RU2792034C2 - Tetrahydroisoquinoline compound, its production method, pharmaceutical composition containing such a compound, and its use - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a compound of tetrahydroisoquinoline of the general formula (I), which has a property of a type 4 phosphodiesterase inhibitor, a method for its production, and a pharmaceutical composition based on it for the prevention, treatment, or adjuvant treatment of immune or inflammatory diseases caused by the activity or expression of PDE4. In the general formula (I), a chiral carbon atom C* independently has type S, type R, or a combination thereof; n = 1; X is -CH₂- ; Y is a binding group selected from linear or branched C1-C6 alkylene, -CH₂O-, -CH₂NH-,

,

, or

; each of R₁ and R₂ groups is independently selected from a group consisting of deuterium, hydroxyl, halogen, substituted or unsubstituted linear or branched C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkoxy, substituted or unsubstituted C3-C7 cycloalkylmethoxy, benzyloxy, carboxy-substituted linear C2-C8 alkoxy, N,N-dimethylamine-substituted linear C2-C8 alkoxy, COOR₅, or CONR₅R₆; the substitute is selected from deuterium or halogen; each of R₃ groups is selected from following groups, which are not substituted or substituted 1-2 substitutes: -C(O)-(5-7-element heteroaryl), -C(O)-(4-7-element heterocyclic group), -C1-C4 acyl, -CHO, R₇SO₂-, NH₂(CH₂)_mSO₂-, R₇SO₂(CH₂)_m-, R₇O(CH₂)_mCO-, R₇OCO(CH₂)_m-, difluoromethyl, benzenesulfonyl, 5-7-element heteroarylsulfonyl; where each of heterocyclic groups or heteroaryl groups contains from 1 to 2 heteroatoms selected from oxygen, sulfur, or nitrogen; and each of substitutes is independently selected from halogen, linear or branched C1-C6 alkoxy, trifluoromethyl group, C0-C4 sulfonyl group; each of R₅, R₆, and R₇ groups is independently selected from hydrogen, substituted or unsubstituted linear or branched C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl, in which the substitute is selected from halogen; m is selected from 0, 1, or 2; R₄ is a group, which is not substituted or substituted with 1-2 substitutes and is selected from 5-12-element heteroaryl group; where each of the specified heteroaryls contains from 1 to 2 heteroatoms selected from oxygen, sulfur, or nitrogen; each of the specified substitutes is independently selected from deuterium, halogen, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy, linear or branched C1-C6 alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, COOR₅.

EFFECT: provision of a compound of the general formula (I), having properties of a type 4 phosphodiesterase inhibitor.

11 cl, 7 tbl, 234 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to a new tetrahydroisoquinoline compound, a method for its preparation, a pharmaceutical composition containing such a compound, and its use, and relates to the technical field of medicine. Novel tetrahydroisoquinoline compound represented by the general formula (I), pharmaceutically acceptable salts, isomers, solvates, metabolites, metabolic precursors, as well as pharmaceutical compositions containing them, and their use for the prevention and/or treatment or adjuvant treatment of diseases associated with PDE 4 type, such as psoriasis, psoriatic arthritis, allergic dermatitis, chronic obstructive pulmonary disease, asthma, allergic rhinitis, ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, ADHD, depression and schizophrenia, especially PDE type 4 associated immune and inflammatory diseases such as psoriasis and arthritis.

BACKGROUND OF THE INVENTION Cyclic nucleotide phosphodiesterases (PDEs) selectively catalyze the hydrolysis of 3-phosphate bonds of the second messenger cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) in the cell to form the product, 5-AMP or 5-GMP, thereby inactivating the cAMP or cGMP signal. The normal functioning of PDE directly affects the intracellular concentration of cAMP and/or cGMP, which in turn affects the downstream signaling pathways associated with these second messengers (Omori K, et al. Circ. Res. 2007, 100:309-327; Maurice DH, et al Nat Rev Drug Discov 2014 13:290-314). Downstream of cAMP, many proteins are known to interact directly with cAMP, including PDE, classical cAMP concentration-dependent protein kinases, cAMP-directly activated metabolic proteins, cyclic nucleotide-gated ion channels, and bind to a DNA-binding protein directly bound to cAMP. cAMP receptor protein/catabolic gene activator protein; and some proteins containing the domain of GAF proteins. Accordingly, besides PDE, there are also other proteins that interact directly with cGMP, such as cGMP concentration-dependent protein kinases, cyclic nucleotide-dependent ion channels, and some proteins containing GAF protein domains. These signaling pathways are closely related to physiological processes such as cell cycle control, cell differentiation, inflammation, cardiac function, smooth muscle relaxation and contraction, visual signaling, learning and memory, and related pathological processes. Inhibition of PDE hydrolysis activity alters the intracellular concentration of cAMP or cGMP, thereby directly regulating signaling pathways associated with cAMP or cGMP and altering associated functional symptoms. Thus, PDEs belong to an important family of drug target molecules. PDE inhibitors are widely used in the study and treatment of the pathophysiological mechanisms of various diseases. (Maurice DH, et al. Nat. Rev. Drug Discov. 2014, 13:290-314; Menniti FS, et al. Nat. Rev. Drug Discov. 2006, 5(8), 660-670).

The PDEs are a superfamily with several genes. To date, 21 PDE genes have been found in mammals, which are divided into 11 subfamilies containing more than 100 different PDE isoenzymes (or subtypes) with different substrate specificities, enzyme kinetic characteristics, heterogeneous regulatory characteristics, and different distribution in tissues and subcells that are involved in different signaling pathways and show different sensitivity to inhibitors (Lugnier C, Pharmacol. Ther. 2006, 109:366-398; Francis SH, et al. Handb. Exp. Pharmacol. 2011, 204:47-84). For example, PED types 4, 7, and 8 mainly hydrolyze cAMP; PDE types 5, 6 and 9 act selectively on cGMP; while PED types 1, 2, 3, 10, and 11 can hydrolyze both cAMP and cGMP, although the affinity and hydrolytic activity of various isoenzymes with respect to the two substrates differ. In contrast to the difference in substrate selectivity, the structural characteristics of the members of the PDE family are similar, typically consisting of a regulatory domain near the N-terminus and a catalytic domain near the C-terminus. The catalytic domain (about 270 amino acids) is responsible for the hydrolysis reaction of the substrate. Presently known PDE inhibitors mainly act on the catalytic domain of PDE, thereby achieving the function of inhibiting their activity.

Type 4 PDE specifically hydrolyzes the second messenger molecule cAMP in the cell, inhibition of type 4 PDE activity will lead to cAMP accumulation, high concentration of cAMP will activate protein kinase A, and activated protein kinase A will phosphorylate downstream transcription factors, thereby regulating transcription and expression of a large number of cytokines (Houslay MD, et al. Biochem. J., 2003, 370:1-18). The type 4 PDE family includes four genes (PDE 4A/B/C/D) that are alternatively spliced during expression to form more than 25 isoenzymes. PDE type 4 is widely distributed in the body, mainly expressed in immune-related cells such as neutrophils, eosinophils and monocytes (Maurice DH, et al. Mol. Pharmacol., 2003, 64:533-546). PDE type 4 includes a wide range of diseases, among which chronic obstructive pulmonary disease, asthma, psoriasis, allergic rhinitis, idiopathic pulmonary fibrosis and rheumatoid arthritis are associated with the role of type 4 PDE in the inflammatory process. Nervous system disorders include Alzheimer's disease, Parkinson's disease, depression and schizophrenia (Menniti FS, et al. Nat. Rev. Drug Discov., 2006, 5:660-670; Burgin AB, et al. Nat. Biotechnol., 2010 , 28:63-70; Garcia-Osta A, et al. ACS Chem. Neurosci., 2012, 3: 832-844.).

Psoriasis is an immune-mediated, chronic, relapsing skin inflammation characterized by proliferation of keratinocytes and infiltration of large numbers of leukocytes. The disease is persistent and difficult to treat, seriously affects the quality of life, as well as the physical and mental health of patients, and is one of the important diseases that must be treated in dermatology. The disease is one of the most common autoimmune diseases in the world, the incidence of which is 0.1-3% of the total world population. In addition, psoriasis is also closely associated with other inflammatory diseases such as psoriatic arthritis, inflammatory bowel disease, and coronary artery disease. Although a number of drugs (including topical, oral and biological agents) have been used for the symptomatic treatment of psoriasis, there is still a huge gap and an urgent need to discover new targets and new drugs. TNF-α is highly expressed in psoriasis, and blocking therapy against TNF-α shows a significant clinical effect. Increasing the concentration of cAMP by inhibiting PDE type 4 hydrolysis activity can suppress the expression of pro-inflammatory factors such as TNF-α. Thus, the type 4 PDE inhibitor Apremilast was approved by the FDA in 2014 as an oral drug for the treatment of plaque psoriasis and psoriatic arthritis. (Man H-W, et al. J. Med. Chem., 2009, 52:1522-1524). In addition, in December 2016, the FDA approved a topical therapeutic drug for eczema (allergic dermatitis) (Crysaborol) from Anacor Pharmaceuticals. Like psoriasis, allergic dermatitis is a common relapsing chronic inflammatory skin disease, and Crisaborol is a type 4 non-steroidal PDE inhibitor that is the first new molecule approved by the FDA in the last 15 years for the treatment of allergic dermatitis.

Accordingly, since type 4 PDE includes many important diseases, and some type 4 PDE inhibitors are used in clinical treatment, the development and discovery of new inhibitors that target type 4 PDE is a priority in the field of new drug development. .

SUMMARY OF THE INVENTION

The objective of the present invention is to create a new type of phosphodiesterase type 4 (PDE-4) inhibitors, namely a new class of tetrahydroisoquinoline compounds and intermediates, methods for their preparation, pharmaceutical compositions and their use.

In the first aspect of the present invention, a tetrahydroisoquinoline compound represented by the general formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof is provided:

in which

the chiral carbon atom C* is independently S-type, R-type, or a combination thereof;

n = 1 or 2;

X is -CH ₂ - or -NH-;

,

или

;Y is a linking group selected from C1-C6 linear or branched alkylene, C2-C6 linear or branched alkylene, -CH ₂ O-, -CH ₂ NH ₂ -, -CH ₂ S-, -CONH-, -NHCO- , -COO-, -OOC-,

,

or

;

each of R ₁ and R ₂ is independently selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, substituted or unsubstituted linear or branched C1-C6 alkoxy, substituted or unsubstituted linear or branched C2-C6 alkenyloxy, substituted or unsubstituted linear or branched C2-C6 alkynyloxy, substituted or unsubstituted C3-C7 cycloalkoxy, substituted or unsubstituted C3-C7 cycloalkylmethoxy, benzyloxy, C1-C6 acyloxy, C2-C8 carboxy-substituted linear alkoxy, N,N-dimethylamine-substituted C2-C8 linear alkoxy, COOR ₅ or CONR ₅ R ₆ ; the substituent is selected from deuterium or halogen; or R ₁ and R ₂ together with the carbon atom to which they are attached to form a 5-7 membered carbocyclic or heterocyclic ring (including a saturated ring, an unsaturated ring or an aromatic ring);

each of the R ₃ groups is selected from the following groups, which are unsubstituted or substituted with 1-3 substituents: -C(O)-(5-7 membered heteroaryl), -C(O)-(4-7 membered heterocyclic group) , acyl -C1-C4 (preferably formyl-CHO), alkyl -C1-C4, R ₇ SO ₂ -, NH ₂ (CH ₂ ) _m SO ₂ -, R ₇ SO ₂ (CH ₂ ) _m -, R ₇ O (CH ₂ ) _m CO-, R ₇ OCO(CH ₂ ) _m -, difluoromethyl, trifluoromethyl, C1-C4-sulfinyl, benzenesulfonyl, 5-7-membered heteroarylsulfonyl, phenyl, benzyl, 5-7-membered heteroaryl, 4- 7-membered heterocyclic group; where each of the heterocyclic groups or heteroaryl groups contains from 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen; and each of the substituents is independently selected from deuterium, halogen, C1-C6 linear or branched alkoxy, C1-C6 linear or branched alkylcarbonyloxy, C1-C6 linear or branched alkoxycarbonyl, cyano, hydroxyl, amino, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy - groups of carboxyl group, hydroxyme group, phosphorate-, mercapto-group, C1-C4 amide, C0-C4 sulfonyl group, amino C0-C4 sulfonyl group, C1-C4 alkyl-substituted sulfonylphenyl, benzyl, 5-7-membered heteroaryl, 4- 7-membered heterocyclic group, in which each of the heterocyclic groups or heteroaryl groups contains from 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen;

each of the groups R ₅ , R ₆ and R ₇ is independently selected from hydrogen, substituted or unsubstituted linear or branched alkyl C1-C4, substituted or unsubstituted cycloalkyl C3-C8, substituted or unsubstituted aryl C6-C10, in which the substituent is selected from deuterium or halogen;

m is selected from 0, 1, 2, 3 or 4;

R ₄ is a group which is unsubstituted or substituted with 1-3 substituents and is selected from C3-C7 cycloalkyl, 5-12 membered heterocyclic group, C7-C12 aryl, 5-12 membered heteroaryl group (preferably benzo 5-7 -membered heteroaryl); where each of these heterocyclic groups or heteroaryls contains from 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen; each of said substituents is independently selected from deuterium, halogen, C1-C6 linear or branched alkyl, C2-C6 linear or branched alkenyl, C2-C6 linear or branched alkynyl, C1-C6 linear or branched alkoxy, C1-C6 linear or branched alkylcarbonyloxy , cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, COOR ₅ , CONR ₅ R ₆ , carboxyl C1-C6, mercapto, acyl C1-C4, amide C1-C4, sulfonyl, aminosulfonyl, C1- C4-alkyl-substituted sulfonyl, C1-C4-alkyl-substituted sulfonamide, N,N-dimethyl-substituted C1-C6 alkoxy, C1-C6 carboxy-substituted alkoxy or two adjacent substituents together with the carbon atom to which they are attached to form a 5-7 membered carbocyclic or a heterocyclic compound (including a saturated ring, an unsaturated ring or an aromatic ring).

In another preferred example of general formula (I):

n = 1;

The groups R1 and R2 are each independently selected from the group consisting of substituted or unsubstituted linear or branched C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkoxy, substituted or unsubstituted C3-C7 cycloalkylmethoxy, C1-C6 acyloxy, carboxy-substituted C2- C8, N,N-dimethylamino-substituted linear alkoxy C2-C8, carboxy-substituted linear alkoxy C2-C8, N,N-dimethylamino-substituted linear alkoxy C2-C8, COOR ₅ or CONR ₅ R ₆ ; and the substituent is selected from deuterium or halogen (including fluorine, chlorine, bromine and iodine).

In another preferred example, each of the R ₅ and R ₆ groups is selected from hydrogen, C1-C4 linear or branched alkyl;

In another preferred example of general formula (I):

X is -CH ₂ -;

,

и

.Y is selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -, -CH=CH-,

,

And

.

R ₄ is a group which is unsubstituted or substituted with 1-3 substituents and which is selected from 5-12 membered heterocyclic group, C6-C12 aryl, 5-12 membered heteroaryl group (preferably benzo 5-7 membered heteroaryl); preferably, the heterocyclic and heteroaryl moieties in the group are selected from indole, benzodioxole, isoxazole, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, pyrrole, benzofuran, indazole, benzimidazole, quinoline, 1,3-dioxoisoindole.

In another preferred example of general formula (I):

R ₃ is a group which is unsubstituted or substituted with 1-3 substituents and which is selected from acyl C1-C4 (preferably formyl), alkyl C1-C4, R ₇ SO ₂ -, NH ₂ (CH ₂ ) _m SO ₂ -, R ₇ SO ₂ (CH ₂ ) _m -, R ₇ O (CH ₂ ) _m CO-, difluoromethyl, trifluoromethyl, C1-C3-sulfinyl, benzenesulfonyl, 5-7-membered heteroarylsulfonyl, phenyl, benzyl, 5-7-membered heteroaryl, 4-7 membered heterocyclic group; where each of the heterocyclic groups or heteroaryls contains from 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen; each of the substituents is independently selected from deuterium, halogen, C1-C6 linear or branched alkoxy, C1-C6 linear or branched alkylcarbonyloxy, C1-C6 linear or branched alkoxycarbonyl, cyano, hydroxy, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, hydroxyl group oxime, phosphate, thiol, C1-C4 amido, C1-C4 sulfonyl, amino C1-C4 sulfonyl, C1-C4 alkyl-substituted sulfonylphenyl, benzyl, 5-7 membered heteroaryl, 4-7 membered heterocyclic group; wherein each heterocyclic group or heteroaryl contains 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen;

R ₇ is selected from hydrogen, linear or branched C1-C4 alkyl;

m is chosen from 0, 1 or 2.

In another preferred example, each of the groups R ₁ and R ₂ independently represents a linear or branched alkoxy, trifluoromethoxy, difluoromethoxy C1-C6, COOR ₅ , CONR ₅ R ₆ .

In another preferred example, R4 is indolyl, unsubstituted or substituted with 1-3 substituents; preferably the indolyl is substituted with a substituent selected from the group consisting of halo, C1-C4 alkyl, alkoxy, cyano, trifluoromethyl, trifluoromethoxy, difluoromethyl, C1-C4 difluoromethoxy, COOR ₅ , CONR ₅ R ₆ .

In another preferred example of general formula (I):

Chiral carbon atom C* type S.

In the second aspect of the present invention, a method for producing the compound (I) of the first aspect of the present invention is provided, which includes the following steps:

(1) in an inert solvent in the presence of a condensing agent, a compound of formula II and a compound of formula Ic are reacted to obtain a compound of formula Id; preferably, EDKI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride) is used as the condensing agent;

(2) a compound of formula Id undergoes a Bischler-Napieralski ring closure reaction in an inert solvent to give a compound of formula Ie; preferably, phosphorus oxychloride is used as the Lewis acid in the ring closing reaction;

(3) in an inert solvent, the compound of formula Ie enters into a reduction reaction to obtain a compound of formula If; preferably, boron hydride is used as the reducing agent, and Noyori catalyst is used as the asymmetric reduction catalyst in the reduction reaction;

(4) in an inert solvent, the compound of formula If undergoes a condensation or N-alkylation reaction, or a Buchwald-Hartwig reaction to give a compound of formula (I),

where the groups are defined as in the first aspect of the present invention.

In the third aspect of the present invention, a pharmaceutical composition is provided which contains: a therapeutically effective amount of one or more compounds (I) from the first aspect of the invention, or a pharmaceutically acceptable salt thereof.

In a fourth aspect of the present invention, there is provided the use of the general formula (I) as described in the first aspect of the present invention for the preparation of a pharmaceutical composition for the prevention, treatment or adjuvant treatment of diseases associated with PDE-4 activity or expression; typically, the disease is an immune or inflammatory disease associated with PDE-4 activity or expression.

In another preferred example, the disease associated with PDE-4 activity or expression is selected from the group consisting of psoriasis, psoriatic arthritis, allergic dermatitis, chronic obstructive pulmonary disease, asthma, allergic rhinitis, ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), depression and schizophrenia.

It should be understood that in the present invention, each of the technical characteristics detailed above and below (such as those described in the examples) may be combined with each other, thereby forming new or preferred technical solutions, which need not be re-described.

DESCRIPTION OF THE DRAWINGS

Figure 1 shows the therapeutic effect of test compounds ZN17 and ZN42 in a mouse model of acute spinal cord inflammation.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

After long and intensive research, the inventors have obtained a class of compounds of formula I capable of inhibiting phosphodiesterase (PDE-4). Compared with prior art phosphodiesterase type 4 (PDE-4) inhibitory compounds, these compounds exhibit higher inhibitory activity. The present invention has been made on this basis.

An object of the present invention is to provide a tetrahydroisoquinoline compound represented by the general formula (I), a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

Another object of the present invention is to provide a method for producing a compound represented by the general formula (I).

Yet another object of the present invention is a pharmaceutical composition containing a therapeutically effective amount of one or more compounds represented by the above general formula (I), or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide the aforementioned compound represented by the general formula (I) for use in medicaments for the treatment of autoimmune diseases such as psoriasis, psoriatic arthritis, atopic dermatitis, etc.

The compounds of the present invention can be used to inhibit phosphodiesterase type 4 (PDE-4).

Terms

Unless otherwise expressly stated, in the present invention, the term "substituent" means that one or more hydrogen groups from a group are substituted with substituents selected from the group consisting of C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, halogen, hydroxy , carboxy (-COOH), aldehyde group C1-C10, acyl group C2-C10, ester group C2-C10, amino group, phenyl group; wherein the phenyl comprises unsubstituted phenyl or phenyl substituted with 1-3 substituents, wherein the substituent is selected from the group consisting of halo, C1-C10 alkyl, cyano, OH, nitro, C3-C7 cycloalkyl, alkoxy, C1-C10 amino.

Unless otherwise indicated, in the compounds of the present invention, each chiral carbon atom may additionally have the R-configuration or the S-configuration, or a mixture of the R-configuration and the S-configuration.

The term "C1-C6 alkyl" as used herein refers to linear or branched C1-C6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl or the like groups.

The term "3-8 membered heterocyclic group" refers to a group formed by the loss of one hydrogen atom from a 3-8 membered saturated ring having 1-3 heteroatoms selected from the group: N, S, O; for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or similar groups.

The term "6-10 membered aryl group" refers to a group formed by the loss of one hydrogen atom from a 6-10 membered aryl; for example phenyl, naphthyl or similar groups.

The term "5-10 membered heteroaryl group" refers to a group formed by the loss of one hydrogen atom from a 5-8 membered aryl having 1-3 heteroatoms selected from the group: N, S or O, where each heteroaryl ring system can be monocyclic or polycyclic; for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinolinyl or similar groups.

The term "C1-C6 alkoxy" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, or similar groups. .

The term "ester group C2-C6" refers to a ROC(=O)- group having 2-6 carbon atoms, such as -COOCH ₃ , -COOC ₂ H ₅ , -COOC ₃ H ₇ , -COOC ₄ H ₉ or the like groups.

The term "alkenyl C2-C6" refers to a group formed by the loss of one or two hydrogen atoms from an olefin containing from 2 to 6 carbon atoms. The olefin may be a monoolefin, diolefin or triolefin such as -CH=CH ₂ , -C ₂ H ₄ ═CH ₂ , -CH=C ₂ H ₄ or the like.

The term "halogen" refers to F, Cl, Br and I.

Unless otherwise noted, the structural formula described herein is intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers)): e.g., R, S-configuration of asymmetric centers, (Z), ( E) double bond isomers, (Z), (E) conformational isomer, etc. Therefore, individual stereochemical isomers or enantiomers, diastereomers or geometric isomers (or conformers) of the compounds of the present invention, or mixtures thereof, are all within the scope of the invention.

The term "tautomer" means that structural isomers having different energies can overcome a low energy barrier and thus be converted among themselves. For example, proton tautomers (ie, proton shifts) include proton transfer interconversions such as 1H-carbazole and 2H-carbazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomers involve interconversion through the recombination of some bonding electrons.

In this document, terms such as "C1-C6" mean that the group may have from 1 to 6 carbon atoms, such as 1, 2, 3, 4 or 5 carbon atoms.

Unless otherwise indicated, the compounds in this application may include compounds formed from isotopes known in the art, such as isotopes of hydrogen (deuterium, tritium, etc.) and isotopes of carbon (C14). Generally, the abundance of the above isotope does not exceed its abundance in the natural environment, but it can also be obtained using a reactive source material containing the isotope to produce isotopically substituted compounds with abundances above the abundance in nature, such as deuterated compounds, etc. in a preferred embodiment, the content of deuterium atoms in the deuterated compound is > 99%.

Tetrahydroisoquinoline compounds represented by formula (I)

The present invention describes a tetrahydroisoquinoline compound represented by the general formula (I), enantiomers, diastereomers, racemates and mixtures thereof, or a pharmaceutically acceptable salt thereof,

where the definition of each group is as described above.

In another preferred example, n, X, Y, R1, R2, R3 and R4 individually represent the appropriate group that corresponds to each specific compound in the example.

In particular, the tetrahydroisoquinoline compounds of the present invention are preferably selected from the compounds shown in Table A below:

Preparation of a compound of formula (I)

The present invention also provides a method for synthesizing a compound of general formula I. In particular, a compound of formula I is prepared according to the following scheme:

Step a: I _c is diluted in a solvent and condensed with II in the presence of a condensing agent to give compound I _d ; solvent - dichloromethane;

Step b: I _d is diluted in solvent, excess phosphorus oxychloride is added and stirred at reflux to give compound I _e ; solvent - anhydrous acetonitrile;

Step c: I _e is diluted in solvent, an excess of sodium borohydride is added and stirred until the reaction is complete. The solvent is dried in vacuo to give compound I _f in which methanol acts as the solvent; or a Noyori catalyst is added and stirred until the reaction is complete, using a mixed solution of water and dichloromethane as the solvent.

Stage d: I _f is diluted in a solvent and subjected to reaction with the appropriate source material to obtain compound I _g ; ethyl formate or DMF or tetrahydrofuran is used as the solvent;

X, Y, R1, R2, R3, R4 are defined in the previous requirements.

Pharmaceutical composition containing a compound of formula (I)

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a tetrahydroisoquinoline compound represented by formula (I), a pharmaceutically acceptable salt, prodrug, hydrate and solvate thereof, and, in some cases, one or more pharmaceutically acceptable carriers that can be used to treat autoimmune diseases such as psoriasis. The pharmaceutical composition can be prepared in various forms depending on the route of administration.

One or more of the aldehyde compounds represented by formula (I), pharmaceutically acceptable salts, prodrugs, hydrates and solvates thereof according to the present invention, or a pharmaceutical composition containing a therapeutically effective amount of a compound selected from the group consisting of a tetrahydroisoquinoline compound represented by formula (I) , their pharmaceutically acceptable salts, prodrugs, hydrates and solvates can be used as phosphodiesterase type 4 (PDE-4) inhibitors for the treatment of autoimmune diseases such as psoriasis.

A pharmaceutically acceptable salt of a compound of the present invention can be prepared by a direct salt formation reaction using the free base of the compound with an inorganic or organic acid. The inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid , ethanesulfonic acid and p-toluenesulfonic acid, and the like.

Since the compound of the present invention has a high phosphodiesterase type 4 (PDE-4) inhibitory activity, the compound of the present invention and its various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present of the invention as the main active substance can be used for the treatment or alleviation of diseases associated with phosphodiesterase type 4 (PDE-4), for example, for the treatment of diseases associated with abnormal expression of phosphodiesterase type 4 (PDE-4). Based on the prior art, the compounds of the present invention can be used to treat the following diseases: psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, and the like.

The pharmaceutical composition according to the present invention includes the compound of the present invention or its pharmaceutically acceptable salts in the range of safe and effective doses and pharmaceutically acceptable excipients or carriers. In this case, "safe and effective dose" means that the amount of the compound is sufficient to significantly improve the condition without significant side effects. Typically, the pharmaceutical composition contains 1-2000 mg of a compound of the invention per dose, preferably 5-200 mg of a compound of the invention per dose. Preferably a "dose" is a single capsule or tablet.

A "pharmaceutically acceptable carrier" means one or more compatible solid or liquid excipients or gel-like materials that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatibility" means that each component in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the effectiveness of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils. (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents ( such as sodium dodecyl sulfate), colors, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

There are no particular restrictions on the method of application of the compound or pharmaceutical compositions of the present invention, and the usual method of application includes (but is not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical application.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compounds are mixed with at least one conventional excipient (or carrier) such as sodium citrate or CaHPO4 or any of the following: (a) excipients or a compatibilizer such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) a humectant such as glycerin; (d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) dissolution retardants such as paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; and (i) lubricants such as talc, calcium stearin, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and dragees, dosage forms may also contain buffer substances.

Solid dosage forms such as tablets, sugar pills, capsules, dragees and granules can be prepared using film formers and coating materials such as enteric coatings and any other materials known in the art. They may contain substances that provide opacity. The active compounds or compounds in the compositions may be released in a sustained manner at a particular site in the digestive tract. Examples of potting agents include polymers and waxes. If necessary, the active compounds and one or more of the above excipients can form microcapsules.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, liquid dosage forms may contain any of the usual inert diluents known in the art, such as water or other solvents, solubilizers and emulsifiers, for example ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide , as well as oils, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or combinations thereof.

In addition to these inert diluents, the composition may also contain additives such as wetting agents, emulsifiers and a suspending agent, sweetener, flavors and fragrances.

In addition to the active compounds, the suspension may contain a suspending agent such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methanol-aluminum and agar, or a combination thereof.

Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders which can be reconstituted in sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and any suitable mixtures thereof.

Dosage forms for topical application of the compounds of the invention include ointments, powders, patches, aerosols, and inhalants. The active ingredients are mixed with physiologically acceptable carriers and any preservatives, buffers or propellant, if necessary, under sterile conditions.

The compounds of the present invention may be administered alone or in combination with any other pharmaceutically acceptable compounds.

The compounds of the present invention, as described above, can be used in clinical practice in mammals, including humans and animals, and can be administered orally, nasally, subcutaneously, into the lungs or into the gastrointestinal tract, and more preferably orally. The preferred daily dose is from 0.01 to 200 mg/kg of body weight, administered at a time, or from 0.01 to 100 mg/kg of body weight, in divided doses. Regardless of the route of administration, the optimal individual dose should be based on the specific treatment. Usually, the reception begins with a small dose, which is gradually increased until the most suitable one is found. Of course, the specific dosage will also depend on various factors such as the method of administration, the state of health of the patient, which can easily be adjusted by an experienced physician.

Compared to the prior art, the main advantages of the present invention include:

The tetrahydroisoquinoline compounds of the present invention have a good inhibitory effect on phosphodiesterase type 4 (PDE-4), so they can be used for the prophylactic, main or auxiliary treatment of diseases associated with phosphodiesterase activity, such as psoriasis and psoriatic arthritis, allergic dermatitis, chronic obstructive pulmonary disease, asthma, allergic rhinitis, ankylosing spondylitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, ADHD, depression and schizophrenia, especially immune and inflammatory diseases associated with PDE-4, such as psoriasis and arthritis.

The present invention will be further illustrated below with reference to specific examples. It should be understood that these examples are only intended to illustrate the invention and do not limit the scope of the invention. Experimental methods without specific conditions, described in the following examples, are usually used under normal conditions or in accordance with the manufacturer's instructions. Unless otherwise stated, parts and percentages are by weight.

The invention will be further illustrated by the following examples. These examples are only intended to illustrate the present invention, and in no way limit the scope of the present invention. Unless otherwise noted, all parameters and other descriptions in the examples refer to quality.

Sample analysis data is determined using the following instruments: NMR spectroscopy was performed using GEMINI-300, Bruker AMX-400 and INVOA-600 devices, and TMS (tetramethylsilane) was used as an internal standard. Chemical shift unit - ppm, coupling constants - Hz; The mass spectrum was determined using Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometers.

