RU2793918C2 - Cell necrosis inhibitor, method for its production and application - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, where X is O or S; the ring M has the structure

where ring A is selected from the group consisting of a 5–6 membered heteroaryl containing 1–3 heteroatoms independently selected from nitrogen and oxygen, and a 5-membered heterocyclyl containing 2 nitrogen heteroatoms; ring B is selected from the group consisting of a substituted or unsubstituted 6-membered aryl and a substituted or unsubstituted 5–6 membered heteroaryl containing 1–4 heteroatoms independently selected from nitrogen and oxygen; where "substituted" refers to the substitution of 1 hydrogen atom in the group Deputy selected from C₁-C ₆ alkyl; C is selected from the group consisting of substituted or unsubstituted 6-membered aryl, substituted or unsubstituted 6-membered heteroaryl containing 1 nitrogen heteroatom; where "substituted" refers to the substitution of 1–3 hydrogen atoms in the group Deputy selected from the group consisting of halogen and C₁-C₆ alkyl; L is selected from the group consisting of O, NH, C₁-C ₆ alkylene; R₁ is selected from the group consisting of H and C₁-C₆ alkyl; R₂ is selected from the group consisting of halogen, hydroxyl, oxo, benzyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ acyl; and m is 0 or 1; n is 1. The invention also relates to a method for preparing a compound of formula (I), a pharmaceutical composition based on a compound of formula (I), the use of a compound of formula (I), a method for inhibiting RIP1 kinase in a subject, and an intermediate compound of formula (II).

EFFECT: treatment or prevention of diseases mediated by RIP1 kinase provided by the compound of formula (I).

24 cl, 3 dwg, 1 tbl, 29 ex

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Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001] The present application relates to a compound that inhibits cell necrosis and/or receptor-interacting protein kinase 1 (RIP1), as well as to a method for its preparation and use. The compound according to the present application and the composition comprising it can be used in methods for the prevention and/or treatment of diseases, including cell necrosis and/or inflammation.

BACKGROUND OF THE INVENTION

[0002] Programmed necrotic cell death, also known as programmed necrosis, is a novel cell death pathway discovered in recent years. Programmed necrosis is a highly inflammatory form of cell death and is considered an important pathological factor in many degenerative and inflammatory diseases, which include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, degenerative retinal diseases, inflammatory bowel disease, kidney disease, liver disease. and many other related diseases.

[0003] Activation of nuclear factor kappa B (NF-kB) induced by tumor necrosis factor alpha (TNF-α) plays an important role in the immune system and inflammatory response. RIP1 is a multifunctional signal transducer involved in mediating NF-kB activation, apoptosis and cell necrosis, and is a transition point that determines cell death, thus playing an important role in processes such as cell survival and apoptosis or programmed necrosis, etc. P. The involvement of RIP1 kinase activity is extremely important in mediating programmed cell necrosis, a caspase-independent pathway of necrotic cell death.

[0004] Studies show that Necrostatin-1 (Nec-1), a RIP1 kinase inhibitor known in the art, exhibits effective therapeutic effects in various inflammatory diseases. More recently, several RIP1 kinase inhibitors with different structures have been discovered in the art. However, existing RIP1 kinase inhibitors have disadvantages in various aspects such as poor activity, poor pharmacokinetic properties or low oral bioavailability, etc., some of which cannot cross the blood-brain barrier to enter the central nervous system. All these shortcomings hinder their further research and clinical application.

[0005] Thus, there remains a need in the art to provide clinically relevant, highly potent and selective small molecule inhibitors of RIP1 kinase that block RIP1-dependent programmed cell death, as well as the prevention and treatment of diseases or disorders mediated by RIP1 kinase, or diseases or disorders. caused by programmed cell necrosis.

SUMMARY OF THE INVENTION

[0006] The present application provides a novel RIP1 kinase inhibitor that can be used to prevent and treat diseases or disorders mediated by RIP1 kinase, or diseases or disorders caused by programmed cell death.

[0007] In one aspect of the present application, a compound of Formula (I) is provided:

or a pharmaceutically acceptable salt thereof, wherein: X is O, S or CH ₂ ;

где кольцо А выбрано из группы, состоящей из замещенного или незамещенного 5-6-членного гетероарила и замещенного или незамещенного 5-6-членного гетероциклила;ring M has the structure

where ring A is selected from the group consisting of substituted or unsubstituted 5-6 membered heteroaryl and substituted or unsubstituted 5-6 membered heterocyclyl;

ring B is selected from the group consisting of substituted or unsubstituted 5-12 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, and substituted or unsubstituted 5-12 membered heterocyclyl;

C is selected from the group consisting of substituted or unsubstituted (C ₃ -C ₁₂ ) cycloalkyl, substituted or unsubstituted 5-12 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, and substituted or unsubstituted 5-12 membered heterocyclyl;

L is selected from the group consisting of O, S, NH, N(CH ₃ ), substituted or unsubstituted C ₁ -C ₆ alkylene-O-, substituted or unsubstituted C ₁ -C ₆ alkylene-NH-, (substituted or unsubstituted C ₁ -C ₆ alkylene) ₂ -N-, substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted C ₃ -C ₆ alkenylene, substituted or unsubstituted, or C ₃ -C ₆ alkenylene-O-;

R ₁ is selected from the group consisting of H and substituted or unsubstituted C ₁ -C ₆ alkyl;

R ₂ is selected from the group consisting of H, halogen, hydroxyl, ekeioxo, benzyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and C ₁ -C ₆ acyl;

m is 0, 1, 2, or 3;

n is 1, 2 or 3;

where "substituted" refers to the replacement of one or more hydrogen atoms in the group with a substituent selected from the group consisting of halogen, cyano, alkyl, acyl, sulfonyl, hydroxyl, amino, benzyl, ekeioxo, (C ₁ -C ₄ ) alkyl, halogen (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen (C ₁ -C ₄ ) alkoxy, nitro and (C ₁ -C ₄ ) alkylC(O)-.

[0008] In another aspect of the present application, a method for preparing a compound of Formula (I) is provided:

where R ₄ represents-COOH or-COO-G ⁺ , where G ⁺ is an alkali metal ion;

when R is H, the method includes: reacting a compound of Formula (II) with a compound of Formula (III) in an inert solvent in the presence of a condensing agent and a base to obtain a compound of Formula (I); And

when R is an amino protecting group, the method comprises: removing R from a compound of Formula (II) under acidic conditions and then reacting the compound of Formula (II) from which R has been removed with a compound of Formula (III) in an inert solvent in the presence of a condensing agent, and base to give a compound of Formula (I).

[0009] In yet another aspect of the present application, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] In another aspect, the present application provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, in the manufacture of medicaments for the treatment or prevention of diseases or disorders mediated by RIP1 kinase, or diseases or disorders caused by programmable cell necrosis.

[0011] In another aspect of the present application, there is provided a method for inhibiting RIP1 kinase in a subject, comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0012] In yet another aspect of the present application, a combination of drugs is provided, including: (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) at least one additional active ingredient.

[0013] In another aspect of the present application, an intermediate compound of Formula (II) is provided:

Where:

R represents H or an amino protecting group; X represents O, S or CH ₂ ;

R ₁ is selected from the group consisting of H and substituted or unsubstituted C ₁ -C ₆ alkyl;

R ₂ is selected from the group consisting of H, halogen, hydroxyl, oxyoxo, benzyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and C ₁ -C ₆ acyl;

m is 0, 1, 2, or 3; And

n is 1, 2 or 3;

where "substituted" refers to the replacement of one or more hydrogen atoms in a group with a substituent selected from the group consisting of halogen, cyano, alkyl, acyl, sulfonyl, hydroxyl, amino, benzyl, oxo, (C ₁ -C ₄ ) alkyl, halogen (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen (C ₁ -C ₄ ) alkoxy, nitro and (C ₁ -C ₄ ) alkylC(O)-.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In FIG. 1 shows mouse body temperature versus time after administration of different doses (10 mg/kg, 20 mg/kg and 30 mg/kg) of RIP1-034 in a TNF-α-induced lethal shock mouse model.

[0015] In FIG. 2 shows the plasma concentration in each mouse as a function of time after a single oral administration (10 mg/kg) of Compound RIP1-034 according to the present application.

[0016] In FIG. 3 shows the mean plasma concentration in mice as a function of time after a single oral administration (10 mg/kg) of the RIP1-034 compound of the present application.

DETAILED DESCRIPTION

[0017] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and claims. Although the invention will be described in conjunction with the numbered embodiments, it should be understood that the invention is not to be limited to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. A person skilled in the art will be able to determine a variety of methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the described methods and materials. In the event that one or more of the included literature and similar materials differ from or contradict this application, including, without limitation, certain terms, use of terms, described techniques, and the like, this application shall prevail.

[0018] It should be understood that some features of the present invention, which are described in the context of separate embodiments for clarity, may also be presented in combination in one embodiment. On the other hand, various features of the present invention, which for brevity are described in the context of one embodiment, may also be presented separately or in any suitable subcombination.

[0019] Definitions

[0020] As used herein, unless otherwise indicated, the following definitions are used. Within the scope of this application, the chemical elements are identified in accordance with the Periodic Table of Chemical Elements, CAS version, Handbook of Chemistry and Physics, 75th ed. In addition, the general principles of organic chemistry and certain functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito, 1999 and "March's Advanced Organic Chemistry", 5th Edition, Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entirety.

[0021] Linking substituents are described herein. If a structure explicitly requires the presence of a linking group, the Markush variables listed for that group are considered linking groups. For example, if the structure requires the presence of a linking group, and the definition of the Markush group for this variable includes "alkyl", then "alkyl" is understood to represent a linking alkylene group.

[0022] As used herein, the term "substituted", whether or not preceded by the term "optional", means that one or more hydrogen atoms in the chemical group have been removed and replaced with suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from certain groups, the substituents may be the same or different in every position. The combinations of substituents contemplated in this application are preferably such combinations that lead to the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that remains substantially unchanged when it is subjected to conditions that allow it to be prepared, detected and, in some embodiments, isolated and purified, and when it is used for one or more of the purposes described in this document. Unless a chemical group is specifically listed as "unsubstituted", the chemical group described herein should be understood to include a substituent. For example, when referring to "aryl", it includes substituted aryl and unsubstituted aryl.

[0023] If a bond to a substituent is shown to cross a bond linking two atoms in the ring, then that substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atom through which such substituent is bonded to the remainder of a compound of a given formula, such substituent may be bonded through any atom in that formula. Combinations of substituents and/or variables are allowed, but only if such combinations result in stable compounds.

[0024] In the event that any variable (such as R ⁱ ) appears more than once in any constituent or compound formula, its definition at each occurrence is independent of each other. Thus, for example, if a group is shown to be substituted by 0-2 R ⁱ groups, then the group may optionally be substituted by no more than two R ⁱ groups, each R ⁱ at each occurrence being independently selected from the definition of R ⁱ .

[0025] The term "C _ij " as used herein indicates a carbon number range, where i and j are integers, where j is greater than i, and the carbon number range includes boundary values (i.e., i and j ) and every integer between the boundary values. For example, C _1-6 means the range of 1-6 carbons, including 1 carbon, 2 carbons, 3 carbons, 4 carbons, 5 carbons, and 6 carbons. In some embodiments, the term "C _1-12 " means 1 to 12, in particular 1-10, in particular 1-8, in particular 1-6, in particular 1-5, in particular 1-4, in particular 1 -3, or in particular 1-2 carbon atoms.

[0026] As used herein, the term "hydrocarbon" refers to a group attached via a carbon atom having a ═O or ═S substituent, which typically contains at least one carbon-hydrogen bond and a basic carbon skeleton, and may optionally contain heteroatom(s). Thus, a hydrocarbon group may include, but is not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and the like.

[0027] As used herein, the term "alkyl", either as part of another term or used independently, refers to a saturated straight or branched hydrocarbon group. The term "C _ij alkyl" refers to alkyl containing ij carbon atoms. In some embodiments, the implementation of the alkyl group contains 1-12 carbon atoms. In some embodiments, the alkyl group contains 1-11 carbons, 1-10 carbons, 1-9 carbons, 1-8 carbons, 1-7 carbons, 1-6 carbons, 1-5 carbons, 1 -4 carbons, 1-3 carbons, or 1-2 carbons. Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2- butyl (neobutyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl , 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2 -pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc. Examples of "C ₁ -12 alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, nondecyl, and dodecyl. Examples of "C _1-6 alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neobutyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2- methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2- butyl, etc.

[0028] The term "halogen" as used herein refers to F, Cl, Br, or I.

[0029] The term "cyano" as used herein refers to -CN.

[0030] The term "hydroxyl" as used herein refers to -OH.

[0031] The term "amino" as used herein refers to -NH ₂ .

[0032] The term "nitro" as used herein refers to -NO ₂ .

[0033] The term "oxy", as used herein, refers to an oxygen atom double bonded to another atom (such as carbon or sulfur). For example, if it is directly bonded to a carbon atom, a carbonyl group (C=O) is formed.

[0034] The term "acyl" as used herein refers to a functional group containing a carbonyl group, such as -C(=O)R', where R' is hydrogen or a hydrocarbon group. In some embodiments, the acyl is a group represented by the formula alkylC(O)-.

[0035] The term "sulfonyl" as used herein refers to the group -S(O) ₂ -R', where R' is a hydrocarbon group.

[0036] The term "haloalkyl" as used herein refers to an alkyl group that is substituted by one or more halogen atoms, where one or more halogen atoms independently replace one or more hydrogen atoms on one or more carbon atoms of the alkyl group. For example, the term "C _1-6 haloalkyl" includes C _1-6 alkyl containing 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 halogen atoms, and examples include, without limitation listed, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 2,2-difluoropropyl, 2,2,2-trifluoropropyl, 4,4,4-trifluorobutyl, 5, 5,5-trifluoropentyl and 6,6,6-trifluorohexyl, etc.

[0037] The term "alkenyl" as used herein, whether used as part of another term or used independently, refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond, which may optionally be independently substituted one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or "E" and "Z" orientations. In some embodiments, the implementation of the alkenyl group contains 2-12 carbon atoms. In some embodiments, the implementation of the alkenyl group contains 2-11 carbon atoms. In some embodiments, the alkenyl group contains 2-10 carbons, 2-9 carbons, 2-8 carbons, 2-7 carbons, 2-6 carbons, 2-5 carbons, 2-4 carbons, or 2 -3 carbon atoms. In some embodiments, the implementation of the alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

[0038] The term "alkynyl" as used herein, whether used as part of another term or used independently, refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond, which may optionally be independently substituted one or more substituents described herein. In some embodiments, the implementation of the alkynyl group contains 2-12 carbon atoms. In some embodiments, the implementation of the alkynyl group contains 2-11 carbon atoms. In some embodiments, the alkynyl group contains 2-10 carbons, 2-9 carbons, 2-8 carbons, 2-7 carbons, 2-6 carbons, 2-5 carbons, 2-4 carbons, or 2 -3 carbon atoms. In some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0039] The term "alkylene" as used herein refers to a divalent alkyl group, the term "alkenylene" as used herein refers to a divalent alkenyl group, and the term "alkynylene" as used herein refers to a divalent alkynyl group.

[0040] As used herein, the term "alkoxy", whether used as part of another term or used independently, refers to an alkyl group, as defined above, attached to the primary molecule through an oxygen atom. The term "C _ij alkoxy" refers to an alkyl group of an alkoxy group containing ij carbon atoms. In some embodiments, the implementation of the alkoxy group contains 1-12 carbon atoms. In some embodiments, the implementation of the alkoxy group contains 1-11 carbon atoms. In some embodiments, the alkoxy group contains 1-10 carbon atoms, 1-9 carbon atoms, 1-8 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, 1- 3 carbons or 1-2 carbons. Examples of "C _1-12 alkoxy groups" include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy, neopentyloxy, and n-hexyloxy, and the like.

[0041] The term "haloalkoxy" as used herein refers to an alkoxy group substituted with one or more halogen atoms, where one or more halogen atoms independently replace one or more hydrogen atoms on one or more carbon atoms of the alkoxy group. For example, the term "C _1-6 haloalkoxy" includes C _1-6 alkoxy groups containing 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 halogen atoms.

[0042] As used herein, the term "aryl", whether used as part of another term or used independently, refers to a monocyclic or polycyclic ring system containing a total of 5-20 ring members, where at least one ring in ring system is aromatic, with each ring in the ring system containing 3-12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may carry one or more substituents. Also included within the scope of the term "aryl" as used herein is a group in which an aromatic ring is fused to one or more additional rings. In the case of a polycyclic ring system, only one of the rings must be aromatic (eg 2,3-dihydroindole), although all rings may be aromatic (eg quinoline). The second ring may be fused or bridged. Examples of polycyclic aryl groups include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, tetrahydronaphthyl, and the like. The aryl group may optionally be substituted at one or more ring positions with one or more substituents as described herein.

[0043] The term "benzyl" as used herein refers to -CH ₂ -phenyl.

[0044] As used herein, the terms "cycloalkyl", "carbocyclyl", and "carbocyclic ring" are used interchangeably and are used either as part of another term, or independently, to refer to saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) monocyclic and polycyclic ring systems where all ring atoms are carbon and which contain at least 3 ring-forming carbon atoms. In some embodiments, the cycloalkyl group may contain 3-12 ring carbons, 3-11 ring carbons, 3-10 ring carbons, 3-9 ring carbons, 3-8 ring carbons, 3-7 ring carbons, 3-6 ring carbons, 3-5 ring carbons, 4-12 ring carbons, 4-11 ring carbons, 4-10 ring-forming carbons, 4-9 ring-forming carbons, 4-8 ring-forming carbons, 4 -7 ring-forming carbon atoms, 4-6 ring-forming carbon atoms, or 4-5 ring-forming carbon atoms. The cycloalkyl group may optionally be substituted at one or more ring positions with one or more substituents as described herein. Cycloalkyl may be saturated, partially unsaturated or fully unsaturated. In some embodiments, the cycloalkyl may be a saturated cyclic alkyl group. In some embodiments, cycloalkyl may be an unsaturated cyclic alkyl group containing at least one double bond or triple bond in the ring system.

