:>200℃, colorless powder;FTIR ν max / cm -1 (Net): 3317, 3148, 2974, 1690, 1639, 1562; 1 H NMR (500 MHz, MeOD, δ H , 52℃): 6.83 (s,1H, C3-H), 6.69 (s, 1H, C5-H), 4.35-4.31 (s, 1H, C11-H), 4.20-4.16 (br s, 1H,C7-H), 4.14 (s, 1H, C12-H), 3.84 (dd, 1H, J = 6.0, 15.0 Hz, C7-H), 3.27-2.98(m, 3H, C10-H C11-H C12-H), 2.49 (s, 1H, C8-H), 2.12-1.97 (m, 2H, C9-H), 1.41-1.06 (s, 9H, Boc); 13 C NMR (125 MHz, MeOD, δ C(52℃): 167.8 (CO amide), 163.4 (CO pyridone), 154.6 (CO Boc), 150.8 (C6), 144.4 (C4), 114.3 (C3), 104.6 (C5), 80.2 (q Boc), 67.4 (C11, C12), 49.3 (C7), 35.2 (C10), 27.7 (C8), 26.9 (3C, Boc), 25.1 (C9); HRMS (ESI) + ): Calculated value C 17 H 24 N3O4: 334.1761, measured value [M+H] + 334.1753; Calculated value C 17 H 23 N3NaO4: 356.1581, measured value [M+Na] + : 356.1570.

[0409] Example 44b — (-)4-(carboxyacylamino)indigo base hydrochloride (142)

[0410] Following the general procedure A, N-Boc-4-amino-indigo 141 (0.44 mmol) yielded 142 (90 mg, 88%) as a colorless solid.

[0411] mp: >200℃, colorless powder; [α] D 25 = -2 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 1646, 1543; 1 H NMR (500 MHz, MeOD, δ H ):6.92 (d, 1H, J = 2.0 Hz, C3-H), 6.75 (d, 1H, J =2.0 Hz, C3-H), 4.21 (d, 1H, J = 16.0 Hz, C7-H), 4.05 (dd, 1H, J = 16.0, 6.5 Hz,C7-H), 3.53-3.41 (m, 5H, C11-H, C12-H, C10-H), 2.82 (s, 1H, C8-H), 2.20 (d,1H, J= 13.5 Hz, C9-H), 2.12 (d, 1H, J = 13.5 Hz, C9-H); 13 C NMR (125 MHz, MeOD, δ) C ): 167.7 (CO CONH2), 164.1 (CO), 147.4 (C4), 144.8 (C6), 115.8 (C3), 105.3 (C5), 49.4 (C7), 32.1 (C10), 25.2 (C8), 22.8 (C9), (C11 and C12 under solvent signal); HRMS (ESI) + ): Calculated value C 12 H 16 N3O2: 234.1237, measured value [M+H-HCl] + :234.1229.

[0412] Example 45a—N-Boc 4-(aminomethyl)indigoline (143)

[0413] Raney nickel (0.3 mL, cement slurry) was added to a solution of N-Boc-4-cyano-indigo 139 (320 mg, 1.0 mmol) and KOH (84 mg, 1.5 mmol) in EtOH (10 mL, 0.1 M). The reaction vessel was placed under vacuum and purged three times with hydrogen, and stirred at room temperature for 18 h. The reaction was then analyzed by Celite. ® The reaction mixture was filtered and the crude reaction mixture was concentrated. Amine 143 (260 mg, 82%) was purified by rapid column chromatography [DCM:MeOH (10% MeOH) + 0.1% ammonia (35% aqueous solution)] to give amine 143 as a colorless solid.

[0414] R f 0.22 [DCM:MeOH (10% MeOH)]; mp: 157-160℃, colorless powder (toluene); FTIR ν max / cm -1 (Net): 2928, 1673, 1644, 1542; 1 H NMR (500 MHz, MeOD, δ H , 52℃):6.40 (s, 1H,C3-H), 6.34 (d, 1H, J= 2.0 Hz, C5-H), 4.27 (s, 1H, C11-H), 4.16 (s, 1H, C12-H), 4.12 (s, 1H, C7-H), 3.30 (dd, 1H, J = 6.0, 15.0 Hz, C7-H), 3.67 (s, 2H,C13-H), 3.22-3.04 (m, 3H, C11-H, C12-H, C10-H), 2.45 (s, 1H, C8-H), 2.08-1.99(m, 2H, C9-H), 1.42-1.11 (s, 9H, Boc); 13 C NMR (125 MHz, MeOD, δ C , 52℃): 164.3 (CO), 155.6 (CO), 154.7 (C6), 149.3 (C4), 112.3 (C3), 106.5 (C5), 79.97 (qBoc), 50.3 (C11, C12), 48.9 (C7), 44.1 (C13), 34.9 (C10), 27.7 (C8), 27.0(3C, Boc), 25.4 (C9);HRMS (ESI + ): Calculated value C 17 H 25 N3O3: 319.1896, measured value [M+H] + 320.1958, Calculated value C 17 H 24 N3NaO3: 342.1794, measured value [M+Na] + : 342.1783.

[0415] Example 45b — (-)4-(aminomethyl)indigo dihydrochloride (144)

[0416] Following the general process A, N -Boc-4-methylamino-indigo 143 (0.76 mmol) was converted to its HCl salt to give 144 (150 mg, 89%) as a colorless solid.

[0417] mp: >200℃, colorless powder; [α] D 26 = -46 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2789, 1653, 1518;1 H NMR (500 MHz, D2O, δ H ):6.50 (s, 1H, C3-H), 6.46 (s, 1H, C5-H), 4.07 (d, 1H, J = 16.0 Hz, C7-H), 4.02 (s, 2H, C13-H), 3.94 (dd, 1H, J = 16.0, 6.5Hz, C7-H), 3.45-3.29 (m, 5H, C11-H, C12-H, C8-H), 2.75 (s, 1H, C10-H), 2.06(d, 1H, J = 13.6 Hz, C9-H), 2.00 (d, 1H, J = 13.6 Hz, C9-H); 13 C NMR (125 MHz, D2O, δ) C ):164.6 (CO), 148.0 (C4), 16.9 (C6), 115.4 (C3), 108.5 (C5), 48.7 (C7),49.3, 48.2 (C11, C12), 41.2 (C13), 31.5 (C8), 24.8 (C10), 22.4 (C9); HRMS (ESI + ): Calculated value C 12 H 18 N3O: 220.1444, measured value [M+H-HCl] + :220.1441.

[0418] Example 46a—— N -Boc 4-( N -Boc aminomethyl) indigoline

[0419] Towards N Boc-4-aminomethyl-indigoline 143 (264 mg, 0.83 mmol) was added to a solution of Boc2O (0.2 mL, 0.91 mmol) and triethylamine (0.16 mL, 1.16 mmol) in THF (8 mL), and the reaction mixture was stirred at room temperature for 18 h. Water (15 mL) was then added, and the aqueous phase was extracted with DCM (3 × 25 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated. The product was purified by rapid column chromatography [DCM:MeOH (3% MeOH)] to obtain... N -Boc-4-(N -Boc-aminomethyl)-indigoferazone (280 mg, 82%) is a colorless oil.

[0420] FTIR ν max / cm -1 (Net): 3316, 2975, 1683, 1653, 1546, 1423; 1 H NMR (500 MHz, CDCl3, δ) H , 52℃):6.33 (s, 1H, C3-H), 5.98 (d, 1H, J = 2.0 Hz, C5-H), 4.82 (s,1H, NH), 4.36-4.07 (m, 5H, C7-H, C11-H, C12-H, C13-H), 3.81 (dd, 1H, J = 5.5,15.5 Hz, C7-H), 3.10-2.94 (m, 3H, C11-H, C12-H, C10-H), 2.41 (s, 1H, C8-H), 1.99 (d, 1H, J = 13.5 Hz, C9-H), 1.92 (d, 1H, J = 13.5 Hz, C9-H), 1.46 (s, 9H, Boc), 1.38-1.23 (s, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C , 52℃): 166.4 (CO), 155.8 (CO Boc), 154.5 (CO Boc), 150.9 (C6), 148.7 (C4), 113.8 (C3), 104.4(C5), 79.6 (2C, q Boc), 50.8, 50.5 (C11, C12), 48.7 (C7), 43.5 (C13), 35.0(C10), 28.3, 28.0 (6C, Boc), 27.6 (C8), 26.3 (C9);HRMS (ESI + ): Calculated value C 22 H 34 N3O5: 420.2492, measured value [M+H] + : 420.2490.

[0421] Example 46b——(-)4-(( N -Methyl)aminomethyl)indigoline (152)

[0422] Towards N -Boc-4-( N NaH (17 mg, 0.70 mmol, 60% dispersion oil) was added to a solution of -Boc-aminomethyl)-indigo (255 mg, 0.61 mmol) in THF (6.0 mL), and the solution was stirred for 30 min. Iodomethane (0.05 mL, 0.70 mmol) was added, and the reaction mixture was stirred at room temperature for 18 h. The crude material separated into layers between water (10 mL) and EtOAc (10 mL), and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The obtained compound was deprotected and converted to its HCl salt using general procedure A to give 152 (89 mg, 65%) as a colorless solid.