Silica gel 200-300 mesh (manufactured by Qingdao Ocean Chemical Plant) was used for column chromatography; silica gel TLC plate is HSGF-254 thin layer chromatography plate manufactured by Yantai Chemical Plant; petroleum ether boiling point range 60-90 °; color development was carried out using an ultraviolet lamp, iodine tube. Unless otherwise indicated, the usual reagents and drugs used in the following examples were purchased from Sinopharm Group. The reagents and solvents used in the experiment are processed according to specific conditions reactions.

Example A1: Synthesis of Compound A1

Synthesis path:

Synthesis of compound 1-3:

Compound 1-2 was dissolved in dichloromethane, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), hydroxybenzotriazole (HOBT) and triethylamide (TEA) were added and stirred for 30 min. A solution of compound 1-1 in dichloromethane was added and stirred overnight, diluted with dichloromethane, then washed successively with saturated sodium bicarbonate, 1N. hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by passing through a 1:1 mixture of petroleum ether and ethyl acetate through a chromatographic column to give 1.2 g of a yellow-white solid (92% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (s., 1H), 7.57 (d.d., J = 7.5, 1.4 Hz, 1H), 7.33 (d .-d., J = 7.5, 1.4 Hz, 1H), 7.23 - 7.15 (m., 2H), 6.98 (t.-d., J = 7.4, 1 .5 Hz, 1H), 6.79 (d., J = 7.5 Hz, 1H), 6.74 (d., J = 1.4 Hz, 1H), 6.60 (d.-d. , J = 7.5, 1.4 Hz, 1H), 5.62 (s., 1H), 3.83 (s., 3H), 3.75 (s., 3H), 3.37 (t ., J = 7.7 Hz, 2H), 2.68 (t., J = 8.1 Hz, 2H), 2.60 (t., J = 7.7 Hz, 2H), 2.28 ( t., J = 8.1 Hz, 2H). MS-ESI m/z 353.2 [M+H] ⁺ .

Synthesis of compound 1-4:

1 g of compound 1-3 was dissolved in 100 ml of anhydrous acetonitrile, phosphorus oxychloride was added, the mixture was refluxed and stirred under argon. The solution was evaporated to dryness under reduced pressure after completion of the reaction as shown by TLC. Ice-cold saturated sodium bicarbonate was added to make the solution slightly alkaline, then the solution was extracted with dichloromethane, dried over anhydrous sodium sulfate and evaporated to dryness to give an orange oil which was used in the further reaction without purification.

Synthesis of compound 1-5:

Compound 1-4 was dissolved in methanol, sodium borohydride was added in portions in an ice bath and stirred at room temperature for 4 hours. The reaction was then quenched with saturated ammonium chloride solution, the solution was extracted with dichloromethane, washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over sodium sulfate, concentrated and purified by passing through a 20:1 mixture of dichloromethane and methanol through a chromatographic column to give a yellow solid in a two-step yield of 70%. ¹ H NMR (400 MHz, CDCl3) δ 8.19 (br.s., 1H), 7.53 (d., J = 7.8 Hz, 1H), 7.32 (d., J = 8, 1 Hz, 1H), 7.20 - 7.03 (m., 3H), 6.51 (s., 1H), 6.23 (s., 1H), 4.41 (t., J = 5 .8 Hz, 1H), 3.81 (s., 3H), 3.58 (s., 3H), 3.54 - 3.43 (m., 1H), 3.31 - 3.18 (m ., 1H), 3.08 - 2.78 (m., 4H), 2.39 (d.d., J = 13.7, 7.1 Hz, 2H). MS-ESI m/z 337.2 [M+H] ⁺ .

Synthesis of compound A1:

100 mg of compound 1-5 was dissolved in ethyl formate, a catalytic amount of triethylamine was added dropwise, stirred and refluxed overnight. After completion of the reaction, as shown by TLC, the solvent was evaporated to dryness and purified by passage through a chromatographic column with a mixture of petroleum ether and ethyl acetate in a ratio of 1:1 to obtain a white solid A1 (yield 90%). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H (sec)), 8.21 (s, 1H (bas)), 8.13 (br.s., 1H (bas) )), 8.06 (br.s., 1H (sec.)), 7.63 (d., J = 8.0 Hz, 1H (prim.)), 7.58 (d., J = 7 .9 Hz, 1H (sec.)), 7.39 (d., J = 8.1 Hz, 1H (prim.)), 7.36 (d., J = 8.1 Hz, 1H (sec.) )), 7.24 - 7.06 (m, 2H (prim, sec) 1H (sec)), 7.03 (s, 1H (prim)), 6.57 (s, 1H(bas)), 6.55(s, 1H(sec)), 6.41(s, 1H(sec)), 6.39(s, 1H(base)), 5 .47 (d.d., J = 7.6, 6.3 Hz, 1H (sec)), 4.55 (d.d., J = 13.4, 5.2 Hz, 1H ( basal)), 4.44 (d-d, J = 9.5, 4.1 Hz, 1H (prim)), 3.84 (s, 3H (prim)), 3.83 (s, 3H (sec)), 3.78 - 3.70 (m, 1H (sec) 3H (bas)), 3.68 (s, 3H (sec)), 3, 62 (d.d.d., J = 13.4, 12.0, 4.4 Hz, 1H(sec)), 3.13 (d.d.d., J = 13, 4, 12.0, 4.4 Hz, 1H (basic)), 3.02 - 2.63 (m, 4H), 2.36 - 2.17 (m, 2H). MS-ESI m/z 365.2 [M+H] ⁺ .

Example (S)-A1: Synthesis of compound (S)-A1:

Compound 1-4 was dissolved in a small amount of dichloromethane, deionized water, (R,R) Noyori catalyst, silver hexafluoroantimonate, lanthanum trifluoromethanesulfonate, tryptose blood agar base (TBAB) and sodium formate were added and stirred at 40°C under argon for night, extracted with dichloromethane, washed with water, and the organic layer was filtered through celite, concentrated, purified by passing through a chromatographic column with a mixture of dichloromethane and methanol in a ratio of 40:1 to obtain compound 2-5. Compound (S)-A1 was obtained by the method of synthesis of compound A1. Compound (S)-A1 can also be obtained from compound A1 by passing through a chiral chromatography column. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H (sec)), 8.21 (s, 1H (bas)), 8.13 (br.s., 1H (bas) )), 8.06 (br.s., 1H (sec.)), 7.63 (d., J = 8.0 Hz, 1H (prim.)), 7.58 (d., J = 7 .9 Hz, 1H (sec.)), 7.39 (d., J = 8.1 Hz, 1H (prim.)), 7.36 (d., J = 8.1 Hz, 1H (sec.) )), 7.24 - 7.06 (m, 2H (prim, sec) 1H (sec)), 7.03 (s, 1H (prim)), 6.57 (s, 1H(bas)), 6.55(s, 1H(sec)), 6.41(s, 1H(sec)), 6.39(s, 1H(base)), 5 .47 (d.d., J = 7.6, 6.3 Hz, 1H (sec)), 4.55 (d.d., J = 13.4, 5.2 Hz, 1H ( basal)), 4.44 (d-d, J = 9.5, 4.1 Hz, 1H (prim)), 3.84 (s, 3H (prim)), 3.83 (s, 3H (sec)), 3.78 - 3.70 (m, 1H (sec) 3H (bas)), 3.68 (s, 3H (sec)), 3, 62 (d.d.d., J = 13.4, 12.0, 4.4 Hz, 1H(sec)), 3.13 (d.d.d., J = 13, 4, 12.0, 4.4 Hz, 1H (basic)), 3.02 - 2.63 (m, 4H), 2.36 - 2.17 (m, 2H). MS-ESI m/z 365.2 [M+H] ⁺ .

Example (R)-A1: Synthesis of Compound (R)-A1

Compound (R)-A1 was prepared by the method of synthesizing compound (S)-A1 by replacing Noyori's (R,R) catalyst in Example (S)-A1 with Noyori's (S,S) catalyst. Compound (R)-A1 can also be obtained from compound A1 by passing through a chiral chromatography column. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H (sec)), 8.21 (s, 1H (bas)), 8.13 (br.s., 1H (bas) )), 8.06 (br.s., 1H (sec.)), 7.63 (d., J = 8.0 Hz, 1H (prim.)), 7.58 (d., J = 7 .9 Hz, 1H (sec.)), 7.39 (d., J = 8.1 Hz, 1H (prim.)), 7.36 (d., J = 8.1 Hz, 1H (sec.) )), 7.24 - 7.06 (m, 2H (prim, sec) 1H (sec)), 7.03 (s, 1H (prim)), 6.57 (s, 1H(bas)), 6.55(s, 1H(sec)), 6.41(s, 1H(sec)), 6.39(s, 1H(base)), 5 .47 (d.d., J = 7.6, 6.3 Hz, 1H (sec)), 4.55 (d.d., J = 13.4, 5.2 Hz, 1H ( basal)), 4.44 (d-d, J = 9.5, 4.1 Hz, 1H (prim)), 3.84 (s, 3H (prim)), 3.83 (s, 3H (sec)), 3.78 - 3.70 (m, 1H (sec) 3H (bas)), 3.68 (s, 3H (sec)), 3, 62 (d.d.d., J = 13.4, 12.0, 4.4 Hz, 1H(sec)), 3.13 (d.d.d., J = 13, 4, 12.0, 4.4 Hz, 1H (basic)), 3.02 - 2.63 (m, 4H), 2.36 - 2.17 (m, 2H). ¹ H NMR MS-ESR m/z 365.2 [M+H] ⁺ .

Example A2: Synthesis of Compound A2

Synthesis of compound 4-3:

Compound 4-1 was dissolved in acetone, potassium carbonate was added, compound 4-2 was added dropwise, and stirred at reflux overnight. The reaction solution was filtered, evaporated to dryness, diluted with dichloromethane, stirred with water for 10 minutes and left to separate the layers. The organic layer was evaporated to dryness to give a yellow solid 4-3 which was immediately added dropwise to the next step without purification.

Synthesis of compound 4-4:

Compound 4-3 was dissolved in nitromethane, ammonium acetate was added and refluxed for 2 hours and the solvent was evaporated to dryness. The residue was added to ice water and stirred for 2 hours, allowed to stand and filtered to give a yellow solid (90% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.96 (s., 2H), 7.42 (d.d., J = 7.5, 1.4 Hz, 1H), 7.23 (d. , J = 1.4 Hz, 1H), 6.93 (d., J = 7.5 Hz, 1H), 4.58 (d.d., J = 7.8 Hz, 1H), 3, 85 (s, 3H), 2.12-2.00 (m, 2H), 1.84-1.66 (m, 2H), 1.67-1.54 (m, 1H). MS-ESI m/z 264.1 [M+H] ⁺

Synthesis of compound 4-5:

Lithium aluminum hydride was added in portions to argon-protected tetrahydrofuran in an ice bath. A solution of compound 4-4 and tetrahydrofuran was added dropwise with stirring. After completion of the addition, the solution was refluxed for 2 hours. Water was added slowly in an ice bath to quench the reaction, then filtered. The filter cake was washed with ethyl acetate and evaporated to a yellowish clear oil. The product was used fresh in the next step without purification.

Compound A2 was obtained according to the method for the synthesis of compound A1, with compound 1-1 in Example A1 replaced by compound 4-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.20 (s, 1H (bas)), 8.14 (br.s., 1H ( prim.)), 8.07 (b.s., 1H (sec.)), 7.63 (d., J = 7.9 Hz, 1H (prim.)), 7.58 (d., J = 7.9 Hz, 1H (sec.)), 7.39 (d., J = 8.1 Hz, 1H (main)), 7.36 (d., J = 8.1 Hz, 1H ( sec)), 7.24 - 7.16 (m, 2H (bas)), 7.15 (s, 1H (bas)), 7.13 - 7.06 (m, 2H ( sec)), 7.02 (s, 1H (sec)), 6.56 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.41 (s, 1H (sec)), 6.39 (s, 1H (prim)), 5.45 (d-d, J = 8.6, 5.0 Hz, 1H (sec) )), 4.57 (m., 1H), 4.52 (m., 1H (basic)), 4.41 (d.d., J = 9.5, 4.4 Hz, 1H ( basal)), 3.80 (s., 3H (bas.)), 3.79 (s., 3H (sec.)), 3.72 (d.d., J = 13.4.5 .3 Hz, 1H (sec)), 3.62 (d-d-d, J = 13.6, 12.0, 4.5 Hz, 1H (sec)), 3.12 ( d-d-d, J = 13.0, 12.0, 4.7 Hz, 1H (basic)), 3.01 - 2.61 (m, 4H), 2.32 - 2 .17 (m, 2H), 1.92-1.66 (m, 6H), 1.64-1.48 (m, 2H). MS-ESI m/z 419.2 [M+H] ⁺ .

Example (S)-A2: Synthesis of Compound (S)-A2

Compound (S)-A2 was prepared according to the method for synthesizing compound (S)-A1, with compound 1-1 in Example A1 replaced by compound 4-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.20 (s, 1H (bas)), 8.14 (br.s., 1H ( basal)), 8.07 (br.s., 1H (sec.)), 7.63 (d., J = 7.9 Hz, 1H (prim.)), 7.58 (d., J = 7.9 Hz, 1H (sec.)), 7.39 (d., J = 8.1 Hz, 1H (main)), 7.36 (d., J = 8.1 Hz, 1H ( sec)), 7.24 - 7.16 (m, 2H (bas)), 7.15 (s, 1H (bas)), 7.13 - 7.06 (m, 2H ( sec)), 7.02 (s, 1H (sec)), 6.56 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.41 (s, 1H (sec)), 6.39 (s, 1H (prim)), 5.45 (d-d, J = 8.6, 5.0 Hz, 1H (sec) )), 4.57 (m., 1H), 4.52 (m., 1H (basic)), 4.41 (d.d., J = 9.5, 4.4 Hz, 1H ( basal)), 3.80 (s., 3H (bas.)), 3.79 (s., 3H (sec.)), 3.72 (d.d., J = 13.4.5 .3 Hz, 1H (sec)), 3.62 (d-d-d, J = 13.6, 12.0, 4.5 Hz, 1H (sec)), 3.12 ( d-d-d, J = 13.0, 12.0, 4.7 Hz, 1H (basic)), 3.01 - 2.61 (m, 4H), 2.32 - 2 .17 (m, 2H), 1.92-1.66 (m, 6H), 1.64-1.48 (m, 2H). MS-ESI m/z 419.2 [M+H] ⁺ .

Example (R)-A2: Synthesis of Compound (R)-A2

Compound (R)-A2 was prepared according to the method for synthesizing compound (R)-A1, with compound 1-1 in Example A1 replaced by compound 4-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.20 (s, 1H (bas)), 8.14 (br.s., 1H ( basal)), 8.07 (br.s., 1H (sec.)), 7.63 (d., J = 7.9 Hz, 1H (prim.)), 7.58 (d., J = 7.9 Hz, 1H (sec.)), 7.39 (d., J = 8.1 Hz, 1H (main)), 7.36 (d., J = 8.1 Hz, 1H ( sec)), 7.24 - 7.16 (m, 2H (bas)), 7.15 (s, 1H (bas)), 7.13 - 7.06 (m, 2H ( sec)), 7.02 (s, 1H (sec)), 6.56 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.41 (s, 1H (sec)), 6.39 (s, 1H (prim)), 5.45 (d-d, J = 8.6, 5.0 Hz, 1H (sec) )), 4.57 (m., 1H), 4.52 (m., 1H (basic)), 4.41 (d.d., J = 9.5, 4.4 Hz, 1H ( basal)), 3.80 (s., 3H (bas.)), 3.79 (s., 3H (sec.)), 3.72 (d.d., J = 13.4.5 .3 Hz, 1H (sec)), 3.62 (d-d-d, J = 13.6, 12.0, 4.5 Hz, 1H (sec)), 3.12 ( d-d-d, J = 13.0, 12.0, 4.7 Hz, 1H (basic)), 3.01 - 2.61 (m, 4H), 2.32 - 2 .17 (m, 2H), 1.92-1.66 (m, 6H), 1.64-1.48 (m, 2H). MS-ESI m/z 419.2 [M+H] ⁺ .

Example A3: Synthesis of Compound A3

Compound A3 was prepared according to the method for the synthesis of compound A2, with compound 4-2 in Example A2 being replaced by compound 6-1. ¹ H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H (sec)), 8.21 (s, 1H (bas)), 8.20 (s, 1H (bas) ), 8.12 (s, 1H (sec)), 7.62 (d, J = 7.9 Hz, 1H (prim)), 7.56 (d, J = 7.9 Hz) , 1H (sec)), 7.38 (d, J = 8.1 Hz, 1H (prim)), 7.36 (d, J = 8.1 Hz, 1H (sec)), 7.24 - 7.16 (m, 2H (b)), 7.13 (s, 1H (b)), 7.12 - 7.05 (m, 2H (s)), 7.02 (s, 1H (sec)), 6.57 (s, 1H (bas)), 6.55 (s, 1H (sec)), 6.42 (s, 1H (sec)), 6.40 (s, 1H (prim)), 5.44 (d-d, J = 8.6, 5.0 Hz, 1H (sec)), 4, 54 (d.d., J = 13.2, 5.0 Hz, 1H (basic)), 4.40 (d.d., J = 9.3, 4.3 Hz, 1H (basic) .)), 3.83 (s., 3H), 3.77 - 3.56 (m., 2H (sec.), 2H (prim., sec.)), 3.12 (d.-d. -d., J = 12.4, 4.7, 4.7 Hz, 1H (basic)), 3.00 - 2.62 (m., 4H), 2.32 - 2.15 (m. , 2H), 1.36 - 1.17 (m, 1H), 0.68 - 0.51 (m, 2H), 0.29 (m, 2H). MS-ESI m/z 405.2 [M+H] ⁺ .

Example (S)-A3: Synthesis of Compound (S)-A3

Compound (S)-A3 was prepared according to the method for synthesizing compound (S)-A2, with compound 4-2 in Example A2 being replaced by compound 6-1. ¹ H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H (sec)), 8.21 (s, 1H (bas)), 8.20 (s, 1H (bas) ), 8.12 (s, 1H (sec)), 7.62 (d, J = 7.9 Hz, 1H (prim)), 7.56 (d, J = 7.9 Hz) , 1H (sec)), 7.38 (d, J = 8.1 Hz, 1H (prim)), 7.36 (d, J = 8.1 Hz, 1H (sec)), 7.24 - 7.16 (m, 2H (b)), 7.13 (s, 1H (b)), 7.12 - 7.05 (m, 2H (s)), 7.02 (s, 1H (sec)), 6.57 (s, 1H (bas)), 6.55 (s, 1H (sec)), 6.42 (s, 1H (sec)), 6.40 (s, 1H (prim)), 5.44 (d-d, J = 8.6, 5.0 Hz, 1H (sec)), 4, 54 (d.d., J = 13.2, 5.0 Hz, 1H (basic)), 4.40 (d.d., J = 9.3, 4.3 Hz, 1H (basic) .)), 3.83 (s., 3H), 3.77 - 3.56 (m., 2H (sec.), 2H (prim., sec.)), 3.12 (d.-d. -d., J = 12.4, 4.7, 4.7 Hz, 1H (basic)), 3.00 - 2.62 (m., 4H), 2.32 - 2.15 (m. , 2H), 1.36 - 1.17 (m, 1H), 0.68 - 0.51 (m, 2H), 0.29 (m, 2H). MS-ESI m/z 405.2 [M+H] ⁺ .

Example (R)-A3: Synthesis of Compound (R)-A3

Compound (R)-A3 was prepared according to the method for synthesizing compound (R)-A2, with compound 4-2 in Example A2 being replaced by compound 6-1. ¹ H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H (sec)), 8.21 (s, 1H (bas)), 8.20 (s, 1H (bas) ), 8.12 (s, 1H (sec)), 7.62 (d, J = 7.9 Hz, 1H (prim)), 7.56 (d, J = 7.9 Hz) , 1H (sec)), 7.38 (d, J = 8.1 Hz, 1H (prim)), 7.36 (d, J = 8.1 Hz, 1H (sec)), 7.24 - 7.16 (m, 2H (b)), 7.13 (s, 1H (b)), 7.12 - 7.05 (m, 2H (s)), 7.02 (s, 1H (sec)), 6.57 (s, 1H (bas)), 6.55 (s, 1H (sec)), 6.42 (s, 1H (sec)), 6.40 (s, 1H (prim)), 5.44 (d-d, J = 8.6, 5.0 Hz, 1H (sec)), 4, 54 (d.d., J = 13.2, 5.0 Hz, 1H (basic)), 4.40 (d.d., J = 9.3, 4.3 Hz, 1H (basic) .)), 3.83 (s., 3H), 3.77 - 3.56 (m., 2H (sec.), 2H (prim., sec.)), 3.12 (d.-d. -d., J = 12.4, 4.7, 4.7 Hz, 1H (basic)), 3.00 - 2.62 (m., 4H), 2.32 - 2.15 (m. , 2H), 1.36 - 1.17 (m, 1H), 0.68 - 0.51 (m, 2H), 0.29 (m, 2H). MS-ESI m/z 405.2 [M+H] ⁺ .

Example A4: Synthesis of Compound A4

Compound A4 was obtained in accordance with the method of synthesis of compound A2, while the compound 4-2 in example A2 was replaced by bromoethane.¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H (sec)), 8.20 (s, 1H (bas)), 8.13 (br.s., 1H (bas)), 8.06 ( br.s., 1H (sec.)), 7.62 (d., J = 7.8 Hz, 1H (prim.)), 7.57 (d., J = 7.9 Hz, 1H (sec. .)), 7.39 (d., J = 8.1 Hz, 1H (main)), 7.36 (d., J = 8.1 Hz, 1H (second)), 7.24 - 7.00 (m, 3H), 6.57 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.41 (s, 1H (sec) ), 6.40 (s, 1H (prim)), 5.45 (d-d, J = 8.2, 5.1 Hz, 1H (sec)), 4.54 (d. -d, J = 13.0, 4.4 Hz, 1H (basic)), 4.42 (d.d., J = 9.2, 4.7 Hz, 1H (basic)), 4.01 - 3.83 (m, 2H), 3.83 (s, 3H (b)), 3.82 (s, 3H (s)), 3.73 (d-d ., J = 13.3, 5.3 Hz, 1H (sec)), 3.62 (d.d.d., J = 13.4, 11.8, 4.6 Hz, 1H ( sec)), 3.12 (d.d.d., J = 13.0, 11.7, 4.7 Hz, 1H (basic)), 2.99 - 2.63 (m. , 4H), 2.31 - 2.17 (m., 2H), 1.40 (t., J = 7.0 Hz, 3H (basic)), 1.36 (t., J = 7, 0 Hz, 3H (sec)). MS-ESM m/z 379.2 [M+H]⁺.

Example (S)-A4: Synthesis of Compound (S)-A4

Compound (S)-A4 was prepared according to the method for the synthesis of compound (S)-A2, with compound 4-2 in Example A2 replaced by bromoethane. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.20 (s, 1H (bas)), 8.13 (br.s., 1H ( basal)), 8.06 (br.s., 1H (sec.)), 7.62 (d., J = 7.8 Hz, 1H (prim.)), 7.57 (d., J = 7.9 Hz, 1H (sec.)), 7.39 (d., J = 8.1 Hz, 1H (main)), 7.36 (d., J = 8.1 Hz, 1H ( sec)), 7.24 - 7.00 (m, 3H), 6.57 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.41 (s, 1H (sec)), 6.40 (s, 1H (prim)), 5.45 (d-d, J = 8.2, 5.1 Hz, 1H (sec) )), 4.54 (d.d., J = 13.0, 4.4 Hz, 1H (basic)), 4.42 (d.d., J = 9.2, 4.7 Hz, 1H (prim)), 4.01 - 3.83 (m, 2H), 3.83 (s, 3H (prim)), 3.82 (s, 3H (sec)) , 3.73 (d.d., J = 13.3, 5.3 Hz, 1H(sec)), 3.62 (d.d.d., J = 13.4, 11, 8, 4.6 Hz, 1H (sec)), 3.12 (d-d-d, J = 13.0, 11.7, 4.7 Hz, 1H (prim)), 2 .99 - 2.63 (m., 4H), 2.31 - 2.17 (m., 2H), 1.40 (t., J = 7.0 Hz, 3H (basic)), 1, 36 (t., J = 7.0 Hz, 3H (sec.)). MS-ESI m/z 379.2 [M+H] ⁺ .

Example (R)-A4: Synthesis of Compound (R)-A4

Compound (R)-A4 was obtained according to the method for the synthesis of compound (R)-A2, with compound 4-2 in Example A2 replaced by bromoethane. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.20 (s, 1H (bas)), 8.13 (br.s., 1H ( basal)), 8.06 (br.s., 1H (sec.)), 7.62 (d., J = 7.8 Hz, 1H (prim.)), 7.57 (d., J = 7.9 Hz, 1H (sec.)), 7.39 (d., J = 8.1 Hz, 1H (main)), 7.36 (d., J = 8.1 Hz, 1H ( sec)), 7.24 - 7.00 (m, 3H), 6.57 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.41 (s, 1H (sec)), 6.40 (s, 1H (prim)), 5.45 (d-d, J = 8.2, 5.1 Hz, 1H (sec) )), 4.54 (d.d., J = 13.0, 4.4 Hz, 1H (basic)), 4.42 (d.d., J = 9.2, 4.7 Hz, 1H (prim)), 4.01 - 3.83 (m, 2H), 3.83 (s, 3H (prim)), 3.82 (s, 3H (sec)) , 3.73 (d.d., J = 13.3, 5.3 Hz, 1H(sec)), 3.62 (d.d.d., J = 13.4, 11, 8, 4.6 Hz, 1H (sec)), 3.12 (d-d-d, J = 13.0, 11.7, 4.7 Hz, 1H (prim)), 2 .99 - 2.63 (m., 4H), 2.31 - 2.17 (m., 2H), 1.40 (t., J = 7.0 Hz, 3H (basic)), 1, 36 (t., J = 7.0 Hz, 3H (sec.)). MS-ESI m/z 379.2 [M+H] ⁺ .

Example A5: Synthesis of Compound A5

Compound A5 was obtained in accordance with the method of synthesis of compound A2, while compound 4-2 in example A2 was replaced by benzyl bromide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H (sec)), 8.15 (s, 1H (bas)), 8.11 (br.s., 1H ( basal)), 8.05 (br.s., 1H (sec.)), 7.59 (d., J = 8.0 Hz, 1H (prim.)), 7.56 (d., J = 7.9 Hz, 1H (sec)), 7.44 - 7.27 (m, 6H), 7.24 - 7.11 (m, 2H), 7.09 (s, 1H ( sec)), 6.95 (s, 1H (base)), 6.59 (s, 1H (base)), 6.57 (s, 1H (sec)), 6.45 (s, 1H (sec)), 6.41 (s, 1H (prim)), 5.38 (d-d, J = 9.2, 4.3 Hz, 1H (sec) )), 5.06 - 4.88 (m., 2H), 4.52 (d.d., J = 13.1, 4.9 Hz, 1H (basic)), 4.34 (d .-d., J = 8.4, 5.6 Hz, 1H (prim.)), 3.85 (s., 3H (prim.)), 3.84 (s., 3H (sec.)) , 3.71 (d-d, J = 13.4, 5.2 Hz, 1H (sec)), 3.64 - 3.55 (m, 1H (sec)), 3.15 - 3.03 (m, 1H (bas)), 2.80 (m, 4H), 2.13 (m, 2H). MS-ESI m/z 441.2 [M+H] ⁺ .

Example (S)-A5: Synthesis of Compound (S)-A5

Compound (S)-A5 was prepared according to the method for the synthesis of compound (S)-A2, with compound 4-2 in Example A2 being replaced by benzyl bromide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H (sec)), 8.15 (s, 1H (bas)), 8.11 (br.s., 1H ( basal)), 8.05 (br.s., 1H (sec.)), 7.59 (d., J = 8.0 Hz, 1H (prim.)), 7.56 (d., J = 7.9 Hz, 1H (sec)), 7.44 - 7.27 (m, 6H), 7.24 - 7.11 (m, 2H), 7.09 (s, 1H ( sec)), 6.95 (s, 1H (base)), 6.59 (s, 1H (base)), 6.57 (s, 1H (sec)), 6.45 (s, 1H (sec)), 6.41 (s, 1H (prim)), 5.38 (d-d, J = 9.2, 4.3 Hz, 1H (sec) )), 5.06 - 4.88 (m., 2H), 4.52 (d.d., J = 13.1, 4.9 Hz, 1H (basic)), 4.34 (d .-d., J = 8.4, 5.6 Hz, 1H (prim.)), 3.85 (s., 3H (prim.)), 3.84 (s., 3H (sec.)) , 3.71 (d-d, J = 13.4, 5.2 Hz, 1H (sec)), 3.64 - 3.55 (m, 1H (sec)), 3.15 - 3.03 (m, 1H (bas)), 2.80 (m, 4H), 2.13 (m, 2H). MS-ESI m/z 441.2 [M+H] ⁺ .

Example (R)-A5: Synthesis of Compound (R)-A5

Compound (R)-A5 was obtained in accordance with the method of synthesis of compound (R)-A2, while the compound 4-2 in example A2 was replaced by benzyl bromide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H (sec)), 8.15 (s, 1H (bas)), 8.11 (br.s., 1H ( basal)), 8.05 (br.s., 1H (sec.)), 7.59 (d., J = 8.0 Hz, 1H (prim.)), 7.56 (d., J = 7.9 Hz, 1H (sec)), 7.44 - 7.27 (m, 6H), 7.24 - 7.11 (m, 2H), 7.09 (s, 1H ( sec)), 6.95 (s, 1H (base)), 6.59 (s, 1H (base)), 6.57 (s, 1H (sec)), 6.45 (s, 1H (sec)), 6.41 (s, 1H (prim)), 5.38 (d-d, J = 9.2, 4.3 Hz, 1H (sec) )), 5.06 - 4.88 (m., 2H), 4.52 (d.d., J = 13.1, 4.9 Hz, 1H (basic)), 4.34 (d .-d., J = 8.4, 5.6 Hz, 1H (prim.)), 3.85 (s., 3H (prim.)), 3.84 (s., 3H (sec.)) , 3.71 (d-d, J = 13.4, 5.2 Hz, 1H (sec)), 3.64 - 3.55 (m, 1H (sec)), 3.15 - 3.03 (m, 1H (bas)), 2.80 (m, 4H), 2.13 (m, 2H). MS-ESI m/z 441.2 [M+H] ⁺ .

Example A6: Synthesis of Compound A6

Compound A5 was hydrogenated on a palladium-carbon catalyst to remove benzyl and then reacted with (2-bromomethyl)dimethylamine in a mixture containing potassium carbonate and acetonitrile to give compound A6.

Example (S)-A6: Synthesis of Compound A6

Compound (S)-A5 was hydrogenated on a palladium-carbon catalyst to remove benzyl and then reacted with (2-bromomethyl)dimethylamine in a mixture containing potassium carbonate and acetonitrile to give compound (S)-A6.

Example (R)-A6: Synthesis of Compound A6

Compound (R)-A5 was hydrogenated on a palladium-carbon catalyst to remove benzyl and then reacted with (2-bromomethyl)dimethylamine in a mixture containing potassium carbonate and acetonitrile to give compound (R)-A6.