[0045] In some embodiments, cycloalkyl may be a saturated or unsaturated monocyclic carbocyclic ring system, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopentyl -3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0046] In some embodiments, the cycloalkyl may be a saturated or unsaturated polycyclic (eg, bicyclic and tricyclic) carbocyclic ring system, which may be a fused, spiro, or bridged ring system. As used herein, the term "fused ring" refers to a ring system in which two rings share two adjacent atoms in common, the term "spiro ring" refers to a ring system in which two rings are connected through one common atom, and the term "bridged ring" " refers to a ring system in which two rings share three or more atoms. Examples of fused carbocyclic groups include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl, and the like. Examples of spirocarbocyclyl include, but are not limited to, spiro[5.5]undecyl, spiro-pentadienyl, spiro[3.6]-decyl, and the like. Examples of bridged carbocyclyl include, but are not limited to, bicyclo[1.1.1]pentenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]-octanyl, bicyclo[3.3 .1]nonanil, bicyclo[3.3.3]undecanyl, etc.

[0047] The term "heteroatom" as used herein refers to nitrogen, oxygen, sulfur or phosphorus and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen.

[0048] The term "heteroaryl" as used herein, whether used as part of another term or used independently, refers to an aryl group containing one or more heteroatoms in addition to carbon atoms, which may optionally be independently substituted with one or more substituents described herein. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl and pteridinyl, etc. A heteroaryl group also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocyclyl rings. Неограничивающие примеры включают индолил, изоиндолил, бензотиенил, бензофуранил, дибензофуранил, индазолил, бензимидазолил, бензотиазолил, хинолинил, изохинолинил, циннолинил, фталазинил, хиназолинил, хиноксалинил, 4Н-хиназинил, карбазолил, акридинил, феназинил, фенотиазинил, феноксазинил, тетрагидрохинолинил, тетрагидроизохинолинил, пиридо [2,3-b](4H)-1,4-oxazin-3-one. In some embodiments, the term "5-10 membered heteroaryl" refers to a 5-6 membered heteroaryl ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus, or an 8-10 membered bicyclic heteroaryl group, containing 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur or phosphorus.

[0049] The term "heterocycle" or "heterocyclyl" as used herein refers to a saturated, partially unsaturated, or fully unsaturated carbocyclic group in which one or more ring atoms are heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus, and the remaining ring atoms are carbon, where one or more ring atoms may optionally be independently substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is an unsaturated heterocyclyl containing one or more double bonds in the ring system. In some embodiments, heterocyclyl may include carbon, nitrogen, sulfur, or phosphorus in any oxidized form and basic nitrogen in any quaternized form. "Heterocyclyl" also includes radicals wherein the heterocyclyl radicals are fused to a saturated, partially unsaturated or fully unsaturated (ie aromatic) carbocyclic or heterocyclic ring. The heterocyclyl can be attached via carbon or nitrogen. In some embodiments, the heterocyclyl is attached via carbon. In some embodiments, the heterocyclyl is attached via nitrogen. For example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen-bound) or pyrrol-3-yl (carbon-bound). In addition, the group derived from imidazole may be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

[0050] In some embodiments, the term "3-12 membered heterocyclyl" refers to a 3-12 membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system containing 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus. Fused, spiro and bridged ring systems are also included in the above definition. Examples of monocyclic heterocyclic groups include, but are not limited to, oxetanyl, 1,1-dioxythiethanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidinonyl, pyrazinonyl, pyridazinonyl, pyrrolidinyl and triazinonyl, etc. Examples of fused heterocyclic groups include, but are not limited to, a phenyl fused ring or a pyridyl fused ring such as quinolyl, isoquinolyl, quinoxalinyl, quinazinyl, quinazolinyl, azaindolizinyl, pteridinyl, benzopyranyl, isobenzopyranyl, indolyl, isoindolyl, indazinyl, indazolyl, purinyl, benzofuryl, isobenzofuryl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl and [1,2, 3]triazolo[4,3-a]pyridyl, etc. Examples of the spiroheterocyclic group include, but are not limited to, spiropyranil and spirooxazinil, etc. Examples of bridged heterocyclic groups include, but are not limited to, morpholinyl, hexamethylenetetramine, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, and 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

[0051] Suitable monovalent substituents on the substitutable carbon atoms of the "optionally substituted" groups are independently halogen; -(CH ₂ ) _0-4 R°; - (CH ₂ ) _0-4 OR°; -O (CH ₂ ) _0-4 Ro; -O-(CH ₂ ) _0-4 C(O)OR°; -(CH ₂ ) _0-4 CH(OR°)2; -(CH ₂ ) _0-4 SR°; -(CH ₂ ) _0-4 Ph, which may be substituted by R°; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph, which may be substituted by R°; -CH=CHPh, which may be substituted with R°;

(CH ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridyl which may be substituted with R°; -NO ₂ ; CN; -N ₃ ; -(CH ₂ ) _0-4 N(R°) ₂ ; -(CH ₂ ) _0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH ₂ ) _0-4 N(R°)C(O)NR° ₂ ; -N(R°)C(S)NR° ₂ ; -(CH ₂ ) _0-4 N(R°)C(O)OR°; N(R°)N(R°)C(O)R°; -N (R °) N (R °) C (O) NR ° ₂ ; -N(R°)N(R°)C(O)OR°; (CH ₂ ) _0-4 C(O)R°; -C(S)R°; -(CH ₂ ) _0-4 C(O)OR°; -(CH ₂ ) _0-4 C(O) SR°; -(CH ₂ ) _0-4 C(O)OSiR° ₃ ; -(CH ₂ ) _0-4 OC(O)R°; -OC(O)(CH ₂ ) _0-4 SR°-; -(CH ₂ ) _0-4 SC(O)R°; -(CH ₂ ) _0-4 C(O)NR° ₂ ; -C(S)NR° ₂ ; -C(S)SR°; -SC(S)SR°; -(CH ₂ ) _0-4 OC(O)NR° ₂ ; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH ₂ ) _0-4 SSR°; -(CH ₂ ) _0-4 S(O) ₂ R°; -(CH ₂ ) _0-4 S(O) ₂ OR°; -(CH ₂ ) _0-4 OS(O) ₂ R°; -S(O) ₂ NR° ₂ ; -(CH ₂ ) _0-4 S(O)R°; -N(R°)S(O) ₂ NR° ₂ ; -N(R°)S(O) ₂ R°; -N(OR°)R°; -C(NH)NR° ₂ ; -P(O) ₂ R°; -P(O)R° ₂ ; OP(O)R° ₂ ; -OP(O)(OR°) ₂ ; SiR° ₃ ; -(C ₁ -4 normal or branched alkylene)ON(R°) ₂ ; or -(C _1-4 straight or branched alkylene)C(O)ON(R°) ₂ where each R° may be substituted as defined below and is independently hydrogen, C _1-6 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -CH ₂ -(5-6 membered heteroaryl ring) or 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur; or, notwithstanding the above definition, two independently present R° form, together with their atom present between them, a 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen , oxygen or sulfur, and may be substituted as defined below.

[0052] A suitable monovalent substituent on R° (or on a ring formed by two independently present R° together with an atom in between) is independently a halogen,

(CH ₂ ) _0-2 R ^• , -(halogenR ^• ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^• , -(CH ₂ ) _0-2 CH(OR ^• ) ₂ , -O (halogen R ^• ), -CN, -N ₃ , -(CH ₂ ) _0-2 C (O) R ^• , - (CH ₂ ) _0-2 C (O) OH, - (CH ₂ ) _0-2 C(O)OR ^• , -(CH ₂ ) _0-2 SR ^• , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^• , -(CH ₂ ) _0-2 NR ^• ₂ , -NO ₂ , -SiR ^• ₃ , -OSiR ^• ₃ , -C(O)SR ^• , -(C _1-4 normal or branched alkylene) C( O)OR ^• or -SSR ^• where each R ^• is unsubstituted or substituted with only one or more halogens, when the prefix "halogen" is present, and is independently selected from a C _1-4 aliphatic group, -CH ₂ Ph, -O( CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or fully unsaturated ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituent on the saturated carbon atom in R° includes ═O and ═S.

[0053] Suitable divalent substituent on the saturated carbon atom of the "optionally substituted group" includes: ═O, ═S, ═NNR* ₂ , ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O) ₂ R*, =NR*, =NOR*, -O(C(R* ₂ )) _2-3 -O- or -S(C(R* ₂ )) _2-3 -S-, where R* for each occurrence is selected from hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur . A suitable divalent substituent attached to the substitutable carbon at the ortho position of the "optionally substituted group" includes -O(CR* ₂ ) _2-3 -O-, where R* at each occurrence is selected from hydrogen, a C _1-6 aliphatic group which may be substituted as defined below or an unsubstituted 5-6 membered saturated, partially unsaturated or fully unsaturated ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0054] Suitable substituents on the aliphatic group R* include halogen, -R ^• , (haloR ^• ), -OH, -OR ^• , -O(haloR) ^• , -CN, -C(O)OH, -C(O )OR ^• , -NH ₂ , -NHR ^• , -NR ₂ ^• or -NO ₂ , where each R ^• is unsubstituted or substituted by only one or more halogens, when the prefix "halogen" is present, and is independently C _{1- 4} aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated or fully unsaturated ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0055] Suitable substituents on the "optionally substituted group" nitrogen atom to be substituted include -R ^† , -NR † ₂ , -C(O)R ^† , -C(O)OR ^† , -C(O)C(O)R ^† , -С(О)CH ₂ C(О)R ^† , S(O) ₂ R ^† , S(O) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , -C(NH)NR ^† ₂ or -N(R ^† )S(O) ₂ R ^† , where each R ^† is independently hydrogen, a C _1-6 aliphatic group, which may be substituted as defined below, unsubstituted -OPh, or unsubstituted 5-6 membered a saturated, partially unsaturated or fully unsaturated ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or despite the above definition, two independently present R ^† forms, together with an atom between them, an unsubstituted 3-12-membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0056] A suitable substituent on the aliphatic group R ^† is independently halogen, -R ^• , (haloR ^• ), -OH, OR ^• , -O(haloR ^• ), -CN, -C(O)OH, -C( O)OR ^• , -NH ₂ , -NHR ^• , -NR ₂ ^• or -NO ₂ , where each R ^• is unsubstituted or substituted by only one or more halogens when the prefix "halogen" is present, and is independently C _{1 -4} aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0057] The term "protected group" as used herein refers to a group of atoms that blocks, reduces, or interferes with the reactivity of a functional group when attached to a reactive functional group in a molecule. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects an amino functional group in a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, triphenylmethyl, allyloxycarbonyl, trimethylsilyl (TMS), t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc), etc. Similarly, "hydroxyl protecting group" refers to a substituent on a hydroxyl group that blocks or protects a hydroxyl functional group. Suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" refers to a substituent on a carboxyl group that blocks or protects a carboxyl functional group. Common carboxyl protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)ethyl, and nitroethyl etc. For a general description of protecting groups and their uses, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006.

[0058] Connections

[0059] In one aspect of the present application, a compound of Formula (I) is provided:

or a pharmaceutically acceptable salt thereof, wherein: X is O, S or CH ₂ ;

где кольцо А выбрано из группы, состоящей из замещенного или незамещенного 5-6-членного гетероарила и замещенного или незамещенного 5-6-членного гетероциклила;ring M has the structure

where ring A is selected from the group consisting of substituted or unsubstituted 5-6 membered heteroaryl and substituted or unsubstituted 5-6 membered heterocyclyl;

ring B is selected from the group consisting of substituted or unsubstituted 5-12 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, and substituted or unsubstituted 5-12 membered heterocyclyl;

C is selected from the group consisting of substituted or unsubstituted (C ₃ -C ₁₂ ) cycloalkyl, substituted or unsubstituted 5-12 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, and substituted or unsubstituted 5-12 membered heterocyclyl;

L is selected from the group consisting of O, S, NH, N(CH ₃ ), substituted or unsubstituted - C ₁ -C ₆ alkylene-O-, substituted or unsubstituted C ₁ -C ₆ alkylene-NH-, (substituted or unsubstituted C ₁ -C ₆ alkylene) ₂ -N-, substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted C ₃ -C ₆ alkenylene, substituted or unsubstituted C ₃ -C ₆ alkenylene-O-;

R ₁ is selected from the group consisting of H and substituted or unsubstituted C ₁ -C ₆ alkyl;

R ₂ is selected from the group consisting of H, halogen, hydroxyl, cyano, oxo, benzyl, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and C ₁ -C ₆ acyl; And

n is 1, 2 or 3;

where "substituted" refers to the replacement of one or more hydrogen atoms in the group with a substituent selected from the group consisting of halogen, cyano, alkyl, acyl, sulfonyl, hydroxyl, amino, benzyl, wkeioxo, (C ₁ -C ₄ ) alkyl, halogen (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen (C ₁ -C ₄ ) alkoxy, nitro and (C ₁ -C ₄ ) alkylC(O)-.

[0060] In some embodiments, X is O or S.

[0061] In some embodiments, X is O.

[0062] In some embodiments, X is S.

[0063] In some embodiments, Ring A is a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted 5-membered heterocyclyl. In some embodiments, Ring A is a substituted or unsubstituted 5-membered heteroaryl, or a substituted or unsubstituted 5-membered heterocyclyl, where the 5-membered heteroaryl and the 5-membered heterocyclyl contain one or more heteroatoms selected from N or O.

[0064] In some embodiments, Ring A is a substituted or unsubstituted 6-membered heteroaryl or a substituted or unsubstituted 6-membered heterocyclyl. In some embodiments, Ring A is a substituted or unsubstituted 6-membered heteroaryl, or a substituted or unsubstituted 6-membered heterocyclyl, wherein the 6-membered heteroaryl and 6-membered heterocyclyl contain one or more heteroatoms selected from N or O.

[0065] In some embodiments, Ring B is a substituted or unsubstituted 5-12 membered aryl, a substituted or unsubstituted 5-6 membered heteroaryl, or a substituted or unsubstituted 5-6 membered heterocyclyl.

[0066] In some embodiments, ring B is a substituted or unsubstituted 5-10 membered aryl. In some embodiments, ring B is a substituted or unsubstituted 5-6 membered aryl. In some embodiments, Ring B is a substituted or unsubstituted phenyl.

[0067] In some embodiments, ring B is a substituted or unsubstituted 5-6 membered heteroaryl or a substituted or unsubstituted 5-6 membered heterocyclyl. In some embodiments, Ring B is a substituted or unsubstituted 5-6 membered heteroaryl, or a substituted or unsubstituted 5-6 membered heterocyclyl, wherein the 5-6 membered heteroaryl and the 5-6 membered heterocyclyl contain one or more heteroatoms selected from N or O.

[0068] In some embodiments, ring B is a group selected from the group consisting of:

each of which is optionally substituted with one or more substituents described herein.

[0069] In some embodiments, C is a substituted or unsubstituted 5-12 membered aryl. In some embodiments, C is a substituted or unsubstituted 5-10 membered aryl. In some embodiments, C is a substituted or unsubstituted 5-6 membered aryl. In some embodiments, C is a substituted or unsubstituted 6-membered aryl. In some embodiments, C is substituted or unsubstituted phenyl. In some embodiments, C is substituted with one or more groups selected from the group consisting of halo, cyano, hydroxyl, amino, nitro, alkyl, haloalkyl, alkoxy, and haloalkoxy. In some embodiments, C is substituted with one or more groups selected from the group consisting of halo, cyano, hydroxyl, amino, nitro, and alkyl. In some embodiments, C is substituted with one or more groups selected from the group consisting of halo and alkyl.

[0070] In some embodiments, L is O, NH, or substituted or unsubstituted C ₁ -C ₆ alkylene. In some embodiments, L is O, NH, or unsubstituted C ₁ -C ₆ alkylene. In some embodiments, L is O. In some embodiments, L is NH. In some embodiments, L is methylene.

[0071] In some embodiments, R ₁ is H. In some embodiments, R ₁ is substituted or unsubstituted C ₁ -C ₆ alkyl. In some embodiments, R ₁ is unsubstituted C ₁ -C ₆ alkyl. In some embodiments, R ₁ is methyl, ethyl, or propyl. In some embodiments, R ₁ is methyl.

[0072] In some embodiments, R ₂ is selected from the group consisting of H, halogen, hydroxyl, oxo, benzyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and C ₁ -C ₆ acyl. In some embodiments, R ₂ is H, halogen, hydroxyl, oxo, benzyl, methyl, trifluoromethyl, methoxy, or acetyl.

[0073] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0074] In some embodiments, n is 1 or 2. In some embodiments, n is 1.

[0075] In some embodiments, the present application provides a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, C, L, R ₁ , R ₂ , m and n are as defined above.

[0076] In some embodiments, the present application provides a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R ₁ , R ₂ , and m are as defined above, L is O or CH ₂ , Z is N or CH, R ₃ is selected from halogen or substituted or unsubstituted C ₁ -C ₆ alkyl, and p is 0, 1, 2 or 3.

[0077] In some embodiments, in the compounds of Formula (Ia) and (Ib), the structural group represented by the formula

selected from the group consisting of:

[0078] In some embodiments, R ₂ is selected from the group consisting of H, halogen, hydroxyl, oxo, benzyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and C ₁ -C ₆ acyl. In some embodiments, R ₂ is H, Cl, hydroxyl, oxo, benzyl, methyl, trifluoromethyl, methoxy, or acetyl.