[0423] mp:>200℃;FTIR ν max / cm -1 (Net): 2728, 1651, 1548; 1 H NMR (500 MHz, D2O, δ H ):6.57 (s, 1H, C3-H), 6.51 (s, 1H, C5-H), 4.14-4.05 (m, 3H, C7-H, CH2), 3.97(dd, J = 6.0, 15.5 Hz, 1H, C7-H), 3.50-3.31 (m, 5H, C10-H, C11-H, C12-H), 2.79(s, 1H, C10-H), 2.70 (s, 3H, NHMe), 2.13-2.00 (m, 2H, C9-H); 13 C NMR (125 MHz, D2O, δ) C ):164.5 (CO), 148.3 (C6), 145.0 (C4), 117.2 (C3), 109.1 (C5), 50.4(CH2), 49.4, 48.1 (C11, C12), 48.7 (C7), 32.6 (NHMe), 31.7 (C10), 24.8 (C8),22.5 (C9) ;HRMS (ESI + ): Calculated value C 13 H 20 N3O: 234.1601, measured value [M+H-HCl] +: 234.1595.

[0424] Example 47a—(1R, 5R)-10-(hydroxymethyl)-8-oxoylide-1,5,6,8,-tetrahydro-2H-1,5-methylenepyrido[1,2-a][1,5]diazo-octano-3(4H)-carboxylic acid tert-butyl ester (153)

[0425] Will N -Boc-4-cyano-indigo 139 (200 mg, 0.63 mmol) was dissolved in a mixture of pyridine, acetic acid, and water in a (2:1:1) ratio, and NaH₂PO₂ (340 mg, 3.27 mmol) and Ni Raney (1.0 mL, cement slurry) were added. The reaction mixture was stirred at 50 °C for 6 h. The solution was then passed through a Celite tube. ® The mixture was filtered and concentrated. The crude material separated into layers between water (15 mL) and DCM (15 mL), and the aqueous phase was extracted with DCM (3 × 25 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by column chromatography [DCM / MeOH (4% MeOH)] to give 153 (170 mg, 86%) as a colorless pale yellow solid.

[0426] R f 0.10 [DCM / MeOH (4% MeOH)]; mp: 75-78℃, pale yellow solid (toluene); FTIR ν max / cm -1 (Net): 2928, 1651, 1543, 1423; 1 H NMR (500 MHz, MeOD, δ H , 52℃):6.44 (s, 2H,C3-H), 6.39 (d, 2H, J = 2.0 Hz, C5-H), 4.31 (m, 6H, C11-H, C12-H, NH), 4.15 (d,2H, J = 15.0 Hz, C7-H), 3.80 (dd, 2H, J = 15.0, 6.5 Hz, C7-H), 3.64 (s, 4H, C14-H), 3.13 (s, 5H, C10-H, C11-H, C12-H), 2.45 (s, 2H, C8-H), 2.05 (m, 4H, C9-H), 1.28 (s, 18H, Boc); 13C NMR (125 MHz, MeOD, δ C , 52℃): 164.1 (2 x CO), 157.7 (2 x CO), 153.3 (2 x C4), 149.7 (2 x C6), 113.6 (2 x C3), 107.3 (2 x C5), 80.0 (2 xq Boc), 50.8, 50.7 (4 x C11, C12), 50.6 (2 x C14), 48.8 (2 x C7), 35.0 (2 x C10), 27.7 (2 x C8), 27.0 (6 x C Boc), 25.4 (2 x C9); HRMS (ESI + ): Calculated value C 34 H 48 N5O6: 622.3605, measured value [M+H] + : 622.3591, Calculated value C 34 H 46 NaN5O6: 644.3424, measured value [M+Na] + : 644.3412.

[0427] Example 47b – Aminebis(indigo) derivative (154)

[0428] Following the general process A, (1 R 5 R )-10-(hydroxymethyl)-8-oxoylide-1,5,6,8-tetrahydro-2 H -1,5-methylene-pyrido[1,2-a][1,5]diazo-3(4) H 153 (0.53 mmol) of tert-butyl carboxylate was reacted to give 154 (113 mg, 97%) as a colorless solid.

[0429] mp:>200℃; colorless solid; [α] D 23 = +116 [c 0.18, DMF];FTIR ν max / cm -1 (Net): 2955, 2590, 1654, 1584, 1547, 1099, 857; 1 H NMR (500 MHz, D2O, δ H):6.47 (s, 2H, C3-H), 6.44 (s, 2H, C5-H), 4.07 (s, 4H, C13-H), 4.00 (d, J =15.0Hz, 2H, C7-H), 3.86 (dd, J = 15.0, 6.65 Hz, 2H, C7-H), 3.40-3.20 (m, 10H, C11-H C12-H C10-H), 2.69 (s, 2H, C8-H), 1.98 (d, J = 14.5 Hz, 2H, C9-H), 1.94 (d, J = 14.5 Hz, 2H, C9-H); 13 C NMR (125 MHz, D2O, δ C ):164.6 (2 x CO), 148.5 (2 x C4), 144.6 (2 xC6), 117.5 (2 x C3), 109.2 (2 x C5), 49.4, 48.2 (2 x C11, 2 x C12), 49.1,48.8 (2 x C7, 2 x C13), 31.6 (2 x C10), 24.7 (2 x C8), 22.5 (2 x C9);HRMS(ESI + ): Calculated value C 24 H 32 N5O2: 422.2550, measured value [M+H] + : 422.2544.

[0430] Example 48 – Methamidobis(indigo) derivative (156)

[0431] Formaldehyde (0.14 mL, 6 equivalents, 37% aqueous solution) was added to a solution of 153 (200 mg, 0.32 mmol) in an equimolar mixture (3 mL) of MeOH / THF, followed by the addition of NaCNBH3 (74 mg, 3.5 equivalents), and the reaction mixture was stirred for 24 h. The solution was concentrated, and the crude material separated into layers between ammonia (20 mL, 15% aqueous solution) and DCM (20 mL), with the aqueous phase extracted with DCM (3 × 20 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The corresponding organic layer was purified by rapid column chromatography [DCM / MeOH (3% MeOH)] to obtain the desired product. N-Boc-protected bis(indigo) derivative (160 mg, 82%) was a colorless solid. Subsequent deprotection and conversion to HCl salt using general process B yielded 156 (89 mg, 87%) a colorless solid.

[0432] mp:>200℃; colorless solid; [α] D 23 = -30 [c 0.3, water];FTIR ν max / cm -1 (Net): 3341, 1655, 1548, 1455; 1 H NMR (500 MHz, D2O, δ H ):6.67 (s, 2H, C3-H, C3'-H)), 6.65(s, 2H, C5-H, C5'-H), 4.35 (s, 4H, C13-H, C13-H), 4.18 (d, 2H, J = 15.0 Hz, C7-H, C7'-H), 4.04 (dd, 2H, J = 6.0, 15.0 Hz, C7-H, C7'-H), 3.60-3.40 (m, 10H,C10-H, C10'-H, C11-H, C11'-H, C12-H, C12'-H), 2.93 (s, 3H, NMe), 2.89 (s, 2H,C8-H, C8'-H), 2.23-2.06 (m, 4H, C9-H, C9'-H); 13 C NMR (125 MHz, D2O, δ C ):161.9(CO, CO'), 146.5 (C4, C4'), 140.6 (C6, C6'), 117.1 (C3, C3'), 107.9 (C5,C5'), 56.2 (C13, C13'), 47.0, 46.6 (C11, C11', C12, C12'), 45.9 (C7, C7'), 38.7 (C NMe), 29.4 (C10, C10'), 22.5 (C8, C8'), 20.2 (C9, C9'); HRMS (ESI + ): Calculated value C 25 H 34 N5O2: 436.2707, measured value [M+H] + : 436.2692.

[0433] Example 49 – (-)4-Tetrazonoindole dihydrochloride (149)

[0434] Pour into the Schlenk flask N -Boc-4-cyano-indigo 139 (240 mg, 0.75 mmol), zinc bromide (170 mg, 0.75 mmol), and sodium azide (58 mg, 0.90 mmol) were placed under nitrogen atmosphere. Water (2.5 mL, 0.3 M) and isopropanol (0.8 mL, 1.0 M) were added, and the reaction mixture was heated at 60 °C for 18 h. The solvent was removed under vacuum, and the residue was dissolved in DCM (20 mL) and poured into water (20 mL). The mixture was acidified with HCl (0.1 M aqueous solution) to pH ≈ 4–5 and washed with DCM (3 × 20 mL). The aqueous phase was acidified to pH ≈ 1 and extracted with DCM (3 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and the solvent was evaporated under vacuum. The product was converted to an HCl salt using general procedure A to give 149 (102 mg, 53%) as a colorless solid.