Example A7: Synthesis of Compound A7

Compound A5 was subjected to hydrogenation on a palladium-carbon catalyst to remove benzyl and then reacted with 3-bromopropionic acid in a mixture containing potassium carbonate and acetonitrile to give compound A7.

Example (S)-A7: Synthesis of Compound A7

Compound (S)-A5 was hydrogenated on a palladium-carbon catalyst to remove benzyl and then reacted with 3-bromopropionic acid in a mixture containing potassium carbonate and acetonitrile to give compound (S)-A7.

Example (R)-A7: Synthesis of Compound A7

Compound (R)-A5 was hydrogenated on a palladium-carbon catalyst to remove benzyl and then reacted with 3-bromopropionic acid in a mixture containing potassium carbonate and acetonitrile to give compound (R)-A7.

Example B1: Synthesis of Compound B1

Compound 11-1 was dissolved in dichloromethane, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), hydroxybenzotriazole (HOBT) and triethylamide (TEA) were added and stirred for 30 min. A solution of compound 1-5 in dichloromethane was added slowly and stirred overnight, diluted with dichloromethane, then washed successively with saturated sodium bicarbonate, 1N. hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by passing through a 1:1 mixture of petroleum ether and ethyl acetate through a chromatographic column to give a white solid B1 (50 mg, % yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J = 5.7 Hz, 2H (prim)), 8.56 (d, J = 4.5 Hz, 2H (sec) )), 8.14 (br.s., 1H (prim.)), 8.06 (br.s., 1H (sec.)), 7.61 (d., J = 7.8 Hz, 1H (main)), 7.49 (d., J = 7.9 Hz, 1H (sec.)), 7.40 - 7.32 (m., 1H), 7.31 - 7.08 (m ., 4H (sec., main) 1H (main)), 6.65 (s., 1H (sec.)), 6.60 (s., 1H (sec.)), 6.56 (s. ., 1H (basic)), 6.48 (s., 1H (basic)), 6.23 (s., 1H (sec.)), 5.83 (d.d., J = 9 .5, 4.4 Hz, 1H (prim.)), 4.82 (d.d., J = 13.2, 5.1 Hz, 1H (sec.)), 4.64 (d.- d., J = 8.3, 5.5 Hz, 1H (sec)), 3.87 (s, 3H (sec)), 3.84 (s, 3H (prim)), 3 .75 - 3.62 (m., 3H (sec., main) 1H (main)), 3.57 (d.d.d., J = 13.7, 11.6, 4, 2 Hz, 1H (primary)), 3.39 (d.d.d., J = 13.2, 11.4, 5.0 Hz, 1H (sec.)), 3.16 - 2 .74 (m, 3H), 2.71 - 2.57 (m, 1H), 2.47 - 2.36 (m, 1H (bas)), 2.35 - 2.23 (m ., 1H), 2.20 - 2.10 (m., 1H (sec)). MS-ESI m/z 442.2 [M+H] ⁺ .

Example (S)-B1: Synthesis of Compound (S)-B1

Compound 1-5 in example B1 was replaced with compound 2-5 to give compound (S)-B1 as a white solid (50 mg, 60% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J = 5.7 Hz, 2H (prim)), 8.56 (d, J = 4.5 Hz, 2H (sec) )), 8.14 (br.s., 1H (prim.)), 8.06 (br.s., 1H (sec.)), 7.61 (d., J = 7.8 Hz, 1H (main)), 7.49 (d., J = 7.9 Hz, 1H (sec.)), 7.40 - 7.32 (m., 1H), 7.31 - 7.08 (m ., 4H (sec., main) 1H (main)), 6.65 (s., 1H (sec.)), 6.60 (s., 1H (sec.)), 6.56 (s. ., 1H (basic)), 6.48 (s., 1H (basic)), 6.23 (s., 1H (sec.)), 5.83 (d.d., J = 9 .5, 4.4 Hz, 1H (prim.)), 4.82 (d.d., J = 13.2, 5.1 Hz, 1H (sec.)), 4.64 (d.- d., J = 8.3, 5.5 Hz, 1H (sec)), 3.87 (s, 3H (sec)), 3.84 (s, 3H (prim)), 3 .75 - 3.62 (m., 3H (sec., main) 1H (main)), 3.57 (d.d.d., J = 13.7, 11.6, 4, 2 Hz, 1H (primary)), 3.39 (d.d.d., J = 13.2, 11.4, 5.0 Hz, 1H (sec.)), 3.16 - 2 .74 (m, 3H), 2.71 - 2.57 (m, 1H), 2.47 - 2.36 (m, 1H (bas)), 2.35 - 2.23 (m ., 1H), 2.20 - 2.10 (m., 1H (sec)). MS-ESI m/z 442.2 [M+H] ⁺ .

Example (R)-B1: Synthesis of Compound (R)-B1

Compound 1-5 in example B1 was replaced with compound 3-5 to give compound (R)-B1 as a white solid (50 mg, 60% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J = 5.7 Hz, 2H (prim)), 8.56 (d, J = 4.5 Hz, 2H (sec) )), 8.14 (br.s., 1H (prim.)), 8.06 (br.s., 1H (sec.)), 7.61 (d., J = 7.8 Hz, 1H (main)), 7.49 (d., J = 7.9 Hz, 1H (sec.)), 7.40 - 7.32 (m., 1H), 7.31 - 7.08 (m ., 4H (sec., main) 1H (main)), 6.65 (s., 1H (sec.)), 6.60 (s., 1H (sec.)), 6.56 (s. ., 1H (basic)), 6.48 (s., 1H (basic)), 6.23 (s., 1H (sec.)), 5.83 (d.d., J = 9 .5, 4.4 Hz, 1H (prim.)), 4.82 (d.d., J = 13.2, 5.1 Hz, 1H (sec.)), 4.64 (d.- d., J = 8.3, 5.5 Hz, 1H (sec)), 3.87 (s, 3H (sec)), 3.84 (s, 3H (prim)), 3 .75 - 3.62 (m., 3H (sec., main) 1H (main)), 3.57 (d.d.d., J = 13.7, 11.6, 4, 2 Hz, 1H (primary)), 3.39 (d.d.d., J = 13.2, 11.4, 5.0 Hz, 1H (sec.)), 3.16 - 2 .74 (m, 3H), 2.71 - 2.57 (m, 1H), 2.47 - 2.36 (m, 1H (bas)), 2.35 - 2.23 (m ., 1H), 2.20 - 2.10 (m., 1H (sec)). MS-ESI m/z 442.2 [M+H] ⁺ .

Example B2: Synthesis of Compound B2

Compound 1-5 was dissolved in acetonitrile, potassium carbonate solution and compound 12-1 were added, followed by reflux overnight. The resulting mixture was evaporated to dryness, purified by passing through a 1:1 mixture of petroleum ether and ethyl acetate through a chromatographic column to give a white solid B2 (50 mg, % yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (br.s., 1H), 7.61 (d., J = 7.9 Hz, 1H), 7.36 (d., J = 8 .1 Hz, 1H), 7.21 - 7.15 (m., 1H), 7.13 - 7.05 (m., 2H), 6.56 (s., 1H), 6.37 (s ., 1H), 3.84 (s., 4H), 3.75 (s., 3H), 3.67 (s., 3H), 3.65 - 3.54 (m., 2H), 3 .36 (s., 3H), 3.11 - 3.00 (m., 1H), 2.96 (t., J = 7.5 Hz, 2H), 2.92 - 2.77 (m. , 3H), 2.57 (d, J = 16.0 Hz, 1H), 2.31 (m, 1H), 2.15 - 2.01 (m, 1H). MS-ESI m/z 395.2 [M+H] ⁺ .

Example (S)-B2: Synthesis of Compound (S)-B2

To obtain compound (S)-B2, compound 1-5 in Example B1 was replaced with compound 2-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (br.s., 1H), 7.61 (d., J = 7.9 Hz, 1H), 7.36 (d., J = 8 .1 Hz, 1H), 7.21 - 7.15 (m., 1H), 7.13 - 7.05 (m., 2H), 6.56 (s., 1H), 6.37 (s ., 1H), 3.84 (s., 4H), 3.75 (s., 3H), 3.67 (s., 3H), 3.65 - 3.54 (m., 2H), 3 .36 (s., 3H), 3.11 - 3.00 (m., 1H), 2.96 (t., J = 7.5 Hz, 2H), 2.92 - 2.77 (m. , 3H), 2.57 (d, J = 16.0 Hz, 1H), 2.31 (m, 1H), 2.15 - 2.01 (m, 1H). MS-ESI m/z 395.2 [M+H] ⁺ .

Example (R)-B2: Synthesis of Compound (R)-B2

To obtain compound (R)-B2, compound 1-5 in Example B1 was replaced with compound 3-5. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (br.s., 1H), 7.61 (d., J = 7.9 Hz, 1H), 7.36 (d., J = 8 .1 Hz, 1H), 7.21 - 7.15 (m., 1H), 7.13 - 7.05 (m., 2H), 6.56 (s., 1H), 6.37 (s ., 1H), 3.84 (s., 4H), 3.75 (s., 3H), 3.67 (s., 3H), 3.65 - 3.54 (m., 2H), 3 .36 (s., 3H), 3.11 - 3.00 (m., 1H), 2.96 (t., J = 7.5 Hz, 2H), 2.92 - 2.77 (m. , 3H), 2.57 (d, J = 16.0 Hz, 1H), 2.31 (m, 1H), 2.15 - 2.01 (m, 1H). MS-ESI m/z 395.2 [M+H] ⁺ .

Example B3: Synthesis of Compound B3

Compound B3 was prepared according to the method for synthesizing compound B1, with compound 11-1 in Example B1 replaced by compound 13-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.54 (t, J = 2.4 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.38 - 7.31 ( m., 1H), 7.17 (d.d.d., J = 8.1, 7.4, 1.0 Hz, 1H), 7.14 - 7.07 (m., 2H) , 6.73 (d., J = 1.1 Hz, 1H), 6.62 (t., J = 1.0 Hz, 1H), 4.91 (t.d., J = 6.1 , 0.9 Hz, 1H), 3.90 - 3.81 (m., 7H), 3.78 (d.d.d., J = 11.5, 7.3, 5.0 Hz , 2H), 3.60 (d.d.d., J = 12.1, 6.5, 4.1 Hz, 1H), 3.40 (d.d.d., J = 11.7, 7.4, 5.1 Hz, 2H), 3.08 (d.d.d.d., J = 14.7, 6.4, 4.1, 0.9 Hz , 1H), 2.94 (d.-t., J = 14.7, 7.3 Hz, 1H), 2.88 - 2.74 (m., 2H), 2.52 (d.-t. .-d., J = 12.6, 7.3, 6.0 Hz, 1H), 2.44 (p., J = 6.5 Hz, 1H), 2.25 (d.-t.- d., J = 12.6, 7.3, 6.1 Hz, 1H), 1.93 - 1.82 (m., 2H), 1.68 (d.d.d.d. , J = 13.2, 7.3, 6.5, 5.0 Hz, 2H). MS-ESI m/z 449.2 [M+H] ⁺ .

Example (S)-B3: Synthesis of Compound (S)-B3

Compound (S)-B3 was prepared according to the method for synthesizing compound (S)-B1, with compound 11-1 in Example B1 replaced by compound 13-1. MS-ESI m/z 449.2 [M+H] ⁺ .

Example (R)-B3: Synthesis of Compound (R)-B3

Compound (R)-B3 was prepared according to the method for synthesizing compound (R)-B1, with compound 11-1 in Example B1 replaced by compound 13-1. MS-ESI m/z 449.2 [M+H] ⁺ .

Example B4: Synthesis of Compound B4

Compound B4 was prepared according to the method for synthesizing compound B1, with compound 11-1 in Example B1 replaced by compound 14-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (br.s., 1H (sec.)), 8.15 (br.s., 1H (bas.)), 7.61-7.54 (m, 1H), 7.39 - 7.33 (m, 1H), 7.24 - 7.00 (m, 3H), 6.60 (s, 1H (sec)), 6 .57 (s, 1H (bas)), 6.53 (s, 1H (sec)), 6.40 (s, 1H (bas)), 5.66 (d.-d.) , J = 9.2, 4.8 Hz, 1H (main)), 4.77 (d.d., J = 7.1, 7.1 Hz, 1H (second)), 4.66 (d-d-d, J = 7.5, 6.3, 2.0 Hz, 1H(sec)), 4.27 - 4.05 (m, 2H), 3.90 - 3.82 (m, 3H (sec, main) 1H (bas)), 3.81 (s, 3H (sec)), 3.65 (s, 3H (bas)), 3.55 (d-d-d, J = 13.7, 11.0, 4.6 Hz, 1H (basic)), 3.48 (s, 3H (basic)), 3 .32 (s, 3H (sec)), 3.21 (d-d-d, J = 13.3, 11.5, 4.9 Hz, 1H (sec)), 2, 97 - 2.64 (m, 4H), 2.35 - 2.10 (m, 2H). MS-ESI m/z 409.2 [M+H] ⁺ .

Example (S)-B4: Synthesis of Compound (S)-B4

Compound (S)-B4 was prepared according to the method for synthesizing compound (S)-B1, with compound 11-1 in Example B1 replaced by compound 14-1. MS-ESI m/z 409.2 [M+H] ⁺ .

Example (R)-B4: Synthesis of Compound (R)-B4

Compound (R)-B4 was prepared according to the method for synthesizing compound (R)-B1, with compound 11-1 in Example B1 replaced by compound 14-1. MS-ESI m/z 409.2 [M+H] ⁺ .

Example B5: Synthesis of Compound B5

Compound B5 was prepared according to the method for synthesizing compound B1, with compound 12-1 in Example B2 being replaced by compound 15-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (b.s., 1H), 7.60 (d., J = 7.9 Hz, 1H), 7.35 (d., J = 8 .1 Hz, 1H), 7.17 (d.d.d., J = 8.2, 7.2, 1.1 Hz, 1H), 7.09 (d.d.d. , J = 7.9, 7.1, 1.0 Hz, 1H), 7.04 (d., J = 2.0 Hz, 1H), 6.56 (s., 1H), 6.37 ( s., 1H), 3.84 (s., 3H), 3.78 - 3.70 (m., 4H), 3.68 (s., 3H), 3.48 (d.-d., J = 39.3, 16.6 Hz, 2H), 3.34 (d-d-d, J = 13.5, 9.8, 5.2 Hz, 1H), 3.04 (d .-t., J = 9.7, 5.2 Hz, 1H), 3.00 - 2.87 (m., 2H), 2.82 (d.-d.-d., J = 15, 6, 9.7, 5.6 Hz, 1H), 2.60 (d.t., J = 16.5, 4.5 Hz, 1H), 2.27 - 2.15 (m., 1H ), 2.14 - 2.03 (m., 1H). MS-ESI m/z 409.2 [M+H] ⁺ .

Example (S)-B5: Synthesis of Compound (S)-B5

Compound (S)-B5 was prepared according to the method for synthesizing compound (S)-B2, with compound 12-1 in Example B2 replaced by compound 15-1.

Example (R)-B5: Synthesis of Compound (R)-B5

Compound (R)-B5 was prepared according to the method for synthesizing compound (R)-B2, with compound 12-1 in Example B2 replaced by compound 15-1.

Example B6: Synthesis of Compound B6

Compound B6 was prepared according to the method for synthesizing compound B2, with compound 12-1 in Example B2 being replaced by compound 16-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (b.s., 1H), 7.61 (d., J = 7.8 Hz, 1H), 7.36 (d., J = 8 .1 Hz, 1H), 7.21 - 7.14 (m., 1H), 7.13 - 7.06 (m., 1H), 7.02 (s., 1H), 6.56 (s ., 1H), 6.37 (s., 1H), 3.84 (s., 3H), 3.72 (s., 3H), 3.67 (d.-d., J = 8.4 , 4.1 Hz, 1H), 3.43 - 3.31 (m, 1H), 3.24 (psi, J = 15.4, 9.5 Hz, 1H), 3.11 - 2.81 (m., 5H), 2.52 (d., J = 14.7 Hz, 1H), 2.16 (d.-t., J = 13.9, 7.0 Hz, 1H ), 2.10 - 1.98 (m, 1H). MS-ESI m/z 419.2 [M+H] ⁺ .

Example (S)-B6: Synthesis of Compound (S)-B6

Compound (S)-B6 was prepared according to the method for synthesizing compound (S)-B2, with compound 12-1 in Example B2 replaced by compound 16-1. MS-ESI m/z 419.2 [M+H] ⁺ .

Example (R)-B6: Synthesis of Compound (R)-B6

Compound (R)-B6 was prepared according to the method for synthesizing compound (R)-B2, with compound 12-1 in Example B2 replaced by compound 16-1. MS-ESI m/z 419.2 [M+H] ⁺ .

Example B7: Synthesis of Compound B7

Compound B7 was prepared according to the method for synthesizing compound B2, with compound 12-1 in Example B2 being replaced by compound 17-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (br.s., 1H), 7.59 (d., J = 7.8 Hz, 1H), 7.36 (d., J = 8 .1 Hz, 1H), 7.18 (t., J = 7.1 Hz, 1H), 7.11 (d.d., J = 11.0, 3.9 Hz, 1H), 6, 99 (s, 1H), 6.56 (s, 1H), 6.46 (s, 1H), 3.98 (d-d, J = 11.4, 2.9 Hz, 1H ), 3.84 (s., 3H), 3.76 (s., 3H), 3.63 - 3.47 (m., 1H), 3.38 (t.d., J = 10, 9, 3.3 Hz, 2H), 3.31 - 3.16 (m, 1H), 3.05 - 2.67 (m, 4H), 2.60 - 2.30 (m, 3H ), 2.24 - 1.96 (m, 2H), 1.88 - 1.67 (m, 3H), 1.28 (m, 1H). MS-ESI m/z 435.3 [M+H] ⁺ .

Example (S)-B7: Synthesis of Compound (S)-B7

Compound (S)-B7 was prepared according to the method for synthesizing compound (S)-B2, with compound 12-1 in Example B2 replaced by compound 17-1. MS-ESI m/z 435.3 [M+H] ⁺ .

Example (R)-B7: Synthesis of Compound (R)-B7

Compound (R)-B7 was prepared according to the method for synthesizing compound (R)-B2, with compound 12-1 in Example B2 replaced by compound 17-1. MS-ESI m/z 435.3 [M+H] ⁺ .

Example B8: Synthesis of Compound B8

Compound B8 was prepared according to the method for synthesizing compound B2, with compound 12-1 in Example B2 being replaced by compound 18-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d., J = 7.9 Hz, 1H), 7.36 (d., J = 8.2 Hz, 1H), 7.26 (t ., J = 7.6 Hz, 1H), 7.14 (m., 2H), 6.56 (s., 1H), 6.36 (s., 1H), 4.77 - 4.58 ( m., 2H), 3.84 (s., 3H), 3.73 (s., 3H), 3.53 (t., J = 6.4 Hz, 2H), 3.31 - 3.21 (m, 1H), 3.18 - 3.06 (m, 2H), 3.04 - 2.81 (m, 7H), 2.38 - 2.15 (m, 1H), 2 .17 - 2.04 (m., 1H). MS-ESI m/z 443.2 [M+H] ⁺ .

Example (S)-B8: Synthesis of Compound (S)-B8

Compound (S)-B8 was prepared according to the method for synthesizing compound (S)-B2, with compound 12-1 in Example B2 replaced by compound 18-1. MS-ESI m/z 443.2 [M+H] ⁺ .

Example (R)-B8: Synthesis of Compound (R)-B8

Соединение (R)-B8 получали в соответствии с методом синтеза соединения (R)-B2, при этом соединение 12-1 в примере B2 заменяли соединением 18-1. МС-ИЭР m/z 443,2 [M+H]⁺.

Compound (R)-B8 was prepared according to the method for synthesizing compound (R)-B2, with compound 12-1 in Example B2 replaced by compound 18-1. MS-ESI m/z 443.2 [M+H] ⁺ .

Example B9: Synthesis of Compound B9

Compound B9 was prepared according to the method for synthesizing compound B1, with compound 11-1 in Example B1 replaced by compound 19-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.55 (t., J = 2.4 Hz, 1H), 7.61 (d.t., J = 7.3, 0.9 Hz, 1H ), 7.38 - 7.31 (m, 1H), 7.17 (d-d-d, J = 8.1, 7.4, 1.0 Hz, 1H), 7.14 - 7.06 (m., 2H), 6.90 (d., J = 0.9 Hz, 1H), 6.62 (t., J = 1.0 Hz, 1H), 5.00 (t .-d., J = 6.0, 1.0 Hz, 1H), 4.38 (d., J = 17.2 Hz, 1H), 4.04 (d., J = 17.0 Hz, 1H), 3.91 (d.d.d., J = 12.1, 6.3, 4.3 Hz, 1H), 3.83 (s., 6H), 3.75 (d. -d.d., J = 11.9, 6.2, 4.2 Hz, 1H), 2.98 (s., 3H), 3.03 - 2.87 (m., 3H), 2 .81 (d.t., J = 14.9, 7.3 Hz, 1H), 2.39 (d.t.-d., J = 12.6, 7.3, 6.1 Hz , 1H), 2.26 (d.t.d., J = 12.6, 7.3, 6.1 Hz, 1H). MS-ESM m/z 457.2 [M+H] ⁺

Example (S)-B9: Synthesis of Compound (S)-B9

Compound (S)-B9 was prepared according to the method for synthesizing compound (S)-B1, with compound 11-1 in Example B1 replaced by compound 19-1. MS-ESI m/z 457.2 [M+H] ⁺ .

Example (R)-B9: Synthesis of Compound (R)-B9

Compound (R)-B9 was prepared according to the method for synthesizing compound (R)-B1, with compound 11-1 in Example B1 replaced by compound 19-1. MS-ESI m/z 457.2 [M+H] ⁺ .

Example B10: Synthesis of Compound B10

Compound 1-5 was dissolved in tetrahydrofuran (THF), compound 20-1 was added and stirred at room temperature for 20 h, diluted with dichloromethane (DCM), washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated dry. The residue was purified by passing through a 1:1 mixture of petroleum ether and ethyl acetate through a chromatographic column to give 20 mg of a white oil (yield 58%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.63 (t., J = 2.4 Hz, 1H), 7.59 (d.d.d., J = 7.3, 1.1 , 0.6 Hz, 1H), 7.38 - 7.32 (m., 1H), 7.17 (t.d., J = 7.7, 1.1 Hz, 1H), 7.15 - 7.07 (m., 2H), 6.83 (d., J = 1.1 Hz, 1H), 6.61 (t., J = 1.0 Hz, 1H), 4.96 (t .-d., J = 5.4, 1.0 Hz, 1H), 3.95 (d.-d.-d., J = 11.9, 6.4, 4.0 Hz, 1H), 3.86 - 3.78 (m, 7H), 3.12 - 2.98 (m, 2H), 2.89 - 2.78 (m, 2H), 2.42 - 2.25 ( m., 2H). MS-ESI m/z 433.2 [M+H] ⁺ .

Example (S)-B10: Synthesis of Compound (S)-B10

Compound (S)-B10 was obtained by replacing compound 1-5 in Example B10 with compound 2-5. MS-ESI m/z 433.2.

Example (R)-B10: Synthesis of Compound (R)-B10

Compound (S)-B10 was obtained by replacing compound 1-5 in example B10 with compound 3-5. MS-ESI m/z 433.2 [M+H] ⁺ .

Example B11: Synthesis of Compound B11

Compound B11 was synthesized according to the method for synthesizing compound B1, with compound 11-1 in Example B1 replaced by compound 14-1. 25 mg of a white solid was obtained (88% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (br.s., 1H (sec.)), 8.15 (br.s., 1H (bas.)), 7.61-7.54 (m, 1H), 7.39 - 7.33 (m, 1H), 7.24 - 7.00 (m, 3H), 6.60 (s, 1H (sec)), 6 .57 (s, 1H (bas)), 6.53 (s, 1H (sec)), 6.40 (s, 1H (bas)), 5.66 (d.-d.) , J = 9.2, 4.8 Hz, 1H (main)), 4.77 (d.d., J = 7.1, 7.1 Hz, 1H (second)), 4.66 (d-d-d, J = 7.5, 6.3, 2.0 Hz, 1H(sec)), 4.27 - 4.05 (m, 2H), 3.90 - 3.82 (m, 3H (sec, main) 1H (bas)), 3.81 (s, 3H (sec)), 3.65 (s, 3H (bas)), 3.55 (d-d-d, J = 13.7, 11.0, 4.6 Hz, 1H (basic)), 3.48 (s, 3H (basic)), 3 .32 (s, 3H (sec)), 3.21 (d-d-d, J = 13.3, 11.5, 4.9 Hz, 1H (sec)), 2, 97 - 2.64 (m, 4H), 2.35 - 2.10 (m, 2H). MS-ESI m/z 409.2 [M+H] ⁺ .

Example (S)-B11: Synthesis of Compound (S)-B11

Compound (S)-B11 was prepared according to the method for synthesizing compound (S)-B1, with compound 11-1 in Example B1 replaced by compound 14-1. MS-ESI m/z 409.2 [M+H] ⁺ .

Example (R)-B11: Synthesis of Compound (R)-B11

Compound (R)-B11 was prepared according to the method for synthesizing compound (R)-B1, with compound 11-1 in Example B1 replaced by compound 14-1. MS-ESI m/z 409.2 [M+H] ⁺ .

Example B12: Synthesis of Compound B12

Compound B12 was obtained according to the method for the synthesis of compound B1, with compound 4-2 in example A2 replaced by ethyl bromide, and compound 11-1 in example B1 was replaced by compound 14-1, 85% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (br.s., 1H (sec.)), 8.13 (br.s., 1H (bas.)), 7.62-7.52 (m, 1H), 7.41 - 7.32 (m, 1H), 7.23 - 6.98 (m, 3H), 6.60 (s, 1H (sec)), 6 .57 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.40 (s, 1H (bas)), 5.64 (d.-d.) , J = 9.1, 4.7 Hz, 1H (main)), 4.76 (d.d., J = 7.6, 6.7 Hz, 1H (second)), 4.64 (d.d.d., J = 8.2, 5.7, 1.9 Hz, 1H (sec)), 4.20 (sq., J = 13.6 Hz, 2H (basic) )), 4.06 (s, 2H (sec)), 3.89 - 3.78 (m, 3H (sec, main) 1H (sec) 1H (bas)), 3, 55 (d-d-d, J = 13.5, 10.8, 4.4 Hz, 1H (basic)), 3.48 (s, 3H (basic)), 3.31 (s, 3H (sec)), 3.21 (d-d-d, J = 12.6, 11.0, 4.2 Hz, 1H (sec)), 3.03 - 2.61 (m, 4H), 2.38 - 2.20 (m, 2H (bas)), 2.18 - 2.08 (m, 2H (sec)), 1.44 ( t., J = 7.0 Hz, 3H (sec.)), 1.35 (t., J = 7.0 Hz, 3H (prim.)). MS-ESI m/z 423.0 [M+H] ⁺ .

Example (S)-B12: Synthesis of Compound (S)-B12

Compound (S)-B12 was synthesized according to the method for the synthesis of compound (S)-B11, with compound 4-2 in example A2 replaced by ethyl bromide, and compound 11-1 in example B1 was replaced by compound 14-1, 85% yield. MS-ESI m/z 423.0 [M+H] ⁺ .

Example (R)-B12: Synthesis of Compound (R)-B12

Compound (R)-B12 was synthesized according to the method for the synthesis of compound (R)-B11, replacing compound 4-2 in Example A2 with ethyl bromide and compound 11-1 in Example B1 with compound 14-1 (85% yield). MS-ESI m/z 423.0 [M+H] ⁺ .

Example B13: Synthesis of Compound B13

Intermediate 1-5 was dissolved in dichloromethane, pyridine and compound 46-1 were added. The mixture was stirred at room temperature for 1 hour and the reaction was quenched by adding 0.1 N sodium hydroxide. NaOH solution, extracted with dichloromethane, washed with 1 N. hydrochloric acid solution, the organic layer was dried and evaporated to dryness, and then passed through a chromatographic column to obtain compound B13. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s., 1H), 7.55 (d.d., J = 14.9, 3.1 Hz, 1H), 7.32 (d .-d., J = 15.0, 3.1 Hz, 1H), 7.23 - 7.12 (m., 2H), 7.02 - 6.91 (m., 2H), 6.87 (s., 1H), 4.49 (t., J = 13.0 Hz, 1H), 3.74 (s., 6H), 3.42 (d.-t., J = 24.7, 10.8 Hz, 1H), 3.14 (d.t., J = 24.7, 10.8 Hz, 1H), 2.94 (s., 3H), 2.86 - 2.66 ( m., 4H), 2.12 (t.d., J = 15.7, 13.1 Hz, 2H). MS-ESI m/z 415.2 [M+H] ⁺ .

Example (S)-B13: Synthesis of Compound (S)-B13

Compound (S)-B13 was obtained by replacing compound 1-5 in example B13 with compound 2-5. MS-ESI m/z 415.2 [M+H] ⁺ .

Example (R)-B13: Synthesis of Compound (R)-B13

Compound (S)-B13 was obtained by replacing compound 1-5 in Example B13 with compound 3-5. MS-ESI m/z 415.2 [M+H] ⁺ .

Example B14: Synthesis of Compound B14

Intermediate 1-5 was dissolved in methylene chloride, compound B14-1 and triethylamine were added. The mixture was stirred at room temperature for 2 hours and quenched by addition of saturated ammonium chloride solution, extracted with methylene chloride and washed with saturated brine. The organic layer was dried and evaporated to dryness and then passed through a chromatographic column to obtain compound B14. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.41 (t., J = 2.4 Hz, 1H), 7.61 (d.d.t., J = 7.3, 1.1 , 0.6 Hz, 1H), 7.39 - 7.32 (m., 1H), 7.21 - 7.13 (m., 1H), 7.14 - 7.07 (m., 2H) , 6.64 (t., J = 1.0 Hz, 1H), 6.50 (d., J = 1.1 Hz, 1H), 5.09 (t.-d., J = 5.4 , 1.0 Hz, 1H), 4.03 (d.d.d., J = 11.9, 6.2, 4.2 Hz, 1H), 3.83 (d., J = 2 .4 Hz, 6H), 3.64 - 3.53 (m., 5H), 3.17 - 3.08 (m., 4H), 3.04 - 2.87 (m., 3H), 2 .79 - 2.69 (m., 1H), 2.50 (d.-t.-d., J = 12.6, 7.3, 5.3 Hz, 1H), 2.28 (d. -t.d., J = 12.6, 7.3, 5.4 Hz, 1H). MS-ESI m/z 450.2 [M+H] ⁺ .

Example (S)-B14: Synthesis of Compound (S)-B14

Compound (S)-B14 was obtained by replacing compound 1-5 in example B14 with compound 2-5. MS-ESI m/z 450.2 [M+H] ⁺ .

Example (R)-B14: Synthesis of Compound (R)-B14

Compound (R)-B14 was obtained by replacing compound 1-5 in example B14 with compound 3-5. MS-ESI m/z 450.2 [M+H] ⁺ .