[0079] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0080] In some embodiments, the present application provides a compound of Formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein ring A is a substituted or unsubstituted 6-membered heteroaryl or a substituted or unsubstituted 6-membered heterocyclyl, and ring B, C, L, R ₁ , R ₂ , m and n are as defined above.

[0081] In some embodiments, the present application provides a compound of Formula (Id):

or a pharmaceutically acceptable salt thereof, wherein ring A is a substituted or unsubstituted 6-membered heteroaryl or a substituted or unsubstituted 6-membered heterocyclyl, L is O or CH ₂ , Z is N or CH, R ₃ is halogen and substituted or unsubstituted C ₁ -C ₆ alkyl, p is 0, 1, 2 or 3, and ring B, R ₁ , R ₂ and m are as defined above.

[0082] In some embodiments, in compounds of Formula (Ic) and (Id), the structural group represented by the formula

selected from the group consisting of:

[0083] In some embodiments, R ₂ is selected from the group consisting of H, halogen, hydroxyl, oxo, benzyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and C ₁ -C ₆ acyl. In some embodiments, R ₂ is H.

[0084] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0085] In some embodiments, provided herein is a compound of Formula (I) selected from the group consisting of the following:

[0086] The compound provided herein may exist in a number of different forms or derivatives, which are included within the scope of this application. Such forms or derivatives include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs, solvated forms, various crystal forms or polymorphs, and active metabolites.

[0087] A compound provided herein may include one or more centers of asymmetry and thus may exist in various stereoisomeric forms such as enantiomers and/or diastereomers. Thus, a compound and composition provided herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers. In some embodiments, the compounds provided herein are enantiomerically pure compounds. In some embodiments, mixtures of enantiomers or diastereomers are provided.

[0088] The term "enantiomer" as used herein refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "diastereomer" as used herein refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity.

[0089] In addition, unless otherwise indicated, some of the compounds provided herein may have one or more double bonds, which may exist as the Z or E isomer. The present application further covers such compounds as single isomers, substantially free of other isomers, and alternatively as mixtures of different isomers, eg racemic mixtures of enantiomers. In addition to the above compounds, as such, the present application also covers compositions comprising one or more compounds.

[0090] The term "isomer" as used herein includes any possible geometric isomers and stereoisomers. For example, "isomers" include cis and trans isomers, E and Z isomers, R and S enantiomers, diastereomers, D isomers, L isomers, racemic mixtures thereof, and other mixtures thereof. For example, in some embodiments, a stereoisomer may be provided in a form that is substantially free of one or more of the corresponding enantiomers, which may be referred to as "stereochemically enriched".

[0091] If a particular enantiomer is preferred, the compound of the present application may be presented as an enantiomer that is substantially free of the opposite enantiomer and may be referred to as "optically enriched". As used herein, the term "optically enriched" means that a compound consists of a significantly larger portion of a single enantiomer. In some embodiments, the implementation of the connection consists of at least about 90 wt.% the preferred enantiomer. In some embodiments, the implementation of the connection consists of at least about 95, 98 or 99 wt.% the preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known in the art, including chiral high performance liquid chromatography (HPLC), formation and crystallization of chiral salts, or obtained by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al. Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0092] The compound provided herein may also exist in various tautomeric forms, and all such forms are included within the scope of this application. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are capable of interconversion across a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions via proton migration, such as keto-enol, amide-imido acid, lactam-lactim, enamine-imine isomerization, and ring forms in which the proton can occupy two or more positions. a heterocyclic system such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Valence tautomers involve interconversions by rearranging some of the bonding electrons. The tautomeric forms may be in equilibrium or may be sterically locked in one form with appropriate substitution. Unless otherwise indicated, the compounds of this application, identified by name or structure as one particular tautomeric form, are intended to include other tautomeric forms.

[0093] In some embodiments, the implementation of the connection according to the present application is the S-enantiomer. In some embodiments, the implementation of the connection of the present application is the R-enantiomer.

[0094] The compounds of this application also include prodrugs, active metabolic derivatives (active metabolites), active intermediates, and pharmaceutically acceptable salts thereof.

[0095] The term "prodrug" as used herein refers to a compound, or a pharmaceutically acceptable salt thereof, which, when metabolized under physiological conditions or converted by solvolysis, provides the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates or hydrates of the active compound. Typically, the prodrug is inactive or less active than the active compound, but may provide one or more benefits such as improved processing properties, ease of administration, and/or improved metabolic properties. For example, some Prodrugs are esters of the active compound; during metabolic hydrolysis, the ester group is cleaved off to form the active drug. In addition, some prodrugs are activated enzymatically to produce the active compound or compounds which, in a subsequent chemical reaction, yield the active compound. Prodrugs may change from the prodrug form to the active form in a single step, or may have one or more intermediate forms, which may themselves be active or may be inactive. The production and use of prodrugs is described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. edited by Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0096] The term "metabolite" as used herein, such as an active metabolite, overlaps with prodrugs as described above. Therefore, such metabolites are pharmacologically active compounds or compounds that are subsequently metabolized to pharmacologically active compounds that are derivatives resulting from the metabolic process in the body of the subject. For example, such metabolites may be formed by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, and the like. the compound, salt, or prodrug being administered. Of these, active metabolites are pharmacologically active derivatives of the compound. In the case of prodrugs, the prodrug compound is usually inactive or has lower activity than the metabolite. In the case of active metabolites, the parent compound may be either an active compound or an inactive prodrug.

[0097] Prodrugs and active metabolites can be identified using standard techniques known in the art. See, for example, Bertolini et al., 1997, J Med Chem 40: 2011-2016; Shan et al., J Pharm Sci 86: 756-757; and Bagshawe, 1995, DrugDev Res 34: 220-230.

[0098] The term "active intermediate" as used herein refers to an intermediate in a synthesis process that exhibits the same or substantially the same biological activity as the final synthesized compound.

[0099] The compounds of this application may be formulated or may be in the form of pharmaceutically acceptable salts. Unless otherwise indicated, a compound provided herein includes pharmaceutically acceptable salts of such a compound.

[0100] The term "pharmaceutically acceptable" as used herein means that the substance or composition is chemically and/or toxicologically compatible with other constituents and/or subjects being treated with them.

[0101] Unless otherwise indicated, the term "pharmaceutically acceptable salt" as used herein includes a salt that retains the biological potency of the free acids and free bases of said compound and is not biologically undesirable. Pharmaceutically acceptable salt forms contemplated include, but are not limited to, mono, bis, tris, tetrakis, and the like. The pharmaceutically acceptable salts are non-toxic in the amounts and concentrations in which they are administered. The preparation of such salts may facilitate pharmacological use by changing the physical properties of the compound without interfering with its physiological effect. Beneficial changes in physical properties include lowering the melting point to facilitate cross-mucosal administration and increasing solubility to facilitate administration of higher concentrations of drugs.

[0102] Pharmaceutically acceptable salts may include acid addition salts such as salts including sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfonate and hinat. Pharmaceutically acceptable salts can be derived from acids such as sulfuric acid, hydrochloric acid, fumaric acid, maleic acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfonic acid and quinic acid.

[0103] Pharmaceutically acceptable salts may also include base addition salts such as salts including benzathine, chlorprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, zinc and alkylamines in the presence of acid functional groups such as carboxyl groups or phenol. See, for example. Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA, Volume 2, Page 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using suitable appropriate bases.

[0104] Pharmaceutically acceptable salts can be obtained by standard methods. For example, a compound in free base form can be dissolved in a suitable solvent, such as an aqueous or hydroalcoholic solution containing a suitable acid, and then isolated upon evaporation of the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be obtained by any suitable method available in the art, for example, by treating the free base with an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.) or an organic acid (such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosilic acids such as glucuronic acid or galacturonic acid, α-hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, and sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid) .

[0105] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt can be obtained by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or hydroxide alkaline earth metal, etc. Illustrative examples of suitable salts include organic salts derived from amino acids (such as L-glycine, L-lysine and L-arginine), ammonia, primary amines, secondary amines, tertiary amines, cyclic amines (such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine ), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0106] It is also to be understood that the compound of the present application may exist in unsolvated form, solvated form (e.g., hydrated form), and solid form (e.g., crystalline or polymorphic form), and the present application is intended to encompass all such forms. .

[0107] The term "solvate" or "solvated form" as used herein refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture fixed molar ratios of solvent molecules in a crystalline solid state, thus forming a solvate. If the solvent is water, the resulting solvate is a hydrate; and if the solvent is an alcohol, the resulting solvate is an alcoholate. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, methanol, ethanol, DMSO, ethyl acetate, acetic acid, ethanolamine, acetone, and ether, etc.

[0108] The terms "crystal form", "polymorph", and "polymorph" as used herein may be used interchangeably and refer to a crystal structure in which a compound (or a salt or solvate thereof) is crystallized in various crystal packing configurations that have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility, etc. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystal form to predominate. Polymorphic modifications of the compound can be obtained by crystallization under different conditions.

[0109] The present application also provides for the inclusion of all isotopes of atoms in the compound. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise noted, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compound of this application also includes their isotopes, such as, but not limited to, ¹ H, ² H, ³ H , ¹¹ C, ¹² C, ¹³ C ^, 14 C, ¹⁴ N, ¹⁵ N, ¹⁶ O, ^{17 O, 18 O} , ³¹ P, ³² P, ³² S, ³³ S, ³⁴ S, ³⁶ S, ¹⁷ F, ¹⁹ F, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, ¹²⁷ I, and ¹³¹ I. In some embodiments, hydrogen includes protium, deuterium, tritium, or a combination thereof. In some embodiments, the carbon comprises ¹² C, ¹³ C, or a combination thereof. In some embodiments, the abundance of different isotopic atoms of a particular element may correspond to the state in which the element normally occurs in nature, or the state in which the particular isotope is enriched.

[0110] Synthesis of compounds

[0111] The synthesis of compounds (including their pharmaceutically acceptable salts) according to the present application is shown in the synthesis scheme in the examples below. The compound according to the present application can be obtained using any known methods of organic synthesis and can be synthesized according to any possible routes of synthesis. Thus, the schemes presented herein are exemplary only and should not be considered as limiting other possible methods that can be used to obtain the connection according to this application.

[0112] the Reactions used to obtain compounds according to this application can be carried out in suitable solvents. Suitable solvents may be substantially unreactive with starting materials (reagents), intermediates, or products at the temperatures at which the reactions are carried out (eg, at temperatures that may vary from the solvent's freezing point to the solvent's boiling point). This reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for the particular reaction step can be selected by those skilled in the art.

[0113] Obtaining compounds according to the present application may include protection and deprotection of various chemical groups. The need for protection and deprotection and the choice of suitable protecting groups can be determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley & Sons, Inc., New York (1999).

[0114] Reactions can be monitored using any suitable method known in the art. For example, product formation can be monitored using spectral methods such as nuclear magnetic resonance spectroscopy (such as ¹ H or ¹³ C-NMR), infrared spectroscopy, spectrophotometry (such as UV Vis), mass spectrometry, or using a chromatographic method. such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LC-MS), or thin layer chromatography (TLC). Compounds can be purified by a variety of methods, including HPLC and silica gel normal phase chromatography.

[0115] For illustrative purposes, the general synthetic route for obtaining compounds according to this application, as well as intermediate compounds is shown below.

[0116] In one aspect of the present application, a method for preparing the compound of Formula (I) according to the present application is provided, as shown below:

where R ₄ represents-COOH or-COO-G ⁺ , where G ⁺ is an alkali metal ion;

when R is H, the method comprises reacting a compound of Formula (II) with a compound of Formula (III) in an inert solvent in the presence of a condensing agent and a base to give a compound of Formula (I); And

when R is an amino protecting group, the method comprises removing R from a compound of Formula (II) under acidic conditions and then reacting the compound of Formula (II) from which R has been removed with a compound of Formula (III) in an inert solvent in the presence of a condensing agent and a base to obtain a compound of Formula (I).

[0117] In some embodiments, G ⁺ is Li ⁺ , Na ⁺ , or K ⁺ .

[0118] In some embodiments, the implementation of the compound of Formula (I) according to this application can be obtained according to a scheme selected from the group consisting of the following:

And

[0119] In some embodiments, R is H and a compound of Formula (II) is reacted with a compound of Formula (III) in an inert solvent in the presence of a condensing agent and a base to give a compound of Formula (I).

[0120] In some embodiments, the inert solvent is selected from DMF, DMSO, acetonitrile, THF, DCM, or combinations thereof.

[0121] In some embodiments, the condensing agent is selected from HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, PyBOP, or combinations thereof.

[0122] In some embodiments, the base is selected from DIEA (diisopropylethylamine), triethylamine, DMAP, pyridine, or a combination thereof.

[0123] In some embodiments, R is an amino protecting group and R is removed from the compound of Formula (II) under acidic conditions, and then the compound of Formula (II) from which R has been removed is reacted with a compound of Formula (III) under inert conditions. solvent in the presence of a condensing agent and a base to give a compound of Formula (I).

[0124] In some embodiments, acidic conditions mean that the reaction system contains hydrochloric acid or trifluoromethanesulfonic acid.

[0125] In some embodiments, the inert solvent is selected from DMF, DMSO, acetonitrile, THF, DCM, or combinations thereof.

[0126] In some embodiments, the condensing agent is selected from HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, PyBOP, or combinations thereof.

[0127] In some embodiments, the base is selected from DIEA, triethylamine, DMAP, pyridine, or a combination thereof.

[0128] In some embodiments, a functional group including, but not limited to, acyl and alkyl, etc., may be further introduced into a compound of Formula (I) in a standard manner, for example, as shown in the scheme below:

[0129] In yet another aspect of the present application, an intermediate compound of Formula (II) is provided to obtain a compound of Formula (I):

Where:

R represents H or an amino protecting group;

X is O, S or CH ₂ ;

R ₁ is selected from the group consisting of H and substituted or unsubstituted C ₁ -C ₆ alkyl;

r ₂ is selected from the group consisting of H, halogen, hydroxyl, oxo, benzyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and C ₁ -C ₆ acyl;

m is 0, 1, 2, or 3; And

n is 1, 2 or 3;

where "substituted" refers to the replacement of one or more hydrogen atoms in a group with a substituent selected from the group consisting of halogen, cyano, alkyl, acyl, sulfonyl, hydroxyl, amino, benzyl, oxo, (C ₁ -C ₄ ) alkyl, halogen (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen (C ₁ -C ₄ ) alkoxy, nitro and (C ₁ -C ₄ ) alkyl C (O)-.

[0130] In some embodiments, the intermediate of Formula (II) is selected from the group consisting of:

и

And

where R' is selected from H, Boc, SEM, (C ₁ -C ₄ ) alkyl and benzyl.

[0131] In some embodiments, the intermediate of Formula (II) is selected from the group consisting of:

where R is H, Boc or TFA, and R' is selected from H, Boc or SEM.

[0132] In some embodiments, the implementation of the compound of Formula (II) according to this application can be obtained according to the scheme shown below:

which includes:

(a) reacting a compound of Formula IIa with a compound of Formula IIb in an inert solvent in the presence of a base to give a compound of Formula IIc;

(b) reduction of the nitro group in the compound of Formula IIc in an alcoholic solvent under a hydrogen atmosphere and/or in the presence of a metal catalyst, followed by cyclization in an inert solvent in the presence of a condensing agent and a base to obtain a compound of Formula II'; And

(c) reacting a compound of Formula II' with R ₁ I in the presence of a base to give a compound of Formula II.

[0133] In some embodiments, the base in Step (a) is selected from cesium carbonate, potassium carbonate, NaOH, NaH, n-BuLi, KHMDS, or combinations thereof.

[0134] In some embodiments, the inert solvent in Steps (a) and (b) is selected from DMF, DMSO, acetonitrile, THF, or combinations thereof.

[0135] In some embodiments, Step (a) is carried out at -20°C to 100°C.

[0136] In some embodiments, the alcoholic solvent in Step (b) is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, or a combination thereof.

[0137] In some embodiments, the metal catalyst in Step (b) is Pd/C.

[0138] In some embodiments, the condensing agent in Step (b) is selected from the group consisting of HATU, DCC, HOBt, HBTU, HCTU, TBTU, TSTU, TNTU, EDCI, CDI, PyBOP, or combinations thereof.

[0139] In some embodiments, the base in Step (c) is selected from DIEA, triethylamine, DMAP, pyridine, or a combination thereof.

[0140] In some embodiments, the implementation of the compound of Formula (II) according to this application can be obtained according to the scheme shown below:

which includes

(a) subjecting the compound of Formula IId to a coupling reaction with aqueous ammonia in an inert solvent in the presence of a copper catalyst and ligand L to obtain a compound of Formula IIe; And

(b) subjecting the compound of Formula IIe to a dehydration and ring closure reaction under acidic or basic conditions to obtain a compound of Formula II''.

[0141] In some embodiments, R ₃ is methyl or trifluoromethyl, R ₁ ', R ₂ ', and R ₃ ' may be H, methyl, methoxy, phenyl, benzyl, phenoxy, naphthyl, etc., and other groups have the meaning given above.

[0142] In some embodiments, the ligand L in Step (a) is selected from the group consisting of:

[0143] In some embodiments, the inert solvent in Step (a) is selected from DMSO, DMF, 1,4-dioxane, or combinations thereof.

[0144] In some embodiments, the copper catalyst in Step (a) is selected from CuI, CuCN, CuBr, CuCl, Cu ₂ O, or combinations thereof.

[0145] In some embodiments, the weight ratio of aqueous ammonia to inert solvent in Step (a) is from 1:10 to 1:1.

[0146] In some embodiments, the implementation of the amount of copper catalyst in Step (a) is 0.5-20 mol.% relative to the compounds of Formula IId.

[0147] In some embodiments, the implementation of the amount of ligand L in Stage (a) is 0.5-30 mol.% relative to the compounds of Formula IId.