[0435] mp: >200℃, colorless solid; [α] D 23 = -23 [c 0.13, DMF];FTIR ν max / cm -1 (Net): 3005, 2807, 1653, 1565; 1 H NMR (500 MHz, D2O, δ H ):6.47 (s, 1H, C3-H), 6.44 (s, 1H,C5-H), 4.07 (s, 2H, C13-H), 4.00 (d, J =15.0Hz, 1H, C7-H), 3.86 (dd, J = 15.0,6.65 Hz, 1H, C7-H), 3.40-3.20 (m, 5H, C10-H, C11-H, C12-H), 2.69 (s, 1H, C8-H), 1.98 (d, J = 14.5 Hz, 1H, C9-H), 1.94 (d, J = 14.5 Hz, 1H, C9-H); 13 C NMR (125MHz, D2O, δ C):164.6 (CO), 155.9 (C4), 148.7 (C6), 137.3 (C13), 114.4 (C3), 106.7 (C5), 49.4, 48.2 (C11, C12), 48.8 (C7), 31.7 (C10), 24.8 (C8), 22.5(C9);HRMS (ESI + ): Calculated value C 12 H 15 N6O: 259.1301, measured value [M+H-2HCl] + :259.1301.

[0436] Example 50—— N -Boc-4-(dimethylamino)methyl-noindigo and 4-(dimethylamino)methyl-(-)-noindigo dihydrochloride (151)

[0437] Formaldehyde (480 mg, 6 equivalents, 35% aqueous solution) and NaCNBH3 (219 mg, 3.5 equivalents) were continuously added to a solution of amine 143 (320 mg, 1.0 mmol) in an equimolar mixture of THF / water (12 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 10 mL of water and the aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (1% MeOH)] to give the product as a green oil (207 mg, 60%).

[0438] N Data for -Boc4-((dimethylamino)methyl)indigoline: FTIR ν max / cm -1 (Net): 2973, 2866, 1680, 1650, 1545; 1 H NMR (500 MHz, CDCl3, δ H ):6.35 (s, 1H, C3-H), 6.20 (s, 1H,C5-H), 4.44-4.08 (m, 3H, C11-H, C12-H, C7-H); 3.84 (dd, 1H, J= 15.0, 6.0 Hz,C7-H), 3.29 (s, 1H, C13-H), 3.20 (s, 1H, C13-H), 3.13-2.91(m, 3H, C10-H, C11-H, C12-H), 2.41 (s, 1H, C8-H), 2.27 (s, 6H, NMe2), 2.03-1.90 (m, 2H, C9-H), 1.41-1.15 (m, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C ): 163.5 (CO), 154.4 (C4), 150.6 / 148.4 (C6 rotomer), 116.1 (C3), 106.5 / 105.5 (C5 rotomer), 80.3 / 79.7 (q Boc rotomer), 63.2 (C13), 51.6 / 50.5 / 49.3 (C11, C12 rotomer), 48.8 (C7), 45.5 (2C, NMe2), 34.8 (C10), 28.0 (3C, Boc), 27.5 (C8), 26.2 (C9) (No carbonyl carbon with Boc group found); HRMS (ESI) + ): Calculated value C 19 H 30 N3O3: 348.2282, measured value [M+H] + :348.2281.

[0439] Following the general process A, N -Boc-4-(dimethylamino)methyl-indigoferazone (0.60 mmol) yielded 151 (120 mg, 81%) as a colorless solid, which turned into a viscous oil after being exposed to air for several days.

[0440] Data for 4-((dimethylamino)methyl-indigoferazone): mp: >200 ℃, colorless foam; [α] D 26 = -46 [c 0.5,MeOH];FTIR ν max / cm -1 (Net): 2948, 1656, 1549, 1457; 1 H NMR (500 MHz, D2O, δ H ):6.70(d, J = 1.5 Hz, 1H, C3-H), 6.62 (d, J= 1.5 Hz, 1H, C5-H), 4.24 (s, 2H, C13-H), 4.19 (d, J = 15.0 Hz, 1H, C7-H), 4.06 (dd, J = 15.0, 6.0 Hz, 1H, C7-H), 3.58-3.39(m, 5H, C10-H, C11-H, C12-H), 2.92 (s, 6H, NMe2), 2.88 (s, 1H, C8-H), 2.15(m, 2H, C9-H); 13 C NMR (MHz, D2O, δ) C ):164.5 (CO), 148.6 (C6), 143.2 (C4),118.9 (C3), 109.7 (C5), 59.1 (C13), 49.3, 48.7 (C11, C12), 48.1 (C7), 42.7(2C, NMe2), 31.5 (C10), 24.7 (C8), 22.4 (C9);HRMS (ESI + ): Calculated value C 14 H 22 N3O: 248.1757, measured value [M+H-HCl] + : 248.1755.

[0441] Example 51 – (-)4-((trimethylammonium)methyl)indigo iodide salt (150)

[0442] Iodomethane (0.1 mL, 1.3 mmol) was added to a solution of amine 143 (220 mg, 0.63 mmol) in EtOH (6.3 mL), and the reaction mixture was stirred at 60 °C for 18 h. The solution was concentrated. Deprotection and conversion to HCl salt were carried out using general process A to give 150 (80 mg, 42%) as a gray-green amorphous solid.

[0443] Mp: ≥ 200℃; [α] D 23 = -65 [c 1.3, MeOH];FTIR ν max / cm -1 (Net): 1656, 1551, 1479; 1 H NMR (500 MHz, D2O, δ H):6.77 (s, 1H, C3-H), 6.70 (s, 1H, C5-H), 4.42(s, 2H, C13-H), 4.20 (d, J = 15.0 Hz, 1H, C7-H), 4.09 (dd, J = 15.0, 6.0 Hz, 1H,C7-H), 3.60-3.41 (m, 5H, C10-H C11-H C12-H), 3.19 (s, 9H, NMe3), 2.89 (s, 1H,C8-H), 2.20 (d, J = 14.0 Hz, 1H, C9-H), 2.12 (d, J = 14.0 Hz, 1H, C9-H); 13 C NMR (125 MHz, D2O, δ) C ):164.3 (CO), 148.4 (C4), 140.8 (C6), 121.9 (C3), 111.7 (C5), 67.5 (C13), 53.2 (3C, NMe3), 49.4, 48.2 (C11, C12), 48.8 (C7), 31.6 (C10),24.7 (C8), 22.5 (C9);HRMS (ESI + ): Calculated value C 15 H 24 N3O: 262.1913, measured value [M+H] + -HCl-Cl - ]:262.1924.

[0444] Example 52 – (-)4-(N-acetyl)aminomethyl)indigo (148)

[0445] Amine 143 (310 mg, 1.0 mmol) was dissolved in isopropyl acetate (0.33 mL, 3 equivalents) and stirred at room temperature for 24 h. The reaction mixture was then concentrated. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH (3% MeOH)] to give the product (330 mg, 92%) as a colorless solid. Deprotection and conversion were performed using general procedure A to give 148 (237 mg, 80%) as a colorless foam.

[0446] mp: >200 ℃, colorless foam; [α] D 23= -20 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 2197(w), 1678, 1640, 1571, 1468; 1 H NMR (500 MHz, D2O, δ H ):6.54-6.44 (m, 2H, C3-H,C5-H), 4.29 (s, 2H, C13-H), 4.17 (d, J = 15.0 Hz, 1H, C7-H), 4.04 (dd, J = 15.0,6.0 Hz, 1H, C7-H), 3.55-3.38 (m, 5H, C10-H, C11-H, C12-H), 2.83 (s, 1H, C8-H), 2.18-2.05 (m, 5H, C9-H C16-H); 13 C NMR (125 MHz, D2O, δ C ):174.6 (C14),164.7 (CO), 153.3 (C4), 146.9 (C6), 112.3 (C3), 108.7 (C5), 49.5, 48.2 (C11,C12), 48.6 (C7), 41.7 (C13), 31.5 (C10), 24.8 (C8), 22.60 (C9), 21.7 (C15);HRMS (ESI + ): Calculated value C 14 H 20 N3O: 262.1550, measured value [M+H-HCl] + : 262.1543.

[0447] Example 53—— N -Boc 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)noindole(89)

[0448] Bromide 61 (180 mg, 0.5 mmol), Cu2O (8 mg, 0.1 equivalent) and 1- ZA solution of piperazine (0.5 mL, 2.5 mmol) in water (1.0 mL) was stirred in a sealed tube at 100 °C for 18 h. The reaction mixture was cooled and the residue was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude reaction mixture was purified by rapid column chromatography on silica gel [DCM / MeOH (2% MeOH)] to give 89% as a colorless solid (220 mg, 89%), which was used in the next step without further purification.

[0449] 1 H NMR (500 MHz, CDCl3, δ H ):7.37-7.30 (m, 5H, Ar), 5.74 (d, J = 2.5 Hz,1H, C3-H), 5.64 (s, 1H, C5-H), 5.16 (s, 2H, CH2-Ph), 4.39-4.06 (m, 3H, C7-H,C11-H, C12-H), 3.77 (dd, J = 15.0, 6.0 Hz, 1H, C7-H), 3.60 (m, 4H, C13-H), 3.27(m, 4H, C14-H), 3.01 (m, 2H, C11-H C12-H), 2.87 (s, 1H, C10-H), 2.35 (s, 1H,C8-H), 1.97 (d, J = 12.5 Hz, 1H, C9-H), 1.89 (d, J = 12.5 Hz, 1H, C9-H), 1.40-1.18 (s, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C):164.3 (CO), 156.4 (CO), 155.1(CO), 154.6 (C4), 148.3 (C6), 136.4 (Ar), 128.5 (2C, Ar), 128.1 (Ar), 127.9(2C, Ar), 96.4 (C3), 95.0 (C5), 80.1 (q Boc), 67.7 (CH2-Ph), 50.6, 50.5 (C11,C12), 47.9 (C7), 46.1 (2C, C13), 43.1 (2C, C14), 35.4 (C10), 28.1 (3C, Boc),27.7 (C8), 26.5 (C9);HRMS (ESI + ): Calculated value C 28 H 37 N4O5: 509.2758, measured value [M+H] + : 509.2733.