Example B15: Synthesis of Compound B15

Compound B14-1 in example B14 was replaced with methyl chloroformate to give compound B15. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.62 - 7.56 (m., 1H), 7.38 - 7.32 (m., 1H), 7.20 - 7.11 (m., 2H), 7.06 (t.d., J = 7.5, 1.6 Hz, 1H), 6.84 (d., J = 0.9 Hz, 1H), 6.73 (t. , J = 0.9 Hz, 1H), 5.04 (t.d., J = 5.3, 1.0 Hz, 1H), 3.85 - 3.73 (m., 8H), 3 .68 (s., 2H), 3.19 (q.t., J = 14.8, 7.3 Hz, 2H), 2.92 (d.d.d., J = 6, 2, 5.0, 1.1 Hz, 2H), 2.47 (d-t-d, J = 12.7, 7.3, 5.3 Hz, 1H), 2.39 (d .-t.-d., J = 12.7, 7.3, 5.4 Hz, 1H). MS-ESI m/z 395.2 [M+H] ⁺ .

Example (S)-B15: Synthesis of Compound (S)-B15

Compound (S)-B15 was obtained according to the synthetic method in Example B15, with Compound 1-5 in Example B14 replaced with Compound 2-5 and Compound B14-1 in Example B15 replaced with methyl chloroformate. MS-ESI m/z 395.2 [M+H] ⁺ .

Example (R)-B15: Synthesis of Compound (R)-B15

Compound (R)-B15 was prepared according to the synthetic method in Example B15, with Compound 1-5 in Example B14 replaced with Compound 3-5 and Compound B14-1 in Example B15 replaced with methyl chloroformate. MS-ESI m/z 395.2 [M+H] ⁺ .

Example B16: Synthesis of Compound B16

Compound B16 was obtained according to the synthetic method in Example B2, with compound 4-2 in Example A2 being replaced by ethyl bromide and compound B12-1 in Example B2 being replaced by 2-iodoacetamide.

Example (S)-B16: Synthesis of Compound (S)-B16

Compound B16 was obtained according to the synthetic method in Example B2, with compound 4-2 in Example A2 being replaced by ethyl bromide and compound B12-1 in Example B2 being replaced by 2-iodoacetamide.

Example (R)-B16: Synthesis of Compound (R)-B16

Compound B16 was obtained according to the synthetic method in Example B2, with compound 4-2 in Example A2 being replaced by ethyl bromide and compound B12-1 in Example B2 being replaced by 2-iodoacetamide.

Example C1: Synthesis of Compound C1

Synthesis of compound 23-3:

Compound 23-2 was dissolved in methylene chloride and zirconium tetrachloride was added. A solution of compound 23-1 in dichloromethane was added slowly dropwise and stirred for 1 h. The mixture was diluted with dichloromethane, washed with water and the organic layer was evaporated to dryness for subsequent use without purification.

Synthesis of compound 23-4:

Compound 23-3 was dissolved in a 1:1 mixture of tetrahydrofuran and water, lithium hydroxide was added and stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate, the aqueous layer was collected and acidified with 1N HCl. hydrochloric acid and then extracted three times with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate, then evaporated to give 420 mg of a brown solid (68% yield from two steps). ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.04 (br.s., 1H) 7.66 (d., J=1.9 Hz, 1H), 7.24 (d., J= 8.6 Hz, 1H), 7.16 (d.d., J = 8.6, 1.9 Hz, 1H), 7.08 (s., 1H), 3.01 (t., J = 7.4 Hz, 2H), 2.65 (t., J = 7.5 Hz, 2H). MS-ESI m/z 268.0 [M+H] ⁺

Compound C1 was prepared according to the method for synthesizing compound A1, with compound 1-1 in Example A1 replaced by compound 4-5 and compound 1-2 in Example A1 replaced by compound 23-4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.19 (s, 2H (bas)), 8.13 (br.s., 1H ( sec)), 7.77 (s, 1H (sec)), 7.70 (s, 1H (bas)), 7.32 - 7.27 (m, 1H), 7.26 - 7.23 (m, 1H), 7.21 (s, 1H (sec)), 7.04 (s, 1H (bas)), 6.56 (s, 1H (bas) )), 6.54 (s, 1H (sec)), 6.37 (s, 1H (bas)), 6.33 (s, 1H (sec)), 5.40 (d .-d., J = 9.0, 4.2 Hz, 1H (sec.)), 4.67 - 4.61 (m., 1H (sec.)), 4.58 - 4.54 (m ., 1H (sec.)), 4.54 - 4.48 (m., 1H (basic)), 4.37 (d.d., J = 9.2, 4.4 Hz, 1H ( bas)), 3.80 (s, 3H (bas)), 3.79 (s, 3H (sec)), 3.73 (d-d, J = 13.3.5 .6 Hz, 1H (primary)), 3.61 (d.d.d., J = 12.6, 12.6, 4.2 Hz, 1H (sec.)), 3.10 ( d-d-d, J = 12.6, 12.6, 4.8 Hz, 1H (basic)), 2.96 - 2.63 (m, 4H), 2.31 - 2 .13 (m, 2H), 1.98 - 1.70 (m, 6H), 1.68 - 1.47 (m, 2H). MS-ESI m/z 497.1 [M+H] ⁺ .

Example (S)-C1: Synthesis of Compound (S)-C1

Compound (S)-C1 was prepared according to the synthetic method given in Example (S)-A2 and Example C1. MS-ESI m/z 497.1 [M+H] ⁺ .

Example (R)-C1: Synthesis of Compound (R)-C1

Compound (R)-C1 was prepared according to the synthetic method given in Example (R)-A2 and Example C1. MS-ESI m/z 497.1 [M+H] ⁺ .

Example C2: Synthesis of Compound C2

Compound C2 was prepared according to the method for synthesizing compound C1, with compound 23-1 in Example C1 replaced by compound 24-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.21 (s, 1H (bas)), 8.02 (br.s., 1H ( basal)), 7.95 (br.s., 1H (sec.)), 7.41 (s., 1H (bas.)), 7.35 (s., 1H (sec.)), 7 .31 - 7.22 (m., 1H), 7.11 (s., 1H (sec.)), 7.07 - 6.99 (m., 1H), 6.99 (s., 1H ( bas)), 6.56 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.40 (s, 1H (sec)), 6.38 (s., 1H (prim.)), 5.45 (d.d., J = 8.1, 5.6 Hz, 1H (sec.)), 4.62 - 4.48 (m., 1H(prim, sec), 1H(prim)), 4.42(d-d, J=9.9, 3.9 Hz, 1H(prim)), 3.80(s). , 3H), 3.73 (d.d., J = 13.2, 5.8 Hz, 1H (sec)), 3.62 (d.d.d., J = 13.3 , 11.9, 4.4 Hz, 1H (sec)), 3.12 (d-d-d, J = 12.5, 12.5, 4.7 Hz, 1H (main) ), 2.98 - 2.63 (m, 4H), 2.46 (s, 3H (bas)), 2.44 (s, 3H (sec)), 2.30 - 2, 16 (m, 2H), 1.91-1.68 (m, 6H), 1.61-1.48 (m, 2H). MS-ESI m/z 433.2 [M+H] ⁺ .

Example (S)-C2: Synthesis of Compound (S)-C2

Compound (S)-C2 was prepared according to the method for synthesizing compound (S)-C1, with compound 23-1 in Example C1 replaced by compound 24-1. MS-ESI m/z 433.2 [M+H] ⁺ .

Example (R)-C2: Synthesis of Compound (R)-C2

Compound (R)-C2 was prepared according to the method for synthesizing compound (R)-C1, with compound 23-1 in Example C1 replaced by compound 24-1. MS-ESI m/z 433.2 [M+H] ⁺ .

Example C3: Synthesis of Compound C3

Compound C3 was prepared according to the method for synthesizing compound C1, with compound 23-1 in Example C1 replaced by compound 25-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s., 1H(sec)), 8.19 (s., 1H(bas)), 8.02 (br.s., 1H( basal)), 7.94 (br.s., 1H (sec.)), 7.51 (d., J = 8.0 Hz, 1H (prim.)), 7.45 (d., J = 8.0 Hz, 1H (sec)), 7.18 (s, 1H (prim)), 7.15 (s, 1H (sec)), 7.06 (s, 1H ( sec)), 6.99 - 6.90 (m, 1H(bas, sec) 1H(base)) 6.56 (s, 1H(base)), 6.53 (s). , 1H(sec)), 6.40(s, 1H(sec)), 6.38(s, 1H(bas)), 5.44(d-d, J = 8, 4, 5.3 Hz, 1H(sec)), 4.61 - 4.47(m, 1H(prim, sec) 1H(prim)), 4.40(d-d, J = 9.4, 4.1 Hz, 1H (prim)), 3.80 (s, 3H (prim)), 3.79 (s, 3H (sec)), 3.72 ( d-d, J = 13.2, 6.4 Hz, 1H (sec)), 3.62 (d-d, J = 18.3, 7.1 Hz, 1H (sec) ), 3.11 (d-d-d, J = 12.4, 4.6, 4.6 Hz, 1H (basic)), 2.97 - 2.58 (m, 4H) , 2.46 (s, 3H (bas)), 2.45 (s, 3H (sec)), 2.32 - 2.13 (m, 2H), 1.92 - 1.64 (m, 6H), 1.65 - 1.45 (m, 2H). MS-ESI m/z 433.2 [M+H] ⁺ .

Example (S)-C3: Synthesis of Compound (S)-C3

Compound (S)-C3 was prepared according to the method for synthesizing compound (S)-C1, with compound 23-1 in Example C1 replaced by compound 25-1. MS-ESI m/z 433.2 [M+H] ⁺ .

Example (R)-C3: Synthesis of Compound (R)-C3

Compound (R)-C3 was prepared according to the method for synthesizing compound (R)-C1, with compound 23-1 in Example C1 replaced by compound 25-1. MS-ESI m/z 433.2 [M+H] ⁺ .

Example C4: Synthesis of Compound C4

Compound C4 was prepared according to the method for the synthesis of compound A3, with compound 23-1 in Example C1 replaced by compound 25-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s., 1H(sec)), 8.18 (s., 1H(bas)), 7.97 (br.s., 1H( basal)), 7.90 (br.s., 1H (sec.)), 7.50 (d., J = 8.1 Hz, 1H (prim.)), 7.44 (d., J = 8.0 Hz, 1H (sec)), 7.18 (s, 1H (prim)), 7.15 (s, 1H (sec)), 7.05 (s, 1H ( sec)), 6.95 (m, 1H (sec, main) 1H (bas)), 6.57 (s, 1H (bas)), 6.55 (s, 1H ( sec)), 6.43 (s, 1H (sec)), 6.40 (s, 1H (bas)), 5.44 (d-d, J = 8.5, 5 .3 Hz, 1H(sec)), 4.53(d-d, J = 13.1, 5.7 Hz, 1H(sec)), 4.39(d-d, J = 9.6, 4.2 Hz, 1H(prim)), 3.83(s, 3H), 3.77 - 3.55(m, 2H(sec), 2H(prim, sec) .)), 3.11 (d.d.d., J = 12.5, 12.5, 4.8 Hz, 1H (basic)), 2.98 - 2.60 (m., 4H), 2.47 (s, 3H (bas)), 2.45 (s, 3H (sec)), 2.29 - 2.13 (m, 2H), 0.67 - 0 .54 (m, 2H), 0.35 - 0.24 (m, 2H). MS-ESI m/z 419.2 [M+H] ⁺ .

Example (S)-C4: Synthesis of Compound (S)-C4

Compound (S)-C4 was prepared according to the method for synthesizing compound (S)-A3, with compound 23-1 in Example C1 replaced by compound 25-1. MS-ESI m/z 419.2 [M+H] ⁺ .

Example (R)-C4: Synthesis of Compound (R)-C4

Compound (R)-C4 was prepared according to the method for synthesizing compound (R)-A3, with compound 23-1 in Example C1 replaced by compound 25-1. MS-ESI m/z 419.2 [M+H] ⁺ .

Example C5: Synthesis of Compound C5

Compound C5 was prepared according to the method for the synthesis of compound A1, with compound 23-1 in Example C1 replaced by compound 25-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.19 (s, 1H (bas)), 7.97 (br.s., 1H ( basal)), 7.89 (br.s., 1H (sec.)), 7.51 (d., J = 8.0 Hz, 1H (prim.)), 7.45 (d., J = 8.1 Hz, 1H (sec)), 7.18 (s, 1H (prim)), 7.15 (s, 1H (sec)), 7.04 (s, 1H ( sec)), 7.00 - 6.89 (m, 1H (sec, main) 1H (bas)), 6.57 (s, 1H (bas)), 6.55 (s ., 1H(sec)), 6.43(s, 1H(sec)), 6.40(s, 1H(bas)), 5.46(d-d, J = 7 .3, 6.3 Hz, 1H (sec.)), 4.54 (d.d., J = 13.2, 6.1 Hz, 1H (sec.)), 4.43 (d.- d., J = 9.8, 3.8 Hz, 1H (basic)), 3.83 (s., 3H), 3.75 (s., 3H (basic)), 3.78 - 3 .68 (m., 3H (sec., main) 1H (sec.)), 3.62 (d.d.d., J = 12.2, 12.2, 4.2 Hz, 1H (second)), 3.12 (d.d.d., J = 12.2, 12.2, 4.5 Hz, 1H (main)), 2.98 - 2.63 (m ., 4H), 2.46 (s, 3H (bas)), 2.45 (s, 3H (sec)), 2.31-2.17 (m, 2H). MS-ESI m/z 379.2 [M+H] ⁺ .

Example (S)-C5: Synthesis of Compound (S)-C5

Compound (S)-C5 was prepared according to the method for synthesizing compound (S)-A1, with compound 23-1 in Example C1 replaced by compound 25-1. MS-ESI m/z 379.2 [M+H] ⁺ .

Example (R)-C5: Synthesis of Compound (R)-C5

Compound (R)-C5 was prepared according to the method for synthesizing compound (R)-A1, with compound 23-1 in Example C1 replaced by compound 25-1. MS-ESI m/z 379.2 [M+H] ⁺ .

Example C6: Synthesis of Compound C6

Compound C6 was obtained in accordance with the method of synthesis of compound A1, while compound 23-1 in example C1 was replaced by compound 29-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H (sec)), 8.20 (s, 1H (bas)), 8.19 (br.s., 1H ( basal)), 8.11 (br.s., 1H (sec.)), 7.51 (d.d., J = 8.7, 5.3 Hz, 1H (prim.)), 7 .46 (d-d, J = 8.7, 5.3 Hz, 1H (sec)), 7.14 - 6.98 (m, 2H), 6.94 - 6.81 (m ., 2H), 6.58 (s, 1H (base)), 6.55 (s, 1H (sec)), 6.41 (s, 1H (sec)), 6.40 (s., 1H (main)), 5.45 (d.-d., J = 8.5, 5.3 Hz, 1H (sec.)), 4.54 (d.-d.-d ., J = 13.1, 6.4, 1.4 Hz, 1H (base)), 4.43 (d.d., J = 7.0, 7.0 Hz, 1H (base) ), 3.84 (s, 3H (bas)), 3.84 (s, 3H (sec)), 3.77 (s, 3H (bas)), 3.76 - 3, 68 (m, 4H (sec)), 3.62 (d-d-d, J = 13.4, 11.9, 4.5 Hz, 1H (sec)), 3.12 (d.d.d., J = 13.1, 11.8, 4.7 Hz, 1H (basic)), 2.98 - 2.63 (m., 4H), 2.30 - 2.15 (m, 2H). MS-ESI m/z 383.2 [M+H] ⁺ .

Example (S)-C6: Synthesis of Compound (S)-C6

Compound (S)-C6 was prepared according to the method for the synthesis of compound (S)-A1, with compound 23-1 in Example C1 replaced by compound 29-1. MS-ESI m/z 383.2 [M+H] ⁺ .

Example (R)-C6: Synthesis of Compound (R)-C6

Compound (R)-C6 was prepared according to the method for synthesizing compound (R)-A1, with compound 23-1 in Example C1 replaced by compound 29-1. MS-ESI m/z 383.2 [M+H] ⁺ .

Example C7: Synthesis of Compound C7

Compound C7 was obtained according to the method for the synthesis of compound A4, with compound 23-1 in Example C1 replaced by compound 25-1. ¹ H NMR (400 MHz, chloroform) δ 8.02 (s., 1H), 7.60 (s., 1H), 7.53 (s., 1H), 7.25 - 7.16 (m. , 3H), 6.97 (s., 1H), 6.88 (s., 1H), 4.70 (s., 1H), 4.13 (s., 2H), 3.92 (s. , 1H), 3.75 (s., 3H), 3.33 (s., 1H), 2.91 (d., J = 15.0 Hz, 2H), 2.76 (s., 1H) , 2.44 (s., 3H), 2.26 (s., 2H), 1.42 (s., 3H). ESI-MS m/z 393.2 [M+H] ⁺ .

Example (S)-C7: Synthesis of Compound (S)-C7

Compound (S)-C7 was prepared according to the method for synthesizing compound (S)-A4, with compound 23-1 in Example C1 replaced by compound 25-1. MS-ESI m/z 393.2 [M+H] ⁺ .

Example (R)-C7: Synthesis of Compound (R)-C7

Compound (R)-C7 was prepared according to the method for synthesizing compound (R)-A4, with compound 23-1 in Example C1 replaced by compound 25-1. MS-ESI m/z 393.2 [M+H] ⁺ .

Example C8: Synthesis of Compound C8

Compound C8 was obtained in accordance with the method of synthesis of compound A4, while compound 23-1 in example C1 was replaced by compound 31-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H (sec)), 8.21 (s, 1H (bas)), 8.03 (br.s., 1H ( basal)), 7.96 (br.s., 1H (sec.)), 7.28 (d., J = 8.8 Hz, 1H (prim.)), 7.25 (d., J = 8.8 Hz, 1H (sec)), 7.11 (s, 1H (sec)), 7.03 (d, J = 2.3 Hz, 1H (prim)), 7, 00 (d., J = 2.0 Hz, 1H (sec) 1H (main)), 6.88 (d.d., J = 8.8, 2.4 Hz, 1H (main) ), 6.84 (d-d, J = 8.8, 2.4 Hz, 1H (sec)), 6.57 (s, 1H (bas)), 6.55 (s). , 1H (sec)), 6.42 (s, 1H (bas)), 6.42 (s, 1H (sec)), 5.45 (d-d, J = 8, 3, 5.5 Hz, 1H (sec)), 4.53 (d-d-d, J = 13.0, 6.3, 1.7 Hz, 1H (prim)), 4 .43 (d.d., J = 7.9, 5.2 Hz, 1H (basic)), 3.98 - 3.84 (m., 5H), 3.83 (s., 3H ( basal)), 3.82 (s, 3H (sec)), 3.73 (d-d, J = 12.9, 6.1 Hz, 1H (sec)), 3.66 - 3.57 (m, 1H (sec)), 3.12 (d-d-d, J = 13.1, 11.8, 4.8 Hz, 1H (prim)), 2.96 - 2.64 (m, 4H), 2.28 - 2.16 (m, 2H), 1.43 - 1.34 (m, 3H). MS-ESI m/z 409.2 [M+H] ⁺ .

Example (S)-C8: Synthesis of Compound (S)-C8

Compound (S)-C8 was prepared according to the method for synthesizing compound (S)-A4, with compound 23-1 in Example C1 replaced by compound 31-1. MS-ESI m/z 409.2 [M+H] ⁺ .

Example (R)-C8: Synthesis of Compound (R)-C8

Compound (R)-C8 was prepared according to the method for the synthesis of compound (R)-A4, with compound 23-1 in Example C1 replaced by compound 31-1. MS-ESI m/z 409.2 [M+H] ⁺ .

Example C9: Synthesis of Compound C9

Соединение C9

получали в соответствии с методом синтеза соединения A1, при этом соединение 1-1 в примере A1 заменяли соединением 32-1. ¹H ЯМР (400 МГц, CDCl3) δ 8,32 (ш.с., 1H (осн.)), 8,18 (с., 1H (втор.)), 8,16 (ш.с., 1H (втор.)), 7,65 (д., J = 7,7 Гц, 1H (осн.)), 7,60 (м., 1H (втор.) 1H (осн.)), 7,41 (д., J = 7,9 Гц, 1H (осн.)), 7,36 (д., J = 8,1 Гц, 1H (втор.)), 7,28 - 7,07 (м., 2H), 6,95 (с., 1H (осн.)), 6,93 (с., 1H (втор.)), 6,70 (с., 1H (осн.)), 6,67 (с., 1H (осн.)), 6,57 (с., 1H (втор.)), 6,34 (с., 1H (втор.)), 5,69 (д.-д., J = 6,5 Гц, 1H (втор.)), 4,74 (д.-д., J = 9,8, 3,8 Гц, 1H (осн.)), 4,53 (д.-д., J = 13,0, 4,4 Гц, 1H (осн.)), 3,91 (с., 3H (осн.)), 3,88 (с., 3H (осн.)), 3,87 (с., 3H (втор.)), 3,64 - 3,54 (м., 4H (втор.)), 3,48 - 3,13 (м., 3H), 3,00 - 2,81 (м., 1H), 2,77 (д.-д., J = 16,0, 2,5 Гц, 1H (осн.)), 2,69 (д.-д., J = 16,2, 2,3 Гц, 1H (втор.)). МС-ИЭР m/z 351,2 [M+H]⁺.

Compound C9

was obtained in accordance with the method of synthesis of compound A1, while compound 1-1 in example A1 was replaced by compound 32-1. ¹ H NMR (400 MHz, CDCl3) δ 8.32 (b.s., 1H(b)), 8.18 (s., 1H(s)), 8.16 (br.s., 1H (sec)), 7.65 (d, J = 7.7 Hz, 1H (prim)), 7.60 (m, 1H (sec) 1H (prim)), 7.41 ( d., J = 7.9 Hz, 1H (prim.)), 7.36 (d., J = 8.1 Hz, 1H (sec.)), 7.28 - 7.07 (m., 2H ), 6.95 (s, 1H (bas)), 6.93 (s, 1H (sec)), 6.70 (s, 1H (bas)), 6.67 (s). , 1H(base)), 6.57(s, 1H(sec)), 6.34(s, 1H(sec)), 5.69(d-d, J=6, 5 Hz, 1H (sec)), 4.74 (d-d, J = 9.8, 3.8 Hz, 1H (prim)), 4.53 (d-d, J = 13.0, 4.4 Hz, 1H (prim)), 3.91 (s, 3H (prim)), 3.88 (s, 3H (prim)), 3.87 (s). , 3H (sec.)), 3.64 - 3.54 (m., 4H (sec.)), 3.48 - 3.13 (m., 3H), 3.00 - 2.81 (m. , 1H), 2.77 (d.d., J = 16.0, 2.5 Hz, 1H (basic)), 2.69 (d.d., J = 16.2, 2, 3 Hz, 1H (sec)). MS-ESI m/z 351.2 [M+H] ⁺ .

Example (S)-C9: Synthesis of Compound (S)-C9

Compound (S)-C9 was prepared according to the method for synthesizing compound (S)-A1, with compound 1-2 in Example A1 replaced by compound 32-1. MS-ESI m/z 351.2 [M+H] ⁺ .

Example (R)-C9: Synthesis of Compound (R)-C9

Compound (R)-C9 was prepared according to the method for synthesizing compound (R)-A1, with compound 1-2 in Example A1 replaced by compound 32-1. MS-ESI m/z 351.2 [M+H] ⁺ .

Example C10: Synthesis of Compound C10

Compound C10 was prepared according to the method for the synthesis of compound A4, with compound 1-2 in Example A1 being replaced by compound 32-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (br.s., 1H (b.)), 8.15 (s., 1H (s.)), 8.11 (br.s., 1H (sec)), 7.62 (d, J = 7.5 Hz, 1H (prim)), 7.59 - 7.53 (m, 1H (sec), 1H (prim) ), 7.38 (d, J = 8.0 Hz, 1H (prim)), 7.33 (d, J = 8.1 Hz, 1H (sec)), 7.25 - 7, 04 (m, 2H), 6.93 (s, 1H (bas)), 6.93 (s, 1H (sec)), 6.71 (s, 1H (bas)), 6.64 (s, 1H (b)), 6.55 (s, 1H (s)), 6.37 (s, 1H (s)), 5.66 (t, J = 6.5 Hz, 1H (sec)), 4.69 (d.d., J = 9.8, 3.8 Hz, 1H (main)), 4.49 (d.-d.) -d., J = 13.1, 6.2, 2.1 Hz, 1H (basic)), 4.07 (q.d., J = 7.0, 1.9 Hz, 2H (basic) .)), 3.87 (s., 3H (b.)), 3.83 (s., 3H (sec.)), 3.81 - 3.65 (m., 2H (sec.)), 3.54 (d-d-d, J = 13.0, 6.0, 1.7 Hz, 1H (sec)), 3.43 - 3.07 (m, 3H), 2 .97 - 2.58 (m., 2H), 1.47 (t., J = 7.0 Hz, 3H (basic)), 1.32 (t., J = 7.0 Hz, 3H ( sec.)). MS-ESI m/z 365.2 [M+H] ⁺ .

Example (S)-C10: Synthesis of Compound (S)-C10

Compound (S)-C10 was prepared according to the method for synthesizing compound (S)-A1, with compound 1-2 in Example A1 replaced by compound 32-1. MS-ESI m/z 365.2 [M+H] ⁺ .

Example (R)-C10: Synthesis of Compound (R)-C10

Compound (R)-C10 was prepared according to the method for synthesizing compound (R)-A1, with compound 1-2 in Example A1 replaced by compound 32-1. MS-ESI m/z 365.2 [M+H] ⁺ .

Example C11: Synthesis of Compound C11

Compound C11 was prepared according to the method for synthesizing compound B1, with compound 1-2 in Example A1 being replaced by compound 32-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (br.s., 1H (sec.)), 8.08 (br.s., 1H (bas.)), 7.67 (m., 1H), 7.40 (d, J = 7.4 Hz, 1H (sec)), 7.33 (d, J = 8.1 Hz, 1H (prim)), 7.24 - 7 .05 (m, 2H), 6.93 (s, 1H (sec)), 6.88 (s, 1H (bas)), 6.64 (s, 1H (sec)) , 6.58 (s, 1H (bas)), 6.54 (s, 1H (sec)), 6.20 (s, 1H (bas)), 5.79 (d.- d., J = 7.1, 6.0 Hz, 1H (prim.)), 4.92 (d.d., J = 8.6, 5.7 Hz, 1H (sec.)), 4 .80 (d-d, J = 12.6, 5.7 Hz, 1H (sec)), 4.14 (s, 1H (prim)), 3.87 (s, 3H ( sec)), 3.84 (s, 3H (bas)), 3.78 (s, 3H (sec)), 3.69 (m, 1H), 3.49 (s, 3H (basic)), 3.48 - 3.41 (m, 1H (sec)), 3.39 (s, 3H (basic)), 3.37 - 3.15 (m, 3H), 2.98 (s, 3H (sec)), 2.96-2.79 (m, 1H), 2.77-2.63 (m, 1H). MS-ESI m/z 395.2 [M+H] ⁺ .

Example (S)-C11: Synthesis of Compound (S)-C11

Compound (S)-B11 was prepared according to the method for synthesizing compound (S)-B1, with compound 1-2 in Example A1 replaced by compound 32-1. MS-ESI m/z 395.2 [M+H] ⁺ .

Example (R)-C11: Synthesis of Compound (R)-C11

Compound (R)-C11 was prepared according to the method for synthesizing compound (R)-B1, with compound 1-2 in Example A1 replaced by compound 32-1. MS-ESI m/z 395.2 [M+H] ⁺ .

Example C12: Synthesis of Compound C12

Compound C12 was prepared according to the method for synthesizing compound B8, with compound 1-2 in Example A1 being replaced by compound 32-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (br.s., 1H), 7.57 (d.d., J = 14.9, 3.0 Hz, 1H), 7.33 (d-d, J = 15.0, 3.1 Hz, 1H), 7.24 - 7.13 (m, 2H), 7.05 - 6.93 (m, 2H), 6 .88 (s., 1H), 3.96 (t., J = 14.0 Hz, 1H), 3.84 (d.d., J = 16.4, 15.4 Hz, 1H), 3.77 - 3.68 (m, 6H), 3.55 - 3.23 (m, 4H), 3.15 - 2.96 (m, 2H), 2.84 - 2.66 ( m., 5H), 2.58 (m., 1H). MS-ESI m/z 429.2 [M+H] ⁺ .

Example (S)-C12: Synthesis of Compound (S)-C12

Compound (S)-C12 was prepared according to the method for synthesizing compound (S)-B8, with compound 1-2 in Example A1 replaced by compound 32-1. MS-ESI m/z 429.2 [M+H] ⁺ .

Example (R)-C12: Synthesis of Compound (R)-C12

Compound (R)-C12 was prepared according to the method for synthesizing compound (R)-B8, with compound 1-2 in Example A1 replaced by compound 32-1. MS-ESI m/z 429.2 [M+H] ⁺ .

Example C13: Synthesis of Compound C13

Compound C13 was prepared according to the synthetic method given in Example B9, with Compound 1-2 in Example A1 being replaced by Compound 32-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (br.s., 1H (sec.)), 8.12 (br.s., 1H (bas.)), 7.62 (d., J = 7.8 Hz, 1H (main)), 7.57 (d., J = 7.6 Hz, 1H (second)), 7.39 (d., J = 7.8 Hz, 1H (sec.)), 7.33 (d., J = 8.1 Hz, 1H (basic)), 7.26 - 7.07 (m., 2H), 7.02 (s., 1H ( sec)), 6.87 (s, 1H (base)), 6.68 (s, 1H (sec)), 6.64 (s, 1H (sec)), 6.58 (s., 1H (basic)), 6.19 (s., 1H (basic)), 5.81 (d.d., J = 6.8, 6.8 Hz, 1H (basic) )), 5.01 (d.d., J = 9.7, 4.4 Hz, 1H (sec)), 4.74 (d.d., J = 13.3, 3.2 Hz, 1H(sec)), 4.09(q, J=14.4Hz, 2H(prim)), 3.87(s, 3H(prim)), 3.86(s). , 3H (sec)), 3.84 (s, 3H (bas)), 3.74 - 3.64 (m, 1H (bas)), 3.50 (s, 2H), 2.99 (s, 3H), 2.78 (s, 2H). MS-ESI m/z 443.2 [M+H] ⁺ .

Example (S)-C13: Synthesis of Compound (S)-C13

Compound (S)-C13 was prepared according to the synthetic method in Example (S)-B9, with Compound 1-2 in Example A1 replaced with Compound 32-1. MS-ESI m/z 443.2 [M+H]+.

Example (R)-C13: Synthesis of Compound (R)-C13

Compound (R)-C13 was prepared according to the synthetic method in Example (R)-B9, with Compound 1-2 in Example A1 replaced with Compound 32-1. MS-ESI m/z 443.2 [M+H]+.