[0148] In some embodiments, the implementation of Stage (a) is carried out at a temperature of from 40°C to 150°C.

[0149] In some embodiments, the acidic conditions in Step (b) mean that the reaction system contains an acid selected from the group consisting of acetic acid, 15% sulfuric acid, or a combination thereof.

[0150] In some embodiments, the basic conditions in Step (b) mean that the reaction system contains a base selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, potassium phosphate, or a combination thereof.

[0151] In some embodiments, Step (b) is carried out at room temperature (10°C-40°C) to 80°C, e.g., 10°C to 80°C, 15°C to 80°C , 20°C to 80°C, 25°C to 80°C, 30°C to 80°C, 35°C to 80°C or 40°C to 80°C.

[0152] An exemplary compound of Formula (II) can be prepared according to the scheme shown below:

where Compound 25 is reacted with methyl chloroformate in dichloromethane under basic conditions at -5°C to room temperature to give Intermediate 29. The trifluoroacetyl protecting group of Intermediate 29 is removed under basic conditions, and then the primary amino group is protected with a Boc group by reaction with Boc anhydride, thus obtaining. Compound 30. Then, in an inert solvent, in the presence of a copper catalyst and ligand L, Compound 30 is coupled with aqueous ammonia to give Compound 31. This is followed by a dehydration and cyclization reaction with heating under basic conditions to give a compound of Formula II-10.

[0153] Application of the compound

[0154] In one aspect, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, capable of inhibiting RIP1 kinase activity.

[0155] Thus, in another aspect of the present application, there is provided a method for inhibiting RIP1 kinase in a subject, comprising administering to the subject an effective amount of a compound of the present application, or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the compound according to the present application can inhibit the activity of RIP1 kinase with an IC ₅₀ value of 0.1 nM-1000 μM, 1 nM-500 μM, 0.1 nM-100 μM, 0.1 nM-80 μM, 0.1 nM-50 µM, 0.1 nM-40 µM, 0.1 nM-30 µM, 0.1 nM-20 µM, 0.1 nM-10 µM, 0.1 nM-5 µM, 0, 1 nM-1 µM, 0.1 nM-0.5 µM, 0.1 nM-0.1 µM, 0.1 nM-0.05 µM, 0.1 nM-40 nM, 0.1 nM-30 nM, 0.1 nM-20 nM, 0.1 nM-10 nM, 0.1 nM-5 nM, 0.1 nM-4 nM, 0.1 nM-3 nM, 0.1 nM-2 nM, 0.1 nM-1 nM and 0.1 nM-0.5 nM.

[0157] Thus, in another aspect, the compound of the present application, or a pharmaceutically acceptable salt thereof, can be used in the manufacture of a medicament for inhibiting RIP1 kinase activity.

[0158] In another aspect, the compound of the present application, or a pharmaceutically acceptable salt thereof, can be used in the manufacture of a medicament for the prevention or treatment of diseases associated with RIP1 kinase.

[0159] In another aspect, the compound of the present application, or a pharmaceutically acceptable salt thereof, can be used in the manufacture of a medicament for the prevention or treatment of diseases or disorders caused by programmed cell death.

[0160] Pharmaceutical composition

[0161] In one aspect of the present application, a pharmaceutical composition is provided, comprising a compound of the present application, or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the implementation of the pharmaceutical composition according to the present application includes more than one compound according to the present application or its pharmaceutically acceptable salt.

[0163] In some embodiments, the implementation of the pharmaceutical composition according to the present application includes one or more compounds according to the present application or their pharmaceutically acceptable salts and a pharmaceutically acceptable carrier.

[0164] Pharmaceutically acceptable carriers are standard pharmaceutical carriers in this field and can be obtained by methods known in the pharmaceutical field. In some embodiments, the implementation of the compounds according to the present application or their pharmaceutically acceptable salts can be mixed with pharmaceutically acceptable carriers to obtain pharmaceutical compositions.

[0165] The term "pharmaceutically acceptable" as used herein means that the compound, material, composition and/or dosage form are suitable for contact with human or animal tissues and do not cause excessive toxic effects, irritation, allergic reactions, other problems or complications and demonstrate a reasonable benefit/risk ratio. In some embodiments, the pharmaceutically acceptable compounds, materials, compositions, and/or dosage forms are approved by regulatory authorities (e.g., US Food and Drug Administration, China National Health Products Administration, and European Medicines Agency) or listed in certified pharmacopoeial reference books (eg USP, Chinese Pharmacopoeia and European Pharmacopoeia) for use in animals, especially humans.

[0166] The term "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid excipient, diluent, excipient, solvent, or packaging material, used in the transfer or delivery of a compound of this application. or a pharmaceutically acceptable salt thereof from one position, bodily fluid, tissue, organ (internal or external) or body part to another position, bodily fluid, tissue, organ or body part. A pharmaceutically acceptable carrier may be a solvent, diluent, excipient, or other materials that can be used in contact with animal tissues without undue toxicity or adverse reactions. Examples of pharmaceutically acceptable carriers include, but are not limited to, carbohydrates, starch, cellulose, malt, tragacanth, gelatin, Ringer's solution, alginic acid, isotonic sodium chloride solution and buffers, etc. Pharmaceutically acceptable carriers that may be used in this application include those known in the art, such as those disclosed in "Remington Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991).

[0167] The pharmaceutical composition may also contain pharmaceutically acceptable additives necessary to approximate physiological conditions, including, without limitation, for example, pharmaceutically acceptable liquid, gel or solid carriers, aqueous media (for example, sodium chloride for injection, Ringer's solution for injection , isotonic dextrose for injection, sterile water for injection or dextrose and lactated Ringer's solution for injection), non-aqueous medium (eg, vegetable oil, cottonseed oil, corn oil, sesame oil, or peanut oil), antimicrobial agents, isotonic agents (such as sodium chloride or glucose), buffers (such as phosphate or citrate buffers), antioxidants (such as sodium bisulfate), anesthetics (such as procaine hydrochloride), suspending agents/dispersants (such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone), chelating agents (e.g. EDTA (ethylenediaminetetraacetic acid) or EGTA (ethylene glycol bis(2-aminoethyl ester) tetraacetic acid)), emulsifiers (e.g. polysorbate 80 (Tween-80)), diluents, flavors, flavors, sweeteners, adjuvants, auxiliaries additives or non-toxic excipients, other components known in the art, or various combinations of the above. Suitable components may include, for example, fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickeners, colorants, or emulsifiers.

[0168] The form of the pharmaceutical composition depends on a variety of factors, including, for example, the route of administration, the severity of the disease or the administered dose, and so on.

[0169] In some embodiments, the pharmaceutical composition may be formulated for administration to a subject by a suitable route, including but not limited to oral route, injection (such as intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, intracardiac injection, intrathecal injection, intrapleural injection and intraperitoneal injection, etc.), transmucosal routes (such as intranasal, intraoral, etc.), sublingual, rectal, transdermal, intraocular, and pulmonary. Depending on the desired route of administration, the pharmaceutical composition can be prepared in the form of tablets, capsules, pills, dragees, powders, granules, cachets, lozenges, suppositories, suspensions, emulsions, syrups, aerosols (solid or liquid), sprays, ointments, pastes, patches, creams, lotions, gels and inhalants, etc.

[0170] In some embodiments, the implementation of the pharmaceutical composition is a drug for oral administration. The oral preparation includes, without limitation, capsules, sachets, pills, tablets, lozenges (often based on sucrose, gum arabic or tragacanth), powders, granules, aqueous or non-aqueous solutions or suspensions, water-in-water emulsions. oil or oil in water, tinctures or syrups, lozenges (wherein suitable inert bases include, for example, gelatin and glycerin, or sucrose or gum arabic) and/or mouth rinses or their equivalents.

[0171] A solid preparation for oral administration (such as capsules, tablets, pills, dragees, powders and granules, etc.) includes the active substance and one or more pharmaceutically acceptable auxiliary additives, such as sodium citrate or dicalcium phosphate, and /or the following substances: (1) fillers or additives such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) wetting agents such as glycerin; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and/or sodium carbonate; (5) solutions of absorption retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) lubricants such as acetol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and (10) dyes.

[0172] The oral liquid preparation includes pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and tinctures. In addition to the active ingredient, the liquid dosage form may also contain a commonly used inert diluent, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and a sorbitol fatty acid ester, or a mixture of two or more of them. In addition to the inert diluent, adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, pigments, flavoring agents and preservatives may also be added to the oral liquid preparation.

[0173] In some embodiments, the pharmaceutical composition is an injectable. The preparation for injection includes sterile aqueous solutions, dispersions, suspensions or emulsions. Whenever possible, the injectable preparation must be sterile and in a liquid state for ease of injection, must remain stable under the conditions of manufacture and storage, and must be resistant to contamination by microorganisms (eg bacteria and fungi). The carrier may be a solvent or dispersion medium including, for example, water, ethanol, polyhydroxy compounds (eg glycerol, propylene glycol, liquid polyethylene glycol, etc.) and suitable mixtures thereof and/or vegetable oils. The injectable preparation must have proper fluidity, which can be maintained in various ways, for example, by using coatings such as lecithin, by using surfactants, etc. Resistance to contamination by microorganisms can be achieved by adding various antibacterial and antifungal agents (eg paraben, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0174] In some embodiments, the pharmaceutical composition is an oral spray formulation or a nasal spray formulation. Spray formulations include, but are not limited to, aqueous aerosols, non-aqueous suspensions, liposomal or particulate formulations, and the like. Aqueous aerosols are prepared by preparing an aqueous solution or suspension of the active ingredient with the usual pharmaceutically acceptable excipient and stabilizer. The carrier and stabilizer may vary depending on the needs of the particular compound and typically include non-ionic surfactants (Tween series or polyethylene glycol), oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugar or sugar alcohols. Aerosols are usually made from isotonic solutions and can be delivered using a nebulizer.

[0175] The pharmaceutical composition can be formulated to provide rapid release, sustained release, or delayed release of the active ingredient after administration to a subject. In some embodiments, the implementation of the pharmaceutical composition can be made in the form of sustained release. As used herein, the term "sustained release form" means that the active substance is released from the pharmaceutical composition over a longer period of time (sustained release) or at a specific site (controlled release), as a result of which it is biologically absorbed in the body of the subject ( for example, in the subject's gastrointestinal tract). In some embodiments, a longer period of time may be 1 to 24 hours, 2 to 12 hours, 3 to 8 hours, 4 to 6 hours, 1 to 2 days, or more. In some embodiments, a longer period of time may be at least about 4 hours, at least about 8 hours, at least about 12 hours, or at least about 24 hours. In some embodiments, the pharmaceutical composition may be in the form of a tablet. For example, the release rate of the active substance can be controlled not only by the active substance, which dissolves in the gastro-intestinal juice regardless of pH and then diffuses out of the tablet or pill, but also depends on the physical process of disintegration and dissolution of the tablet. In some embodiments, the polymeric materials disclosed in "Medical Applications of Controlled Release", Langer and Wise eds, CRC Pres., Boca Raton, Florida (1974), "Controlled Drug Bioavailability", Drug Product Design and Performance, Smolen and Ball eds , Wiley, New York (1984), Ranger and Peppas, 1983, J Macromol. sci. Rev. Macromol Chem. 23:61, Levy et al., 1985, Science 228:190, During et al., 1989, Ann. Neurol. 25:351, and Howard et al., 1989, J. Neurosurg. 71:105 can be used for sustained release.

[0176] In some embodiments, the implementation of the pharmaceutical composition includes 1-99% by weight of the compounds of Formula I or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition comprises 5-99% by weight, 10-99% by weight, 15-99% by weight, 20-99% by weight, 25-99% by weight, 30-99% by weight, 35 -99% by weight, 40-99% by weight, 45-99% by weight, 50-99% by weight, 55-99% by weight, 60-99% by weight or 65-99% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, the pharmaceutical composition may be formulated into a unit dosage form that contains 0.01-1000 mg, 0.01-900 mg, 0.01-800 mg, 0.01-700 mg, 0. 01-600 mg, 0.01-500 mg, 0.01-400 mg, 0.01-300 mg, 0.01-200 mg, 0.01-100 mg, 0.01-50 mg, 0.05 -900 mg, 0.05-800 mg, 0.05-700 mg, 0.05-600 mg, 0.05-500 mg, 0.05-400 mg, 0.05-300 mg, 0.05- 200 mg, 0.05-100 mg, 0.05-50 mg, 0.1-1000 mg, 0.1-900 mg, 0.1-800 mg, 0.1-700 mg, 0.1-600 mg, 0.1-500 mg, 0.1-400 mg, 0.1-300 mg, 0.1-200 mg, 0.1-100 mg or 0.1-50 mg of a compound of Formula I or a pharmaceutically acceptable compound thereof salt. The term "unit dosage form" as used herein refers to a physically discrete unit suitable as a dosage unit, each such unit containing a predetermined amount of the active ingredient, calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powders, cachets, suppositories, injection solutions or suspensions and similar dosage forms and their divided multi-dose form. Of course, the daily dose of the compound according to the present application will vary depending on the compound used, the route of administration, the desired treatment and the particular disease being treated. In some embodiments, the daily dose of a compound of the present application is 0.01-200 mg/kg body weight administered as a single dose, or 0.01-100 mg/kg mg/kg body weight administered separately. Regardless of the route of administration, the optimal dose for a person depends on the particular treatment. Usually, starting with a low dose, the dose is gradually increased until the most appropriate dose is determined.

[0178] Combination of drugs

[0179] In one aspect of the present application, a drug combination is provided, comprising a compound according to the present application, or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient.

[0180] In some embodiments, the combination of drugs is used to treat or prevent RIP1 kinase-mediated diseases or disorders, or diseases or disorders caused by programmed cell death.

[0181] In some embodiments, at least one additional active ingredient includes, without limitation, a thrombolytic agent, tissue plasminogen activator, anticoagulant, platelet aggregation inhibitor, antimicrobial agent (antibiotics, broad spectrum antibiotics, β-lactam, antimycobacterial agents, bactericidal antibiotics and anti-MRSA therapy), long-acting beta-agonist, combination of inhaled corticosteroid and long-acting beta-agonist, short-acting beta-agonist, leukotriene modulator, anti-IgE antibodies, methylxanthine bronchodilator, mast cell inhibitor, protein tyrosine kinase inhibitor, prostaglandin receptor antagonist CRTH2/D-type, epinephrine aerosol for inhalation, phosphodiesterase inhibitor, combination of phosphodiesterase-3 inhibitor and phosphodiesterase-4 inhibitor, long-acting inhaled anticholinergic agent, muscarinic receptor antagonist, long-acting muscarinic receptor antagonist, low-dose steroids, inhaled corticosteroid, oral corticosteroid , topical corticosteroid, antithymocyte globulin, thalidomide, chlorambucil, calcium channel blocker, topical moisturizer, ACE inhibitor, serotonin reuptake inhibitor, endothelin-1 receptor inhibitors, antifibrosis agent, proton pump inhibitor, transmembrane conductance regulator in cystic fibrosis, mucolytics, pancreatin, bronchodilator, intravitreal injection, inhibitor against vascular endothelial growth factor, ciliary neurotrophic growth factor, trivalent inactivated influenza vaccine (IIV3), quadrivalent inactivated influenza vaccine (IIV4), trivalent recombinant influenza vaccine, quadrivalent live attenuated influenza vaccine influenza, antiviral agent, inactivated influenza vaccine, ciliary neurotrophic growth factor, gene transfer agent, immunomodulator, calcineurin inhibitor, interferon γ, antihistamine, PD-1 inhibitor, PD-L1 inhibitor, monoclonal antibody, anti-T cell polyclonal antibody, an equine anti-thymocyte gamma globulin antibody, a rabbit anti-thymocyte globulin antibody, an anti-CD40 antagonist, a JAK inhibitor, and a mouse anti-TCR mAb.

[0182] In some embodiments, the implementation of the connection according to the present application or its pharmaceutically acceptable salt and at least one additional active ingredient is administered separately, simultaneously or sequentially, in any order.

[0183] Methods of treatment and indications

[0184] The compound of the present application, or a pharmaceutically acceptable salt thereof, is capable of inhibiting RIP1 kinase activity. Thus, in one aspect, the present application provides a method for treating or preventing RIP1 kinase-mediated diseases or disorders or diseases or disorders caused by programmed cell necrosis, comprising administering to a subject an effective amount of a compound of this application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, or a combination medicines according to the present application.

[0185] The term "subject" as used herein refers to an organism, tissue, or cell. Subjects may include human subjects for medical purposes (eg, diagnosis and/or treatment of existing conditions or diseases, or prophylactic treatment to prevent the onset of conditions or diseases) or animal subjects for medical or veterinary or development purposes. Subjects also include samples from tissue culture, cell culture, organ reconstitution and stem cell production, etc. Suitable animal subjects include mammals and birds. The term "mammal" as used herein includes, without limitation, primates (such as humans, apes, and apes, etc.), bovines (such as bulls, etc.), sheep (such as sheep, goats, etc.), pigs, horses, cats, dogs, rabbits, rodents (eg mice, rats, etc.) and the like. The term "birds" as used herein includes, without limitation, chickens, ducks, geese, quails, turkeys and pheasants, etc. In some embodiments, the subject is a mammal or a mammalian cell. In some embodiments, the subject is a human or a human cell. Human subjects include, but are not limited to, fetus, neonate, infant, adolescent, and adult subjects. In addition, "subject" may include patients suffering from or suspected of having a particular condition or disease. Thus, in this document, the terms "subject" and "patient" are used interchangeably. Subject can also refer to cells in a laboratory or biotech environment in tests.