[0450] Example 54—— N -Boc 4-(piperazin-1-yl)noindine

[0451] A solution of 89 (160 mg, 0.32 mmol) in methanol (5 mL) was placed under nitrogen atmosphere, and 10 wt% (5 mg, 0.1 equivalent) of palladium supported on activated carbon was added. The container was placed under vacuum and purged three times with hydrogen, and stirred for 18 h. The solution was then analyzed using Celite. ® The reaction mixture was filtered and the solvent was concentrated to give a piperazine derivative (85 mg, 71%) as a colorless solid, which was used in the next step without further purification.

[0452] 1 H NMR (500 MHz, CDCl3, δ H ):5.85 (s, 1H, C3-H), 5.72 (s, 1H, C5-H), 5.49 (br, 1H, NH), 4.33-4.01 (m, 3H, C7-H, C11-H, C12-H), 3.74 (dd, J= 15.0,6.0 Hz, 1H, C7-H), 3.55 (s, 4H, C13-H), 3.19 (s, 4H, C14-H), 3.07-2.94 (m,2H, C11-H, C12-H), 2.92 (s, 1H, C10-H), 2.36 (s, 1H, C8-H), 1.96 (d, J = 13.5Hz, 1H, C9-H), 1.89 (d, J = 13.5 Hz, 1H, C9-H); 1.38-1.19 (s, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ) C ):164.6 (CO), 156.4 (CO), 154.5 (C4), 148.8 (C6), 96.9(C3), 95.0 (C5), 80.0 (q Boc), 50.6, 50.5 (C11, C12), 48.2 (C7), 44.7 (2C,C13), 43.6 (2C, C14), 35.2 (C10), 28.1 (3C, Boc), 27.5 (C8), 26.4 (C9);HRMS(ESI + ): Calculated value C 20 H 31 N4O3: 375.2391, measured value [M+H] + : 375.2383.

[0453] Example 55——(+)4-( N -piperazinyl)noindoline trihydrochloride (90)

[0454] Will N -Boc 4- N -( N A solution of '-Cbz'-piperazine-indigo (323 mg, 0.64 mmol) in MeOH (6.4 mL) was placed under nitrogen atmosphere, and Pd / C (10 wt%) (6.5 mg, 0.1 equivalent) was added. The container was placed under vacuum and purged three times with hydrogen, and stirred for 24 h. The mixture was then passed through Celite. ® The sample was filtered and concentrated under vacuum. Deprotection and conversion to its HCl salt were performed using standard process A, yielding 90 (237 mg, 96%) of a colorless solid.

[0455] mp: >200℃, colorless powder; [α]D 25 = +52 [c 1.0, MeOH];FTIR ν max / cm -1 (Net): 3374, 2924, 2712, 2585, 2451, 1638, 1538; 1 H NMR (400 MHz, D2O, δ H ):6.55 (s, 1H, C3-H), 4.10 (d, J = 15.0 Hz, 1H, C7-H a ), 3.98 (dd, J = 6.5, 15.0 Hz, 1H, C7-H b ), 3.69-3.66 (m, 4H, C14-H), 3.47-3.26 (m, 9H, C10-H, C11-H, C12-H, C13-H), 2.70 (s, 1H, C8-H), 2.07-1.96 (m, 2H, C9-H), C5-H was not detected due to deuterium exchange; 13 C NMR (100MHz, D2O, δ C ): 162.1 (CO), 157.2 (C4), 148.1 (C6), 102.4 (C3), 92.2-91.7 (m,C5), 49.2 (C11 or C12), 48.8 (C7), 48.1 (C11 or C12), 42.7 (2C, C13), 42.5 (2C, C14), 31.7 (C10), 24.5 (C8), 22.5 (C9); HRMS (ESI) + ): Calculated value C 15 H 23 N4O: 275.1866, measured value [M+H-3HCl] + : 275.1868.

[0456] Example 56a—N-Boc 3-(trifluoromethyl)-4-bromoindole 161

[0457] Will NA solution of 4-bromo-indigo 61 (370 mg, 1.0 mmol) in a mixture of DMSO (3.8 mL) and H2O (1.6 mL) was cooled to 0 °C and sodium trifluoromethanesulfonate (470 mg, 3.0 mmol) was added. Tert-butyl hydroperoxide (0.7 mL, 70% aqueous solution) was added dropwise over 5 min, and the solution was allowed to warm to room temperature and stirred for 24 h. The solvent was removed under vacuum. The crude material separated into layers between ammonia (15 mL, 15% aqueous solution) and DCM (15 mL), and the aqueous phase was extracted with DCM (3 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude material was purified by rapid column chromatography on silica gel [n-hexane / EtOAc (1:1)] to give 161 (130 mg, 30%) as a colorless solid, and 3% [other components]. N -Boc-5-CF3-4-bromo-indigo. [1H NMR: 98% (C3-substituted), 2% (C5-substituted; 87% conversion)].

[0458] FTIR ν max / cm -1 (Net): 2972, 2923, 2865, 1677, 1645, 1543; 1 H NMR (500 MHz, CDCl3, δ) H ):6.41 (s, 1H, C5-H), 4.45-4.10 (m, 3H, C7-H, C11-H, C12-H), 3.88-3.76 (dd, J = 6.5, 15.5 Hz, 1H, C7-H), 3.23-2.91 (m, 3H, C11-H, C12-H, C10-H), 2.48 (s, 1H, C8-H), 1.99 (s, 2H, C9-H), 1.44-1.18 (m, 9H, Boc); 13 C NMR (125MHz, CDCl3, δ C ):158.7 (CO), 154.5 / 154.0 (CO, rotatimer), 152.2 / 151.7 (C6), 135.0 / 134.7 (C4), 122.6 (q, J = 276 Hz, CF3), 116.2 (q, J= 30 Hz, C3), 121.3 / 110.5 (C5, rotifer), 80.9 / 80.3 (q Boc, rotifer), 51.2 / 50.4 / 49.8 / 49.1 (C11, C12, rotifer), 49.4 (C7, rotifer), 34.7 (C10), 28.0 (3C, Boc), 27.2 (C8), 25.5 (C9); HRMS (ESI) + ): Calculated value C 17 H 21 BrF3N2O: 437.0682, measured value [M+H] + : 437.0679.

[0459] Example 56b — (-)3-(trifluoromethyl)-4-bromoindole hydrochloride (162)

[0460] Following general procedure A, bromide 161 (0.25 mmol) yielded 162 (0.45 mg, 48%).

[0461] mp: >200℃, colorless powder; [α] D 23 = -19 [c 0.20, MeOH];FTIR ν max / cm -1 (Net): 1651, 1543, 1130, 1076; 1 H NMR (400 MHz, D2O, δ H ):6.83 (s, 1H, C5-H), 4.04 (d, J = 15.5Hz, 1H, C7-H), 3.89 (dd, J = 6.5, 15.5 Hz, 1H, C7-H), 3.46-3.28 (m, 5H, C10-H,C11-H, C12-H), 2.76 (s, 1H, C8-H), 2.06 (d, J = 13.5 Hz, 1H, C9-H), 2.00 (d, J =13.5 Hz, 1H, C9-H); 13 C NMR (100 MHz, D2O, δ C ):160.7 (CO), 150.3 (C6), 136.5(C4), 122.4 (q, J= 275 Hz, CF3), 116.2 (q, J = 30 Hz, C3-H), 114.3 (C5-H), 48.9,48.0 (C11, C12), 48.8 (C7), 31.4 (C10), 24.5 (C8), 22.1 (C9);HRMS (ESI + ): Calculated value C 12 H 13 BrF3N2O: 337.0158, measured value [M+H] + : 337.0162.

[0462] Example 57a—— N -Boc 3-bromo-4-iodonoindole (159)

[0463] Will N -Boc-4-iodo-indigo 65 (120 mg, 0.286 mmol) was dissolved in THF (6 mL, 0.05 M) and added N - Bromosuccinimide (51 mg, 0.286 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (15 mL) and the aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude material was purified by rapid column chromatography on silica gel [n-hexane / EtOAc (1:1)] to give 159 (91 mg, 65%). N -Boc-5-bromo-4-iodo-indigo alkaloid contamination (at a ratio of 22:3).