Example C14: Synthesis of Compound C14

Compound C14 was prepared according to the synthetic method given in Example A4 and Example B8, with Compound 1-2 in Example A1 being replaced by Compound 32-1. ¹ H NMR (400 MHz, CDCl3) δ 8.13 (br.s., 1H), 7.58 (d., J = 7.8 Hz, 1H), 7.36 (d., J = 8, 1 Hz, 1H), 7.20 (t., J = 7.3 Hz, 1H), 7.13 (t., J = 7.3 Hz, 1H), 6.98 (s., 1H), 6.59 (s., 1H), 6.36 (s., 1H), 4.02-3.93 (m., 1H), 3.92-3.74 (m., 5H), 3. 51 - 3.38 (m., 1H), 3.20 (m., 2H), 3.12 - 2.83 (m., 6H), 2.55 (d., J = 15.6 Hz, 1H), 2.41 (s., 3H), 1.36 (t., J = 7.0 Hz, 3H). MS-ESI m/z 443.2 [M+H] ⁺ .

Example (S)-C14: Synthesis of Compound (S)-C14

Compound (S)-C14 was prepared according to the synthetic method in Example (S)-A4 and Example (S)-B8, with Compound 1-2 in Example A1 being replaced with Compound 32-1. MS-ESI m/z 443.2 [M+H] ⁺ .

Example (R)-C14: Synthesis of Compound (R)-C14

Compound (R)-C14 was prepared according to the synthetic method in Example (R)-A4 and Example (R)-B8, with Compound 1-2 in Example A1 replaced with Compound 32-1. MS-ESI m/z 443.2 [M+H] ⁺ .

Example C15: Synthesis of Compound C15

Compound C15 was prepared according to the synthetic method given in Example A4 and Example B9, with Compound 1-2 in Example A1 being replaced by Compound 32-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (b.s., 1H), 7.57 (d.d., J = 7.5, 1.4 Hz, 1H), 7.33 (d-d, J = 7.5, 1.4 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.02 - 6.94 (m, 2H), 6 .88 (s., 1H), 5.66 (t., J = 7.1 Hz, 1H), 4.35 (s., 2H), 4.17 - 4.05 (m., 3H), 3.75 (s., 3H), 3.58 (d.-d., J=12.4, 7.1 Hz, 1H), 3.49 (d.-t., J=12.4, 5.5 Hz, 1H), 3.32 (d-d, J = 12.5, 7.0 Hz, 1H), 2.98 - 2.84 (m, 5H), 1.42 ( t., J = 5.9 Hz, 3H). MS-ESI m/z 457.2 [M+H] ⁺ .

Example (S)-C15: Synthesis of Compound (S)-C15

Compound C15 was prepared according to the synthetic method in Example (S)-A4 and Example (S)-B9, with Compound 1-2 in Example A1 replaced with Compound 32-1. MS-ESI m/z 457.2 [M+H] ⁺ .

Example (R)-C15: Synthesis of Compound (R)-C15

Compound (R)-C15 was prepared according to the synthetic method in Example (R)-A4 and Example (R)-B9, with Compound 1-2 in Example A1 replaced with Compound 32-1. MS-ESI m/z 457.2 [M+H] ⁺ .

Example C16: Synthesis of Compound C16

Compound C16 was prepared according to the synthetic method in Example A4 and Example B4, with Compound 1-2 in Example A1 replaced with Compound 32-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (br.s., 1H (sec.)), 8.14 (br.s., 1H (bas.)), 7.66 (d., J = 7.1 Hz, 1H (sec.)), 7.63 (d., J = 7.9 Hz, 1H (prim.)), 7.39 (d., J = 7.2 Hz, 1H (sec.)), 7.33 (d., J = 8.1 Hz, 1H (basic)), 7.25 - 7.05 (m., 2H), 6.93 (s., 1H ( sec)), 6.87 (s, 1H(sec)), 6.63 (s, 1H(sec)), 6.60 (s, 1H(sec)), 6.57 (s., 1H (basic)), 6.26 (s., 1H (basic)), 5.78 (d.d., J = 6.6, 6.6 Hz, 1H (basic) )), 4.88 (d.d., J = 9.0, 4.8 Hz, 1H(sec)), 4.80 (d.d., J = 12.7, 5.2 Hz, 1H (sec)), 4.13 (s, 2H (prim)), 3.99 (dt, J = 16.4, 9.4 Hz, 2H (prim))) , 3.86 (s, 3H (sec)), 3.83 (s, 3H (bas)), 3.78 - 3.57 (m, 1H (sec) 1H (bas) ), 3.48 - 3.13 (m, 3H (basic) 3H (sec, major) 2H (sec)), 2.95 (s, 3H (sec)), 2.76 (m, 2H), 1.44 (t, J = 7.0 Hz, 3H (sec)), 1.28 (t, J = 7.0 Hz, 3H (prim)). MS-ESI m/z 409.2 [M+H] ⁺ .

Example (S)-C16: Synthesis of Compound (S)-C16

Compound (S)-C16 was prepared according to the synthetic method in Example (S)-A4 and Example (S)-B4, with Compound 1-2 in Example A1 replaced with Compound 32-1.

Example (R)-C16: Synthesis of Compound (R)-C16

Compound (R)-C16 was prepared according to the synthetic method in Example (R)-A4 and Example (R)-B4, with Compound 1-2 in Example A1 replaced with Compound 32-1.

Example C17: Synthesis of Compound C17

Synthesis of compound 43-1

Compound 24-1 was dissolved in anhydrous tetrahydrofuran under a protective argon atmosphere, and a solution of n-butyllithium was slowly added dropwise at -78°C. After 30 min, a solution of zinc chloride in tetrahydrofuran was added dropwise, warmed to room temperature, compound 15-1 was added and stirred at a temperature of 24 h. The reaction mixture was transferred to a saturated ammonium chloride solution, dried over anhydrous sodium sulfate, and extracted three times with ethyl acetate. The organic layer was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by passing through a 10:1 mixture of petroleum ether and ethyl acetate through a chromatographic column to give 605 mg of an oily substance (70% yield).

Synthesis of compound 43-2

Compound 43-1 was dissolved in a 1:1 mixture of tetrahydrofuran and water, lithium hydroxide was added and stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate, the aqueous layer was collected and acidified with 1N HCl. hydrochloric acid and then extracted three times with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate, then evaporated to dryness to give ... g of a brown solid (95% yield).

White solid compound C17 was obtained in accordance with the method of synthesis of compound C10, while compound 1-2 in example A1 was replaced by compound 43-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (br.s., 1H (b.)), 8.15 (s., 1H (s.)), 8.03 (br.s., 1H (sec)), 7.57 (s, 1H (bas)), 7.36 (s, 1H (bas)), 7.29 (s, 1H (sec)), 7 .27 (d., J = 7.5 Hz, 1H (prim)), 7.21 (d., J = 8.3 Hz, 1H (sec.)), 7.05 (d., J = 8.4 Hz, 1H (main)), 6.99 (d, J = 8.4 Hz, 1H (second)), 6.88 (s, 1H (main)), 6.84 (s, 1H (sec)), 6.72 (s, 1H (bas)), 6.64 (s, 1H (bas)), 6.55 (s, 1H (sec) )), 6.39 (s, 1H (sec)), 5.64 (d-d, J = 6.3, 6.3 Hz, 1H (sec)), 4.69 (d .-d., J = 9.8, 4.0 Hz, 1H (basic)), 4.47 (d.-d.-d., J = 13.3, 6.3, 2.2 Hz , 1H (basic)), 4.07 (sq.d., J = 6.9, 1.7 Hz, 2H (basic)), 3.87 (s, 3H (basic)), 3.84 (s, 3H (sec)), 3.83 - 3.68 (m, 2H (sec)), 3.54 (d-d-d, J = 13.3 , 6.3, 2.3 Hz, 1H (sec)), 3.42 - 3.05 (m, 3H), 2.96 - 2.78 (m, 1H), 2.78 - 2 .59 (m, 1H), 2.49 (s, 3H (prim)), 2.41 (s, 3H (sec)), 1.48 (t, J = 7.0 Hz) , 3H (main)), 1.33 (t., J = 7.0 Hz, 3H (second)). MS-ESI m/z 379.2 [M+H] ⁺ .

Example (S)-C17: Synthesis of Compound (S)-C17

White solid compound (S)-C17 was obtained in accordance with the synthesis method in example (S)-C10, while compound 1-2 in example A1 was replaced by compound 43-2.

Example (R)-C17: Synthesis of Compound (R)-C17

White solid compound (R)-C17 was obtained in accordance with the synthesis method in example (R)-C10, while compound 1-2 in example A1 was replaced by compound 43-2.

Example C18: Synthesis of Compound C18

Compound C18 (white solid) was synthesized according to the method for the synthesis of compound C17, with compound 24-1 replaced by compound 44-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (s, 1H (basic) 1H (sec)), 8.00 (br.s., 1H (sec)), 7.62 ( s., 1H (basic)), 7.27 (d., J = 8.9 Hz, 1H), 7.21 (d., J = 8.8 Hz, 1H (basic)), 7, 00 (d, J = 2.4 Hz, 1H (sec)), 6.98 (d, J = 2.4 Hz, 1H (prim)), 6.91 (s, 1H (prim) .)), 6.88 (d.d., J = 8.8, 2.4 Hz, 1H (prim.)), 6.86 (s., 1H (sec.)), 6.82 ( d-d, J = 8.7, 2.4 Hz, 1H (sec)), 6.69 (s, 1H (prim)), 6.63 (s, 1H (prim) ), 6.54 (s, 1H (sec)), 6.39 (s, 1H (sec)), 5.63 (t, J = 6.1 Hz, 1H (sec)) , 4.68 (d.d., J = 9.6, 4.4 Hz, 1H (basic)), 4.46 (d.d.d., J = 12.7, 6, 2, 2.1 Hz, 1H (prim)), 4.05 (q.d., J = 6.9, 2.3 Hz, 2H (prim)), 3.87 (s, 3H (b)), 3.87 (s, 3H (s)), 3.85 - 3.71 (m, 3H (s, main) 2H (s)), 3.54 ( d-d-d, J = 8.2, 6.1, 2.5 Hz, 1H (sec)), 3.37 - 3.08 (m, 3H), 2.95 - 2 .77 (m., 1H), 2.77 - 2.56 (m., 1H), 1.46 (t., J = 7.0 Hz, 3H (basic)), 1.33 (t. , J = 7.0 Hz, 3H (sec)). MS-ESI m/z 395.2 [M+H] ⁺ .

Example (S)-C18: Synthesis of Compound (S)-C18

Compound (S)-C18 (white solid) was synthesized according to the method for synthesizing compound (S)-C17, with compound 24-1 in Example (S)-C17 replaced by compound 44-1.

Example (R)-C18: Synthesis of Compound (R)-C18

Compound (R)-C18 (white solid) was synthesized according to the method for synthesizing compound (R)-C17, replacing compound 24-1 in Example (R)-C17 with compound 44-1.

Example C19: Synthesis of Compound C19

Compound C19 was prepared according to the method for the synthesis of compound A4, with compound 23-1 in Example C1 replaced by 5-acetamido-indole-3-propionic acid.

Example (S)-C19: Synthesis of Compound (S)-C19

Compound (S)-C19 was prepared according to the method for synthesizing compound (S)-A4, with compound 23-1 in Example C1 replaced by 5-acetamido-indole-3-propionic acid.

Example (R)-C19: Synthesis of Compound (R)-C19

Compound (R)-C19 was prepared according to the method for the synthesis of compound (R)-A4, with compound 23-1 in Example C1 replaced by 5-acetamido-indole-3-propionic acid.

Example C20: Synthesis of Compound C20

Compound C20 was prepared according to the method for the synthesis of compound A4, with compound 1-2 in example A1 replaced by intermediate C20-1. MS-ESI m/z 407.0 [M+H] ⁺ .

Example (S)-C20: Synthesis of Compound (S)-C20

Compound (S)-C20 was prepared according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by intermediate C20-1. ¹ H NMR (500 MHz, chloroform-d) δ 9.74 (t., J = 2.4 Hz, 1H), 8.20 (s., 1H), 7.48 (d.d., J = 2.5, 0.5 Hz, 1H), 7.34 (d.t., J = 2.7, 0.6 Hz, 1H), 7.08 (d.d.d., J = 8.4, 2.2, 0.6 Hz, 1H), 6.93 (d.d., J = 15.4, 0.9 Hz, 1H), 6.84 - 6.77 ( m., 2H), 6.65 (d.d., J = 15.6, 6.4 Hz, 1H), 6.49 (d., J = 1.0 Hz, 1H), 5.22 (d.-t., J = 6.4, 0.9 Hz, 1H), 4.20 - 4.03 (m., 2H), 3.85 (d., J = 13.4 Hz, 5H ), 3.73 (d.d.d., J = 11.7, 6.4, 4.3 Hz, 1H), 3.65 (d.d.d., J = 11, 5, 6.4, 4.3 Hz, 1H), 2.97 (d-d-d-d, J = 14.6, 6.4, 4.2, 1.0 Hz, 1H ), 2.89 (d.d.d.d., J = 14.6, 6.4, 4.2, 1.0 Hz, 1H), 1.43 (t., J = 6 .9 Hz, 3H). MS-ESI m/z 407.2 [M+H] ⁺ .

Example (R)-C20: Synthesis of Compound (R)-C20

Compound (R)-C20 was prepared according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C20-1. MS-ESI m/z 407.0 [M+H] ⁺ .

Example C21: Synthesis of Compound C21

Compound C21 was prepared according to the method for the synthesis of compound A4, with compound 1-2 in Example A1 replaced by intermediate C21-1. MS-ESI m/z 463.0 [M+H] ⁺ .

Example (S)-C21: Synthesis of Compound (S)-C21

Compound (S)-C21 was prepared according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by intermediate C21-1. ¹ H NMR (500 MHz, chloroform-d) δ 9.04 (t., J = 2.4 Hz, 1H), 8.28 (s., 1H), 7.28 - 7.22 (m., 1H), 7.11 - 7.06 (m, 2H), 6.83 (d, J = 1.0 Hz, 1H), 6.72 (d-d, J = 8.4, 2.7 Hz, 1H), 6.63 (t., J = 1.0 Hz, 1H), 4.66 (d.d., J = 6.0, 1.1 Hz, 1H), 4 .20 - 4.02 (m., 2H), 3.84 (d., J = 10.1 Hz, 6H), 3.68 (d.d.d., J = 11.7, 6 .3, 4.4 Hz, 1H), 3.50 (d.d.d., J = 11.7, 6.3, 4.4 Hz, 1H), 3.42 (p., J = 5.9 Hz, 1H), 2.99 - 2.84 (m., 2H), 2.31 (g., J = 6.0 Hz, 1H), 2.07 - 1.96 (m. , 2H), 1.82 - 1.70 (m., 4H), 1.70 - 1.60 (m., 2H), 1.42 (t., J = 6.9 Hz, 3H). MS-ESI m/z 463.3 [M+H] ⁺ .

Example (R)-C21: Synthesis of Compound (R)-C21

Compound (R)-C21 was prepared according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C21-1. MS-ESI m/z 463.3 [M+H] ⁺ .

Example C22: Synthesis of Compound C22

Compound C22 was prepared according to the method for the synthesis of compound A4, with compound 1-2 in example A1 replaced by intermediate C21-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.29 (s., 1H), 7.74 (d.d.d., J = 7.9, 1.3, 0.6 Hz, 1H ), 7.53 - 7.47 (m., 1H), 7.37 (t.d., J = 7.7, 1.3 Hz, 1H), 7.21 - 7.14 (m. , 1H), 6.67 (d., J = 0.9 Hz, 1H), 6.60 (t., J = 1.0 Hz, 1H), 4.98 - 4.91 (m., 1H ), 4.20 - 4.03 (m, 2H), 3.84 (s, 2H), 3.73 (d-d-d, J = 11.5, 6.2, 4 .2 Hz, 1H), 3.56 (d.d.d., J = 11.7, 6.4, 4.3 Hz, 1H), 3.04 - 2.83 (m., 3H ), 2.48 - 2.29 (m., 3H), 1.42 (t., J = 6.9 Hz, 3H). MS-ESI m/z 380.2 [M+H] ⁺ .

Example (S)-C22: Synthesis of Compound (S)-C22

Compound (S)-C22 was obtained according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by intermediate C22-1. MS-ESI m/z 380.2 [M+H] ⁺ .

Example (R)-C22: Synthesis of Compound (R)-C22

Compound (R)-C22 was prepared according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C22-1. MS-ESI m/z 380.2 [M+H] ⁺ .

Example C23: Synthesis of Compound C23

Compound C23 was prepared according to the method for the synthesis of compound A4, replacing compound 1-2 in Example A1 with intermediate C23-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.28 (s., 1H), 7.55-7.49 (m., 1H), 7.44-7.37 (m., 1H), 7 .32 - 7.25 (m, 1H), 7.18 (d-d-d, J = 7.9, 7.3, 1.1 Hz, 1H), 6.67 (d. , J = 0.9 Hz, 1H), 6.60 (t., J = 1.0 Hz, 1H), 6.47 - 6.42 (m., 1H), 4.85 (t.-d ., J = 5.4, 1.0 Hz, 1H), 4.20 - 4.03 (m., 2H), 3.84 (s., 2H), 3.70 (d.-d.- d., J = 11.5, 6.2, 4.3 Hz, 1H), 3.54 (d.d.d., J = 11.7, 6.3, 4.4 Hz, 1H ), 2.97 - 2.83 (m., 3H), 2.62 (d.t., J = 13.7, 7.3 Hz, 1H), 2.30 - 2.12 (m. , 2H), 1.42 (t., J = 6.9 Hz, 3H). MS-ESI m/z 380.2 [M+H] ⁺ .

Example (S)-C23: Synthesis of Compound (S)-C23

Compound (S)-C23 was obtained according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by intermediate C23-1. MS-ESI m/z 380.0 [M+H] ⁺ .

Example (R)-C23: Synthesis of Compound (R)-C23

Compound (R)-C23 was prepared according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C23-1. MS-ESI m/z 380.0 [M+H] ⁺ .

Example C24: Synthesis of Compound C24

Compound C24 was obtained in accordance with the method of synthesis of compound A4, while the compound 1-2 in example A1 was replaced by intermediate product C24-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.29 (s., 1H), 7.77-7.67 (m., 2H), 7.39-7.32 (m., 1H), 7 .16 - 7.06 (m., 2H), 6.67 (d., J = 0.9 Hz, 1H), 6.61 (t., J = 1.0 Hz, 1H), 4.88 (t.d., J = 5.4, 1.0 Hz, 1H), 4.20 - 4.03 (m., 2H), 3.84 (s., 2H), 3.72 (d .-d.-d., J = 11.7, 6.2, 4.5 Hz, 1H), 3.55 (d.-d.-d., J = 11.7, 6.2, 4 .5 Hz, 1H), 3.00 - 2.91 (m., 1H), 2.94 - 2.84 (m., 2H), 2.76 (d.t., J = 13.7 , 7.3 Hz, 1H), 2.24 (ddtd, J = 35.3, 12.5, 7.3, 5.4 Hz, 2H), 1.42 (t., J = 7.0 Hz , 3H). MS-ESI m/z 396.2 [M+H] ⁺ .

Example (S)-C24: Synthesis of Compound (S)-C24

Compound (S)-C24 was prepared according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by intermediate C24-1. MS-ESI m/z 396.2 [M+H] ⁺ .

Example (R)-C24: Synthesis of Compound (R)-C24

Compound (R)-C24 was obtained according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C24-1. MS-ESI m/z 396.2 [M+H] ⁺ .

Example C25: Synthesis of Compound C25

Compound C25 was prepared according to the method for the synthesis of compound A4, with compound 1-2 in Example A1 replaced by intermediate C25-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.30 (s., 1H), 7.38-7.25 (m., 2H), 7.18-7.08 (m., 2H), 6 .70 (d., J = 1.9 Hz, 1H), 6.65 - 6.59 (m., 2H), 5.06 (t.d., J = 5.3, 1.0 Hz , 1H), 4.20 - 4.03 (m, 2H), 3.84 (s, 2H), 3.71 (d-d-d, J = 11.5, 6.2 , 4.3 Hz, 1H), 3.55 (d.d.d., J = 11.7, 6.2, 4.4 Hz, 1H), 2.97 - 2.83 (m. , 2H), 2.77 (d.t., J = 13.5, 7.3 Hz, 1H), 2.60 (d.t., J = 13.7, 7.4 Hz, 1H ), 2.26 (d.t.d., J = 12.6, 7.3, 5.3 Hz, 1H), 2.16 (d.t.d., J = 12, 5, 7.2, 5.3 Hz, 1H), 1.42 (t., J = 6.9 Hz, 3H). MS-ESI m/z 379.2 [M+H] ⁺ .

Example (S)-C25: Synthesis of Compound (S)-C25

Compound (S)-C25 was prepared according to the method for the synthesis of compound (S)-A4, replacing compound 1-2 in Example A1 with intermediate C25-1. MS-ESI m/z 379.2 [M+H] ⁺ .

Example (R)-C25: Synthesis of Compound (R)-C25

Compound (R)-C25 was prepared according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C25-1. MS-ESI m/z 379.2 [M+H] ⁺ .

Example C26: Synthesis of Compound C26

Compound C26 was prepared according to the method for the synthesis of compound A4, with compound 1-2 in Example A1 replaced by intermediate C26-1. ¹ H NMR (500 MHz, chloroform-d) δ 8.83-8.76 (m, 2H), 8.30 (s, 1H), 8.03-7.97 (m, 1H), 7.34 (d-d, J = 7.9, 3.5 Hz, 1H), 6.87 - 6.82 (m, 1H), 6.65 - 6.60 (m, 2H ), 4.92 (t.d., J = 5.3, 1.0 Hz, 1H), 4.20 - 4.03 (m., 2H), 3.84 (s., 2H), 3.73 (d.d.d., J = 11.5, 6.2, 4.3 Hz, 1H), 3.56 (d.d.d., J = 11.7, 6.3, 4.4 Hz, 1H), 2.97 - 2.88 (m., 1H), 2.92 - 2.84 (m., 1H), 2.88 - 2.79 (m. , 1H), 2.47 - 2.30 (m, 2H), 2.26 (d-t-d, J = 12.6, 7.2, 5.3 Hz, 1H), 1 .42 (t., J = 6.9 Hz, 3H). MS-ESI m/z 380.2 [M+H] ⁺

Example (S)-C26: Synthesis of Compound (S)-C26

Compound (S)-C26 was prepared according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by intermediate C26-1. MS-ESI m/z 380.0 [M+H] ⁺ .

Example (R)-C26: Synthesis of Compound (R)-C26

Compound (R)-C26 was prepared according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C26-1. MS-ESI m/z 380.0 [M+H] ⁺ .

Example C27: Synthesis of Compound C27

Compound C27 was prepared according to the method for the synthesis of compound A4, replacing compound 1-2 in Example A1 with intermediate C27-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.24 (s., 1H), 6.86 (d., J = 1.1 Hz, 1H), 6.61 (t., J = 1.0 Hz, 1H), 4.86 (t.d., J = 5.4, 1.0 Hz, 1H), 4.19 - 4.02 (m., 2H), 3.84 (s., 2H), 3.69 (d.d.d., J = 11.7, 6.3, 4.4 Hz, 1H), 3.51 (d.d.d., J = 11 .7, 6.4, 4.4 Hz, 1H), 2.97 - 2.82 (m., 2H), 2.01 (d.t.d., J = 12.8, 7, 4, 5.3 Hz, 1H), 1.77 (d.t.d., J = 12.8, 7.5, 5.4 Hz, 1H), 1.66 - 1.38 (m ., 11H), 1.35 - 1.12 (m., 7H). MS-ESI m/z 346.2 [M+H] ⁺ .

Example (S)-C27: Synthesis of Compound (S)-C27

Compound (S)-C27 was prepared according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by intermediate C27-1. MS-ESI m/z 346.2 [M+H] ⁺ .

Example (R)-C27: Synthesis of Compound (R)-C27

Compound (R)-C27 was prepared according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C27-1. MS-ESI m/z 346.2 [M+H] ⁺ .

Example C28: Synthesis of Compound C28

Compound C28 was obtained in accordance with the method of synthesis of compound A4, while compound 1-2 in example A1 was replaced by intermediate product C28-1. ¹ H NMR (500 MHz, chloroform-d) δ 8.24 (s., 1H), 6.95 (d., J = 0.9 Hz, 1H), 6.62 (t., J = 1, 0 Hz, 1H), 4.72 (t.d., J = 5.4, 1.0 Hz, 1H), 4.19 - 4.02 (m., 2H), 3.84 (s. , 3H), 3.87 - 3.79 (m., 1H), 3.76 (t., J = 6.0 Hz, 4H), 3.49 (d.d.d., J = 11.7, 6.2, 4.5 Hz, 1H), 2.95 - 2.83 (m., 2H), 2.72 (d.t., J = 11.9, 7.2 Hz , 1H), 2.58 - 2.42 (m, 5H), 2.06 (d-t-d, J = 12.6, 7.3, 5.3 Hz, 1H), 1 .92 (t.-t.-d., J = 12.6, 7.3, 5.5 Hz, 1H), 1.42 (t., J = 7.0 Hz, 3H). ESI MS m/z 349.2[M+H] ⁺ .

Example (S)-C28: Synthesis of Compound (S)-C28

Compound (S)-C28 was obtained according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by intermediate C28-1. MS-ESI m/z 349.2 [M+H] ⁺ .

Example (R)-C28: Synthesis of Compound (R)-C28

Compound (R)-C28 was obtained according to the method for the synthesis of compound (R)-A4, with compound 1-2 in Example A1 replaced by intermediate C28-1. MS-ESI m/z 349.2 [M+H] ⁺ .

Example C29: Synthesis of Compound C29

Compound C29 was prepared according to the method for the synthesis of compound A4, replacing compound 1-2 in Example A1 with intermediate C29-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.48 - 8.38 (m, 2H), 8.27 (s., 1H), 7.46 (d.t., J = 7.9 , 2.1 Hz, 1H), 7.19 (d.d., J = 7.8, 3.5 Hz, 1H), 6.63 (t., J = 1.0 Hz, 1H), 6.55 (d., J = 1.1 Hz, 1H), 4.77 (t.d., J = 5.3, 1.0 Hz, 1H), 4.19 - 4.02 (m ., 2H), 3.84 (s., 2H), 3.76 (d.d.d., J = 11.7, 6.3, 4.4 Hz, 1H), 3.54 ( d-d-d, J = 11.7, 6.4, 4.3 Hz, 1H), 2.96 - 2.80 (m, 3H), 2.66 (d.-t. , J = 13.9, 7.3 Hz, 1H), 2.27 (d.t.d., J = 12.6, 7.3, 5.3 Hz, 1H), 2.15 ( d-t-d, J = 12.6, 7.2, 5.3 Hz, 1H), 1.42 (t., J = 7.0 Hz, 3H). MS-ESI m/z 341.2 [M+H] ⁺ .

Example (S)-C29: Synthesis of Compound (S)-C29

Compound (S)-C29 was prepared according to the method for the synthesis of compound A4, with compound 1-2 in Example A1 replaced by intermediate C29-1. MS-ESI m/z 341.2 [M+H] ⁺ .

Example (R)-C29: Synthesis of Compound (R)-C29

Compound (R)-C29 was obtained according to the method for the synthesis of compound A4, with compound 1-2 in example A1 replaced by intermediate C29-1. MS-ESI m/z 341.2 [M+H] ⁺ .

Example C30: Synthesis of Compound C30

Compound C30-1 was dissolved in anhydrous dichloromethane, and chloroacetyl chloride and triethylamine were added dropwise in an ice bath. The mixture was placed at room temperature and allowed to react for 1 hour. After cessation of the reaction with water, the mixture was extracted with DCM, dried and evaporated to dryness, and then passed through a chromatographic column to obtain compound C30-2. Compound C30-3 was dissolved in acetonitrile, cesium carbonate was added and stirred at room temperature for 2 h. Compound C30-2 was added under nitrogen protection and stirred for 18 h. brine, dried and evaporated to dryness. The residue was purified by passing through a chromatographic column to give compound C30-4. Compound C30 was prepared according to the method for the synthesis of compound A4, replacing compound 1-3 in Example A1 with intermediate C30-4. ¹ H NMR (500 MHz, chloroform-d) δ 9.86 (d.d., J = 2.6, 2.1 Hz, 1H), 8.28 (s., 1H), 7.46 - 7.39 (m, 2H), 7.16 (d.d., J = 2.5, 0.6 Hz, 1H), 6.81 (d.d., J = 8.4, 2.7 Hz, 1H), 6.74 (d., J = 1.0 Hz, 1H), 6.62 (t., J = 1.0 Hz, 1H), 5.23 (t.-d ., J = 5.4, 1.0 Hz, 1H), 4.70 (d.d., J = 10.5, 5.4 Hz, 1H), 4.61 (d.d., J = 10.6, 5.5 Hz, 1H), 4.18 - 4.02 (m, 2H), 3.84 (d, J = 11.7 Hz, 5H), 3.67 (d .-d.-d., J = 11.7, 6.4, 4.2 Hz, 1H), 3.57 (d.-d.-d., J = 11.7, 6.5, 4 .2 Hz, 1H), 2.97 (d.d.d.d., J = 14.6, 6.4, 4.2, 1.1 Hz, 1H), 2.87 (d .-d.d.-d., J = 14.5, 6.2, 4.1, 1.0 Hz, 1H), 1.42 (t., J = 7.0 Hz, 3H). MS-ESI m/z 411.2 [M+H] ⁺ .

Example (S)-C30: Synthesis of Compound (S)-C30

Compound (S)-C30 was obtained in accordance with the synthesis method (S)-A4, while the compound 1-3 in example A1 was replaced by intermediate C30-4. MS-ESI m/z 411.2 [M+H] ⁺ .

Example (R)-C30: Synthesis of Compound (R)-C30

Compound (R)-C30 was prepared according to the method for the synthesis of compound (R)-A4, with compound 1-3 in Example A1 replaced by intermediate C30-4. MS-ESI m/z 411.2 [M+H] ⁺ .

Example C31: Synthesis of Compound C31

Compound C31 was prepared according to the method for the synthesis of compound C30, with compound C30-3 in Example C30 replaced by intermediate C31-1. ¹ H NMR (500 MHz, chloroform-d) δ 9.99 (d.d., J = 2.6, 2.0 Hz, 1H), 8.21 (s., 1H), 7.57 ( d-d, J = 2.5, 0.5 Hz, 1H), 7.47 (d-d-d, J = 8.4, 2.2, 0.5 Hz, 1H) , 7.35 - 7.30 (m., 1H), 6.81 (d.d., J = 8.4, 2.7 Hz, 1H), 6.67 (d., J = 1, 1 Hz, 1H), 6.61 (t., J = 1.0 Hz, 1H), 5.22 (t.d., J = 4.1, 1.0 Hz, 1H), 4.20 - 4.03 (m., 2H), 3.85 (d., J = 17.0 Hz, 5H), 3.75 (d.-d., J = 13.5, 4.1 Hz, 1H ), 3.66 (d.d.d., J = 11.7, 6.1, 4.6 Hz, 1H), 3.56 (d.d., J = 13.5, 4 .1 Hz, 1H), 3.42 (d.d.d., J = 11.7, 6.2, 4.4 Hz, 1H), 2.94 - 2.81 (m., 2H ), 1.43 (t., J = 6.9 Hz, 3H). MS-ESI m/z 427.2 [M+H] ⁺ .