[0186] The term "effective amount" as used herein refers to the amount of a drug or pharmaceutical that produces a biological or medical response, such as that desired by a researcher or clinician, in a tissue, system, animal, or human. In addition, the term "therapeutically effective amount" means any amount that results in improved treatment, healing, prevention or amelioration of a disease, disorder or side effect, or reduction in the progression of a disease or disorder, as compared to a corresponding subject who does not receive such an amount. The term also includes, within its scope, an amount effective to improve normal physiological functions. A therapeutically effective amount of one or more compounds according to the present application is known to the person skilled in the art or can be easily determined by standard methods known in this field.

[0187] In some embodiments, the RIP1 kinase-mediated diseases or disorders or programmed cell death diseases or disorders are selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal degenerative disease, retinal detachment, retinitis pigmentosa , macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, hepatitis B, autoimmune hepatitis C hepatobiliary disease, primary sclerosing cholangitis, acetaminophen poisoning, hepatotoxicity, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of parenchymal organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granuloma, pulmonary sarcoidosis, Behçet's disease, interleukin-1-converting enzyme-associated fever syndrome, chronic obstructive pulmonary disease, factor receptor-associated intermittent syndrome tumor necrosis, periodontitis, stroke, burns, burn shock, traumatic brain injury, atherosclerosis, cisplatin-induced kidney injury, acute kidney injury, pancreatitis, chronic kidney disease, acute respiratory distress syndrome, chronic obstructive pulmonary disease, Gaucher disease, Niemann-Pick, acute liver failure, cancer (eg, pancreatic cancer), bacterial infection, smoking-induced injury, cystic fibrosis, NF-κB key regulatory gene mutation, heme-oxidized ubiquitin ligase-1 IRP2 deficiency, deficiency syndrome ubiquitin linear chain assembly complex, hemoblast malignancies, malignant neoplasms of solid organs, influenza, staphylococcal infections, mycobacterial infections, lysosomal storage diseases, GM2 gangliosidosis, α-mannosidosis, aspartylglucosamineuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon's disease , Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipid accumulation, childhood free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, neuronal ceroid lipofuscinosis, Pompe's disease, pycnodysostosis, Sandhoff's disease, Schindler's disease, Sull's disease, Tay-Sachs disease, Wolman's disease, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

[0188] The present application also includes, without limitation, the following embodiments:

[0189] Item 1. The compound of Formula (I) or its optical isomer, tautomer or pharmaceutically acceptable salt:

Where

X represents O, S or CH ₂ ;

, где кольцо А выбрано из группы, состоящей из замещенного или незамещенного 5-6-членного гетероарила и замещенного или незамещенного 5-6-членного гетероциклила, где кольцевой скелет гетероарильной группы или гетероциклильной группы содержит один или более гетероатомов, выбранных из N, О или S;ring M has the structure

where ring A is selected from the group consisting of substituted or unsubstituted 5-6 membered heteroaryl and substituted or unsubstituted 5-6 membered heterocyclyl, where the ring skeleton of the heteroaryl group or heterocyclyl group contains one or more heteroatoms selected from N, O or S;

n is selected from 1, 2 or 3;

B is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, and substituted or unsubstituted 5-6 membered heterocyclyl;

L is selected from the group consisting of O, S, NH, N(CH ₃ ), substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted C ₁ -C ₆ alkylene-O-, substituted or unsubstituted C ₁ -C ₆ alkylene-NH-, (substituted or unsubstituted C ₁ -C ₆ alkylene) ₂ -N-, substituted or unsubstituted C ₃ -C ₆ alkenylene and substituted or unsubstituted C ₃ -C ₆ alkenylene-O-;

C is selected from the group consisting of H, substituted or unsubstituted (C ₃ -C ₆ ) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, and substituted or unsubstituted 5-6 membered heterocyclyl;

r ₁ is selected from H or substituted or unsubstituted C ₁ -C ₆ alkyl;

R ₂ is any one or more substituents on the phenyl ring selected from the group consisting of H, halogen, halogen-substituted or unsubstituted C ₁ -C ₆ alkyl, and C ₁ -C ₆ acyl;

where, unless otherwise indicated, "substituted" refers to the replacement of one or more hydrogen atoms in a group with a substituent selected from the group consisting of halogen, cyano, alkyl, acyl, sulfonyl, hydroxyl, amino, benzyl, oxo (=O), (C ₁ -C ₄ ) alkyl, halogen (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, halogen (C ₁ -C ₄ ) alkoxy, nitro and (C ₁ -C ₄ ) alkyl C ( O)-; And

the configuration of each chiral center is independently the R-configuration or the S-configuration.

[0190] Item 2. The compound according to Item 1, wherein C is substituted or unsubstituted phenyl or substituted or unsubstituted 5-6 membered heteroaryl.

[0191] Item 3. A compound according to Item 1, wherein L is a substituted or unsubstituted C ₁ -C ₆ alkylene.

[0192] Item 4. A compound according to Item 1, wherein ring A is a 5-membered ring containing one or more N atoms on the cyclic skeleton.

[0193] Item 5. A method for producing a compound according to Item 1, comprising Step (a) or (b):

(a) reacting a compound of Formula II with a compound of Formula III in an inert solvent in the presence of a condensing agent and a base to give a compound of Formula I, where R is H; or

(b) removing the amino protecting group from the compound of Formula II under acidic conditions and then reacting with the compound of Formula III in an inert solvent in the presence of a condensing agent and a base to obtain a compound of Formula I, where R is an amino protecting group (preferably Boc), and others groups have the meaning given in Clause 1.

[0194] Clause 6. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound of Formula I, or an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, or a combination thereof; and (b) a pharmaceutically acceptable carrier.

[0195] Item 7. The use of a compound of Formula I according to Item 1, or a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer, or mixture thereof, in the manufacture of a pharmaceutical composition for the treatment or prevention of RIP1 kinase-mediated diseases or disorders; or in the manufacture of a pharmaceutical composition for the treatment or prevention of diseases or disorders caused by programmed cell death.

[0196] Item 8. Use according to Item 7, wherein the diseases or disorders are selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, non-acetaminophenic poisoning, celiac disease ITP, transplant rejection, ischemia-reperfusion injury of parenchymal organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomas, pulmonary sarcoidosis, Behçet's disease, interleukin-1-converting enzyme-associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis.

[0197] Item 9. Intermediate of Formula II below:

where R is selected from the group consisting of H and an amino protecting group (preferably Boc); and other groups have the meaning given in paragraph 1.

[0198] Item 10. The intermediate compound according to Item 9, selected from the group consisting of:

[0199] This application proposes a new class of compounds that inhibit the activity of RIP1 kinase. Compared with existing compounds, the compound of the present application has a better inhibitory effect against programmed cell death and improved selectivity and pharmacokinetics.

[0200] Examples

[0201] The present application is further described below in conjunction with specific examples. It should be understood that these examples are merely illustrative of the present application and are not intended to limit the scope of the present application. In experimental methods that do not specify specific conditions in the following examples, conventional conditions or conditions recommended by the manufacturer are used. Unless otherwise indicated, percentages and parts are by weight.

[0202] Example 1:. Synthesis of Exemplary Compounds RIP1-001, RIP1-003, RIP1-023, RIP1-136 and RIP1-182

[0203] Method 1:

[0204] Compound II-1 (27.8 mg, 0.08 mmol) was placed in a 25 ml one-neck flask, then TFA (1 ml) and DCM (4 ml) were added and the reaction was carried out at room temperature for 30 min until completion of the reaction as shown by TLC. The solvent was removed under reduced pressure and the residue was dried in vacuo and redissolved in DMF (4 ml). HATU (38 mg, 0.1 mmol), DIEA (51.7 mg, 0.4 mmol) and 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid III-1 (20.3 mg, 0.1 mmol) and reacted overnight at room temperature until the reaction was complete as shown by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by reverse phase column chromatography and lyophilized to give RIP1-001: white solid, 14.0 mg (40.4%).

[0205] When changing the compound of Formula II and the compound of Formula III, Compounds RIP1-002, RIP1-013 - RIP1-020, RIP1-026 - RIP1-030, RIP1-036 - RIP1-040, RIP1-092 - RIP1-135, RIP1-145 -RIP1-150, RIP1-156 - RIP1-165, RIP1-168 - RIP1-180, RIP1-187 -RIP1-189, RIP1-193 - RIP1-205, RIP1-207 - RIP1-210 and RIP1- 214 -RIP1-215 can also be obtained by Method 1.

[0206] Method 2:

[0207] II-1 (30.0 mg) was dissolved in dichloromethane (1 ml), then TFA (0.3 ml) was added and stirred at room temperature for 3 hours. Dichloromethane and TFA were removed by rotary evaporation to give Boc-unprotected aminotrifluoroacetate.

[0208] The intermediate Boc-unprotected compound obtained in the previous step (17.7 mg) was dissolved in DMF (1 ml), then DIEA (43.3 mg), EDCI (19.3 mg) and HOBt (13 ,6 mg), stirred at normal temperature for 1 h and then cooled to 0°C. The trifluoroacetate obtained in the previous step was dissolved in DMF (1 ml), and then slowly added dropwise to the reaction solution. The reaction solution was transferred to room temperature and left to react overnight. After completion of the reaction, water (10 ml) was slowly added, stirred for 0.5 h and extracted with ethyl acetate (10 ml). The ethyl acetate layer was collected, dried, rotary evaporated to dryness, and the residue was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=3:1) to give RIP1-003 (19.0 mg, 66% yield).

[0209] By changing the compound of Formula II and the compound of Formula III, Compounds RIP1-004 - RIP1-012, RIP1-041 - RIP1-058 and RIP1-061 - RIP1-088 can also be obtained by Method 2.

[0210] Method 3:

[0211] Compound 11-4 (27.8 mg, 0.06 mmol) was placed in a 15 ml sealed tube, then 3N HCl (1 ml) and EtOH (0.5 ml) were added and the reaction was carried out at 100°C for 2 h until the reaction is complete, as shown by TLC. The solvent was removed under reduced pressure and the residue was dried in vacuo and redissolved in DMF (4 ml). HATU (28.5 mg, 0.075 mmol), DIEA (38.8 mg, 0.3 mmol) and 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (15.2 mg, 0.075 mmol) were added. mmol) and reacted overnight at room temperature until the reaction was complete as shown by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by reverse phase column chromatography and lyophilized to give RIP1-023: white solid, 10 mg (40%).

[0212] When changing the compound of Formula II and the compound of Formula III, Compounds RIP1-021 - RIP1-025, RIP1-031 - RIP1-035, RIP1-059 - RIP1-060, RIP1-089 - RIP1-091 and RIP1-190 also can be obtained by Method 3.

[0213] Method 4:

[0214] Compound II-25 (1.0 eq.) was placed in a one-necked flask, then a mixed solvent of TFA/H ₂ O (1:1) was added and the reaction was carried out at 50°C for 2 h until the reaction was complete, as was shown by TLC. The solvent was removed under reduced pressure and the residue was dried in vacuo and redissolved in anhydrous DMF. HATU (1.2 eq.), DIPEA (5 eq.) and the crude product from the compound of Step 1) (1.1 eq.) were added and reacted overnight at room temperature until the reaction was complete as shown TLC. The reaction solution was extracted with ethyl acetate, washed with deionized water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was separated by reverse phase column chromatography and lyophilized to give Compound RIP1-136.

[0215] By changing the compound of Formula II and the compound of Formula III, Compounds RIP1-137 - RIP1-143, RIP1-153, RIP1-166 - RIP1-167 and RIP1-181 can also be obtained by Method 4.

[0216] Method 5:

[0217] II-21 (60 mg, 0.1823 mmol) and K ₂ CO ₃ (51 mg, 0.3646 mmol) were added to a 50 ml reaction flask, then THF (3 ml) and H ₂ O (3 ml) and reacted overnight at room temperature. After completion of the reaction, the solvent was removed by rotary evaporation. HATU (84 mg, 0.2187 mmol), III-1 (43 mg, 0.1914 mmol) and DIPEA (150 μl, 0.9118 mmol) were added and then DMF (4 ml) was added as solvent. The reaction was continued at room temperature for 1 hour. After completion of the reaction, reverse phase column chromatography gave RIP1-182 (28 mg, 36.8% yield).

[0218] By changing the compound of Formula II and the compound of Formula III, Compounds RIP1-183 - RIP1-186, RIP1-206, RIP1-211 - RIP1-213 and RIP1-217 - RIP1-222 can also be obtained by Method 5.

[0219] The synthesis method, intermediates and yield of the compound of Formula (I) according to the present application are shown below:

[0220] The analysis data for each compound is shown below.

[0221] RIP1-001

[0222] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.86 (s, 1H), 8.31 (d, J=7.8, 1H), 7.63 (s, 1H), 7 .49 (s, 1H), 7.31-7.26 (m, 2H), 7.25-7.17 (m, 5H), 6.50 (s, 1H), 4.83-4.76 (m, 1H), 4.08 (s, 2H), 3.76 (dd, J=11.1, 6.9, 1H), 3.46 (s, 3H), 2.83 (t, J =11.2, 1H); MS-ERI m/z 433.4 (M+H) ⁺ .

[0223] RIP1-002

[0224] ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.79 (t, J=11.2 Hz, 1H), 3.45 (s, 3H), 3.75 (s, 3H), 3.76-3.80 (m, 1H), 4.06 (s, 2H), 4.66-4.73 (m, 1H), 6.41 (s, 1H), 7.04-7.08 (m, 1H), 7.19-7.30 (m, 5H), 7.45 (s, 1H), 7.56 (s, 1H), 8.16 (br, 1H); MS-ERI (M+H) ⁺ = 447.1.

[0225] RIP1-003

[0226] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.49 (s, 1H), 7.84 (d, J=7.4, 1H), 7.71 (s, 1H), 7 .54 (s, 1H), 7.34-7.29 (m, 3H), 7.28-7.24 (m, 1H), 7.21 (d, J=7.1, 2H), 6 .56-6.54 (m, 1H), 6.26 (s, 1H), 4.78-4.73 (m, 1H), 4.09 (s, 2H), 3.82 (dd, J =11.2, 6.9, 1H), 3.48 (s, 3H), 2.84 (t, J=11.2, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 173.86, 169.89, 158.15, 158.01, 137.99, 135.24, 129.36, 128.88, 128.74, 127, 31, 126.83, 119.90, 117.90, 116.81, 103.06, 101.54, 49.68, 38.12, 37.19, 33.16; MS-ERI: 433.3 (M+H) ⁺ .

[0227] RIP1-004

[0228] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.73 (s, 1H), 7.83 (d, J=0.4, 1H), 7.76 (s, 1H), 7 .68 (s, 1H), 7.52 (s, 1H), 7.37-7.31 (m, 3H), 7.28-7.26 (m, 1H), 7.21 (dd, J =7.7, 1.5, 2H), 7.03 (d, J=7.3, 1H), 6.53-6.50 (m, 1H), 5.27 (s, 2H), 4 .81-4.75 (m, 1H), 3.85 (dd, J=11.2, 6.9, 1H), 3.47 (s, 3H), 2.80 (t J=11.1 , 1Н); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 171.01, 161.45, 138.86, 137.98, 135.42, 134.74, 130.83, 129.45, 129.14, 128, 63, 128.12, 126.99, 119.95, 118.52, 118.03, 116.86, 103.08, 56.63, 49.78, 38.65, 37.33; MS-ERI: 432.4 (M+H) ⁺ .

[0229] RIP1-005

[0230] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.75 (s, 1H), 7.66 (s, 1H), 7.59 (d, J=0.6, 1H), 7 .55 (s, 1H), 7.53 (s, 1H), 7.30-7.23 (m, 4H), 7.19 (d, J=7.3, 1H), 7.08 (d , J=1.7, 1H), 7.06 (s, 1H), 6.53-6.51 (m, 1H), 5.44 (s, 2H), 4.75-4.69 (m , 1H), 3.77 (dd, J=11.2, 6.8, 1H), 3.48 (s, 3H), 2.76 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.55, 159.08, 141.63, 137.96, 136.58, 134.72, 132.64, 129.46, 128.94, 128, 08, 127.32, 127.02, 125.32, 119.90, 117.97, 116.92, 103.08, 50.02, 49.66, 38.47, 37.33, 1.16; MS-ERI: 432.4 (M+H) ⁺ .

[0231] RIP1-006

[0232] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=9.01 (s, 1H), 8.07 (d, J=8.0, 1H), 7.65 (s, 1H), 7 .48 (s, 1H), 7.47 (d, J=1.2, 1H), 7.44 (d, J=1.3, 1H), 7.36-7.31 (m, 3H) , 7.23-7.22 (m, 1H), 7.13 (dd, J=7.6, 1.7, 2H), 6.48-6.45 (m, 1H), 5.08 ( s, 2H), 4.83 (ddd, J=11.2, 7.8, 7.0, 1H), 3.80 (dd, J=11.1, 6.8, 1H), 3.47 (s, 3H), 2.88 (t, J=11.2, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.79, 161.75, 138.15, 137.17, 137.13, 135.27, 134.70, 129.39, 129.27, 128, 74, 127.60, 126.93, 122.47, 119.90, 117.99, 116.74, 102.86, 51.44, 49.37, 38.68, 37.27; MS-ERI: 432.4 (M+H) ⁺ .

[0233] RIP1-007

[0234] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.84 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.61 (dt, J =7.1, 1.6, 1H), 7.54 (s, 1H), 7.42 (d, J=7.2, 1H), 7.35-7.25 (m, 5H), 7 .19 (t, J=7.4, 1H), 7.15 (d, J=7.1, 2H), 6.53-6.51 (m, 1H), 4.88-4.81 ( m, 1H), 4.00 (s, 2H), 3.94 (dd, J=11.1, 6.8, 1H), 3.50 (s, 3H), 2.85 (t, J= 11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.95, 166.48, 141.85, 140.53, 137.95, 134.79, 134.04, 132.55, 129.46, 129, 01, 128.86, 128.70, 127.82, 127.07, 126.42, 124.99, 119.89, 118.08, 116.86, 103.00, 50.35, 41.87, 38.55, 37.32; MS-ERI: 442.4 (M+H) ⁺ .