[0464] FTIR ν max / cm -1 (Net): 2925, 2865, 1669, 1634, 1569; 1 H NMR (500 MHz, CDCl3, δ) H ):6.58 (s, 1H, C5-H), 4.43-4.06 (m, 3H, C7-H, C11-H, C12-H), 3.78 (dd, J =6.5, 15.5 Hz, 1H, C7-H), 3.16-2.86 (m, 3H, C10-H, C11-H, C12-H), 2.42 (s, 1H,C8-H), 1.96 (m, 2H, C9-H), 1.40-1.15 (m, 9H, Boc);13 C NMR (125 MHz, CDCl3, δ) C ): 157.7 (CO), 156.5 (CO), 154.6 / 154.1 (C6, rotatable isomer), 147.7 / 147.2 (C4, rotatable isomer), 121.4 (C3), 115.5 / 114.9 (C5, rotatable isomer), 80.6 / 80.1 (q Boc, rotatable isomer), 51.8 / 51.5 / 50.0 / 49.4 (C11, C12, rotatable isomer), 50.4 (C7, rotatable isomer), 34.3 (C10), 28.1 (3C, Boc), 27.4 (C8), 25.9 (C9), HRMS (ESI) + ): Calculated value C 16 H 21 BrIN2O3: 494.9774, measured value [M+H] + : 494.9761.

[0465] Example 57b — (+) 3-bromo-4-iodoindole hydrochloride (160)

[0466] Following the general procedure A, iodine 159 (0.16 mmol) yielded 160 (57 mg, 81%); contaminated with 5-bromo-4-iodo-indigo (ratio 22:3).

[0467] [α] D 23 = +7 [c 0.3, water];FTIR ν max / cm -1 (Net): 2985, 1606, 1566, 1096; 1 HNMR (500 MHz, DMSO, δ H ):6.83 (s, 1H, C5-H), 3.92 (d, J = 15.5 Hz, 1H, C7-H),3.79 (dd, J = 6.5, 15.5 Hz, 1H, C7-H), 3.33-3.12 (m, 5H, C11-H, C12-H, C10-H), 2.62 (s, 1H, C8-H), 1.99 (d, J = 13.5 Hz, 1H, C9-H), 1.87 (d, J= 13.5 Hz, 1H, C9-H); 13 C NMR (125 MHz, DMSO, δ C ):157.7 (CO), 147.7 (C6), 121.0 (C4), 116.4(C3), 115.6 (C5), 49.8 (C7), 48.8, 48.0 (C11, C12), 30.9 (C10), 14.9 (C8),22.9 (C9);HRMS (ESI + ): Calculated value C 11 H 13 BrIN2O: 394.9250, measured value [M+H-HCl] + : 394.9249.

[0468] Example 58a—— N -Boc 3-bromo-4-methylaminoindigoline (157)

[0469] Towards N 83-methylamine (96 mg, 0.30 mmol) was added to a solution of THF (6.0 mL). N - Bromosuccinimide (54 mg, 0.30 mmol) was reacted with stirring at room temperature for 24 h. The reactants were diluted with water (15 mL) and the aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude material was purified by rapid column chromatography on silica gel [DCM / MeOH (2% MeOH)] to give 157 ( N -Boc-3-bromo-4-methylamino-nodoline (84 mg, 70%), and N -Boc-5-bromo-4-methylamino (27 mg, 22%) was used in the next step without further purification.

[0470] Data from 157: FTIR ν max / cm -1 (Net): 3290, 2946, 2761, 2623, 1633, 1493, 1206, 1100, 1025, 567, 521; 1 H NMR (500 MHz, CDCl3, δ H):5.68 (s, 1H, C5-H), 4.84 (s,1H, NH), 4.36-4.05 (m, 3H, C11-H, C12-H, C7-H), 3.79 (dd, J = 6.5, 15.5 Hz, 1H,C7-H), 3.13-2.85 (m, 6H, C11-H, C12-H, C10-H, NHMe), 2.33 (s, 1H, C8-H), 1.91(m, 2H, C9-H), 1.36-1.13 (m, 9H, Boc); 13 C NMR (125 MHz, CDCl3, δ C ):159.2 (CO),154.7, 154.2 (C6, rotatimer), 152.4 (CO), 148.0, 147.7 (C4, rotatimer),93.0, 92.5 (C5-H), 90.4 (C3), 80.3, 79.7 (q Boc, rotatimer), 51.6, 50.6, 50.2, 49.3 (C11, C12), 49.1 (C7), 35.0 (C10), 29.8 (C8), 28.0, 27.7 (Boc, rotatimer), 26.2 (C9).

[0471] Example 58b — (+) 3-bromo-4-N-methylaminoindigo base hydrochloride (158)

[0472] Following the general process A, N 157 (0.21 mmol) of methylamine yielded 158 (45 mg, 73%) as a colorless solid, contaminated with 9% 5-bromo-4-methylamino-indigo.

[0473] [α] D 23 = +38 [c 0.5, MeOH];FTIR ν max / cm -1 (Net): 3291, 2949, 2761, 2624, 1634, 1583; 1 H NMR (500 MHz, D2O, δ H ):6.14 (s, 1H, C5-H), 4.13 (d, J = 15.5 Hz,1H, C7-H), 3.88 (dd, J= 6.5, 15.5 Hz, 1H, C7-H), 3.52-3.32 (m, 5H, C11-H, C12-H, C10-H), 2.84 (s, 3H, NHMe), 2.70 (s, 1H, C8-H), 2.04 (m, 2H, C9-H); 13 C NMR (125 MHz, D2O, δC): 160.5 (CO), 154.3 (C6), 145.6 (C4), 97.0 (C3), 89.6 (C5), 49.3, 48.5 (C11, C12), 48.9 (C7), 31.6 (C10), 28.9 (NHMe), 24.9 (C8), 22.9(C9); HRMS (ESI + ): Calculated value C 12 H 17 BrN3O: 298.0549, measured value [M+H] + 298.0549 Example 59 – Iridium-catalyzed ( CH borylation of )-indigoferrate Synthesis of 4-Bpin indigo alkaloid.

[0474] Inject into the Schlenk tube ( 4-Bpin indigoferazone (190 mg, 1.0 mmol), [Ir(COD)(OMe)]2 (6.6 mg, 0.01 equivalent), 4,4'-2,2'-di-tert-butyl-bispyridine (5.4 mg, 0.02 equivalent), and bis(pinacol)diborane (380 mg, 1.50 equivalent). After purging with nitrogen, THF (1.4 mL) was added and the reaction mixture was heated under reflux for 24 h. After this period, volatiles were removed under reduced pressure, and 4-Bpin indigoferazone was partially characterized without further purification and obtained as a brown foam.

[0475] 1H NMR (500 MHz, CDCl3): δ = 6.88 (d, 1 H, J = 1.0 Hz), 6.27 (s, 1H), 4.11 (d, 1 H, J = 15.5 Hz), 3.86 (dd, 1 H, J = 6.5, 15.5 Hz), 3.15-2.78 (m, 5H), 3.21 (s, 1H), 1.94-1.91 (m, 2H), 1.23 (s, 12H).

[0476] 13C NMR (125 MHz, CDCl3): δ = 163.1, 149.2, 124.1, 108.8, 84.4, 82.7,53.3, 52.3, 49.6, 35.1, 27.5, 25.5, 14.5.

[0477] To identify 4-Bpin indigoline, the compound was further converted to 4-bromoindigoline by treatment with an aqueous solution of CuBr2 in MeOH. The spectroscopic properties of 4-bromoindigoline were consistent with data available in the literature.

[0478] Example 60 – Iridium-catalyzed ( CH borylation of )-indigoferrate Synthesis of 4-Bpin indigo alkaloid.

[0479] The method of Example 59 was carried out using the same equipment and solvent, except that Me4phen was used as the ligand and the borizing agent B2Pin2 was present in 3.00 equivalents. The molar amounts of catalyst and ligand were the same as those summarized above. This method yielded 100% conversion of indigo to 4-Bpin indigo.

[0480] Example 61 – Iridium-catalyzed ( CH borylation of )-indigoferrate Synthesis of 4-Bpin indigo alkaloid.

[0481] The method of Example 59 was carried out using the same equipment and solvent, except that a new copper reagent was used as the ligand, and the molar amounts of catalyst and ligand were the same as described above. This method yielded 100% conversion of indigo to 4-Bpin indigo.

[0482] Example 62 – CH Boration of N-Boc indigo base (56) catalyzed by iridium Synthesis of N-Boc 4-Bpin indigo (58) N-Boc indigoferazone (56) (290 mg, 1.0 mmol), [Ir(COD)(OMe)]2 (6.6 mg, 0.01 equivalent), 4,4'-2,2'-di-tert-butylbispyridine (5.4 mg, 0.02 equivalent), and bis(pinacol)diborane (178 mg, 0.70 equivalent) were injected into a Schlenk tube. After purging with nitrogen, THF (1.4 mL) was added, and the reaction mixture was heated under reflux for 18 h. After this period, 1H NMR showed essentially 100% conversion, with volatiles removed under reduced pressure.

[0483] 1H NMR showed that the crude product N-Boc 4-Bpin indigo alkaloid (58) was essentially pure. Although further purification was feasible, it was not necessary to purify it before using N-Boc 4-Bpin indigo alkaloid (58) as a reactant.