Example (S)-C31: Synthesis of Compound (S)-C31

Compound (S)-C31 was prepared according to the synthesis method for (S)-C30, replacing compound C30-3 in Example C30 with intermediate C31-1. MS-ESI m/z 427.2 [M+H] ⁺ .

Example (R)-C31: Synthesis of Compound (R)-C31

Compound (R)-C31 was prepared according to the method for the synthesis of compound (R)-C30, replacing compound C30-3 in Example C30 with intermediate C31-1. MS-ESI m/z 427.2 [M+H] ⁺ .

Example C32: Synthesis of Compound C32

Compound C32 was prepared according to the method for the synthesis of compound C30, with compound C30-3 in Example C30 replaced by intermediate C32-1. ¹ H NMR (500 MHz, chloroform-d) δ 9.43 (t., J = 2.4 Hz, 1H), 8.26 (s., 1H), 7.45 - 7.39 (m., 1H), 7.22 (d.d.d., J = 14.8, 2.6, 0.6 Hz, 2H), 6.80 (d.d., J = 8.4, 2.7 Hz, 1H), 6.64 (t., J = 1.1 Hz, 1H), 6.53 (d., J = 1.0 Hz, 1H), 4.64 (t.-d ., J = 4.7, 1.0 Hz, 1H), 4.10 (sq., J = 6.9 Hz, 2H), 3.84 (d., J = 17.0 Hz, 5H), 3.66 (d-d-d, J = 11.7, 6.4, 4.3 Hz, 1H), 3.60 - 3.47 (m, 3H), 3.48 - 3 .40 (m., 2H), 2.95 (d.d.d.d., J = 14.6, 6.4, 4.2, 1.0 Hz, 1H), 2.87 (d.d.d.d., J = 14.6, 6.4, 4.2, 1.0 Hz, 1H), 2.82 (d., J = 4.8 Hz, 2H ), 2.75 (t., J = 5.3 Hz, 4H), 1.42 (t., J = 7.0 Hz, 3H). MS-ESI m/z 479.3 [M+H] ⁺ .

Example (S)-C32: Synthesis of Compound (S)-C32

Compound (S)-C32 was prepared according to the synthesis method for (S)-C30, replacing compound C30-3 in Example C30 with intermediate C32-1. MS-ESI m/z 479.3 [M+H] ⁺ .

Example (R)-C32: Synthesis of Compound (R)-C32

Compound (R)-C32 was prepared according to the method for the synthesis of compound (R)-C30, replacing compound C30-3 in Example C30 with intermediate C32-1. MS-ESI m/z 479.3 [M+H] ⁺ .

Example C33: Synthesis of Compound C33

Compound C33 was prepared according to the method for the synthesis of compound A4, with compound 1-2 in Example A1 replaced by the intermediate 5-hydroxy-indole-3-propionic acid.

Example (S)-C33: Synthesis of Compound (S)-C33

Compound (S)-C33 was prepared according to the method for the synthesis of compound (S)-A4, with compound 1-2 in Example A1 replaced by the intermediate 5-hydroxy-indole-3-propionic acid.

Example (R)-C33: Synthesis of Compound (R)-C33

Compound (R)-C33 was obtained in accordance with the method of synthesis of compound (R)-A4, while compound 1-2 in example A1 was replaced by the intermediate product 5-hydroxy-indole-3-propionic acid.

Example C34: Synthesis of Compound C34

Compound C34 was obtained in accordance with the method of synthesis of compound B9, with compound 1-5 in example A1 replaced by compound C33-1. ¹ H NMR (500 MHz, chloroform-d) δ 6.94 (t., J = 1.0 Hz, 1H), 6.74 (t., J = 1.0 Hz, 1H), 4.54 ( d., J = 0.9 Hz, 2H), 4.18 (s., 1H), 4.11 (sq., J = 7.0 Hz, 2H), 3.84 (s., 2H), 3.82 - 3.68 (m., 2H), 2.95 (s., 2H), 2.89 (t.d., J = 5.3, 1.0 Hz, 2H), 1, 42 (t., J = 6.9 Hz, 3H). MS-ESI m/z 328.1 [M+H] ⁺ .

Example C35: Synthesis of Compound C35

Compound C35 was prepared according to the method for synthesizing compound C30, with compound C30-3 in Example C30 being replaced by 3-aminoindole.

Example (S)-C35: Synthesis of Compound (S)-C35

Compound (S)-C35 was prepared according to the synthesis method for (S)-C30, with compound C30-3 in Example C30 being replaced by 3-aminoindole.

Example (R)-C35: Synthesis of Compound (R)-C35

Compound (R)-C35 was prepared according to the method for the synthesis of compound (R)-C30, with compound C30-3 in Example C30 being replaced by 3-aminoindole.

Example C36: Synthesis of Compound C36

Intermediate C36-1 and 3-indolepropionic acid were reacted with EDCI, HOBT and TEA in dichloromethane at room temperature to give compound C36-2. Compound C36-2 was reacted with HCl in dioxane for two hours to give compound C36-3. Compound C36-3 was refluxed with ethyl formate overnight and purified by passing through a column chromatography with petroleum ether and ethyl acetate to give compound C36.

Example (S)-C36: Synthesis of Compound (S)-C36

Compound (S)-C36 was prepared according to the method for synthesizing compound C36, with intermediate C36-1 being replaced by compound (S)-C36-1.

Example (R)-C36: Synthesis of Compound (R)-C36

Compound (R)-C36 was obtained in accordance with the method of synthesis of compound C36, while the intermediate product C36-1 was replaced by compound (R)-C36-1.

Example C37: Synthesis of Compound C37

Compound C37 was obtained in accordance with the method of synthesis of compound A1, while compound 2-1 in example A1 was replaced by compound C37-1. ¹ H NMR (400 MHz, DMSO): δ 10.86, 10.74 (2×s, 1H), 8.18, 8.15 (2×s, 1H), 7.42-7.22 (m, 2H), 7.08 - 6.90 (m, 2H), 6.81 - 6.73 (m, 1H), 6.65 - 6.52 (m, 2H), 5 .55 - 5.46, 5.06 - 4.96 (2xm, 1H), 3.71 - 3.63, 3.41 - 3.25 (2xm, 1H), 3.65 (s, 3H), 3.58, 3.54 (2×s, 3H), 3.21-3.10, 3.06-2.94 (2×m, 1H), 2.80 - 2.57 (m, 4H), 2.08 - 1.68 (m, 4H). MS-ESI m/z 379.2 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₃ H ₂₆ N ₂ O ₃ ⁺ [M+H] ⁺ 379.2016, found 379.2027.

Example (S)-C37: Synthesis of Compound (S)-C37

Compound (S)-C37 was prepared according to the method for the synthesis of compound (S)-A1, with compound 2-1 in Example A1 replaced by compound C37-1. ¹ H NMR (400 MHz, DMSO): δ 10.87, 10.74 (2xs, 1H), 8.18, 8.15 (2xs, 1H), 7.43-7.23 (m, 2H), 7.08 - 6.90 (m, 2H), 6.82 - 6.72 (m, 1H), 6.64 - 6.52 (m, 2H), 5 .55 - 5.46, 5.06 - 4.95 (2xm, 1H), 3.73 - 3.63, 3.41 - 3.24 (2xm, 1H), 3.65 (s, 3H), 3.58, 3.54 (2×s, 3H), 3.22-3.10, 3.09-2.94 (2×m, 1H), 2.81 - 2.57 (m, 4H), 2.08 - 1.71 (m, 4H). MS-ESI m/z 379.2 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₃ H ₂₆ N ₂ O ₃ ⁺ [M+H] ⁺ 379.2016, found 379.2027.

Example (R)-C37: Synthesis of Compound (R)-C37

Compound (R)-C37 was prepared according to the method for synthesizing compound (R)-A1, with compound 2-1 in Example A1 replaced by compound C37-1. ¹ H NMR (400 MHz, DMSO): δ 10.86, 10.74 (2×s, 1H), 8.18, 8.15 (2×s, 1H), 7.44-7.24 (m, 2H), 7.08 - 6.90 (m, 2H), 6.82 - 6.73 (m, 1H), 6.65 - 6.52 (m, 2H), 5 .55 - 5.46, 5.06 - 4.96 (2xm, 1H), 3.71 - 3.63, 3.41 - 3.25 (2xm, 1H), 3.65 (s, 3H), 3.58, 3.54 (2×s, 3H), 3.21-3.10, 3.06-2.94 (2×m, 1H), 2.80 - 2.57 (m, 4H), 2.08 - 1.68 (m, 4H). ESI MS m/z 379.2 [M+H] ⁺ C ₂₃ H ₂₆ N ₂ O ₃ ⁺ [M+H] ⁺ : 379.1943, found: 379.2008.

Example C38: Synthesis of Compound C38

Compound C38 was prepared according to the method for synthesizing compound B14, with compound 1-2 in Example A1 being replaced by compound 32-1 and compound B14-1 in Example B14 being replaced with acetyl chloride. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.89, 8.59 (2×s, 1H), 7.63, 7.58 (2×d, J = 31.9, 7.8 Hz , 1H), 7.34 (2×d, J = 37.5, 7.9 Hz, 1H), 7.22 - 7.03 (m, 2H), 6.87, 6.83 (2 xs, 1H), 6.64, 6.58 (2xs, 1H), 6.20 (s, 1H), 5.85-5.23 (m, 1H), 4, 92, 4.81 (2 x d-d, J = 5.52, 6.32, 5.92, 6.32 Hz, 1H), 3.86, 3.83 (2 x s, 3H ), 3.80 (s., 1H), 3.68 - 3.48 (m., 1H), 3.46 (s., 2H), 3.36 - 3.26 (m., 1H), 3.25 - 3.16 (m, 2H), 2.96 - 2.77 (m, 1H), 2.75 - 2.64 (m, 1H), 2.15, 1.54 ( 2×s., 3H). MS-ESI m/z 365.1 [M+H] ⁺ . MS-HR: (ESI, m/z) calculated for C ₂₂ H ₂₃ N ₂ O ₃ ⁺ [M+H] ⁺ 365.1787, found 365.1863.

Example (S)-C38: Synthesis of Compound (S)-C38

Compound (S)-C38 was prepared according to the method for synthesizing compound (S)-B14, with compound 1-2 in Example A1 replaced with compound 32-1, and compound B14-1 in Example B14 replaced with acetyl chloride. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.88, 8.57 (2×s, 1H), 7.64.7.58 (2×d, J = 31.9, 7.8 Hz , 1H), 7.34 (2×d., J = 37.5.7.9 Hz, 1H), 7.22 - 7.03 (m., 2H), 6.87, 6.83 (2 xs, 1H), 6.64,6.57 (2xs, 1H), 6.20 (s, 1H), 5.85-5.23 (m, 1H), 4.92 .4.81 (2×d.d., J = 5.52, 6.32.5.92.6.32 Hz, 1H), 3.86, 3.83 (2×s., 3H) , 3.80 (s., 1H), 3.68 - 3.48 (m., 1H), 3.46 (s., 2H), 3.36 - 3.26 (m., 1H), 3 .25 - 3.16 (m., 2H), 2.96 - 2.77 (m., 1H), 2.74 - 2.64 (m., 1H), 2.14, 1.52 (2 ×s., 3H). MS-ESI m/z 365.1 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₂ H ₂₃ N ₂ O ₃ ⁺ [M+H] ⁺ 365.1787, found 365.1867.

Example C39: Synthesis of Compound C39

Compound C39 was prepared according to the method for synthesizing compound B1, with compound 1-2 in Example A1 being replaced by compound 32-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63, 8.50 (2xs, 1H), 8.35, 8.18 (2xs, 1H), 7.70, 7.63 (2×s, 1H), 7.39 (d.d., J = 8.1, 3.9 Hz, 1H), 7.22 (t.d., J = 7.2, 3 .5 Hz, 1H), 7.09 - 6.96 (m., 1H), 6.89 (d., J = 1.9 Hz, 1H), 6.71, 6.60 (2×s. , 1H), 6.42 (d.d., J = 16.8,11.8 Hz, 1H), 6.00 (t., J = 6.8 Hz, 1H), 4.93, 4 .82 (2×d.d., J = 5.83, 6.97, 5.83, 5.51 Hz, 1H), 4.14 (sq., J = 7.1 Hz, 1H), 3.90 (d., J = 13.8 Hz, 3H), 3.77 (s., 1H), 3.64 (d., J = 9.5 Hz, 1H), 3.56 - 3, 35 (m, 2H), 3.27-3.06 (m, 2H), 2.92-2.73 (m, 1H), 2.07 (s, 1H). MS-ESI m/z428.1 [M+H] ⁺ . MS-HR: (ESI, m/z) calculated for C ₂₀ H ₂₅ N ₃ O ₃ ⁺ [M+H] ⁺ 428.1896, found 428.1971.

Example C40: Synthesis of Compound C40

Compound C40 was prepared according to the method for synthesizing compound B14, with compound 1-2 in Example A1 being replaced by compound 32-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.26 (s., 1H), 7.67 (d., J = 7.6 Hz, 1H), 7.36 (d., J = 7.9 Hz, 1H), 7.17 (d.t., J = 21.1, 7.1 Hz, 2H), 6.95 (s., 1H), 6.61 (s., 1H), 6 .41 (s., 1H), 5.20 - 5.11 (m., 1H), 3.85 (s., 3H), 3.67 (s., 3H), 3.52 - 3.38 (m, 3H), 3.30 (d.d., J = 14.5, 8.6 Hz, 1H), 3.19 (d.d.d., J = 20.5, 10.7, 5.0 Hz, 3H), 3.06 - 2.97 (m., 2H), 2.96 - 2.88 (m., 1H), 2.71 (d.-d.- etc., J = 27.6, 13.4, 3.5 Hz, 3H). MS-ESI m/z 436.1 [M+H] ⁺ . MS-HR: (ESI, m/z) calculated for C ₂₅ H ₂₉ N ₃ O ₄ ⁺ [M+H] ⁺ 436.2158, found 436.2241.

Example (S)-C40: Synthesis of Compound (S)-C40

Compound (S)-C40 was prepared according to the method for the synthesis of compound (S)-B14, with compound 1-2 in Example A1 replaced by compound 32-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.26 (s., 1H), 7.67 (d., J = 7.6 Hz, 1H), 7.36 (d., J = 7.9 Hz, 1H), 7.17 (d.t., J = 21.1, 7.1 Hz, 2H), 6.95 (s., 1H), 6.61 (s., 1H), 6 .41 (s., 1H), 5.20 - 5.11 (m., 1H), 3.85 (s., 3H), 3.67 (s., 3H), 3.52 - 3.38 (m, 3H), 3.30 (d.d., J = 14.5, 8.6 Hz, 1H), 3.19 (d.d.d., J = 20.5, 10.7, 5.0 Hz, 3H), 3.06 - 2.97 (m., 2H), 2.96 - 2.88 (m., 1H), 2.71 (d.-d.- etc., J = 27.6, 13.4, 3.5 Hz, 3H). MS-ESI m/z 436.1 [M+H] ⁺ . MS-HR: (ESI, m/z) calculated for C ₂₅ H ₂₉ N ₃ O ₄ ⁺ [M+H] ⁺ 436.2158, found 436.2236.

Example C41: Synthesis of Compound C41

Compound C41 was obtained according to the method for synthesizing compound B1, wherein compound 1-2 in Example A1 was replaced by compound 32-1, and compound 11-1 in Example B1 was replaced by compound 13-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.35, 8.13 (2×s, 1H), 7.81-7.58 (m, 1H), 7.43-7.29 (m ., 1H), 7.33 (d., J = 8.1 Hz, 6H), 7.25 (d., J = 3.1 Hz, 1H), 7.15, 7.07 (d.- t., J = 15.1, 15.1 Hz, 1H), 6.94, 6.87 (2×s., 1H), 6.77, 6.65 (2×s., 1H), 6 .57 - 5.83 (m., 1H), 5.07, 4.83 (2×d.d., J = 10.5, 3.0, 12.9, 5.1, Hz, 1H ), 4.04 - 3.96 (m., 1H), 3.94 (s., 2H), 3.88 (s., 2H), 3.84 (s., 1H), 3.81 - 3.67 (m, 1H), 3.50 - 3.43 (m, 2H), 3.41 - 3.12 (m, 3H), 3.02 - 2.65 (m, 3H ). MS-ESI m/z 436.1 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₅ H ₃₀ N ₃ O ₄ ⁺ [M+H] ⁺ 435.2206, found 435.2290.

Example (S)-C41: Synthesis of Compound (S)-C41

Compound (S)-C41 was prepared according to the method for synthesizing compound (S)-B1, with compound 1-2 in Example A1 replaced by compound 32-1 and compound 11-1 in Example B1 replaced by compound 13-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.12, 8.63 (2 x d, J = 32.9, 30.9 Hz, 1H), 7.76, 7.57 (2 x d. , J = 5.12, 8.47 Hz, 1H), 7.39, 7.30 (2×d., J = 7.13, 9.13 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.13, 7.04 (2×t, J=13.8, 14.4 Hz, 1H), 6.92, 6.86 (2×s, 1H), 6.80, 6.66 (2×s, 1H), 6.58, 6.22, 5.85 (2×s, t, J = 6.5 Hz, 1H), 5.09, 4.85 (2×d, J = 10.0, 7.7 Hz, 1H), 4.02 - 3.78 (m, 6H), 3.72 - 3.52 (m, 1H) , 3.46 - 3.27 (m, 3H), 2.96 - 2.70 (m, 3H), 2.09 - 1.87 (m, 2H), 1.76 - 1.40 (m, 3H), 1.36 - 1.12 (m, 2H). MS-ESI m/z 435.1 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₅ H ₃₀ N ₃ O ₄ ⁺ [M+H] ⁺ 435.2206, found 435.2279.

Example C42: Synthesis of Compound C42

Compound C42 was obtained according to the method for synthesizing compound B1, wherein compound 1-2 in Example A1 was replaced by compound 32-1, and compound 11-1 in Example B1 was replaced by compound C42-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09, 7.90 (2×d, J=12.4, 2.5 Hz, 1H), 7.90 (2×d, J=7 .7, 3.1 Hz, 1H), 7.57 - 7.52 (m., 1H), 7.34 - 7.25 (m 1H), 7.23 - 7.15 (m., 1H) , 7.12 - 7.08 (m, 1H), 7.05 - 6.95 (m, 1H), 6.84 - 6.78 (m, 1H), 6.62 (d, J = 16.6 Hz, 1H), 6.34, 6.08 (2xs, 1H), 5.93, 4.77 (2xd-d, J = 8.3, 5, 4, 13.4, 3.7Hz, 1H), 3.85 (d., J = 7.1 Hz, 3H), 3.83 - 3.76 (m., 1H), 3.56 (s. , 1H), 3.54 - 3.44 (m., 1H), 3.44 - 3.37 (m., 2H), 3.28 (d.d., J = 14.2, 6, 7 Hz, 1H), 3.10 - 3.00 (m., 1H), 2.89 - 2.73 (m., 1H), 1.66 (s., 2H). MS-ESI m/z 434.9 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₄ H ₂₄ N ₃ O ₃ S ⁺ [M+H] ⁺ 434.1460, found 434.1546.

Example (S)-C42: Synthesis of Compound (S)-C42

Compound (S)-C42 was prepared according to the method for synthesizing compound B1, with compound 1-2 in Example A1 replaced by compound 32-1 and compound 11-1 in Example B1 replaced by compound C42-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.07 (d., J = 20.6 Hz, 1H), 7.73, 7.67 (3 x d., J = 3.2, 7.9 , 6.1 Hz, 1H), 7.54 (t., J = 6.1 Hz, 2H), 7.38 - 7.21 (m., 1H), 7.17 - 7.07 (m. , 1H), 7.03 - 6.90 (m., 1H), 6.81 (d.d., J = 11.8, 4.5 Hz, 1H), 6.65, 6.60 ( 2×s, 1H), 6.34, 6.09 (2×s, 1H), 5.30 - 4.73 (m, 1H), 3.95 - 3.77 (m, 3H ), 3.56 (s., 2H), 3.52 - 3.41 (m., 1H), 3.42 - 3.37 (m., 2H), 3.34 - 3.25 (m. , 1H), 3.12 - 2.99 (m, 1H), 2.89 - 2.73 (m, 1H), 2.62 (s, 1H). MS-ESI m/z 434.1 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₄ H ₂₄ N ₃ O ₃ S ⁺ [M+H] ⁺ 434.1460, found 434.1542.

Example C43: Synthesis of Compound C43

Compound C43 was obtained according to the method for synthesizing compound B2, wherein compound 1-2 in Example A1 was replaced by compound 32-1, and compound 12-1 in Example B2 was replaced by compound 15-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.14 (d.d.d., J = 14.9, 14.0, 7.0 Hz, 2H), 6.94 (d., J = 2.0 Hz, 1H), 6.56 (s., 1H), 5.96 (s., 1H), 4.14-4.05 (m., 1H), 3.83 (s., 3H), 3.67 (s., 3H), 3.54 (sq., J = 16.7 Hz, 2H), 3.38 (s., 3H), 3.05 (d.d., J = 14.4, 7.9 Hz, 2H), 2.87 (d.d.d., J = 16.4, 10.4, 6.0 Hz, 1H), 2.61 (d.d., J = 12.3, 3.8 Hz, 1H), 1.40 (t., J = 7.3 Hz, 1H). MS-ESI m/z 395.2 [M+H] ⁺ . MS-HR: (ESI, m/z) calculated for C ₂₃ H ₂₇ N ₂ O ₃ ⁺ [M+H] ⁺ 395.1893, found 395.1971.

Example C44: Synthesis of Compound C44

Compound C44 was obtained in accordance with the method of synthesis of compound A1, while the compound 1-2 in example A1 was replaced by compound C44-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05, 8.80 (2xs, 1H), 8.13, 7.52 (2xs, 1H), 7.48, 7.43 (2xd, J=8.7, 8.3Hz, 1H), 7.33, 7.29 (2xd, J=1.3, 1.4Hz, 1H), 7.10 , 7.01 (2×d.d., J=8.4, 1.7, 8.5, 1.7 Hz, 1H), 6.89, 6.84 (2×d., J= 1.6, 1.7 Hz, 1H), 6.67, 6.64 (2×s., 1H), 6.30, 6.61 (s., t., J = 6.5 Hz 1H) , 4.67, 4.48 (2×d.d., J = 9.9, 3.8, 12.1, 5.5 Hz, 1H), 3.87 (d., J = 2, 2 Hz, 3H), 3.84 (s., 1H), 3.57, 3.46 (2×s., 3H), 3.39 - 3.00 (m., 2H), 2.96 - 2.60 (m., 2H), 1.35 (t., J = 7.3 Hz, 1H). MS-ESI m/z 385.1 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₁ H ₂₂ ClN ₂ O ₃ ⁺ [M+H] ⁺ 385.1241, found 385.2241.

Example (S)-C44: Synthesis of Compound (S)-C44

Compound (S)-C44 was prepared according to the method for the synthesis of compound (S)-A1, with compound 1-2 in Example A1 replaced by compound C44-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.48, 8.27 (2xs, 1H), 8.15, 7.57 (2xs, 1H), 7.47 (d.- d., J = 18.5, 8.4 Hz, 1H), 7.34 (d.d., J = 19.3, 1.6 Hz, 1H), 7.09 (2×d.- d., J = 1.8, 1.8, 1.9, 1.7 Hz, 1H), 6.92, 6.87 (2×s., 1H), 6.65 (d., J = 9.2 Hz, 1H), 6.56, 6.32 (2×s, 1H), 4.68 - 4.46 (m, 1H), 3.94 - 3.83 (m, 4H ), 3.59 (s., 1H), 3.58 - f3.34 (m., 1H), 3.26 (d.d., J = 11.3, 5.2 Hz, 1H), 3.23 - 3.10 (m, 1H), 2.96 - 2.77 (m, 1H), 2.79 - 2.61 (m, 1H), 2.06 (d, J = 16.5 Hz, 1H), 1.80 (s., 1H). MS-ESI m/z 385.1 [M+H] ⁺ . MS-VR: (ESI, m/z) calculated for C ₂₁ H ₂₂ ClN ₂ O ₃ ⁺ [M+H] ⁺ 385.1241, found 385.1323.

Example C45: Synthesis of Compound C45

Compound C45 was obtained in accordance with the method of synthesis of compound A1, with compound 1-2 in example A1 replaced by compound C45-1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s., 1H), 7.64-7.53 (m., 2H), 7.33 (d., J = 8.2 Hz, 1H ), 7.18 (d.t., J = 14.8, 7.0 Hz, 1H), 7.08, 6.80 (m, 1H), 6.65 (2×s, 1H ), 6.55, 6.26, 5.64 (2×s, t, J = 6.4 Hz, 1H), 4.72 - 4.47(m, 1H), 3.88 (s ., 1H), 3.85 (d., J = 2.1 Hz, 3H), 3.75 (s., 1H), 3.71 (s., 1H), 3.60 - 3.53 ( m., 1H), 3.52 (s., 1H), 3.38 - 3.07 (m., 3H), 2.96 - 2.79 (m., 1H), 2.79 - 2, 63 (m, 1H), 1.72 (s, 2H). MS-ESI m/z 365.1 [M+H] ⁺ . MS-HR: (ESI, m/z) calculated for C ₂₂ H ₂₅ N ₂ O ₃ ⁺ [M+H] ⁺ 365.1787, found 365.1868.

Example C46: Synthesis of Compound C46

Compound C46 was prepared according to the method of synthesis of compound A2, with 1-2 in example A1 replaced by compound 32-1, and compound 4-2 in example A2 was replaced by benzyl bromide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36, 8.17 (2×s, 1H), 7.55 (d-d, J = 17.0, 8.6 Hz, 2H) , 7.47 (d., J = 7.3 Hz, 1H), 7.38 (d.-d., J = 12.8, 3.9 Hz, 1H), 7.31 (d., J = 7.4 Hz, 1H), 7.26 (t., J = 7.2 Hz, 2H), 7.17 (m., 1H), 6.87, 6.73 (2×s., 1H ), 6.69 (d, J = 4.5 Hz, 1H), 6.58, 6.32 (2×s, 1H), 5.58 (t, 3H), 5.15 (s ., 1H), 4.79 (d.d., J = 39.4, 12.5 Hz, 1H), 4.56 (m., 1H), 4.15 (sq., J = 7, 1 Hz, 1H), 3.92, 3.87 (2×s, 3H), 3.61 - 3.29 (m, 1H), 3.27 - 3.02 (m, 2H), 2.98 - 2.79 (m, 1H), 2.79 - 2.61 (m, 1H), 2.07 (s, 1H). MS-ESI m/z 427.1 [M+H] ⁺ . MS-HR: (ESI, m/z) calculated for C ₂₇ H ₂₇ N ₂ O ₃ ⁺ [M+H] ⁺ 427.1943, found 427.2025.

Example (S)-C47: Synthesis of compound (S)-C47

Compound (S)-C47 was obtained according to the method for the synthesis of compounds (S)-C8 and B13, while methanesulfonyl chloride in example B13 was replaced by benzenesulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.96 (s., 1H), 7.72 (d., J = 7.8 Hz, 2H), 7.41 (t., J = 7, 4 Hz, 1H), 7.30 (t., J = 7.7 Hz, 2H), 7.27 - 7.23 (m., 1H), 7.12 (d., J = 2.2 Hz , 1H), 7.01 (d., J = 2.4 Hz, 1H), 6.85 (d.d., J = 8.8, 2.4 Hz, 1H), 6.29 (d ., J = 2.3 Hz, 2H), 5.01 (d.d., J = 9.4, 4.2 Hz, 1H), 3.95 (d.-t., J = 14, 3, 4.5 Hz, 1H), 3.85 (s., 3H), 3.85 - 3.80 (m., 2H), 3.73 (s., 3H), 3.56 - 3, 46 (m, 1H), 2.98 - 2.86 (m, 2H), 2.40 (d.t., J = 6.2, 3.8 Hz, 2H), 2.23 ( d.t.d., J = 14.6, 8.6, 5.9 Hz, 1H), 2.13 (q.d., J = 9.0, 8.4, 3.8 Hz, 1H), 1.36 (t., J = 7.0 Hz, 3H).

Example (S)-C48: Synthesis of Compound (S)-C48

Compound (S)-C48 was obtained according to the method for the synthesis of compound (S)-C47, with benzenesulfonyl chloride in Example (S)-C47 replaced by chloropropylsulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.84 (s., 1H), 7.25 (s., 1H), 7.12 (d., J = 2.0 Hz, 1H), 7 .03 (d., J = 2.4 Hz, 1H), 6.85 (d.-d., J = 8.8, 2.4 Hz, 1H), 6.56 (s., 1H), 6.30 (s. 1H), 4.78 (d.d., J = 9.9, 3.8 Hz, 1H), 4.02 (d.d., J = 14.8, 6.8 Hz, 1H), 3.85 (s., 3H), 3.85 (sq., J = 7.0 Hz, 2H), 3.82 (s., 3H), 3.54 (d .-d.-d., J = 14.8, 12.0, 5.1 Hz, 1H), 3.11 - 3.00 (m., 1H), 3.00 - 2.90 (m. , 2H), 2.68 (d.d., J = 16.7, 5.0 Hz, 1H), 2.24 (d.d.t., J = 14.2, 8.3 , 4.3 Hz, 1H), 2.15 - 2.03 (m., 2H), 1.36 (t., J = 7.0 Hz, 3H), 1.22 - 1.16 (m. , 1H), 1.07 (d.d.t., J = 10.2, 6.8, 4.9 Hz, 1H), 0.82 (sq.d., J = 7.9 , 4.8 Hz, 1H), 0.72 (d.t., J = 9.6, 6.0 Hz, 1H).

Example (S)-C49: Synthesis of Compound (S)-C49

Compound (S)-C49 was obtained according to the method for the synthesis of compound (S)-C47, while benzenesulfonyl chloride in example (S)-C47 was replaced by cyclohexylsulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.67 (s., 1H), 7.22 (d., J = 7.5 Hz, 1H), 7.13 (s., 1H), 7 .04 (s., 1H), 6.96 (s., 1H), 6.70 (d., J = 7.5 Hz, 1H), 6.26 (s., 1H), 4.61 ( d.sq., J = 12.3, 7.9 Hz, 1H), 4.19 (s., 1H), 4.06 (d.s., J = 12.5, 8.1 Hz , 1H), 3.89 (d., J = 15.0 Hz, 6H), 3.62 - 3.50 (m., 2H), 3.42 (d.-t., J = 16.9 , 7.1 Hz, 1H), 3.26 (d.t., J = 12.5, 7.0 Hz, 1H), 2.88 - 2.72 (m., 2H), 2.50 - 2.39 (m., 3H), 2.02 - 1.85 (m., 6H), 1.78 - 1.66 (m., 1H), 1.61 - 1.31 (m., 6H).