[0235] RIP1-008

[0236] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=9.03 (s, 1H), 8.22 (d, J=7.6, 1H), 8.02 (s, 1H), 7 .70 (s, 1H), 7.50 (s, 1H), 7.39-7.34 (m, 3H), 7.29-7.27 (m, 2H), 7.25 (d, J =1.8, 1H), 6.49 (s, 1H), 5.36 (s, 2H), 4.87-4.81 (m, 1H), 3.92 (dd, J=11.2 , 6.9, 1H), 3.49 (s, 3H), 2.85 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.36, 158.12, 157.01, 144.07, 137.82, 134.82, 133.91, 129.47, 129.31, 129, 08, 128.37, 127.17, 119.62, 118.30, 116.78, 102.83, 54.45, 49.89, 38.52, 37.36; MS-ERI: 433.4 (M+H) ⁺ .

[0237] RIP1-009

[0238] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.84 (d, J=7.4, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 7 .32 (t, J=7.3, 2H), 7.28 (s, 1H), 7.21 (d, J=7.1, 2H), 7.15 (d, J=3.1, 1H), 6.48 (d, J=3.0, 1H), 6.26 (s, 1H), 4.77-4.70 (m, 1H), 4.08 (s, 2H), 3 .85-3.80 (m, 4H), 3.48 (s, 3H), 2.84 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 173.96, 170.03, 158.33, 158.12, 137.72, 135.63, 135.41, 131.53, 129.95, 129, 02, 128.89, 127.46, 119.55, 117.07, 116.41, 101.70, 101.57, 49.83, 38.33, 37.31, 33.31, 31.77; MS-ERI: 447.4 (M+H) ⁺ .

[0239] RIP1-010

[0240] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.82 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.51 (s, 1H ), 7.37-7.31 (m, 3H), 7.23-7.20 (m, 2H), 7.14 (d, J=3.1, 1H), 6.96 (d, J =7.3, 1H), 6.47(d, J=3.0, 1H), 5.27(s, 2H), 4.77-4.71(m, 1H), 3.87-3 .82 (m, 4H), 3.47 (s, 3H), 2.78 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 171.00, 161.31, 138.80, 137.66, 135.66, 135.46, 131.49, 130.81, 129.91, 129, 13, 128.61, 128.12, 119.63, 118.60, 117.04, 116.41, 101.55, 56.62, 49.75, 38.71, 37.30, 33.30; MS-ERI: 446.4 (M+H) ⁺ .

[0241] RIP1-011

[0242] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.66 (s, 1H), 7.63 (s, 1H), 7.59 (d, J=7.3, 1H), 7 .53 (s, 1H), 7.35 (d, J=7.1, 1H), 7.34-7.25 (m, 4H), 7.19 (t, J=7.4, 1H) , 7.16 (d, J=1.2, 1H), 7.15 (d, J=3.0, 2H), 6.48 (d, J=3.7, 1H), 4.83- 4.77 (m, 1H), 4.00 (s, 2H), 3.91 (dd, J=11.1, 6.8, 1H), 3.84 (s, 3H), 3.50 ( s, 3H), 2.82 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.97, 166.28, 141.78, 140.56, 137.68, 135.67, 134.16, 132.43, 131.50, 129, 92, 129.01, 128.81, 128.69, 127.81, 126.40, 124.97, 119.63, 117.06, 116.42, 101.56, 50.29, 41.87, 38.60, 37.27, 33.29; MS-ERI: 456.4 (M+H) ⁺ .

[0243] RIP1-012

[0244] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.18 (d, J=7.5, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 7 .51 (s, 1H), 7.39-7.34 (m, 3H), 7.27 (d, J=2.5, 1H), 7.26 (d, J=2.0, 1H) , 7.15 (d, J=3.1, 1H), 6.47 (dd, J=3.1, 0.7, 1H), 5.35 (s, 2H), 4.83-4, 77 (m, 1H), 3.91 (dd, J=11.2, 6.9, 1H), 3.84 (s, 3H), 3.48 (s, 3H), 2.83 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.36, 157.94, 157.08, 143.97, 137.67, 135.65, 133.95, 131.49, 129.94, 129, 30, 129.06, 128.36, 119.55, 117.06, 116.53, 101.51, 54.42, 49.80, 38.53, 37.32, 33.29; MS-ERI: 447.4 (M+H) ⁺ .

[0245] RIP1-013

[0246] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.89 (s, 1H), 7.68 (s, 1H), 7.37-7.21 ( m, 5H), 4.87-4.74 (m, 1H), 4.13 (s, 2H), 3.87-3.74 (m, 1H), 3.50 (s, 3H), 2 .99-2.87 (m, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.0, 158.2, 138.8, 138.6, 135.9, 134.2, 128.8, 127.2, 126.1, 123, 8, 117.5, 116.8, 49.5, 37.5, 37.3, 33.2. MS-ERI: m/z 434.1 (M+H) ⁺ .

[0247] RIP1-014

[0248] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.82 (s, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.81 (s, 1H) , 7.66 (s, 1H), 7.60-7.54 (m, 2H), 7.38-7.31 (m, 3H), 7.24-7.19 (m, 2H), 5 .25 (s, 2H), 4.90 (dt, J=11.4, 7.4 Hz, 1H), 3.79 (dd, J=11.3, 6.8 Hz, 1H), 3, 43 (s, 3H), 2.93 (t, J=11.4 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.0, 162.1, 139.1, 138.6, 138.5, 135.3, 134.7, 131.1, 129.1, 128, 6, 128.2, 126.0, 123.9, 118.0, 116.8, 116.8, 56.6, 49.6, 37.7, 37.6. MS-ERI: m/z 433.1 (M+H) ⁺ .

[0249] RIP1-015

[0250] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.97 (s, 1H), 8.01 (s, 1H), 7.92 (d, J=7.1 Hz, 1H), 7 .80 (s, 1H), 7.63 (s, 1H), 7.36-7.15 (m, 5H), 6.27 (s, 1H), 4.88-4.72 (m, 1H ), 4.07 (s, 2H), 3.80 (dd, J=11.0, 6.7 Hz, 1H), 3.47 (s, 3H), 2.89 (t, J=11, 2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.2, 169.7, 158.5, 158.1, 138.9, 138.7, 135.3, 135.0, 129.0, 128, 9, 127.5, 126.5, 124.2, 117.0, 116.9, 101.7, 49.6, 37.6, 37.5, 33.3. MS-ERI: m/z 434.1 (M+H) ⁺ .

[0251] RIP1-016

[0252] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.94 (s, 1H), 8.17 (d, J=8.2 Hz, 1H), 7.88 (d, J=0, 7 Hz, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 7.49 (s, 1H), 7.48 (s, 1H), 7.35-7.29 ( m, 3H), 7.15-7.10 (m, 2H), 5.08 (s, 2H), 4.91 (ddd, J=11.4, 8.0, 7.0 Hz, 1H) , 3.79 (dd, J=11.1, 6.7 Hz, 1H), 3.43 (s, 3H), 2.96 (t, J=11.3 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.3, 162.2, 138.7, 138.6, 137.3, 136.7, 135.2, 134.5, 129.3, 128, 7, 127.6, 126.0, 123.8, 122.8, 116.7, 116.6, 51.4, 49.1, 37.8, 37.4. MS-ERI: m/z 433.1 (M+H) ⁺ .

[0253] RIP1-017

[0254] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.61 (br, 1H), 8.00 (s, 1H), 7.80-7.46 (m, 5H), 7.26- 7.13 (m, 3H), 7.12-6.97 (m, 2H), 5.44 (k, J=15.0 Hz, 2H), 4.77 (s, 1H), 3.79 -3.66 (m, 1H), 3.48 (s, ZN), 2.86 (t, J=11.0 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.5, 159.4, 141.8, 138.7, 136.5, 134.8, 133.0, 128.9, 128.1, 127, 3, 126.3, 125.1, 124.0, 117.0, 116.9, 53.6, 50.2, 49.4, 37.6. MS-ERI: m/z 433.1 (M+H) ⁺ .

[0255] RIP1-019

[0256] ¹ H-NMR (400 MHz, CDCl ₃ +CD ₃ OD) δ 7.99 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.64 ( s, 1H), 7.38-7.30 (m, 3H), 7.25-7.19 (m, 2H), 5.58-5.45 (m, 2H), 4.78 (dd, J=11.3, 6.7 Hz, 1H), 3.75 (dd, J=11.1, 6.8 Hz, 1H), 3.46 (s, 3H), 2.91 (t, J =11.3 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ +CD ₃ OD) δ 170.0, 159.4, 142.8, 138.9, 138.7, 134.5, 133.8, 129.3, 129, 2, 128.3, 126.4, 125.7, 124.0, 117.1, 116.9, 54.6, 49.2, 37.51, 37.49. MS-ERI: m/z 434.1 (M+H) ⁺ .

[0257] RIP1-020

[0258] ¹ H-NMR (400 MHz, CDCl ₃ +CD ₃ OD) δ 8.07 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.66 ( s, 1H), 7.40-7.33 (m, 3H), 7.29-7.26 (m, 2H), 5.37 (s, 2H), 4.82 (dd, J=11, 2, 6.8 Hz, 1H), 3.86 (dd, J=11.1, 6.8 Hz, 1H), 3.49 (s, 3H), 2.88 (t, J=11.2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ +CD ₃ OD) δ 170.1, 158.1, 156.6, 144.2, 138.8, 138.6, 134.4, 133.8, 129, 3, 129.1, 128.3, 126.1, 123.9, 117.5, 116.8, 54.4, 49.6, 49.5, 37.52, 37.47. MS-ERI: m/z 434.1 (M+H) ⁺ .

[0259] RIP1-021

[0260] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.49 (s, 1H), 8.05 (s, 1H), 7.80 (d, J=6.3 Hz, 1H), 7 .60 (s, 1H), 7.35-7.27 (m, 4H), 7.24-7.19 (m, 2H), 6.29 (s, 1H), 5.07-4.98 (m, 1H), 4.69 (dd, J=9.8, 7.4 Hz, 1H), 4.24 (dd, J=11.1, 9.9 Hz, 1H), 4.10 ( s, 2H), 3.51 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.3, 168.4, 158.8, 158.0, 150.0, 138.6, 135.3, 135.2, 131.7, 129, 1, 128.9, 127.5, 120.6, 115.4, 103.2, 101.7, 76.6, 49.2, 36.7, 33.3. MS-ERI: m/z 418.0 (M+H) ⁺ .

[0261] RIP1-022

[0262] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.00 (br, 1H), 8.07-7.96 (m, 2H), 7.53 (s, 1H), 7.51- 7.46 (m, 2H), 7.38-7.30 (m, 3H), 7.19-7.11 (m, 2H), 5.15-5.04 (m, 3H), 4. 70-4.63 (m, 1H), 4.31-4.22 (m, 1H), 3.48 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.1, 162.4, 150.0, 137.3, 136.8, 135.2, 134.9, 131.8, 129.3, 128, 8, 127.7, 122.7, 115.1, 103.0, 77.0, 51.5, 48.7, 36.5. MS-ERI: m/z 417.1 (M+H) ⁺ .

[0263] RIP1-023

[0264] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.56 (s, 1H), 7.31-7.27 (m, 2H), 7.26- 7.17 (m, 4H), 5.01 (dd, J=11.2, 7.4 Hz, 1H), 4.67-4.58 (m, 1H), 4.26-4.17 ( m, 1H), 4.10 (s, 2H), 3.47 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.6, 158.7, 154.5, 149.7, 138.7, 135.9, 134.3, 131.4, 128.9, 127, 3, 120.3, 115.2, 103.6, 76.4, 49.0, 36.6, 33.3. MS-ERI: m/z 418.1 (M+H) ⁺ .

[0265] RIP1-024

[0266] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.93 (br, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.91 (s, 1H), 7 .84 (s, 1H), 7.47 (s, 1H), 7.26 (s, 2H), 7.17 (s, 3H), 5.53-5.36 (m, 2H), 5. 07-4.91 (m, 1H), 4.56 (t, J=8.5 Hz, 1H), 4.19 (t, J=10.4 Hz, 1H), 3.41 (s, 3H ); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.6, 159.9, 149.9, 142.8, 138.6, 134.9, 133.8, 131.7, 129.4, 129, 2, 128.4, 125.7, 120.5, 115.2, 103.1, 76.7, 54.7, 48.9, 36.6. MS-ERI: m/z 418.1 (M+H) ⁺ .

[0267] RIP1-025

[0268] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.54 (br, 1H), 8.17-7.86 (m, 3H), 7.47 (s, 1H), 7.33- 7.26 (m, 3H), 7.23-7.16 (m, 2H), 5.30 (s, 2H), 5.09-4.96 (m, 1H), 4.71 (t, J=8.2 Hz, 1H), 4.18 (t, J=10.3 Hz, 1H), 3.43 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.6, 158.8, 156.7, 149.6, 144.3, 138.8, 134.6, 133.8, 131.3, 129, 3, 129.1, 128.5, 120.5, 115.0, 103.7, 76.7, 54.5, 49.4, 36.6. MS-ERI: m/z 418.1 (M+H) ⁺ .

[0269] RIP1-026

[0270] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.81 (s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.81 (s, 1H) , 7.51 (s, 1H), 7.41-7.34 (m, 3H), 7.33-7.27 (m, 2H), 5.38 (s, 2H), 4.88-4 .75 (m, 1H), 3.96 (dd, J=10.7, 6.7 Hz, 1H), 3.51 (s, 3H), 2.92 (t, J=11.1 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.7, 158.5, 156.7, 144.3, 139.9, 139.2, 134.8, 133.7, 129.4, 129, 2, 128.5, 127.4, 121.3, 118.3, 115.2, 54.6, 49.8, 37.6, 37.4. MS-ERI: m/z 468.0 (M+H) ⁺ .

[0271] RIP1-027

[0272] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.23 (brc, 1H), 7.81 (s, 1H), 7.54 (s, 1H), 7.29-7.26 ( m, 1H), 7.25-7.20 (m, 4H), 4.70 (dd, J=11.2, 6.8 Hz, 1H), 4.10 (s, 2H), 3.72 (dd, J=11.0, 6.8 Hz, 1H), 3.47 (s, 3H), 2.86 (t, J=11.2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.8, 158.4, 139.9, 139.4, 135.8, 134.6, 129.0, 128.9, 127.9, 127, 3, 121.2, 118.4, 115.3, 49.5, 37.6, 37.2, 33.2. MS-ERI: m/z 466.0 (M-H) ^- .

[0273] RIP1-028

[0274] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.69 (s, 1H), 8.16 (d, J=7.9 Hz, 1H), 7.68 (s, 1H), 7 .51-7.44 (m, 3H), 7.37-7.31 (m, 3H), 7.17-7.10 (m, 2H), 5.12 (d, J=16.7 Hz , 2H), 4.87 (dt, J=11.5, 7.2 Hz, 1H), 3.82 (dd, J=11.0, 6.6 Hz, 1H), 3.47 (s, 3H), 2.97 (t, J=11.3 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.1, 162.3, 139.7, 139.6, 137.4, 136.6, 135.1, 135.0, 129.3, 128, 8, 127.9, 127.7, 122.9, 121.2, 117.3, 115.3, 51.5, 49.1, 37.7, 37.5. MS-ERI: m/z 467.0 (M+H) ⁺ .

[0275] RIP1-029

[0276] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.90 (brc, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H) , 7.37-7.27 (m, 3H), 7.24-7.19 (m, 2H), 6.28 (s, 1H), 4.78 (dd, J=11.2, 6, 7 Hz, 1H), 4.09 (s, 2H), 3.81 (dd, J=11.1, 6.7 Hz, 1H), 3.50 (s, 3H), 2.92 (t, J=11.3 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.3, 169.5, 158.6, 158.0, 139.7, 139.7, 135.5, 135.3, 129.1, 128, 9, 128.2, 127.5, 121.5, 117.5, 115.6, 101.7, 49.5, 37.6, 37.3, 33.3. MS-ERI: m/z 4 68.0 (M+H) ⁺ .

[0277] RIP1-030

[0278] ¹ H-NMR (400 MHz, CDCl ₃ +CD ₃ OD) δ 11.85 (br, 1H), 8.19 (d, J=7.1 Hz, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.41-7.31 (m, 3H), 7.26-7.19 (m, 2H), 5.57 -5.46 (m, 2H), 4.84-4.68 (m, 1H), 3.76 (dd, J=10.7, 6.7 Hz, 1H), 3.45 (d, J =29.4 Hz, 3H), 2.92 (t, J=11.2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ +CD ₃ OD) δ 169.9, 159.4, 142.8, 139.7, 139.6, 134.9, 133.8, 129.4, 129, 2, 128.3, 128.1, 125.7, 121.3, 117.7, 115.5, 54.6, 49.2, 37.6, 37.4. MS-ERI: m/z 468.1 (M+H) ⁺ .

[0279] RIP1-031

[0280] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.05 (s, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.53-7.46 (m, 2H), 7.43 (s, 1H), 7.39-7.30 (m, 3H), 7.18 (s, 1H), 7.17-7.11 (m, 2H), 5.21 -5.04 (m, 3H), 4.72-4.63 (m, 1H), 4.29 (dd, J=11.3, 9.9 Hz, 1H), 3.51 (s, 3H ); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.8, 162.8, 150.7, 139.7, 137.4, 136.4, 135.1, 134.7, 132.3, 129, 3, 128.8, 127.7, 122.9, 117.6, 113.6, 103.5, 76.8, 51.5, 48.7, 36.5. MS-ERI: m/z 451.1 (M+H) ⁺ .