[0484] The crude N-Boc 4-Bpin indigo alkaloid (58) was further purified by chromatography (DCM-MeOH, 95:5) to obtain pure N-Boc 4-Bpin indigo alkaloid (58) (180 mg, 43%) as a light yellow foam. Rf = 0.23 (DCM-MeOH, 95:5). IR (net): 3433, 2977, 1688, 1657, 1563, 1423 cm⁻¹. 1H NMR (400 MHz, CDCl3): δ = 6.85 (s, 1 H), 6.31 (s, 1 H), 4.34-4.10(m, 3 H), 3.80 (dd, 1 H, J = 6.5, 15.5 Hz), 3.07-2.91 (m, 3 H), 2.41 (s, 1H), 1.95-1.88 (m, 2 H), 1.41-1.09 (m, 21 H). 13C NMR (100 MHz, CDCl3): δ = 162.9, 154.6 / 154.3 (rotational isomer), 147.9 / 147.5 (rotational isomer), 124.4, 109.3 / 108.8 (rotational isomer), 84.4, 82.6 / 80.3, 79.7 / 75.0 (2 C, rotational isomer), 51.7 / 50.6 / 50.3 / 49.2 (2 C, rotational isomer), 48.9, 34.7, 28.0 (4 C), 27.5, 26.1, 24.8 / 24.6 (3 C, rotational isomer); C-Bpin not observed.

[0485] 11B NMR (96.4 MHz, CDCl3): δ = 28.94 (br s).

[0486] HRMS-ESI: m / z [M + H]+ Calculated value C22H33BN2NaO5: 439.2379; obtained: 439.2373.

[0487] Example 63 – CH Boration of N-Boc indigo base (56) catalyzed by iridium Synthesis of N-Boc 4-Bpin indigo (58) The method of Example 62 was carried out using the same equipment and solvent, except that N-methylindocyanine was used as the starting material of Formula IIa, and the molar amounts of catalyst and ligand were the same as those summarized above. This method yielded a 98% conversion of indocyanine to 4-Bpin indocyanine.

[0488] Example 64 – CH Boration of N-Boc indigo base (56) catalyzed by iridium Synthesis of N-Boc 4-Bpin indigo (58) The method of Example 62 was carried out using the same equipment and solvents, except that N-Cbz indigo base was used as the starting material of Formula IIa, and the molar amounts of catalyst and ligands were the same as those summarized above. This method yielded an 88% conversion of indigo base to 4-Bpin indigo base.

[0489] Example 65 – N-Boc 4-p-Tolyl indigo (72) N-Boc 4-Bpin indigo 58 was prepared at a scale of 0.5 mmol according to the general procedure described above. Potassium carbonate (124 mg, 0.90 mmol), tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.05 equivalent), and 4-bromotoluene (0.25 mL, 1.0 mmol) were added to crude N-Boc 4-Bpin indigo 58, along with a mixture of DME / water (5:1) (5 mL, 0.1 M). The mixture was heated at 80 °C for 24 h, then cooled to room temperature and diluted with water (15 mL). The aqueous phase was extracted with DCM (3 × 15 mL), and the combined organic phase was dried over MgSO4, filtered, and concentrated. N-Boc 4-(p-tolyl) indigo 58 (104 mg, 55%) was purified by rapid column chromatography [DCM:MeOH (1.5% MeOH)] to obtain a colorless solid.

[0490] Example 66—— N -Boc 4-methylnoindoline (109) N-Boc 4-Bpin indigo 58 was prepared on a 0.5 mmol scale according to the general procedure described above for the borylation of indigo.

[0491] Using an improved process, Pd2dba3 (11 mg, 0.025 equivalents), tris(p-tolyl)phosphine (7.6 mg, 0.05 equivalents), potassium carbonate (138 mg, 2.0 equivalents), and iodomethane (0.03 mL, 1.0 equivalents) were added to crude N-Boc 4-Bpin indigo 58, and the container was placed under vacuum and purged three times with nitrogen. A mixture of DMF / water (9:1.5 mL) was added, and the reaction mixture was stirred at 60 °C for 18 h. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue separated into layers between EtOAc (15 mL) and water (15 mL), and the aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic phase MgSO4 was dried, filtered, concentrated, and purified by rapid column chromatography on silica gel [DCM / MeOH (3% MeOH)] to give N-Boc 4-methylindigo (98 mg, 64%) as a pale yellow solid.

[0492] Example 67a—— N -Boc(3-bromo-4-hydroxy)indigoline

[0493] Will N A solution of 4-aminonoindoline (512 mg, 1.67 mmol) in THF (32 mL) was cooled to 0°C, and then... N - Bromosuccinimide (312 mg, 1.76 mmol) was added, and the reaction mixture was stirred at 0 °C for 18 hours. Water (25 mL) was added, and the aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by rapid column chromatography [EtOAc / MeOH (1% MeOH)] to obtain... N -Boc(3-bromo-4-hydroxy)indigo (350 mg, 55%) is a colorless solid.

[0494] R f :0.37 [DCM / MeOH (5% MeOH)];FTIR νmax / cm -1 (Net): 2864, 1698, 1581, 1408, 1245, 1129; 1 H NMR (500 MHz, DMSO, δ H ):11.00 (s, 1H), 5.94 (s, 1H), 4.18-3.81 (m, 3H), 3.58 (dd, J= 15.0, 6.5 Hz, 1H), 3.14-2.85 (m, 3H), 2.30 (s, 1H), 1.85 (s, 2H), 1.29-1.02 (m, 9H); 13 C NMR (500 MHz, DMSO, δ C ):162.6, 160.4,154.1, 149.0, 98.0, 93.2, 79.1, 51.7, 50.5, 49.6, 34.3, 28.0, 27.4, 25.7;HRMS(ESI + ): Calculated value C 16 H 22 79 BrN2O4: 385.0757, measured value [M+H] + : 385.0764.

[0495] Example 67b – (–)-(3-bromo-4-hydroxy)noindigo hydrochloride (BS70)

[0496] Following the general process A, N -Boc(3-bromo-4-hydroxy)indole (0.83 mmol) yielded BS70 (236 mg, quantified) as a colorless solid.

[0497] mp:≥200 ℃;[α] D 24 =-0.12 [c 1.0, water]; FTIR νmax / cm -1 (Net): 2573, 1646, 1550, 1408, 1310, 1097, 854; 1 H NMR (500 MHz, D2O, δ H ):6.34 (s, 1H), 4.26 (d, J =15.5 Hz, 1H), 4.00 (dd, J = 15.5, 7.0 Hz, 1H), 3.60 (d, J = 13.5 Hz, 1H), 3.50-3.40 (m, 4H), 2.82 (s, 1H), 2.13 (m, 2H); 13 C NMR (500 MHz, D2O, δ C):163.3,162.3, 146.4, 101.5, 94.8, 49.3, 49.2, 48.3, 31.4, 24.8, 22.7;HRMS (ESI + ): Calculated value C 11 H 14 79 BrN2O2: 285.0160, measured value [M+H] + : 285.0230.

[0498] Example 68a—— N- Boc (3-bromo-4-amino)noindine

[0499] The solution of 4-aminonoindocyanine (250 mg, 0.82 mmol) in THF (16 mL) was cooled to 0°C, and then... N - Bromosuccinimide (153 mg, 0.86 mmol) was added, and the reaction mixture was stirred at 0 °C for 18 hours. Water (25 mL) was added, and the aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by rapid column chromatography [EtOAc] to give N-Boc(3-bromo-4-amino)indigo (95 mg, 30%) as a colorless solid.

[0500] R f :0.43 [DCM / MeOH (6% MeOH)];mp:≥200 ℃ (toluene);FTIR νmax / cm -1 (Net): 3441, 3178, 2917, 1682, 1633, 1591, 1427, 1124, 820, 751; 1 H NMR (500 MHz, CDCl3, δ) H ):5.67 (s, 1H), 4.59 (s, 2H), 4.43-4.00 (m, 3H), 3.82 (dd, J = 15.5,6.5 Hz, 1H), 3.13-2.87 (m, 3H), 2.36 (s, 1H), 1.95 (d, J = 12.5 Hz, 1H), 1.91(d, J = 12.5 Hz, 1H), 1.39-1.18 (m, 9H); 13 C NMR (500 MHz, CDCl3, δ C):159.8,154.4, 151.5, 146.9, 96.1, 91.4, 80.3, 51.5, 50.4, 49.3, 34.7, 28.0, 27.4,26.3;HRMS (ESI + ): Calculated value C 16 H 22 81 BrN3NaO3: 408.0737, measured value [M+Na] + : 408.0713.

[0501] Example 68b — (+)-(3-bromo-4-amino)noindigo hydrochloride (BS71)

[0502] Following the general process A, N -Boc(3-bromo-4-amino)indigo gave BS71 (62 mg, 64%) as a colorless solid.