Example (S)-C50: Synthesis of Compound (S)-C50

Compound (S)-C50 was prepared according to the method for the synthesis of compound (S)-C47, with the benzenesulfonyl chloride in Example (S)-C47 replaced by 3-fluorobenzenesulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.98 - 7.94 (m., 1H), 7.47 (t.d., J = 7.9, 1.7 Hz, 2H), 7.30 - 7.23 (m., 2H), 7.13 - 7.08 (m., 2H), 7.01 (d., J = 2.4 Hz, 1H), 6.86 (d .-d., J = 8.8, 2.4 Hz, 1H), 6.33 (s., 1H), 6.29 (s., 1H), 4.97 (d.-d., J = 9.3, 4.3 Hz, 1H), 3.98 - 3.93 (m., 1H), 3.86 (s., 3H), 3.83 (t., J = 7.0 Hz , 2H), 3.75 (s., 3H), 3.58 - 3.51 (m., 1H), 2.98 - 2.86 (m., 2H), 2.49 - 2.43 ( m., 2H), 2.24 (d.-t.-d., J = 14.6, 8.2, 6.0 Hz, 1H), 2.17 - 2.08 (m., 1H) , 1.36 (t., J = 7.0 Hz, 3H).

Example (S)-C51: Synthesis of Compound (S)-C51

Compound (S)-C51 was obtained according to the method for the synthesis of compound (S)-C47, wherein the benzenesulfonyl chloride in Example (S)-C47 was replaced by 3,4-difluorobenzenesulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.95 (s., 1H), 7.56 (d.d.d., J = 9.5, 7.2, 2.2 Hz, 1H), 7.44 (d.d.d., J = 8.7, 3.8, 1.8 Hz, 1H), 7.26 (d., J = 2.5 Hz, 1H) , 7.12 (d., J = 2.1 Hz, 1H), 7.06 (t.d., J = 9.3, 7.5 Hz, 1H), 7.01 (d., J = 2.4 Hz, 1H), 6.86 (d.d., J = 8.8, 2.4 Hz, 1H), 6.34 (s., 1H), 6.29 (s., 1H), 4.95 (d-d, J = 9.3, 4.3 Hz, 1H), 3.97 - 3.90 (m, 1H), 3.86 (s, 3H) , 3.83 (sq., J = 7.0 Hz, 2H), 3.76 (s., 3H), 3.55 (d.d.d., J = 14.5, 11.0 , 5.7 Hz, 1H), 2.98 - 2.87 (m., 2H), 2.51 - 2.39 (m., 2H), 2.24 (d.-t.-d., J = 14.5, 8.4, 6.0 Hz, 1H), 2.18 - 2.10 (m., 1H), 1.37 (t., J = 7.0 Hz, 3H).

Example (S)-C52: Synthesis of Compound (S)-C52

Compound (S)-C52 was prepared according to the method for the synthesis of compound (S)-C47, with the benzenesulfonyl chloride in Example (S)-C47 being replaced by 2,4-difluorobenzenesulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.97 (s., 1H), 7.95 - 7.88 (m., 1H), 7.24 (d., J = 8.7 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.91 - 6.87 (m, 1H) , 6.85 (d.d., J = 8.8, 2.5 Hz, 1H), 6.69 (d.d.d., J = 10.6, 8.5, 2, 4 Hz, 1H), 6.39 (s., 1H), 6.32 (s., 1H), 5.04 (d.d., J = 9.3, 4.4 Hz, 1H), 4.05 - 3.97 (m, 1H), 3.85 (d, J = 2.7 Hz, 4H), 3.83 (sq., J = 7.0 Hz, 2H), 3, 77 (s., 3H), 3.57 (d.d.d., J = 14.3, 9.5, 7.0 Hz, 1H), 2.95 - 2.81 (m., 2H), 2.55 - 2.48 (m, 2H), 2.24 (d-t-d, J = 14.6, 8.9, 5.7 Hz, 1H), 2, 17 - 2.08 (m., 1H), 1.36 (t., J = 7.0 Hz, 3H).

Example (S)-C53: Synthesis of Compound (S)-C53

Compound (S)-C53 was obtained according to the method for the synthesis of compound (S)-C47, with benzenesulfonyl chloride in Example (S)-C47 replaced by ethylsulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 8.01 (s., 1H), 7.24 (d., J = 8.7 Hz, 1H), 7.10 (d., J = 2, 3 Hz, 1H), 7.02 (d., J = 2.4 Hz, 1H), 6.84 (d.d., J = 8.8, 2.4 Hz, 1H), 6.57 (s., 1H), 6.32 (s., 1H), 4.77 (d.d., J = 9.4, 4.2 Hz, 1H), 4.03 - 3.95 (m ., 1H), 3.84 (s., 3H), 3.83 (sq., J = 7.0 Hz, 2H), 3.82 (s., 3H), 3.54 (d.-d .-d., J = 14.6, 11.8, 5.0 Hz, 1H), 3.01 - 2.78 (m., 5H), 2.68 (d.-d.-d., J = 16.8, 5.0, 1.9 Hz, 1H), 2.25 (d.t.d., J = 14.6, 8.7, 5.8 Hz, 1H), 2 .11 (t.-t.-d., J = 14.3, 8.1, 4.2 Hz, 1H), 1.36 (t., J = 7.0 Hz, 3H), 1.26 (t., J = 7.4 Hz, 3H).

Example (S)-C54: Synthesis of Compound (S)-C54

Compound (S)-C54 was obtained according to the method for the synthesis of compound (S)-C47, with benzenesulfonyl chloride in Example (S)-C47 replaced by trifluoroacetyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 8.32 (d., J = 9.0 Hz, 1H), 7.31 (d., J = 2.4 Hz, 1H), 7.03 - 6.93 (m, 2H), 6.61 (s, 1H), 6.52 (s, 1H), 5.59 (d-d, J = 9.6, 4.5 Hz , 1H), 4.09 - 3.97 (m., 2H), 3.93 - 3.80 (m., 8H), 3.67 (td.d., J = 11.3, 9, 2, 5.0 Hz, 1H), 2.99 (d.d.d., J = 16.7, 11.3, 5.6 Hz, 1H), 2.89 - 2.67 (m ., 3H), 2.38 - 2.16 (m., 2H), 1.41 (t., J = 7.0 Hz, 3H).

Example (S)-C55: Synthesis of Compound (S)-C55

Compound (S)-C55 was obtained according to the method for the synthesis of compound (S)-C47, with the benzenesulfonyl chloride in Example (S)-C47 replaced by pyridine-3-sulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 8.99 (d, J = 2.2 Hz, 1H), 8.64 - 8.57 (m, 1H), 8.03 (s, 1H), 7.92 (d.-t., J = 8.1, 2.0 Hz, 1H), 7.26 (s., 1H), 7.20 (d.-d., J = 8 .1, 4.9 Hz, 1H), 7.14 (d., J = 2.0 Hz, 1H), 7.01 (d., J = 2.3 Hz, 1H), 6.87 (d .-d., J = 8.8, 2.4 Hz, 1H), 6.30 (s., 1H), 6.26 (s., 1H), 4.97 (d.-d., J = 9.4, 4.2 Hz, 1H), 4.01 (d.d.d., J = 14.7, 7.0, 2.4 Hz, 1H), 3.86 (s. , 3H), 3.82 (sq., J = 7.0 Hz, 2H), 3.74 (s., 3H), 3.57 (d.d.d., J = 14.6, 11.0, 5.8 Hz, 1H), 2.94 (Q, J = 7.1, 6.3 Hz, 2H), 2.53 - 2.40 (M, 2H), 2.25 (d.-d.-d.-d., J = 14.8, 13.2, 9.6, 5.7 Hz, 1H), 2.15 (d.-t.-d., J = 14.3, 7.9, 4.4 Hz, 1H), 1.36 (t., J = 6.9 Hz, 3H).

Example (S)-C56: Synthesis of Compound (S)-C56

Compound (S)-C56 was obtained according to the method for the synthesis of compound (S)-C47, with benzenesulfonyl chloride in Example (S)-C47 replaced by 3-fluoro-4-bromosulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.98 (s., 1H), 7.51 - 7.43 (m., 2H), 7.31 (d.d., J = 8, 3, 2.0 Hz, 1H), 7.11 (d., J = 2.3 Hz, 1H), 7.01 (d., J = 2.4 Hz, 1H), 6.86 (d. -d., J = 8.8, 2.4 Hz, 1H), 6.33 (s., 1H), 6.29 (s., 1H), 4.96 (d.-d., J = 9.3, 4.4 Hz, 1H), 3.93 (d.d.d., J = 14.7, 6.4, 2.9 Hz, 1H), 3.86 (s., 3H), 3.83 (sq., J = 6.9 Hz, 2H), 3.76 (s., 3H), 3.55 (d.d.d., J = 14.5, 10 .6, 6.0 Hz, 1H), 2.92 (t.d., J = 7.9, 4.7 Hz, 2H), 2.46 (d.sq., J = 11.4 , 6.3, 4.8 Hz, 2H), 2.24 (d-t-d, J = 14.5, 8.3, 6.0 Hz, 1H), 2.14 (d. -t.-d., J = 14.4, 7.8, 4.3 Hz, 1H), 1.37 (t., J = 7.0 Hz, 3H).

Example (S)-C57: Synthesis of Compound (S)-C57

Compound (S)-C57 was prepared according to the method for the synthesis of compound (S)-C47, with the benzenesulfonyl chloride in Example (S)-C47 replaced by 2-fluorosulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.99 - 7.94 (m, 1H), 7.94 - 7.90 (m, 1H), 7.45 - 7.39 (m. , 1H), 7.17 (t.d., J = 7.7, 1.1 Hz, 1H), 7.07 (d., J = 2.3 Hz, 1H), 7.00 - 6 .93 (m., 2H), 6.84 (d.d., J = 8.8, 2.4 Hz, 1H), 6.36 (s., 1H), 6.31 (s., 1H), 5.07 (d.d., J = 9.4, 4.3 Hz, 1H), 4.04 (d.d.d., J = 14.5, 6.2, 2.7 Hz, 1H), 3.85 (s., 3H), 3.83 (sq., J = 7.0 Hz, 2H), 3.75 (s., 3H), 3.56 (d .-d.-d., J = 14.3, 10.9, 5.6 Hz, 1H), 2.93 - 2.81 (m., 2H), 2.57 - 2.46 (m. , 2H), 2.24 (d.-t.-d., J = 14.6, 9.1, 5.5 Hz, 1H), 2.12 (d.-d.-d.-d. , J = 13.9, 8.9, 7.1, 4.4 Hz, 1H), 1.36 (t., J = 7.0 Hz, 3H).

Example (S)-C58: Synthesis of Compound (S)-C58

Compound (S)-C58 was obtained according to the method for the synthesis of compound (S)-C47, while benzenesulfonyl chloride in example (S)-C47 was replaced by 4-fluorosulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.98 (s., 1H), 7.73 - 7.67 (m., 2H), 7.12 (d., J = 2.3 Hz, 1H), 7.01 (d., J = 2.4 Hz, 1H), 6.96 (t., J = 8.6 Hz, 2H), 6.86 (d.-d., J = 8 .7, 2.4 Hz, 1H), 6.30 (s., 1H), 6.28 (s., 1H), 4.98 (d.d., J = 9.5, 4.1 Hz, 1H), 3.94 (d.d.d., J = 14.4, 7.0, 2.2 Hz, 1H), 3.85 (s., 3H), 3.83 ( sq., J = 6.9 Hz, 2H), 3.74 (s., 3H), 3.52 (d.d.d., J = 14.5, 11.3, 5.5 Hz , 1H), 2.99 - 2.88 (m., 2H), 2.46 - 2.32 (m., 2H), 2.23 (d.-t.-d., J = 14.5 , 8.7, 5.7 Hz, 1H), 2.16 - 2.09 (m., 1H), 1.37 (t., J = 7.0 Hz, 3H).

Example (S)-C59: Synthesis of Compound (S)-C59

Compound (S)-C59 was obtained according to the method for the synthesis of compound (S)-C47, while benzenesulfonyl chloride in example (S)-C47 was replaced by difluoroacetyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.61 (s., 1H), 7.22 (d., J = 7.5 Hz, 1H), 7.14 (d., J = 1, 0 Hz, 1H), 7.04 (s., 1H), 6.79 (d., J = 1.6 Hz, 1H), 6.70 (d.-d., J = 7.5, 1 .5 Hz, 1H), 6.23 - 6.16 (m., 1H), 4.95 (s., 1H), 4.57 (d.sq., J = 12.3, 7.9 Hz, 1H), 4.40 - 4.26 (m., 1H), 3.89 (m., 8H), 3.56 (d.t., J = 12.5, 7.1 Hz, 1H), 3.38 (d.t.d., J = 14.1, 7.0, 1.0 Hz, 1H), 2.95 - 2.76 (m., 2H), 2, 54 (d-d-d, J = 12.5, 9.9, 6.5 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.46 (t., J = 8.0 Hz, 3H).

Example (S)-C60: Synthesis of Compound (S)-C60

Compound (S)-C60 was prepared according to the method for the synthesis of compound (S)-C47, with the benzenesulfonyl chloride in Example (S)-C47 replaced by 4-methoxysulfonyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.92 (s., 1H), 7.63 (d., J = 8.8 Hz, 2H), 7.12 (d., J = 1, 8 Hz, 1H), 7.01 (d., J = 2.4 Hz, 1H), 6.85 (d.d., J = 8.7, 2.4 Hz, 1H), 6.79 - 6.74 (m., 2H), 6.31 (d., J = 11.7 Hz, 2H), 4.98 (d.-d., J = 9.3, 4.3 Hz, 1H ), 3.94 - 3.88 (m., 1H), 3.85 (s., 3H), 3.83 (sq., J = 7.0 Hz, 2H), 3.77 (s., 3H), 3.75 (s., 3H), 3.50 (d.t., J = 14.4, 8.8 Hz, 1H), 2.92 (sq., J = 7.7, 7.0 Hz, 2H), 2.45 - 2.39 (m., 2H), 2.21 (d.d.d., J = 14.7, 10.1, 5.9 Hz, 1H), 2.16 - 2.08 (m., 1H), 1.36 (t., J = 7.0 Hz, 3H).

Example (S)-C61: Synthesis of Compound (S)-C61

Compound (S)-C61 was prepared according to the synthetic method for compound (S)-A1, with compound 1-2 in Example (S)-A1 replaced with compound 61-1. ¹ H NMR (500 MHz, chloroform-d) δ 8.28 (2xs, 1H), 7.86-7.83 (2xm, 1H), 7.71 (2xd-d ., J = 6.7, 2.0 Hz, 1H), 7.45 - 7.37 (2×m, 2H), 7.22 (2×s, 1H), 6.60 (2× s., 1H), 6.47 (2×s., 1H), 4.51 (2×d.d., J = 9.4, 4.7 Hz, 1H), 3.84 (2× s., 3H), 3.74 (2×s., 3H), 3.60 (2×m., 1H), 3.04 (2×d.d., J = 15.4, 7, 9 Hz, 1H), 2.94 - 2.90 (2×m, 3H), 2.71 (2×dd.d., J = 16.2, 4.8, 2.1 Hz, 1H ), 2.26 (2xm, 2H).

Example (S)-C62: Synthesis of Compound (S)-C62

Compound (S)-C62 was obtained according to the method for the synthesis of compound (S)-C47, with benzenesulfonyl chloride in Example (S)-C47 replaced by methoxyacetyl chloride. ¹ H NMR (500 MHz, chloroform-d) δ 7.82 (2×s, 1H), 7.39 (2×d, J = 2.3 Hz, 1H), 7.22 (2×d ., J = 7.5 Hz, 1H), 7.16 (2×d., J = 0.9 Hz, 1H), 7.10 (2×d., J = 1.7 Hz, 1H), 6.70 (2×d.d., J=7.5, 1.5 Hz, 1H), 5.02 (2×d.d., J=7.6, 6.6 Hz, 1H ), 4.93 (2xd, J = 12.5Hz, 1H), 4.66 (2xd, J = 12.3Hz, 1H), 4.35 (2xds ., J = 12.3, 7.9 Hz, 1H), 4.04 - 3.85 (2×m, 8H), 3.64 (2×d.t., J = 12.5, 7.1 Hz, 1H), 3.36 - 3.26 (2×m, 1H), 3.25 (2×s, 3H), 3.01 (2×d.t., J = 12.5, 7.9 Hz, 1H), 2.89 - 2.71 (2×m, 2H), 2.15 - 2.07 (2×m, 2H), 1.46 (2× t., J = 8.0 Hz, 3H).

Example (S)-C63: Synthesis of Compound (S)-C63

Compound (S)-C63 was obtained according to the method for the synthesis of compounds (S)-A1 and (S)-C8, with compound 1-1 in example (S)-A1 replaced by compound 63-1. MS-ESI m/z 449.2.

Example (S)-C64: Synthesis of Compound (S)-C64

Compound (S)-C64 was prepared according to the method for synthesizing compound (S)-C63, with compound 63-1 in Example (S)-C63 being replaced by compound 64-1. MS-ESI m/z 431.2.

Example (S)-C65: Synthesis of Compound (S)-C65

Compound (S)-C65 was prepared according to the method for synthesizing compound (S)-C8, with compound 31-1 in Example (S)-C8 being replaced by compound 65-1. MS-ESI m/z 404.2.

Example (S)-C66: Synthesis of Compound (S)-C66

Compound (S)-C66 was prepared according to the method for synthesizing compound (S)-C63, with compound 63-1 in Example (S)-C63 being replaced by compound 66-1. MS-ESI m/z 423.1.

Example (S)-C67: Synthesis of Compound (S)-C67

Compound (S)-C67 was prepared according to the method for synthesizing compound (S)-C63, with compound 63-1 in Example (S)-C63 being replaced by compound 67-1. MS-ESI m/z 423.1.

Example (S)-C68: Synthesis of Compound (S)-C68

Compound (S)-C66 was dissolved in methanol, 1 M NaOH was added and stirred at room temperature for 2 hours. The mixture was neutralized with 1 M hydrochloric acid, extracted with ethyl acetate, and separated by column chromatography to give compound (S)-C68. MS-ESI m/z 409.2.

Example (S)-C69: Synthesis of Compound (S)-C69

Compound (S)-C68 was dissolved in dichloromethane, 2 equivalents of a solution of methylamine in tetrahydrofuran, 1.5 equivalents of HATU, 2 equivalents of triethylamine were added and stirred at room temperature overnight. Dichloroethane was added and washed with water, the organic phase was dried and purified by column chromatography to give compound (S)-C69. MS-ESM m/z 422.2.

Example (S)-C70: Synthesis of Compound (S)-C70

Compound (S)-C68 was dissolved in dioxane, 2 equivalents of ammonium bicarbonate solution, 2 equivalents of butoxycarbonyl anhydride (BOC), 5 equivalents of pyridine were added and stirred at room temperature overnight. Dichloromethane was added and washed with water, while the dried organic phase was purified by column chromatography to obtain compound (S)-C70. MS-ESI m/z 408.2.

Example (S)-C71: Synthesis of Compound (S)-C71

Compound (S)-C71 was prepared according to the method for synthesizing compound (S)-C63, with compound 63-1 in Example (S)-C63 being replaced by compound 71-1. MS-ESI m/z 415.2.

Example (S)-C72: Synthesis of Compound (S)-C72

Compound (S)-C72 was prepared according to the method for synthesizing compound (S)-B2, with compound 12-1 in Example (S)-B2 replaced with difluoromethyl iodide. MS-ESI m/z 431.2.

Example (S)-C73: Synthesis of Compound (S)-C73

Compound (S)-C73 was prepared according to the method for synthesizing compound (S)-C65, with compound 65-1 in Example (S)-C65 being replaced by compound 73-1. MS-ESI m/z 447.2.

Example (S)-C74: Synthesis of Compound (S)-C74

Compound (S)-C74 was prepared according to the method for synthesizing compound (S)-C65, with compound 65-1 in Example (S)-C65 being replaced by 5-difluoromethylindole. MS-ESI m/z 429.2.

Example (S)-C75: Synthesis of Compound (S)-C75

Compound (S)-C75 was prepared according to the method for the synthesis of compound (S)-C65, with compound 65-1 in Example (S)-C65 replaced with methylindole-5-carboxylate. MS-ESI m/z 437.2.

Example (S)-C76: Synthesis of Compound (S)-C76

Compound (S)-C76 was prepared according to the method for the synthesis of compound (S)-C65, with compound 65-1 in Example (S)-C65 being replaced by 5-trifluoromethoxyindole. MS-ESI m/z 463.2.

Example (S)-C77: Synthesis of Compound (S)-C77

Compound (S)-C77 was prepared according to the method for synthesizing compound (S)-C65, with compound 65-1 in Example (S)-C65 being replaced by 5-difluoromethoxyindole. MS-ESI m/z 445.2.

Example (S)-C78: Synthesis of Compound (S)-C78

Compound (S)-C78 was prepared according to the method for the synthesis of compound (S)-C65, with compound 65-1 in Example (S)-C65 being replaced by 5-fluoroindole. MS-ESI m/z 397.2.

Example (S)-C79: Synthesis of Compound (S)-C79

Compound (S)-C79 was prepared according to the method for synthesizing compound (S)-C63, with compound 63-1 in Example (S)-C63 being replaced by compound 79-1. MS-ESI m/z 409.20.

Example (S)-C80: Synthesis of Compound (S)-C80

Compound (S)-C80 was prepared according to the synthetic method for compound (S)-C65, with compound 65-1 in Example (S)-C65 being replaced by 6-chloro-5-methoxyindole. MS-ESI m/z 443.2.

Example (S)-C81: Synthesis of Compound (S)-C81

Compound (S)-C81 was prepared according to the method for synthesizing compound (S)-C65, with compound 65-1 in Example (S)-C65 being replaced by 5-fluoro-6-chloroindole. MS-ESI m/z 431.1.

Example (S)-C82: Synthesis of Compound (S)-C82

Compound (S)-C82 was prepared according to the method for the synthesis of compound (S)-C62, with 5-methoxyindole in Example (S)-C62 being replaced by 5-fluoroindole. MS-ESI m/z 441.2.

Example (S)-C83: Synthesis of Compound (S)-C83

Compound (S)-C83 was prepared according to the method for synthesizing compound (S)-C72, with difluoroiodomethane in Example (S)-C72 being replaced by 1-chloro-2-(methylsulfonyl)methane. MS-ESI m/z 487.2.

Determination of biological activity

Experimental example B1. Determination of the inhibition of the activity of an enzyme molecule by a compound on PDE4

The scintillation proximity assay (SPA) method was used to determine the inhibitory effect of the compounds on the activity of the PDE4D catalytic domain. The human PDE4D catalytic domain protein was obtained by expression and purification in E. coli. Apremilast positive compound was purchased from Topscience Biochemical, microplate scintillation counter (MicroBeta2, Perkin Elmer), constant temperature water bath (DK420, Shanghai Medical Device Factory), microvibrator (XW-80A, Shanghai Jingke Industrial Co., Ltd.) are conventional instruments in a radioactive laboratory, and a step pipette (Multipette Plus, Eppendorf) and replacement tips were purchased from the Ebende Biotechnology Company, 3.5. [ ³ H]cAMP (cyclic adenosine monophosphate), scintillation beads (RPNQ0150, Perkin Elmer) and 96-well scintillation microplates (Isoplate-96, Perkin Elmer) were purchased from Perkin Elmer. 10x SPA buffer was prepared in the laboratory (500 mmol/L Tris solution pH 7.5, 83 mmol/L MgCl ₂ solution, 17 mmol/L ethylene glycol tetraacetic acid (EGTA) solution).

In the experiment, 60 µl of water and 10 µl of the reaction mixture were added to 100 ml of the total reaction volume until the final concentration of each component was reached (50 mmol/l Tris g/x solution with pH 7.5, 8.3 mmol/l MgCl ₂ solution, 1 .7 mmol/l EGTA, 10 µl compound and 10 µl enzyme (0.1 ng/µl)). Finally, 10 µl of [ ³ H]-cAMP (0.005 µCi/µl) was added and incubated for 30 min at 30 ºC in a water bath. To stop the reaction, 50 µl of SPA beads were added with shaking and allowed to stand for 20 minutes. A microplate scintillation counter was used.

Table B1 shows the degree of inhibition of PDE4D enzyme activity by the compound and the IC ₅₀ values.

Conclusion: After measuring the degree of inhibition of PDE4 at a concentration of 1 μmol/l, the IC ₅₀ value of inhibition of PDE4 activity by compounds with high inhibition efficiency was measured. Of these, 14 compounds had IC ₅₀ values at the level of 100 nmol and 3 compounds (C10, (S)-C10 and (S)-C8) had IC ₅₀ values less than 100 nmol, which were comparable to the IC ₅₀ value of the positive control compound apremilast.

Experimental Example 2 Determination of Inhibitory Activity of a Compound on TNF-α Secretion in PBMC

Among the many functions of PDE4, the most studied is the anti-inflammatory effect. Monocytes and macrophages of the immune system are important producers of tumor necrosis factor TNF-α. PDE4 is the main enzyme in these cells. The anti-inflammatory actions of existing PDE4 inhibitors are closely related to the expression of TNF-α in the immune system. Due to the difference in density of human blood cells, peripheral blood mononuclear cells (PBMCs) were directly separated and purified by gradient centrifugation using lymphocyte separation fluid. By their type, they were blood mononuclear cells, mainly representing lymphocytes (T / B), monocytes, macrophages, dendritic cells, as well as cells of other, less common types, most of which are lymphocytes, which can directly, in vitro, model the immune environment of the blood. Lipopolysacchard (LPS) is a component of the cell membrane of gram-negative bacteria that can significantly stimulate the expression of the inflammatory factor TNF-α through various signaling mechanisms, such as mitogen-activated protein kinase (MAPK), which makes it possible to evaluate the activity of some PDE4 inhibitors and simulate the anti-inflammatory effect in vitro. The inhibitory effect of some PDE4 inhibitors on TNF-α expression in human PBMCs is mainly addressed by George W. Muller et al.

During the experiment, the positive compound apremilast was purchased from Topscience Biochemical Technology Co., Ltd. Whole blood was provided by the Shanghai Blood Center; fetal bovine serum (FBS) was purchased from Hyclone (South Logan, Utah, USA); RPMI-1640 medium and human TNF-α ELISA kit were purchased from Invitrogen (San Diego, CA, USA); bacterial lipopolysaccharide (LPS) was purchased from Sigma (L9764, St. Louis, Missouri, USA).

PBMC isolated from human blood were implanted in 96-well plates at a concentration of 2×10 ⁵ per ml; compounds were added to the gradients, at least three repetitions for each gradient. After incubation of PBMCs at 37 °C with 5% CO ₂ for 1 hour, LPS was added (final concentration was 10 μg/ml) to stimulate PBMCs to express TNF-α and incubated for another 18-20 hours at 37 °C with 5% CO ₂ . A 96-well plate was assembled. Background control without stimulator and wells for stimulation control with a total volume of 200 μl were also installed. The culture supernatant was collected by centrifugation, and the level of TNF-α expression in the culture supernatant was determined by ELISA.

Table 2 shows the results of experiments with compounds that inhibit the secretion of the anti-inflammatory factor TNF-α in PBMC.

Conclusion: Compounds with a higher efficiency of inhibition of enzyme activity at the molecular level have a stronger inhibitory effect on the secretion of TNF-α in PBMC, at which the IC ₅₀ value was approximately at the level of several mmol, and the IC ₅₀ value of the most active compound (S)-C8 reached 26 nmol, which is higher than that of the positive control compound apremilast.

Experimental example B3. Determination of the inhibitory activity of the compound against the secretion of tumor necrosis factor α in RAW 264.7 cells

Tumor necrosis factor-α, being an important mediator of inflammation in the development of diseases such as inflammation, autoimmune diseases, is mainly produced by activated monocytes/macrophages, which are capable of mediating various inflammatory reactions and accelerating the development of the disease. The murine mononuclear/macrophage leukemia cell line RAW 264.7 is one of the traditionally used inflammatory cell models. Upon activation by bacterial lipopolysaccharide (LPS), various inflammatory mediators such as tumor necrosis factor-α are released. Phosphodiesterase PDE4 is also expressed in macrophages, and the inhibitory activity of the compound against phosphodiesterase PDE4 can be reflected by detecting the secretion of tumor necrosis factor α.

(1) Determination of cytotoxicity of a compound on RAW 264.7 cells: The cytotoxicity of a test compound on RAW 264.7 cells was determined by the CCK-8 method. Mouse RAW 264.7 cells were purchased from the American Type Culture Collection (Manassas, VA, USA) and cultured in Dulbecco's Modified Eagle's Minimal Essential Medium (DMEM) (Hyclone, South Logan, UT, USA) containing 10% fetal bovine serum (Hyclone, South Logan, Utah, USA). Cells were collected and counted before use and then inoculated into a 96-well plate manufactured by Corning, NY, USA at a concentration of 1 x 10 ⁵ cells per well. After incubation of the cells for 24 hours, compounds were added at various concentrations, and the corresponding base control and background control of the nutrient medium were established, the total volume of which was 200 μl, and incubated at 37 °C and 5% CO ₂ for 4 hours. 30 min before the end of cultivation, 20 µl of CCK-8 solution (Dojindo, Kumamoto, Japan) was added. At the end of cultivation, the optical density (OD) value was measured at a wavelength of 450 nm (reference wavelength 650 nm) on a microplate reader (Molecular Devices, Sunnyvale, CA, USA). Compound toxicity to RAW 264.7 cells was calculated by dividing the OD value of the test sample by the OD value of the well with control cells, which was referred to as cell viability (%).

(2) Inhibitory activity of compounds on tumor necrosis factor α secretion from RAW 264.7 cells: RAW 264.7 cells (1 x 10 ⁵ per well) were seeded in a 96-well plate, and after incubation for 24 h, compounds were added at various concentrations, and then incubated for 30 min. After stimulation with 1 mg/mL LPS (L5886, Sigma, St. Louis, MO, USA), cells were cultured at 37°C in a 5% _CO2 incubator for 4 h. stimulation control wells with a total volume of 200 µl. The culture supernatant was collected by centrifugation, and the level of tumor necrosis factor-α secretion in the culture supernatant was determined by enzyme immunoassay. The tumor necrosis factor-α detection kit was purchased from BD Pharmingen (San Diego, CA, USA).

Table 2 shows the results of experiments with compounds that inhibit the secretion of anti-inflammatory tumor necrosis factor α in RAW 264.7 cells.

Table B4 shows the results of experiments to determine the cytotoxicity against RAW 264.7 cells (CC50) and inhibition of the secretion of tumor necrosis factor α (IC50) by some compounds.