[0281] RIP1-032

[0282] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.53 (s, 1H), 8.15 (d, J=6.4 Hz, 1H), 8.08 (s, 1H), 7 .46 (s, 1H), 7.40-7.28 (m, 5H), 5.37 (s, 2H), 5.07 (dt, J=11.1, 6.9 Hz, 1H), 4.85 (dd, J=9.6, 7.4 Hz, 1H), 4.35-4.25 (m, 1H), 3.52 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.4, 159.0, 156.5, 150.3, 144.4, 139.9, 134.4, 133.7 131.8, 129.3 , 129.2, 128.5, 117.7, 113.5, 104.6, 76.6, 54.6, 49.5, 36.6. MS-ERI: m/z 452.1 (M+H) ⁺ .

[0283] RIP1-033

[0284] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 11.38 (br, 1H), 7.83 (br, 1H), 7.40 (s, 1H), 7.30-7.11 ( m, 6H), 6.24 (s, 1H), 5.07-4.93 (m, 1H), 4.67-4.55 (m, 1H), 4.21 (t, J=10, 5 Hz, 1H), 4.02 (s, 2H), 3.45 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.4, 168.2, 159.1, 157.8, 150.8, 139.7, 135.2, 135.1, 132.3, 129, 0, 128.9, 127.5, 117.8, 114.0, 103.8, 101.7, 76.4, 49.1, 36.7, 33.3. MS-ERI: m/z 452.1 (M+H) ⁺ .

[0285] RIP1-034

[0286] ¹ H-NMR (400 MHz, CDCl ₃ +CD ₃ OD) δ 7.45 (s, 1H), 7.32-7.12 (m, 6H), 5.05-4.92 (m , 1H), 4.61 (t, J=8.4 Hz, 1H), 4.22 (t, J=10.4 Hz, 1H), 4.08 (s, 2H), 3.46 (s , 3Н); ¹³ C-NMR (100 MHz, CDCl ₃ +CD ₃ OD) δ 168.5, 158.8, 150.5, 139.9, 135.7, 134.3, 132.0, 128.84, 128, 80, 127.2, 117.6, 113.7, 104.2, 76.3, 49.0, 36.6, 33.1. MS-ERI: m/z 452.1 (M+H) ⁺ .

[0287] RIP1-035

[0288] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.49 (s, 1H), 7.36-7.32 (m, 2H), 7.29- 7.18 (m, 5H), 5.51 (s, 2H), 5.07-4.95 (m, 1H), 4.61 (dd, J=9.7, 7.4 Hz, 1H) , 4.29-4.20 (m, 1H), 3.49 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.6, 159.8, 150.6, 142.3, 139.8, 134.3, 133.8, 132.1, 129.2, 129, 0, 128.1, 125.8, 117.5, 113.8, 103.9, 76.3, 54.4, 48.6, 36.5. MS-ERI: m/z 452.1 (M+H) ⁺ .

[0289] RIP1-036

[0290] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.01 (d, J=7.7 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J=1, 8 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=7.7 Hz, 2H), 7.38-7.29 (m, 3H), 7.17-7, 07 (m, 2H), 6.76 (s, 1H), 5.08 (s, 2H), 4.77 (dt, J=11.1, 7.5 Hz, 1H), 3.79 (dd , J=11.0, 6.8 Hz, 1H), 3.45 (s, 3H), 2.89 (t, J=11.2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.6, 161.6, 153.1, 147.4, 141.4, 137.1, 135.3, 129.6, 129.2, 128, 7, 127.6, 123.3, 122.4, 118.3, 117.3, 106.8, 51.4, 49.1, 38.7, 37.1. MS-ERI: m/z 433.1 (M+H) ⁺ .

[0291] RIP1-037

[0292] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J=7.7 Hz, 1H), 8.02 (s, 1H), 7.82 (s, 1H), 7 .70 (d, J=2.2 Hz, 1H), 7.50 (s, 1H), 7.38-7.32 (m, 3H), 7.27-7.22 (m, 2H), 6.77 (dd, J=2.1, 0.9 Hz, 1H), 5.35 (s, 2H), 4.80 (dt, J=11.1, 7.2 Hz, 1H), 3 .89 (dd, J=11.2, 6.9 Hz, 1H), 3.45 (s, 3H), 2.87 (t, J=11.2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.2, 157.9, 156.9, 153.1, 147.5, 144.0, 141.0, 133.9, 129.6, 129, 2, 129.0, 128.3, 123.0, 118.4, 117.3, 106.7, 54.3, 49.5, 38.5, 37.2. MS-ERI: m/z 434.1 (M+H) ⁺ .

[0293] RIP1-038

[0294] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.87-7.79 (m, 2H), 7.71 (d, J=2.1 Hz, 1H), 7.52 (s, 1H), 7.35-7.19 (m, 5H), 6.79 (d, J=1.3 Hz, 1H), 6.27 (s, 1H), 4.74 (dt, J=11 .2, 7.2 Hz, 1H), 4.08 (s, 2H), 3.83 (dd, J=11.1, 6.9 Hz, 1H), 3.46 (s, 3H), 2 .88 (t, J=11.2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.0, 169.9, 158.2, 158.1, 153.1, 147.5, 141.1, 135.3, 129.7, 129, 0, 128.9, 127.4, 123.1, 118.4, 117.4, 106.8, 101.7, 49.6, 38.3, 37.2, 33.3. MS-ERI: m/z 434.1 (M+H) ⁺ .

[0295] RIP1-039

[0296] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J=7.9 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J=2, 1 Hz, 1H), 7.46 (s, 1H), 7.15 (s, 5H), 6.76 (d, J=1.3 Hz, 1H), 4.77 (dt, J=11, 3, 7.4 Hz, 1H), 4.06 (s, 2H), 3.74 (dd, J=11.2, 6.9 Hz, 1H), 3.42 (s, 3H), 2, 87 (t, J=11.3 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.4, 158.7, 153.1, 147.5, 141.1, 136.1, 129.8, 128.9, 128.7, 127, 0, 123.0, 118.3, 117.4, 106.8, 49.6, 38.3, 37.3, 32.9. MS-ERI: m/z 434.1 (M+H) ⁺ .

[0297] RIP1-040

[0298] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J=7.5 Hz, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7 .70 (d, J=1.7 Hz, 1H), 7.51 (s, 1H), 7.39-7.31 (m, 3H), 7.26-7.20 (m, 2H), 6.78 (s, 1H), 5.59-5.45 (m, 2H), 4.77 (dt, J=11.1, 7.3 Hz, 1H), 3.81 (dd, J= 11.1, 6.9 Hz, 1H), 3.46 (s, 3H), 2.91 (t, J=11.2 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.2, 159.1, 153.1, 147.5, 143.1, 141.3, 133.9, 129.7, 129.4, 129, 2, 128.3, 125.4, 123.2, 118.3, 117.3, 106.8, 54.6, 49.3, 38.5, 37.2. MS-ERI: m/z 434.1 (M+H) ⁺ .

[0299] RIP1-041

[0300] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.59 (s, 1H), 8.12 (br, 1H), 7.72 (s, 1H), 7.55 (s, 1H ), 7.34-7.27(m, 6H), 6.56(s, 1H), 4.77-4.70(m, 1H), 4.23(s, 2H), 3.84( dd, J=11.2, 6.9, 1H), 3.49 (s, 3H), 2.84 (t, J=11.1, 1H). MS-ERI: 434.1 (M+H) ⁺ .

[0301] RIP1-042

[0302] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.83 (s, 1H), 8.16 (d, J=7.8, 1H), 7.86 (s, 1H), 7 .67 (s, 1H), 7.51 (s, 1H), 7.37-7.33 (m, 3H), 7.26-7.21 (m, 3H), 6.50 (s, 1H ), 5.51 (d, J=7.1, 2H), 4.85-4.79 (m, 1H), 3.81 (dd, J=11.2, 6.9, 1H), 3 .48 (s, 3H), 2.88 (t, J=11.2, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.33, 159.19, 143.19, 138.10, 134.68, 133.93, 129.45, 129.37, 129.17, 128, 31, 127.00, 125.44, 119.89, 118.01, 116.83, 102.98, 54.59, 49.56, 38.48, 37.33; MS-ERI: 433.2 (M+H) ⁺ .

[0303] RIP1-043

[0304] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.83 (s, 1H), 8.19 (d, J=7.4, 1H), 7.72 (s, 1H), 7 .53 (s, 1H), 7.39-7.34 (m, 5H), 7.31-7.29 (m, 1H), 6.54-6.52 (m, 1H), 5.79 (s, 2H), 4.86-4.81 (m, 1H), 3.92 (dd, J=11.2, 6.9, 1H), 3.49 (s, 3H), 2.85 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 169.94, 159.74, 155.64, 137.78, 134.80, 132.51, 129.54, 129.43, 129.26, 128, 73, 127.21, 119.64, 118.26, 116.88, 103.00, 57.59, 50.07, 38.32, 37.40; MS-ERI: 434.1 (M+H) ⁺ .

[0305] RIP1-044

[0306] ¹ H-NMR (400 MHz, CDCl ₃ ) δ=9.17 (s, 1H), 7.89 (d, J=7.8, 1H), 7.66 (s, 1H), 7 .49 (s, 1H), 7.23 (t, J=2.7, 1H), 7.08 (d, J=7.8, 2H), 6.98 (d, J=7.9, 2H), 6.46 (s, 1H), 6.46 (s, 1H), 4.88-4.80 (m, 1H), 3.91 (s, 2H), 3.86 (dd, J =11.1, 6.8, 1H), 3.69 (s, 3H), 3.48 (s, 3H), 2.87 (t, J=11.2, 1H), 2.30 (s , 3Н); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.84, 161.46, 144.46, 143.36, 137.92, 136.61, 134.74, 133.66, 129.58, 129, 36, 128.34, 127.05, 119.66, 118.07, 116.69, 106.81, 102.72, 77.48, 77.16, 76.84, 49.50, 38.65, 37.27, 37.12, 31.56, 21.12; MS-ERI: 460.2 (M+H) ⁺ .

[0307] RIP1-045

[0308] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.68 (s, 1H), 7.69 (s, 1H), 7.54 (s, 1H), 7.28 (s, 1H ), 7.14-7.07 (m, 5H), 6.54 (s, 1H), 6.30 (s, 1H), 4.75-4.68 (m, 1H), 4.01 ( s, 3H), 3.89 (s, 2H), 3.81 (dd, J=11.0, 6.8, 1H), 3.47 (s, 3H), 2.78 (t, J= 11.1, 1H), 2.33 (s, 3H); MS-ERI: 460.15 (M+H) ⁺ .

[0309] RIP1-046

[0310] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.85 (s, 1H), 8.00 (s, 1H), 7.99 (d, J=8.4, 1H), 7 .68 (s, 1H), 7.52 (s, 1H), 7.35-7.31 (m, 2H), 7.30-7.25 (m, 3H), 6.50 (s, 1H ), 4.83-4.77 (m, 1H), 4.10 (s, 2H), 3.83 (dd, J=11.1, 6.8, 1H), 3.49 (s, 3H ), 2.87 (t, J=11.2, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.31, 162.98, 159.70, 141.31, 137.89, 135.78, 134.64, 134.58, 129.33, 128, 80, 128.80, 127.31, 126.89, 119.70, 117.90, 116.70, 102.85, 49.36, 38.37, 37.16, 34.49; MS-ERI: 433.1 (M+H) ⁺ .

[0311] RIP1-047

[0312] ¹ H-NMR (500 MHz, CD ₃ OD) δ=7.74 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.40 (d, J=3.1, 1H), 7.34-7.29 (m, 2H), 7.26-7.21 (m, 3H), 6.55 (dd, J=3.1, 0.7 , 1H), 4.10 (s, 2H), 3.94-3.90 (m, 1H), 3.64 (dd, J=11.2, 6.9, 1H), 3.45 (s , 3H), 2.95 (t, J=11.4, 1H); MS-ERI: 432.1 (M+H) ⁺ .

[0313] RIP1-048

[0314] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.15 (d, J=7.5, 1H), 7.86 (s, 1H), 7.64 (s, 1H), 7 .52 (s, 1H), 7.38-7.34 (m, 3H), 7.26-7.22 (m, 2H), 7.14 (d, J=2.8, 1H), 6 .47 (d, J=3.0, 1H), 5.52 (d, J=7.6, 2H), 4.81-1.74 (m, 1H), 3.82 (s, 3H) , 3.80 (dd, J=7.0, 4.2, 1H), 3.48 (s, 3H), 2.87 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.30, 159.10, 143.24, 137.88, 135.60, 133.96, 131.45, 129.92, 129.38, 129, 18, 128.32, 125.43, 119.69, 117.06, 116.37, 101.54, 54.60, 49.56, 38.52, 37.30, 33.29; MS-ERI: 447.4 (M+H) ⁺ .

[0315] RIP1-049

[0316] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.00 (s, 1H), 7.95 (d, J=7.6, 1H), 7.65 (s, 1H), 7 .53 (s, 1H), 7.37-7.32 (m, 2H), 7.31-7.27 (m, 3H), 7.15 (d, J=3.0, 1H), 6 .48 (d, J=3.0, 1H), 4.79-4.73 (m, 1H), 4.11 (s, 2H), 3.85-3.81 (m, 4H), 2 .86 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.47, 163.01, 159.70, 141.36, 137.83, 136.05, 135.63, 134.85, 131.47, 129, 94, 128.94, 127.44, 119.65, 119.54, 117.06, 116.40, 101.55, 49.45, 38.56, 37.26, 34.65, 33.30; MS-ERI: 447.4 (M+H) ⁺ .

[0317] RIP1-050

[0318] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.85 (b, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.34 (d, J =7.0, 2H), 7.23 (t, J=7.3, 2H), 7.20-7.16 (m, 2H), 7.14 (d, J=3.0, 1H) , 7.02 (d, J=5.9, 1H), 6.47 (d, J=3.1, 1H), 5.29 (s, 2H), 4.72-4.67 (m, 1H), 3.80 (s, 3H), 3.68 (dd, J=11.4, 7.0, 1H), 3.41 (s, 3H), 3.17 (t, J=11, 4, 1H); ¹³ C-NMR (126 MHz, CDCl ₃ ) δ 171.54, 159.75, 148.15, 137.59, 135.62, 131.65, 129.99, 129.25, 129.17, 128, 78, 128.60, 127.73, 119.59, 117.19, 116.18, 101.75, 101.54, 53.56, 50.53, 49.68, 37.71, 33.29; MS-ERI: 447.3 (M+H) ⁺ .

[0319] RIP1-051

[0320] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.64 (s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 7.65 (d, J = 7.3, 1H), 7.56 (s, 1H), 7.32-7.30 (m, 1H), 7.25-7.19 (m, 5H), 6.57-6.55 (m, 1H), 5.82 (d, J=3.1, 2H), 4.76-4.70 (m, 1H), 3.75 (dd, J=11.3, 7.0, 1H), 3.48 (s, 3H), 2.79 (t, J=11.2, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.38, 156.74, 137.78, 135.46, 134.75, 134.24, 129.92, 129.57, 128.78, 128, 31, 128.05, 127.16, 119.75, 118.03, 117.03, 103.24, 53.28, 50.04, 38.17, 37.49 MS-ERI: 433.1 (M +Н) ⁺ .

[0321] RIP1-052

[0322] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.02 (s, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.41 (d, J =7.2, 1H), 7.26-7.20 (m, 5H), 7.17 (d, J=3.0, 1H), 6.50 (d, J=3.0, 1H) , 5.82 (s, 2H), 4.71-4.65 (m, 1H), 3.84 (s, 3H), 3.77 (dd, J=11.2, 6.9, 1H) , 3.48 (s, 3H), 2.75 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.15, 156.66, 137.40, 135.98, 135.69, 135.45, 134.14, 131.69, 130.00, 128, 78, 128.34, 128.11, 119.33, 117.14, 116.43, 101.64, 53.24, 50.03, 38.26, 37.39, 33.32; MS-ERI: 447.3 (M+H) ⁺ .

[0323] RIP1-054

[0324] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.62 (s, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 7.52 (s, 1H ), 7.27 (s, 1H), 7.26-7.23 (m, 2H), 7.16 (d, J=7.1, 1H), 7.14 (d, J=2.9 , 1H), 7.07 (d, J=7.0, 2H), 6.47 (d, J=3.0, 1H), 5.44 (s, 2H), 4.71-4.65 (m, 1H), 3.81 (s, 3H), 3.77 (dd, J=11.1, 6.7, 1H), 3.47 (s, 1H), 2.75 (t, J =11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.53, 159.00, 141.58, 137.61, 136.60, 135.62, 132.56, 131.51, 129.90, 128, 91, 128.06, 127.35, 127.27, 119.52, 117.06, 116.35, 101.55, 49.97, 49.63, 38.50, 37.26, 33.25; MS-ERI: 446.4 (M+H) ⁺ .

[0325] RIP1-055

[0326] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.03 (d, J=7.7, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7 .45 (s, 1H), 7.43 (s, 1H), 7.35-7.30 (m, 3H), 7.13 (d, J=3.5, 3H), 6.46 (d , J=3.0, 1H), 5.07 (s, 2H), 4.80-4.75 (m, 1H), 3.82-3.78 (m, 4H), 3.47 (s , 3H), 2.86 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.77, 161.55, 138.01, 137.24, 137.06, 135.56, 135.31, 131.33, 129.86, 129, 23, 128.69, 127.57, 122.37, 119.81, 117.00, 116.33, 101.48, 51.40, 49.30, 38.69, 37.21, 33.25; MS-ERI: 446.4 (M+H) ⁺ .