[0503] mp: ≥200 ℃ (toluene); [α] D 24 =+0.08 [c 1.0, water];FTIR νmax / cm -1 (Net): 3313, 3132, 2934, 2756, 1641, 1532, 1454, 1163; 1 H NMR (500 MHz, MeOD, δ H ):6.15 (s,1H), 4.37 (d, J = 15.5 Hz, 1H), 3.92 (dd, J = 15.5, 6.5 Hz, 1H), 3.54 (d, J = 13.0Hz, 1H), 3.49-3.36 (m, 3H), 3.31 (s, 1H), 2.70 (s, 1H), 2.15 (d, J = 13.5 Hz, 1H), 2.07 (d, J = 13.5 Hz, 1H); 13 C NMR (500 MHz, MeOD, δ C ):159.9, 154.7, 144.9,100.2, 89.3, 49.2, 48.9, 48.3, 31.6, 25.4, 23.2;HRMS (ESI + ): Calculated value C 11H 15 79 BrN3O: 284.0393, measured value [M+H] + : 284.0390.

[0504] Example 69a—— N -Boc(3-bromo-4-ethyl)indigoline

[0505] Will N A solution of 4-ethyl-indocyanine (341 mg, 1.07 mmol) in THF (20 mL) was cooled to 0 °C, and then... N - Bromosuccinimide (190 mg, 1.07 mmol) was added, and the reaction mixture was stirred at 0 °C for 18 hours. Water (25 mL) was added, and the aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by rapid column chromatography [DCM / MeOH (2% MeOH)] to obtain... N -Boc(3-bromo-4-ethyl)indigo (296 mg, 70%) is a colorless solid.

[0506] R f :0.22 [DCM / MeOH (2% MeOH)]; 1 H NMR (500 MHz, CDCl3, δ H ):5.99 (s, 1H),4.45-4.02 (m, 3H), 3.86 (dd, J = 15.5, 6.5 Hz, 1H), 3.16-2.86 (m, 3H), 2.66 (m,2H), 2.40 (s, 1H), 2.00-1.88 (m, 2H), 1.44-1.03 (m, 12H); 13 C NMR (500 MHz, CDCl3, δ) C ):159.5, 154.5, 146.8, 112.9, 106.3, 80.3, 51.5, 50.4, 50.0, 29.8, 29.6, 28.0, 27.4, 26.2, 12.7, (C9 not found);HRMS (ESI) + ): Calculated value C 18 H 26 79 BrN2O3: 397.1121, measured value [M+H] + :397.1121.

[0507] Example 69b — (–)-(3-bromo-4-ethyl)noindigo (BS74)

[0508] Following the general process A, N -Boc(3-bromo-4-ethyl)indole (296 mg, 0.75 mmol) yielded BS74 (80 mg, 37%) as a colorless solid.

[0509] mp:≥200℃;[α] D 24 =-0.21 [c 1.0, water];FTIR νmax / cm -1 (Net): 2935, 2544, 1635, 1572, 1450, 1101, 705; 1 H NMR (500 MHz, MeOD, δ H ):6.50 (s, 1H), 4.45 (d, J = 15.5 Hz, 1H), 4.02 (dd, J = 15.5, 6.5 Hz, 1H), 3.63 (d, J = 13.5 Hz, 1H), 3.54-3.42 (m, 4H), 2.81 (s, 1H), 2.72 (m, 2H), 2.22 (d, J = 13.5 Hz, 1H), 2.12 (d, J =13.5 Hz, 1H), 1.25 (t, J = 7.0 Hz, 3H); 13 C NMR (500 MHz, MeOD, δ) C ):159.9,156.0, 144.9,112.9, 108.8, 49.6, 49.3, 48.4, 31.6, 29.4, 25.4, 22.9, 11.5;HRMS (ESI + ): Calculated value C 13 H 18 79 BrN2O: 297.0597, measured value [M+H]+: 297.0591.

[0510] Example 70 Binding with nicotine receptor subtypes The affinity for binding groups of the above compounds was tested in different nAChR isoforms, particularly α4β2, α3β4, and α7. The protocols for these tests are listed below, and the results are provided in Table 1.

[0511] Binding to heterologously expressed human subtypes of α4β2 and α3β4 HEK 293 cells were grown in a humid atmosphere containing 10% CO2 in Dulbecco's modified Eagle medium supplemented with 10% fetal bovine serum, 1% L-glutamine, 100 units / ml penicillin G, and 100 μg / ml streptomycin. cDNA encoding α3 and β4 or α4 and β2 was transfected into HEK 293 cells at a 30% fusion. 30 μL of JetPEI was used. TM Cells were transfected in 100 mm Petri dishes with 1 mg / ml (Polypus, France) cDNA (pH 7.2) and 3 μg of each cDNA. Cells were collected 24 h after transfection, washed with PBS by centrifugation, and used for binding assays.

[0512] Using overnight incubation at 4°C, HEK-transfected α3β4 or α4β2 receptors were subjected to [methods] in the presence (non-specific binding) or absence (total binding) of 100 nM hygroscin in a buffer containing 50 mM Tris-HCl, pH 7, 150 mM NaCl, 5 mM KCl, 1 mM MgCl2, 2.5 mM CaCl2, and 2 mg / ml BSA. 3 [H]-Saturated binding assay of saturated ligands. Specific ligand binding was defined as total binding minus binding in the presence of 100 nM cold saturated ...

[0513] The test compound was incubated at increased concentrations (10 pM - 10 mM) at room temperature (rt) for 30 min, followed by incubation with 0.25 nM [ 3 The final concentrations of H]-spinyrodin (in the α4β2* isoform) or 0.5 nM (in the α3β4 isoform) were measured by overnight incubation at 4°C to measure the effect induced by the compound or nicotinic ligand on [ 3 Inhibition of H-in binding. After incubation, membranes of HEK cells transfected with α4β2* or α3β4 isoforms were washed by filtration through a GFC filter with ice-cold PBS. The GFC filter was pre-soaked in polyethyleneimine and filtered through a harvester device. [The results were determined using a Beta counter with liquid scintillation counting.] 3 H]-binding of thorny-spotted frogin.

[0514] Binding to heterologously expressed α7 isoform Human α7 cDNA was transfected into SH-SY5Y human neuroblastoma cells. 30 μL of JetPEI was used. TM Cells were transfected with 1 mg / ml (Polypus, France) and 6 μg of α7 cDNA in 100 mm Petri culture dishes. Cells were collected 24 h after transfection, washed with PBS by centrifugation, and used for binding assays.

[0515] By using 0.1-10 nM concentrations at room temperature 125 I]-α-Bungarus venom overnight incubation with SH-SY5Y membrane for [… 125 I]-α-Bungarus venom (purchased from Perkin Elmer, Boston, USA) saturated binding. Non-specific binding was measured in parallel by incubation in the presence of 1 μM unlabeled α-Bungarus venom. After incubation, the sample was filtered as described above, and the binding radioactivity was counted directly in a gamma counter. The SH-SY5Y membrane was pre-incubated at room temperature for 30 min with an increased concentration (10 M-1 mM) of the analyte, followed by incubation at room temperature with a final concentration of 2-3 nM of […]. 125 I]-α-Bungarus venom was incubated overnight to determine the effect of the test compound on [ 125 Inhibition of binding of I]-α-Bungarus fasciatus venom.

[0516] After overnight incubation, the membranes of SH-SY5Y cells transfected with α7 were washed by filtration through a GFC filter with ice-cold PBS. The GFC filter was pre-soaked in polyethyleneimine and then filtered through a harvester device. Measurements were determined by direct counting in a gamma counter. 125 I]-α-Bungarus venom binding.

[0517] Data Analysis The ligand binding data were analyzed using Prism version 5 (GraphPad Software, Inc., La Jolla, CA) with the aid of nonlinear regression. K i Values ​​are determined by experimental IC. 50 Values ​​were calculated using the Cheng-Prusoff equation for a single population competing for sites: K i =IC 50 / [1+( L / K d )],in L This refers to the concentration of the radioactive ligands used in each experiment, andK d The values ​​were determined by saturation binding experiments. All these determinations were performed in duplicate and repeated at least two to three times.

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527] The data shows that, compared with both the α3β4 and α7 subtypes (tested in both mouse and human cells), the compounds of the present invention exhibit high selectivity at the human α4β2 receptor subtype, minimizing the possibility of "off-target" effects.

[0528] Example 71 – Relative potency at nicotine receptor subtypes The effects of the compounds of this invention on the function of human α4β2, α3β4, and α7 nicotinic acetylcholine receptors (nAChRs) heterologously expressed in Xenopus oocytes were tested. The human α4β2 nACh receptors were expressed as (α4)3(β2)2 (low sensitivity to ACh) or (α4)2( β 2) 3 receptor (highly sensitive to ACh) (Moroni et al., 2006). Expression in oocytes was obtained as follows: pCI (Promega, UK) plasmids containing complementary DNA of human α4, β2, β4, or α7 were injected as previously described (Moroni et al., 2006). To express the (α4)3(β2)2nACh receptor, a mixture of 10α4:1β2 cDNAs was injected into the nucleus of oocytes, while for the (α4)2(β2)3 receptor, the injected cDNA ratio was 1α4:10β2.

[0529] Functional studies: Recordings were performed manually using a Geneclamp amplifier (Molecular Devices, USA) or an automated HiClamp system. In both cases, oocytes were punctured by two electrodes filled with 3 M KCl throughout the experiment, and the cells were maintained at -60 mV.