Conclusion: During the discovery of the inhibitory activity of the test compounds on the secretion of tumor necrosis factor α in RAW 264.7 cells, some compounds with better inhibitory activity were found. Based on the results of determining the inhibitory activity of the compound against the PDE4D catalytic domain in combination with the results of determining the biological activity of PBMCs of the compound (S)-A1, (S)-C5, (S)-C6, (S)-C8 and (S)-C7 were selected to determine cytotoxicity against RAW 264.7 cells and inhibitory activity against tumor necrosis factor α, the experimental results of which are shown in table B3 and table B4. Compared to the positive compound apremilastom, compounds (S)-C5 and (S)-C8 have comparable or higher tumor necrosis factor-α inhibitory activity.

Experimental example B4. Therapeutic Effects of Compounds (S)-C5 and (S)-C8 on an Acute Inflammation Model of the Dorsal Air Pouch in Mice

As a classical model for evaluating the in vivo anti-inflammatory activity of candidate compounds, the mouse dorsal air sac acute inflammation model has high fitness and good repeatability. Mice were injected subcutaneously into the back with 3 ml of air on the first day of the experiment, then 1.5 ml of air was injected subcutaneously into the back on the 3rd day, and 1 ml of a 2% solution of carrageenan (Sigma-Aldrich, St. Louis, Missouri, USA) on the 6th day of sensitization. After 4 hours of sensitization, the secretion of the air sac was washed with phosphate buffer solution. The wash fluid was used for white blood cell count and inflammatory factor detection. Positive drug apremilast and test drugs (S)-C5 and (S)-C8 were dispersed in 0.5% sodium carboxymethylcellulose (Sigma-Aldrich, St. Louis, MO, USA) + 0.25% Tween -80 (purchased from Sinopharm Group). The drug was administered orally (5 mg/kg) by force feeding for 24 hours and 1 hour before sensitization. Tumor necrosis factor-α and interleukin-6 detection kits were purchased from BD Pharmingen (San Diego, CA, USA).

Conclusion: As shown in Figure 1, oral administration of test compounds (S)-C5 and (S)-C8 by force feeding is able to significantly reduce the inflammatory response and leukocyte infiltration rate, as well as the secretion rate of tumor necrosis factor-α and interleukin-6 during washing. in a mouse model of acute inflammation.

Experimental Example 5: Rat PK Study

1. Stages of the experiment:

Six healthy male rats weighing 150-200 g were randomly divided into 2 groups (n = 3). Compounds 14, 16, 17, 18, 22 and 29 of the present invention were administered by force feeding and intravenous injection, respectively, in an administration volume of 10 ml/kg. The drug was used as a mixture with dimethyl sulfoxide (DMSO), Tween 80 and saline (5:5:90 ratio, v/v/v). The rats were not fed for 12 hours before the test, but were given ad lib water and fed evenly 2 hours before the test.

2. Schedule of feeding, drug administration and blood sampling:

force feeding: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;

intravenous administration: 5 min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;

at the above time points, 0.3 ml of venous blood was taken from the ophthalmic vein of the venous plexus of the rat, placed in a test tube with heparin, centrifuged at a speed of 11000 rpm for 5 min, the plasma was separated and frozen in a freezer at a temperature of 20°C.

3. Sample analysis and data analysis

Compound concentrations in rat blood plasma were determined by LC/MS/MS. Pharmacokinetic parameters after administration were calculated using a non-compartmental model in DAS 3.0 software.

4. Results of the experiment:

Table B5 shows the results of studies of the pharmacokinetics of compounds (S)-C7 and (S)-C8 in rats.

Compound (S)-C7: After administration of 20 mg/kg of compound (S)-C7 to rats by force feeding, the time to peak plasma T _max was 1 hour and the peak C _max itself was 2383.6 ng/mL. The area under the AUC _0-t curve was 9232.3 ng·h/ml; the terminal half-life t _1/2 was 1 hour. After intravenous administration of 10 mg/kg compound (S)-C7 AUC _0-t was 6761.8 ng·h/ml; after administration of 20 mg/kg of compound (S)-C7 to rats by force feeding, the absolute bioavailability was 68.3% based on dosage standardization.

Compound (S)-C8: After administration of 20mg/kg of Compound (S)-C8 to rats by force feeding, the time to peak plasma Tmax was 1.33 hours and the peak Cmax itself was 491ng/mL. The area under the AUC _0-t curve was 508 ng·h/ml; the terminal half-life t _1/2 was 1.03 hours. After intravenous administration of 10 mg/kg compound (S)-C8 AUC _0-t was 2640 ng·h/ml; after administration of 20 mg/kg of compound (S)-C8 to rats by force feeding, the absolute bioavailability was 9.30%, based on dosage standardization.

Experimental Conclusions: From the above experimental results, it can be seen that in pharmacokinetic experiments on rats, a relatively high absolute bioavailability of the compound (S)-C7 was shown, which reached 68.3%.

Experimental Example 6: Pharmacokinetic Study in Beagle Dogs

1. Stages of the experiment:

Six healthy male beagle dogs weighing 9-11 kg were randomly divided into 2 groups (n = 3). Compound (S)-C8 of the present invention was administered by force-feeding and intravenous injection, respectively, with the administration volume being 5 ml/kg and 1 ml/kg, respectively. When force-fed, the compound was given in a mixture with 0.5% CMC-Na + 0.25% Tween 80, and when administered intravenously, in a mixture with 5% DISO, 40% polyethylene glycol (PEG) 400 and 55% saline.

2. Schedule of feeding, drug administration and blood sampling:

force feeding: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;

intravenous administration: 5 min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;

1 ml of venous blood was taken at the above time points from the veins of the limbs, placed in an anticoagulation tube with EDTA-2K and centrifuged at a speed of 3500 rpm for 10 minutes. The plasma was separated and frozen in a freezer at -20°C.

3. Sample analysis and data analysis

The concentration of compound (S)-C8 in the blood plasma of dogs was determined by LC/MS/MS.

Pharmacokinetic parameters after administration were calculated using a non-compartmental model in Phoenix 1.3 software from Pharsight, USA.

4. Results of the experiment:

Table B6 summarizes the results of pharmacokinetic studies of compound and (S)-C8 in beagle dogs.

After administration of 10 mg/kg of compound (S)-C8 to beagle dogs by force feeding, the time to peak plasma T _max was 0.5 h and the peak C _max itself was 4685 ng/mL. The area under the drug concentration-time curve AUC _0-t was 16601 ng·h/ml; the terminal half-life t _1/2 was 2.92 hours. After intravenous administration of 3 mg/kg compound (S)-C8 AUC _0-t was 9610 ng·h/ml; after administration of 10 mg/kg of compound (S)-C8 to beagle dogs by force feeding, the absolute bioavailability was 52.3% based on dosage standardization.

Experimental Conclusions: From the above experimental results, it can be seen that pharmacokinetic experiments on beagle dogs showed a high absolute bioavailability of compound (S)-C8.

All literary publications mentioned in this application are incorporated herein by reference as if each of them were separately incorporated by reference. In addition, it should be understood that after reading the above methods, specialists can make various changes and modifications to the present invention. These equivalents also fall within the scope of the following claims.

Claims (38)

1. Tetrahydroisoquinoline compound represented by the general formula (I)

(I) in which the chiral carbon atom C* is independently of type S , type R , or a combination thereof; n = 1; X is -CH ₂ - ; Y is a linking group selected from C1-C6 linear or branched alkylene, -CH ₂ O-, -CH ₂ NH-,

,

or

; each of the R ₁ and R ₂ groups is independently selected from the group consisting of deuterium, hydroxyl, halogen, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C3-C7 cycloalkoxy, substituted or unsubstituted C3-C7 cycloalkylmethoxy, benzyloxy, carboxy-substituted C2-C8 linear alkoxy, N,N -dimethylamino-substituted C2-C8 linear alkoxy, COOR ₅ or CONR ₅ R ₆ ; the substituent is selected from deuterium or halogen; each of the R ₃ groups is selected from the following groups, which are unsubstituted or substituted with 1-2 substituents: -C(O)-(5-7 membered heteroaryl), -C(O)-(4-7 membered heterocyclic group) , acyl -C1-C4, -CHO, R ₇ SO ₂ -, NH ₂ (CH ₂ ) _m SO ₂ -, R ₇ SO ₂ (CH ₂ ) _m -, R ₇ O (CH ₂ ) _m CO-, R ₇ OCO(CH ₂ ) _m -, difluoromethyl, benzenesulfonyl, 5-7 membered heteroarylsulfonyl; where each of the heterocyclic groups or heteroaryl groups contains from 1 to 2 heteroatoms selected from oxygen, sulfur or nitrogen; and each of the substituents is independently selected from halo, C1-C6 linear or branched alkoxy, trifluoromethyl group, C0-C4 sulfonyl group; each of R ₅ , R ₆ and R ₇ is independently selected from hydrogen, substituted or unsubstituted C1-C4 straight or branched alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C10 aryl, wherein the substituent is selected from halogen; m is selected from 0, 1 or 2; R ₄ is a group which is unsubstituted or substituted with 1-2 substituents and is selected from a 5-12 membered heteroaryl group; where each of these heteroaryls contains from 1 to 2 heteroatoms selected from oxygen, sulfur or nitrogen; each of said substituents is independently selected from deuterium, halogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, C1-C6 linear or branched alkylcarbonyloxy, cyano, nitro, hydroxy, amino, hydroxymethyl, trifluoromethyl, trifluoromethoxy, difluoromethyl , difluoromethoxy, COOR ₅ . 2. The tetrahydroisoquinoline compound according to claim 1, characterized in that in the general formula (I) each of the groups R ₁ and R ₂ is independently selected from the group consisting of substituted or unsubstituted linear or branched C1-C6 alkoxy, substituted or unsubstituted C3-C7 cycloalkoxy, substituted or unsubstituted C3-C7 cycloalkylmethoxy, carboxy-substituted C2-C8 linear alkoxy, N ,N -dimethylamino-substituted linear alkoxy C2-C8, COOR ₅ or CONR ₅ R ₆ and the substituent is selected from deuterium or halogen. 3. The tetrahydroisoquinoline compound according to claim 2, characterized in that in the general formula (I) Y is selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -,

,

And

; R ₄ is benzo 5-7 membered heteroaryl which is unsubstituted or substituted with 1-2 substituents. 4. The tetrahydroisoquinoline compound according to claim 2, characterized in that the heterocyclic and heteroaryl fragments in R ₄ are selected from indole, benzodioxole, isoxazole, pyridine, pyrazole, imidazopyridine, benzothiophene, quinoxaline, pyrrole, benzofuran, indazole, benzimidazole, quinoline. 5. The tetrahydroisoquinoline compound according to claim 3, characterized in that in the general formula (I) R ₃ is a group which is unsubstituted or substituted with 1-2 substituents and which is selected from acyl C1-C4, R ₇ SO ₂ -, NH ₂ (CH ₂ ) _m SO ₂ -, R ₇ O(CH ₂ ) _m CO -, benzenesulfonyl; where each of the heterocyclic groups or heteroaryls contains from 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen; each of the substituents is independently selected from halogen, C1-C6 linear or branched alkoxy, trifluoromethyl group, C1-C4 sulfonyl, R ₇ is selected from hydrogen, C1-C4 linear or branched alkyl; m is chosen from 0, 1 or 2. 6. The tetrahydroisoquinoline compound according to claim 1, characterized in that in the general formula (I) chiral carbon atom C* of type S . 7. A tetrahydroisoquinoline compound, wherein the tetrahydroisoquinoline compound is selected from the following compounds: No. Name Structure A1 1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-A1 ( S )-1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-A1 ( R )-1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

A2 1-(2-( 1H- indol-3-yl)ethyl)-7-(cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-A2 ( S )-1-(2-( 1H- indol-3-yl)ethyl)-7-(cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-A2 ( R )-1-(2-( 1H- indol-3-yl)ethyl)-7-(cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

A3 1-(2-( 1H- indol-3-yl)ethyl)-7-(cyclopropylmethoxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-A3 ( S )-1-(2-( 1H- indol-3-yl)ethyl)-7-(cyclopropylmethoxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-A3 ( R )-1-(2-( 1H- indol-3-yl)ethyl)-7-(cyclopropylmethoxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

A4 1-(2-( 1H- indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-A4 ( S )-1-(2-( 1H -indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-A4 ( R )-1-(2-( 1H -indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

A5 1-(2-( 1H- indol-3-yl)ethyl)-7-(benzyloxy)-6-methoxy-3,4-dihydroisoquinoline-2(1H )-formaldehyde

( S )-A5 ( S )-1-(2-( 1H- indol-3-yl)ethyl)-7-(benzyloxy)-6-methoxy-3,4-dihydroisoquine-2( 1H )-formaldehyde

( R )-A5 ( R )-1-(2-( 1H- indol-3-yl)ethyl)-7-(benzyloxy)-6-methoxy-3,4-dihydroisoquine-2( 1H )-formaldehyde

A6 1-(2-( 1H- indol-3-yl)ethyl)-7-(2-(dimethylamino)ethoxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-A6 ( S )-1-(2-( 1H -indol-3-yl)ethyl)-7-(2-(dimethylamino)ethoxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-A6 ( S )-1-(2-( 1H -indol-3-yl)ethyl)-7-(2-(dimethylamino)ethoxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

A7 3-((1-(2-(1 H -indol-3-yl)ethyl)-2-formyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)oxo)propionic acid

( S )-A7 ( S )-3-((1-(2-( 1H -indol-3-yl)ethyl)-2-formyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)oxo) propionic acid

( R )-A7 ( R )-3-((1-(2-( 1H -indol-3-yl)ethyl)-2-formyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)oxo) propionic acid

A8 1-(2-(1 H -indol-3-yl)ethyl)-7-ethoxy-6-(methoxy- d ₃ )-3,4-dihydroisoquinoline-2(1 H )-formaldehyde

( S )-A8 ( S )-1-(2-( 1H- indol-3-yl)ethyl)-7-ethoxy-6-(methoxy- d ₃ )-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-A8 ( R )-1-(2-( 1H- indol-3-yl)ethyl)-7-ethoxy-6-(methoxy- d ₃ )-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

B1 (1-(2-( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(pyridin-4-yl)-methanone

( S )-B1 ( S )-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(pyridin-4-yl) methanone

( R )-B1 ( R )-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(pyridin-4-yl) methanone

B2 1-(2-(1 H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline

( S )-B2 ( S )-1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline

( R )-B2 ( R )-1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline

B3 (1-(2-( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(tetrahydro-2H - pyran-4-yl )ketone

( S )-B3 ( S )-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(tetrahydro- 2H -pyran -4-yl) methanone

( R )-B3 ( R )-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(tetrahydro- 2H -pyran -4-yl) methanone

B4 1-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethan-1-one

( S )-B4 ( S )-1-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane- 1-he

( R )-B4 ( R )-1-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane- 1-he

B5 methyl-2-(1-(2-(1 H -indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H )-yl)acetate

( S )-B5 ( S )-methyl-2-(1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)acetate

( R )-B5 (R)- methyl-2-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)acetate

B6 1-(2-(1 H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline

( S )-B6 ( S )-1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline

( R )-B6 ( R )-1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline

B7 1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro- 2H- pyran-4-yl)methyl)-1,2,3,4- tetrahydroisoquinoline

( S )-B7 ( S )-1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro- 2H- pyran-4-yl)methyl)-1,2, 3,4-tetrahydroisoquinoline

( R )-B7 (R)-1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro- 2H- pyran-4-yl)methyl)-1,2, 3,4-tetrahydroisoquinoline

B8 1-(2-(1 H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

( S )-B8 ( S )-1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

( R )-B8 (R) 1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

B9 1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-(methanesulfonyl)ethan-1-one

( S )-B9 ( S )-1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-(methanesulfonyl)ethan- 1-he

( R )-B9 ( R )-1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-(methanesulfonyl)ethan- 1-he

B10 1-(1-(2-(1 H -indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H )-yl)-2,2,2-trifluoroethane- 1-he

( S )-B10 ( S )-1-(1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2,2, 2-trifluoroethane-1-one

( R )-B10 (R) 1-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2,2,2 -trifluoroethane-1-one

B11 1-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethan-1-one

( S )-B11 ( S )-1-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane- 1-he

( R )-B11 ( R )-1-(1-(2-( 1H- indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane- 1-he

B12 1-(1-(2-( 1H -indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane-1- He

( S )-B12 ( S )-1-(1-(2-( 1H -indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2- methoxyethane-1-one

( R )-B12 (R) 1-(1-(2-( 1H -indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane -1-he

B13 1-(2-(1 H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

( S )-B13 ( S )-1-(2-( 1H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

( R )-B13 (R)-1-(2-(1 H -indol-3-yl)ethyl)-6,7-dimethoxy-2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

B14 (1-(2-( 1H -indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(morpholino)ketone

( S )-B14 ( S )-(1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(morpholino)ketone

( R )-B14 ( R )-(1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(morpholino)ketone

B15 methyl 1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

( S )-B15 ( S )-methyl-1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

( R )-B15 (R)-methyl-1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

B16 2-(1-(2-( 1H -indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)acetamide

( S )-B16 ( S )-2-(1-(2-( 1H -indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)acetamide

( R )-B16 (R)-2-(1-(2-( 1H -indol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)acetamide

C1 1-(2-(5-bromo- 1H -indol-3-yl)ethyl)-7-(cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C1 (S)-1-(2-(5-bromo- 1H -indol-3-yl)ethyl)-7-(cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C1 (R)-1-(2-(5-bromo- 1H -indol-3-yl)ethyl)-7-(cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C2 7-(cyclopentyloxy)-6-methoxy-1-(2-(5-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C2 ( S )-7-(cyclopentyloxy)-6-methoxy-1-(2-(5-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C2 ( R )-7-(cyclopentyloxy)-6-methoxy-1-(2-(5-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C3 7-(cyclopentyloxy)-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C3 ( S )-7-(cyclopentyloxy)-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C3 ( R )-7-(cyclopentyloxy)-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C4 7-(cyclopropylmethoxy)-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C4 ( S )-7-(cyclopropylmethoxy)-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C4 ( R )-7-(cyclopropylmethoxy)-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C5 6,7-dimethoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2(1H )-formaldehyde

( S )-C5 ( S )-6,7-dimethoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C5 (R)-6,7-dimethoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H)-formaldehyde

C6 1-(2-(6-fluoro- 1H -indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C6 ( S )-1-(2-(6-fluoro- 1H -indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C6 ( R )-1-(2-(6-fluoro- 1H -indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C7 7-ethoxy-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C7 ( S )-7-ethoxy-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C7 (R)-7-ethoxy-6-methoxy-1-(2-(6-methyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C8 7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C8 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C8 ( R )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C9 1-((1 H -indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1 H )-formaldehyde

( S )-C9 ( S )-1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C9 ( R )-1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C10 1-((1 H -indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1 H )-formaldehyde

( S )-C10 ( S )-1-(( 1H- indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C10 ( R )-1-(( 1H- indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C11 1-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethan-1-one

( S )-C11 ( S )-1-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane-1- He

( R )-C11 ( R )-1-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane-1- He

C12 1-((1 H -indol-3-yl)methyl)-6,7-dimethoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

( S )-C12 ( S )-1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

( R )-C12 ( R )-1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

C13 1-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-(methanesulfonyl)ethan-1-one

( S )-C13 ( S )-1-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-(methanesulfonyl)ethane -1-he

( R )-C13 ( R )-1-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-(methanesulfonyl)ethane -1-he

C14 1-((1 H -indol-3-yl)methyl)-7-ethoxy-6-methoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

( S )-C14 ( S )-1-(( 1H- indol-3-yl)methyl)-7-ethoxy-6-methoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

( R )-C14 ( R )-1-(( 1H- indol-3-yl)methyl)-7-ethoxy-6-methoxy-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline

C15 1-(1-((1 H -indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl) - 2-(methanesulfonyl)ethane-1- He

( S )-C15 ( S )-1-(1-(( 1H -indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-(methanesulfonyl )ethane-1-one

( R )-C15 ( R )-1-(1-(( 1H- indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-(methanesulfonyl )ethane-1-one

C16 1-(1-(( 1H- indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethan-1-one

( S )-C16 ( S )-1-(1-(( 1H -indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2( 1H )-yl)-2-methoxyethane- 1-he

( R )-C16 (R)-1-(1-((1 H -indol-3-yl)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinolin-2(1 H )-yl)-2-methoxyethane- 1-he

C17 7-ethoxy-6-methoxy-1-((5-methyl- 1H -indol-3-yl)methyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C17 ( S )-7-ethoxy-6-methoxy-1-((5-methyl- 1H -indol-3-yl)methyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C17 ( R )-7-ethoxy-6-methoxy-1-((5-methyl- 1H -indol-3-yl)methyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C18 7-ethoxy-6-methoxy-1-((5-methoxy- 1H -indol-3-yl)methyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C18 ( S )-7-ethoxy-6-methoxy-1-((5-methoxy- 1H -indol-3-yl)methyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C18 ( R )-7-ethoxy-6-methoxy-1-((5-methoxy- 1H -indol-3-yl)methyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C19 N- (3-(2-(7-ethoxy-2-formyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1 H- indol-5-yl)acetamide

( S )-C19 ( S ) -N- (3-(2-(7-ethoxy-2-formyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl) -1H- indol-5-yl )acetamide

( R )-C19 ( R ) -N- (3-(2-(7-ethoxy-2-formyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl) -1H- indol-5-yl )acetamide

C21 7-ethoxy-6-methoxy-1-(4-(5-methoxy-1H-indol-3-yl)cyclohexyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C21 (1 S )-7-ethoxy-6-methoxy-1-(4-(5-methoxy-1H-indol-3-yl)cyclohexyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C21 (1 R )-7-ethoxy-6-methoxy-1-(4-(5-methoxy-1H-indol-3-yl)cyclohexyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C22 1-(2-(1H-indazol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C22 ( S )-1-(2-(1H-indazol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C22 ( R )-1-(2-(1H-indazol-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C23 1-(2-(benzofuran-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C23 ( S )-1-(2-(benzofuran-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C23 ( R )-1-(2-(benzofuran-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C24 1-(2-(benzo[b]thiophen-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C24 ( S )-1-(2-(benzo[b]thiophen-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C24 ( R )-1-(2-(benzo[b]thiophen-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C25 1-(2-(1H-indol-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C25 ( S )-1-(2-(1H-indol-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C25 ( R )-1-(2-(1H-indol-2-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C26 1-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C26 ( S )-1-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C26 ( R )-1-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C29 7-ethoxy-6-methoxy-1-(2-(pyridin-3-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C29 ( S )-7-ethoxy-6-methoxy-1-(2-(pyridin-3-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C29 (R)-7-ethoxy-6-methoxy-1-(2-(pyridin-3-yl)ethyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C30 7-ethoxy-6-methoxy-1-(((5-methoxy-1H-indol-3-yl)oxo)methyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C30 ( R )-7-ethoxy-6-methoxy-1-(((5-methoxy-1H-indol-3-yl)oxo)methyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C30 (S)-7-ethoxy-6-methoxy-1-(((5-methoxy-1H-indol-3-yl)oxo)methyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C31 7-ethoxy-6-methoxy-1-(((5-methoxy-1H-indol-3-yl)thio)methyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C31 ( R )-7-ethoxy-6-methoxy-1-(((5-methoxy-1H-indol-3-yl)thio)methyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( R )-C31 (S)-7-ethoxy-6-methoxy-1-(((5-methoxy-1H-indol-3-yl)thio)methyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C32 7-ethoxy-6-methoxy-1-((4-(5-methoxy-1H-indol-3-yl)piperazin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C32 ( R )-7-ethoxy-6-methoxy-1-((4-(5-methoxy-1H-indol-3-yl)piperazin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H) -formaldehyde

( R )-C32 ( S )-7-ethoxy-6-methoxy-1-((4-(5-methoxy-1H-indol-3-yl)piperazin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H) -formaldehyde

C33 7-ethoxy-1-(2-(5-hydroxy- 1H -indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C33 ( S )-7-ethoxy-1-(2-(5-hydroxy- 1H -indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C33 ( R )-7-ethoxy-1-(2-(5-hydroxy- 1H -indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C35 1-((( 1H- indol-3-yl)amino)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C35 ( S )-1-((( 1H -indol-3-yl)amino)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C35 ( R )-1-(((1 H -indol-3-yl)amino)methyl)-7-ethoxy-6-methoxy-3,4-dihydroisoquinoline-2(1 H )-formaldehyde

C37 1-(2-( 1H- indol-3-yl)propyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C37 ( S )-1-(2-( 1H- indol-3-yl)propyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( R )-C37 ( R )-1-(2-( 1H- indol-3-yl)propyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C38 1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-ethyl-1-one

( S )-C38 ( S )-1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-ethyl-1-one

C39 (1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(pyridin-4-yl)-methanone

C40 (1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl)(morpholine)-methanone

( S )-C40 ( S )-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H) -yl(morpholine)-methanone

C41 (1-((1 H -indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H )-yl)(tetrahydro-2 H -pyran-4-yl)- methanone

( S )-C41 ( S )-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(tetrahydro-2H - pyran-4- yl)-methanone

C42 (1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2( 1H )-yl(thiazol-2-yl)-methanone

( S )-C42 ( S )-(1-(( 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(thiazol-2-yl)-methanone

C43 methyl-2-(1-((1 H -indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H )-yl)acetate

C44 1-((6-chloro- 1H- indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C44 ( S )-1-((6-chloro- 1H -indol-3-yl)methyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

C45 6,7-dimethoxy-1-((1-methyl-1 H -indol-3-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-formaldehyde

C46 1-(( 1H- indol-3-yl)methyl)-7-benzyloxy-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C47 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-benzylsulfonyl-1,2,3,4-tetrahydroisoquinoline

( S )-C48 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-cyclopropylsulfonyl-1,2,3,4-tetrahydroisoquinoline

( S )-C49 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-cyclohexylsulfonyl-1,2,3,4-tetrahydroisoquinoline

( S )-C50 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(3-fluorophenyl)sulfonyl-1,2,3,4 -tetrahydroisoquinoline

( S )-C51 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(3,4-difluorophenyl)sulfonyl-1,2,3 ,4-tetrahydroisoquinoline

( S )-C52 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(2,4-difluorophenyl)sulfonyl-1,2,3 ,4-tetrahydroisoquinoline

( S )-C53 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-ethylsulfonyl-1,2,3,4-tetrahydroisoquinoline

( S )-C54 ( S )-7-ethoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-trifluoroethane-1- He

( S )-C55 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(pyridin-3-yl)sulfonyl-1,2,3 ,4-tetrahydroisoquinoline

( S )-C56 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(3-fluoro-4-bromophenyl)sulfonyl-1,2 ,3,4-tetrahydroisoquinoline

( S )-C57 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(2-fluorophenyl)sulfonyl-1,2,3,4 -tetrahydroisoquinoline

( S )-C58 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(4-fluorophenyl)sulfonyl-1,2,3,4 -tetrahydroisoquinoline

( S )-C59 ( S )-7-ethoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-2,2- difluoroethane-1-one

( S )-C60 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(4-methoxyphenyl)sulfonyl-1,2,3,4 -tetrahydroisoquinoline

( S )-C61 ( S )-1-(2-(benzo[b]thiothiophen-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C62 ( S )-7-ethoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-ethoxyethane-1- He

( S )-C63 ( S )-7-trifluoromethoxy-1-(2-(5-methoxy- 1H- indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C64 ( S )-7-difluoromethoxy-1-(2-(5-methoxy- 1H- indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C65 ( S )-7-ethoxy-6-methoxy-1-(2-(5-cyano- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C66 methyl-( S )-2-formyl-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

( S )-C67 methyl-( S )-2-formyl-7-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate

( S )-C68 ( S )-2-formyl-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid

( S )-C69 ( S )-2-formyl-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline-7- carboxamide

( S )-C70 ( S )-2-formyl-6-methoxy-1-(2-(5-methoxy- 1H- indol-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide

( S )-C71 ( S )-7-difluoromethyl-1-(2-(5-methoxy- 1H- indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-formaldehyde

( S )-C72 ( S )-2-difluoromethyl-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline

( S )-C73 ( S )-7-ethoxy-6-methoxy-1-(2-(5-trifluoromethyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C74 ( S )-7-ethoxy-6-methoxy-1-(2-(5-difluoromethyl- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C75 methyl-( S )-3-(2-(7-ethoxy-2-formyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1 H -indole-5-carboxylate

( S )-C76 ( S )-7-ethoxy-6-methoxy-1-(2-(5-trifluoromethoxy- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C77 ( S )-7-ethoxy-6-methoxy-1-(2-(5-difluoromethoxy- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C78 ( S )-7-ethoxy-6-methoxy-1-(2-(5-fluoro- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C79 ( S )-6-ethoxy-7-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )-formaldehyde

( S )-C80 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy-6-chloro- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )- formaldehyde

( S )-C81 ( S )-7-ethoxy-6-methoxy-1-(2-(5-fluoro-6-chloro- 1H -indol-3-yl)ethyl)-3,4-dihydroisoquinoline-2( 1H )- formaldehyde

( S )-C82 ( S )-7-ethoxy-1-(2-(5-fluoro- 1H -indol-3-yl)ethyl)-6-methoxy-3,4-dihydroisoquinoline-2( 1H )-ethoxyethane-1- He

( S )-C83 ( S )-7-ethoxy-6-methoxy-1-(2-(5-methoxy- 1H -indol-3-yl)ethyl)-2-(2-(methylsulfonyl)ethyl)-1,2,3 ,4-tetrahydroisoquinoline

8. A method for producing a compound represented by the general formula (I) according to claim 1, comprising the following steps: (1) in an inert solvent in the presence of a condensing agent, a compound of formula II and a compound of formula Ic are reacted to obtain a compound of formula Id; preferably EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride) is used as the condensing agent;

; (2) a compound of formula Id undergoes a Bischler-Napieralski ring closure reaction in an inert solvent to give a compound of formula Ie; preferably, phosphorus oxychloride is used as the Lewis acid in the ring closing reaction;

; (3) in an inert solvent, the compound of formula Ie enters into a reduction reaction to obtain a compound of formula If; preferably, boron hydride is used as the reducing agent, and Noyori catalyst is used as the asymmetric reduction catalyst in the reduction reaction;

; (4) in an inert solvent, the compound of formula If undergoes a condensation or N-alkylation reaction, or a Buchwald-Hartwig reaction to give a compound of formula (I),

, in which the groups are defined in any of paragraphs. 1-7 claims. 9. A pharmaceutical composition which comprises 1-2000 mg of a compound of general formula (I) according to claim 1 or 7 or a pharmaceutically acceptable salt for the prevention, treatment or adjuvant treatment of immune or inflammatory diseases due to PDE4 activity or expression. 10. Pharmaceutical composition according to claim 9, characterized in that the disease is an immune or inflammatory disease caused by PDE4 activity or expression. 11. Pharmaceutical composition according to claim 9, characterized in that the disease caused by PDE4 activity or expression is selected from the group consisting of psoriasis, psoriatic arthritis, allergic dermatitis, chronic obstructive pulmonary disease, asthma, allergic rhinitis, ankylosing spondylitis, systemic red lupus, rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), depression and schizophrenia.

Images