[0530] Oocyte isolation and two-electrode voltage-clamp recording on oocytes were performed as previously described (Moroni et al., 2006; Carbone et al., 2009). Agonist concentration-response curves were obtained by normalizing the compound-induced response to the response induced by 1 mM ACh, which is the concentration of ACh that maximally activates all target receptors (Abin-Carriquiry et al., 2006; Moroni et al., 2006; Carbone et al., 2009). A minimum interval of 5 min was allowed between agonist applications to ensure reproducible recording. Oocytes were exposed to increasing concentrations of the compound until the amplitude of the obtained response no longer increased. This concentration was considered to elicit the maximum response on the target receptor. The data summarized in Tables 1-4 were obtained from at least five experiments performed on oocytes from at least three different donors.

[0531] a) Effect of the compound on (α4)3(β2)2nAChR (low-sensitivity stoichiometry) Maximum gating effectiveness of the compounds: The concentration of the compounds of the invention leading to maximum activation of (α4)3(β2)2nAChR heterologously expressed in Xenopus oocytes was determined using a two-electrode voltage clamp. The maximum current induced by the compounds was compared with the maximum concentration induced by 1 mM ACh (which induces the maximum response to the (α4)3(β2)2 receptor).

[0532] Table 2

[0533] b) Effect of (α4)2(β2)3nAChR Maximum gating efficacy of compounds on (α4)2(β2)3 receptors (highly sensitive receptors): The concentration of the compound leading to maximum activation of (α4)2(β2)3nAChR heterologously expressed in Xenopus oocytes was determined using a two-electrode voltage clamp. The maximum current induced by the compound was compared to the maximum concentration induced by 1 mM ACh (which induces the maximum response to the (α4)2(β2)3 receptor).

[0534] Table 3

[0535] c) Effects of the compound on α3β4 nAChR Maximum gating effectiveness of compounds on α3β4 nAChR: The concentration of the compound leading to maximum activation of α3β4 nAChR heterologously expressed in Xenopus oocytes was determined using a two-electrode voltage clamp. The maximum current induced by the compound was then compared with the maximum concentration induced by 1 mM ACh (which induces the maximum response to the α3β4 receptor).

[0536] Table 4

[0537] d) Effect of the compound on α7 nAChR The relative effectiveness of the compound for α7 nAChR: The magnitude of the current induced by the compound at 100 µM was measured and then compared with the magnitude of the response to 1 mM ACh, which is the concentration of ACh that leads to the maximum activation of α7 nAChR.

[0538] Table 5

[0539] The data in Table 5 show that the compounds of the present invention exhibit lower relative efficacy against α7 receptors compared to indigo and varenicline.

Claims

1. A method for preparing 4-substituted indigo analogs of formula (I) or pharmaceutically acceptable salts, solvates and / or esters thereof: ， in: R 1 yes hydroxyl group; halogen; Optional substitution of aliphatic compounds; Optionally substituted cycloaliphatic ali ... Optionally substituted heterocyclic aliphatic compounds; Optionally substituted aryl groups; Optionally substituted heteroaryl groups; —(CH2) m —NR 6 R 7 R 8 ,in R 6 and R 7 Each is independently selected from the group consisting of: hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, or R 6 Or R 7 One of them is —CO—R 9 And R 6 Or R 7 Another one, as defined above, R 8 Choose from the group consisting of: hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, or none. R 9 Choose from the group consisting of: hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl. And m is 0, 1, 2, 3, 4, or 5. —(CH2) m —O—(CH2) n —R 10 ,in R 10 The group consisting of: hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl pentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, and m and n are each independently 0, 1, 2, 3, 4 or 5. —CN —COOR 12 , where R 12 Choose from the group consisting of: hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl. —(CH2) o —CO—(CH2) p —R 13 ,in R 13 The group consisting of: hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl pentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aromatic acyl, optionally substituted heteroaromatic acyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, and o and p are each independently 0, 1, 2, 3, 4 or 5. amino acids or their esters, Acyl chloride, Protecting group, or Indigo base, R 2 R 3 and R 4 Each is independently selected from the group consisting of: hydrogen, halogen, hydroxyl, oxydimethyl, amino, amide, nitro, cyano, alkoxy, N-alkylamino, N,N-dialkylamino, phosphine, carbonyl, carboxyl, sulfinyloxy, sulfinyl, sulfonyl, thioalkyl, sulfonamide, sulfonyl, mercapto, carbamoyl, methyl neopentanoate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic aliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic alkyl or optionally substituted heterocyclic alkenyl, amino acid or indigo base, or R 4 It is a protecting group, or a group having the structure —(CH2)v- of formula 1, where v is 0, 1, 2, 3, 4, 5, or 6, and formula 1 is a compound of formula (I). The method includes: i) Provide compounds of formula IIa Where R 2 R 3 and R 4 As defined above; ii) To produce compounds of formula IIb by contacting compounds of formula IIa with a borizing agent. Among them, R 2 R 3 and R 4 As defined above, and BComp is a boride complex; iii) Using R 1 Replacing BComp with compounds of formula I: 。 2. The method according to claim 1, wherein, The compound of formula IIa provided in step i) includes R 4 The hydrogen atom at position R is further replaced by a protecting group. 4 Hydrogen atom at position 1.

3. The method according to claim 2, wherein, The protecting group is Boc.

4. The method according to claim 2, wherein, The compound described in formula IIa is indigo alkaloid.

5. The method according to any one of claims 1 to 4, wherein, The borizing agent is selected from: Borating agents having the formula (RO)2—B—B—(OR)2 or HB(OR)2; and B2Pin2 or B2Cat2.

6. The method according to claim 1, wherein, Boring agent: The molar ratio of the starting material of formula IIa is at least about 0.5:1, at least about 0.75:1, at least about 1:1, at least about 1.5:1 or at least about 2:

1.

7. The method according to claim 1, wherein, The reaction in step ii) is carried out in the presence of a transition metal catalyst, which includes iridium, palladium, zinc, nickel and / or rhodium.

8. The method according to claim 1, wherein, The reaction in step ii) is carried out in a solvent selected from ester solvents, ether solvents, ketone solvents, sulfoxide solvents, aromatic solvents, fluorinated aromatic solvents, alkane solvents, or mixtures thereof.

9. The method according to claim 1, wherein, Step ii) is performed in the presence of a ligand selected from: Tetramethyl-1,10-phenanthroline (Me4phen), di-tert-butyl-2,2'-bipyridine (dtbpy), 2,2'-bipyridine (bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or 1,2-bis(dimethylphosphino)ethane (dmpe); as well as phenanthroline (phen), dimethylphenanthroline (me2phen), tetramethyl-1,10-phenanthroline (Me4phen), bathophenanthroline (bathophen), di-tert-butyl-2,2'-bipyridine (dtbpy), 2,2'-bipyridine (bpy), dimethoxy-2,2'-bipyridine (MeO-bpy), 1,1'-bis(diphenylphosphino)ferrocene (dppf), bis(2-di-tert-butylphosphinophenyl) ether, 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)ethane (dppe), hexamethylbenzene (C6Me6), new cuprous reagent, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthone, 1,2-bis(dimethylphosphino)ethane (dmpe), or one of the following: 。 10. The method according to claim 9, wherein, The molar ratio of the starting material of the ligand of formula IIa is less than about 2:1, less than about 1.5:1, less than about 1:1, less than about 0.75:1, less than about 0.5:1, less than about 0.1:1, less than about 0.05:1 to at least about 0.001:

1.

11. The method according to claim 1, wherein, The boronizing in step ii) is carried out at a temperature of about 50°C to about 100°C.

12. The method according to claim 1, wherein, The compound of formula IIb was not separated from the product mixture formed in step ii) before step iii) began, and / or no purification step was performed between steps ii) and iii).

13. The method according to claim 1, wherein, Step iii) begins in the same reaction region as the reaction region in which step ii) was performed.

14. The method according to claim 1, wherein, In step iii), BComp is affected by the first intermediate R. 1 Substituent substitution.

15. The method according to claim 14, wherein, Use the second intermediate R 1 Substituents or substituent R 1 The first intermediate substituent is replaced to provide the compound of formula I; Or use the second intermediate R 1 The substituent replaces the first intermediate substituent, and the third intermediate R is used. 1 Substituents or substituent R 1 The second intermediate substituent is replaced to provide the compound of formula I.

16. The method according to claim 15, wherein, The first intermediate R 1 Substituents, second intermediate R 1 Substituents or third intermediate R 1 The substituents are independently selected from bromine, chlorine, iodine, benzyloxypyridine, alkyl ester, methyl ester, alkenyl, vinyl, ynyl, ethynyl, trimethylsilylacetylene, methyl 1,2,3-triazol-1-ylneoplastate, cyano, aminomethyl, N-Boc-aminomethyl and (benzyloxy)carbonyl)piperazin-1-yl.

17. The method according to claim 1, wherein, Compounds of formula IIb or formula I include R 4 The method further comprises adding a protecting group to the R position of a compound of formula IIb or I. 4 Deprotection of the group, and the R of the compound of formula IIb or formula I after step ii), before step iii), during step iii), or after step iii). 4 Deprotection of functional groups.

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