[0327] RIP1-056

[0328] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.84 (d, J=7.6, 1H), 7.64 (s, 1H), 7.51 (s, 1H), 7 .14 (d, J=2.9, 1H), 7.08 (d, J=7.8, 2H), 6.98 (d, J=7.8, 2H), 6.47 (d, J=3.0, 1H), 6.45(s, 1H), 4.81-4.75(m, 1H), 3.90(s, 2H), 3.86-3.82(m, 4H), 3.69 (s, 3H), 3.48 (s, 3H), 2.84 (t, J=11.1, 1H), 2.31 (s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.86, 161.24, 144.67, 143.21, 137.91, 136.60, 135.60, 133.73, 131.38, 129, 89 129.58 128.34 119.76 117.01 116.39 106.82 101.50 49.46 38.69 37.22 37.09 33.27 31.58, 21.12; MS-ERI: 474.4 (M+H) ⁺ .

[0329] RIP1-057

[0330] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.63 (s, 1H), 7.52 (s, 1H), 7.14 (d, J=3.0, 1H), 7 .13-7.09 (m, 4H), 7.07 (d, J=7.3, 1H), 6.47 (d, J=3.0, 1H), 6.29 (s, 1H) , 4.72-4.66 (m, 1H), 4.01 (s, 3H), 3.89 (s, 2H), 3.83-3.78 (m, 4H), 3.47 (s , 3H), 2.77 (t, J=11.1, 1H), 2.33 (s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.44, 158.73, 150.97, 137.56, 136.44, 136.02, 135.64, 135.30, 131.55, 129, 94, 129.42, 128.74, 119.42, 117.01, 116.37, 105.91, 101.57, 49.71, 39.07, 38.45, 37.18, 34.20 33.26, 21.17; MS-ERI: 474.4 (M+H) ⁺ .

[0331] RIP1-058

[0332] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.32 (s, 1H), 8.12 (d, J=7.4, 1H), 7.65 (s, 1H), 7 .53 (s, 1H), 7.36-7.29 (m, 4H), 7.16 (d, J=3.0, 1H), 6.49 (d, J=3.0, 1H) , 4.74-4.68 (m, 1H), 4.23 (s, 2H), 3.86-3.81 (m, 4H), 3.48 (s, 3H), 2.85 (t , J=11.1, 1H); MS-ERI: 448.4 (M+H) ⁺ .

[0333] RIP1-059

[0334] ¹ H-NMR (400 MHz, Methanol-d ₄ ) δ 8.31 (s, 1H), 7.97 (s, 1H), 7.81 (dd, J=9.0, 1.4 Hz, 1H), 7.79-7.73 (m, 2H), 7.61 (d, J=1.3 Hz, 1H), 7.39-7.24 (m, 6H), 5.26 (s, 1H), 5.22 (s, 2H), 4.69 (dd, J=11.5, 6.9 Hz, 1H), 3.68 (dd, J=11.3, 6.9 Hz, 1H), 3.46 (s, 3H), 2.98 (t, J=11.4 Hz, 1H); ERI: m/z 433.1 (M+H) ⁺ .

[0335] RIP1-060

[0336] ¹ H-NMR (400 MHz, Methanol-d ₄ ) δ 8.55 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.36-7.34 (m, 4H), 7.33 (d, J=3.5 Hz, 5H), 5.44 (s, 2H), 5.42 (s, 1H), 4.71 (dd, J=11.6, 6.9 Hz, 1H), 3.68 (dd, J=11.4, 6.9 Hz, 1H), 3.45 (s, 2H), 3 .15-2.95 (m, 1H); ERI: m/z 434.1 (M+H) ⁺ .

[0337] RIP1-061

[0338] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.82 (d, J=7.0, 1H), 7.38 (br, 1H), 7.35-7.24 (m, 5H), 7.21 (d, J=7.3, 2H), 6.27 (s, 1H), 4.99-4.93 (m, 1H), 4.66 (dd, J=9, 4, 7.9, 1H), 4.22 (t, J=10.5, 1H), 4.09 (s, 2H), 3.42 (s, 3H), 2.61 (s, 3H) ; MS-ERI: 432.1 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₃ H ₂₂ O ₄ N ₅ (M+H) ⁺ : 432.1666, found: 432.1662.

[0339] RIP1-062

[0340] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.87 (s, 1H), 7.79 (s, 1H), 7.37-7.27 (m, 4H), 7.24 -7.20 (m, 3H), 7.17 (d, J=6.8, 1H), 5.27 (s, 2H), 5.00-4.94 (m, 1H), 4.66 (dd, J=9.6, 7.6, 1H), 4.21 (t, J=10.5, 1H), 3.40 (s, 3H), 2.57 (s, 3H); MS-ERI: 431.4 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₃ H ₂₃ O ₃ N ₆ (M+H) ⁺ : 431.1826, found: 431.1827.

[0341] RIP1-063

[0342] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.09 (d, J=7.3, 1H), 7.91 (s, 1H), 7.36-7.31 (m, 3H), 7.29 (s, 1H), 7.25-7.20 (m, 3H), 5.51 (d, J=3.9, 2H), 5.03-4.97 (m, 1H), 4.62 (dd, J=9.3, 7.8, 1H), 4.24 (t, J=0.5, 1H), 3.39 (s, 3H), 2.56 ( s, 3H); MS-ERI: 432.3 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₂ H ₂₂ O ₃ N ₇ (M+H) ⁺ : 432.1779, found: 432.1778.

[0343] RIP1-064

[0344] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.10 (s, 1H), 7.74 (d, J=7.0, 1H), 7.37 (s, 1H), 7 .30 (s, 1H), 7.26-7.18 (m, 5H), 5.80 (s, 2H), 5.05-4.97 (m, 1H), 4.65-4.53 (m, 1H), 4.20 (t, J=10.4, 1H), 3.44 (s, 3H), 2.62 (s, 3H); MS-ERI: 432.4 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₂ H ₂₂ O ₃ N ₇ (M+H) ⁺ : 432.1779, found: 432.1779.

[0345] RIP1-065

[0346] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.04 (s, 1H), 7.94 (d, J=7.3, 1H), 7.35-7.26 (m, 6H), 7.24 (s, 1H), 5.00-4.94 (m, 1H), 4.64 (dd, J=9.6, 7.6, 1H), 4.24 (t, J=10.5, 1H), 4.11(s, 2H), 3.41(s, 3H), 2.58(s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 168.70, 163.42, 160.70, 153.52, 146.05, 141.68, 136.01, 135.52, 134.61, 131, 65, 128.96, 128.92, 128.67, 127.51, 109.29, 107.33, 77.16, 49.14, 36.31, 34.60, 14.95; MS-ERI: 432.3 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₃ H ₂₂ O ₄ N ₅ (M+H) ⁺ : 432.1666, found: 432.1668.

[0347] RIP1-066

[0348] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.68-7.62 (m, 2H), 7.48 (d, J=6.5, 1H), 7.39-7, 27 (m, 4H), 7.24 (d, J=6.5, 2H), 7.18 (t, J=7.3, 1H), 7.15 (d, J=7.6, 2H ), 5.07-4.96 (m, 1H), 4.77 (dd, J=9.5, 7.6, 1H), 4.25 (t, J=10.4, 1H), 4 .00 (s, 2H), 3.44 (s, 3H), 2.55 (s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 169.13, 167.46, 153.51, 146.01, 142.09, 140.34, 133.42, 132.99, 131.31, 129, 02, 128.96, 128.72, 127.82, 126.49, 125.02, 109.75, 109.71, 106.91, 106.87, 77.41, 50.00, 41.83, 36.38, 14.96; MS-ERI: 431.3 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₆ H ₂₅ O ₃ N ₄ (M+H) ⁺ : 431.1921, found: 432.1922.

[0349] RIP1-067

[0350] ¹ H-NMR (500 MHz, CD ₃ OD) δ=7.76 (s, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.36-7, 27 (m, 4H), 7.24 (d, J=7.7, 2H), 5.21 (s, 2H), 5.00-4.94 (m, 1H), 4.53 (dd, J=9.7, 7.8, 1H), 4.29 (t, J=10.6, 1H), 3.43 (s, 3H), 2.58 (s, 3H); ¹³ C-NMR (125 MHz, CD ₃ OD) δ 171.00, 164.12, 155.23, 147.60, 139.43, 137.54, 136.79, 133.32, 130.05, 129 .42, 128.86, 124.35, 110.26, 110.25, 108.27, 108.24, 78.21, 52.01, 50.22, 36.48, 14.35; MS-ERI: 431.4 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₃ H ₂₃ O ₃ N ₆ (M+H) ⁺ : 431.1826, found: 431.1829.

[0351] RIP1-068

[0352] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.18 (d, J=6.8, 1H), 8.10 (s, 1H), 7.38-7.32 (m, 4H), 7.26-7.22 (m, 3H), 5.36 (s, 2H), 5.03-4.97 (m, 1H), 4.77 (dd, J=9.2, 7.9, 1H), 4.25 (t, J=10.4, 1H), 3.42 (s, 3H), 2.56 (s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 168.59, 159.01, 156.58, 153.60, 145.85, 144.35, 133.69, 131.17, 129.35, 129, 17, 128.33, 109.89, 109.84, 107.10, 107.05, 77.36, 54.54, 49.69, 36.35, 14.92; MS-ERI: 432.4 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₂ H ₂₂ O ₃ N ₇ (M+H) ⁺ : 432.1779, found: 432.1777.

[0353] RIP1-069

[0354] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.65 (s, 1H), 7.56 (s, 1H), 7.30-7.26 (m, 2H), 7.26 -7.19 (m, 4H), 7.07 (d, J=1.3, 1H), 7.06 (s, 1H), 5.44 (s, 2H), 4.98-4.91 (m, 1H), 4.60 (dd, J=9.7, 7.6, 1H), 4.23-4.09 (m, 1H), 3.41 (s, 3H), 2.57 (s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 169.19, 159.69, 153.28, 146.06, 141.71, 136.46, 132.94, 131.44, 128.97, 128, 16, 127.25, 125.03, 109.68, 109.66, 107.23, 107.22, 77.36, 50.14, 49.18, 36.39, 15.06; MS-ERI: 431.4 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₃ H ₂₃ O ₆ N ₃ (M+H) ⁺ : 431.1826, found: 431.1829.

[0355] RIP1-070

[0356] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.11 (D, J=6.9, 1H), 7.41 (s, 1H), 7.34-7.26 (m, 6H), 4.99-4.93 (m, 1H), 4.68 (dd, J=9.6, 7.8, 1H), 4.26-4.20 (m, 4H), 3, 43 (s, 3H), 2.61 (s, 3H); MS-ERI: 433.4 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₂ H ₂₁ O ₄ N ₆ (M+H) ⁺ : 433.1619, found: 433.1613.

[0357] RIP1-071

[0358] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.16 (d, J=6.7, 1H), 7.40 (s, 1H), 7.39-7.33 (m, 5H), 7.29 (s, 1H), 5.80 (s, 2H), 5.06-5.00 (m, 1H), 4.77 (dd, J=9.6, 7.7, 1H), 4.25 (t, J=10.4, 1H), 3.44 (s, 3H), 2.60 (s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 168.24, 159.37, 156.51, 153.65, 146.04, 132.32, 131.31, 129.55, 129.32, 128, 76, 110.18, 110.14, 107.06, 107.01, 77.04, 57.75, 49.82, 36.42, 14.96; MS-ERI: 433.3 (M+H) ⁺ ; HRMS (ESI) Calc. for C21H21O3N8 (M+H) ⁺ : 433.1731, found: 433.1733.

[0359] RIP1-072

[0360] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.86 (d, J=7.1, 1H), 7.28 (s, 1H), 7.24 (s, 1H), 7 .08 (d, J=7.8, 2H), 6.98 (d, J=7.7, 2H), 6.45 (s, 1H), 5.02-4.93 (m, 1H) , 4.68 (t, J=8.6, 1H), 4.24 (t, J=10.4, 1H), 3.91 (s, 2H), 3.72 (s, 3H), 3 .40 (s, 3H), 2.57 (s, 3H), 2.30 (s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 168.97, 162.35, 153.60, 145.99, 143.87, 143.82, 136.74, 133.46, 131.58, 129, 62, 128.35, 109.21, 109.16, 107.33, 107.25, 106.77, 77.36, 49.22, 37.21, 36.26, 31.58, 21.10, 14.93; MS-ERI: 459.4 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₅ H ₂₇ O ₃ N ₆ (M+H) ⁺ : 459.2139, found: 59.2141.

[0361] RIP1-073

[0362] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.37 (s, 1H), 7.26 (s, 1H), 7.13-7.08 (m, 5H), 6.36 (s, 1H), 4.96-4.89 (m, 1H), 4.64 (dd, J=9.6, 7.6, 1H), 4.16 (t, J=10.5, 1H), 4.01 (s, 3H), 3.89 (s, 2H), 3.42 (s, 3H), 2.61 (s, 3H), 2.31 (s, 3H); ¹³ C-NMR (126 MHz, CDCl ₃ ) δ 168.86, 159.53, 153.46, 151.15, 146.25, 136.27, 136.10, 134.95, 131.73, 129, 43, 128.71, 107.19, 107.17, 107.13, 107.13, 106.33, 77.29, 49.32, 39.10, 36.34, 34.14, 21.14, 15.01; MS-ERI: 459.4 (M+H) ⁺ ; HRMS (ESI) Calc. for C ₂₅ H ₂₇ O ₃ N ₆ (M+H) ⁺ : 459.2139, found: 459.2140.

[0363] RIP 1-074

[0364] ¹ H-NMR (500 MHz, CD ₃ OD) δ=8.18 (s, 1H), 7.98 (s, 1H), 7.40-7.33 (m, 3H), 7, 31-7.28(m, 2H), 7.11(s, 1H), 6.93(s, 1H), 5.38(s, 2H), 5.08-5.03(m, 1H) , 4.48 (dd, J=9.8, 7.8, 1H), 4.41 (dd, J=11.5, 9.9, 1H), 3.41 (s, 3H); MS-ERI m/z 433.0 (M+H) ⁺ .

[0365] RIP 1-075

[0366] ¹ H-NMR (500 MHz, CD ₃ OD) δ=7.46-7.43 (m, 1H), 7.43-7.38 (m, 2H), 7.11 (s, 1H ), 6.95 (s, 1H), 5.96 (s, 1H), 5.38-5.35 (m, 1H), 5.07 (dd, J=11.4, 7.7, 1H ), 4.46 (dd, J=11.3, 10.0, 1H), 3.42 (s, 2H); MS-ERI m/z 435.3 (M+H) ⁺ .

[0367] RIP 1-076

[0368] ¹ H-NMR (500 MHz, CD ₃ OD) δ=7.35-7.28 (m, 5H), 7.10 (s, 1H), 6.95 (s, 1H), 5, 03 (dd, J=11.2, 7.5, 1H), 4.37 (dd, J=11.1, 10.1, 1H), 4.18 (s, 2H), 4.09-4 .03 (m, 1H), 3.42 (s, 3H); MS-ERI m/z 434.4 (M+H) ⁺ .

[0369] RIP1-077

[0370] ¹ H-NMR (400 MHz, CDCl ₃ ) δ=7.86 (d, J=8.3, 1H), 7.67 (s, 1H), 7.51-7.41 (m, 1H), 7.33-7.25 (m, 3H), 7.21 (d, J=7.0, 2H), 6.27 (s, 1H), 5.02-4.86 (m, 1H), 4.73 (dd, J=11.6, 5.7, 1H), 4.27 (t, J=10.5, 1H), 4.09 (s, 2H), 3.47 ( s, 3H), HRMS (ESI) Calc. for C ₂₃ H ₁₈ F ₃ N ₅ O ₄ (M+H) ⁺ : 486.1389, found: 486.1392.

[0371] RIP1-078

[0372] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=12.22 (s, 1H), 8.23 (s, 2H), 7.90 (s, 1H), 7.65 (s, 1H ), 7.40-7.34 (m, 4H), 7.27 (d, J=3.3, 2H), 5.54 (s, 2H), 5.06-4.98 (m, 1H ), 4.33 (t, J=10.5, 1H), 3.67-3.33 (m, 4H); HRMS (ESI) Calc. for C22H18F3N7O3Na (M+Na) ⁺ : 508.1321, found: 508.1315.

[0373] RIP1-079

[0374] ¹ H-NMR (500 MHz, CDCl ₃ ) δ 12.15 (s, 1H), 8.13 (d, J=6.5 Hz, 1H), 8.05 (s, 1H), 7 .70 (s, 1H), 7.35 (d, J=7.2 Hz, 2H), 7.33-7.30 (m, 4H), 5.04-4.97 (m, 1H), 4.85-4.80 (m, 1H), 4.36 (t, J=10.4 Hz, 1H), 4.14 (s, 3H), 3.54 (s, 2H); HRMS (ESI) Calc. for C ₂₃ H ₁₈ F ₃ N ₅ O ₄ (M+H) ⁺ : 486.1389, found: 486.1390.

[0375] RIP1-080

[0376] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.84 (d, J=7.3, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7 .35-7.27 (m, 3H), 7.21 (d, J=7.5, 2H), 7.15 (d, J=2.7, 1H), 6.48 (d, J= 2.9, 1H), 6.26 (s, 1H), 4.77-4.70 (m, 1H), 4.08 (s, 2H), 3.86-3.77 (m, 4H) , 3.47 (s, 3H), 2.84 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 173.97, 170.04, 158.30, 158.11, 137.68, 135.62, 135.39, 131.53, 129.94, 129, 01, 128.88, 127.45, 119.51, 117.06, 116.39, 101.69, 101.55, 49.82, 38.31, 37.30, 33.29, 29.45; MS-ERI: 447.3 (M+H) ⁺ .

[0377] RIP1-081

[0378] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.12 (d, J=7.2, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7 .34-7.27 (m, 5H), 7.16 (d, J=3.0, 1H), 6.49 (d, J=3.1, 1H), 4.74-4.68 ( m, 1H), 4.23 (s, 2H), 3.86-3.81 (m, 4H), 3.48 (s, 3H), 2.85 (t, J=11.1, 1H) ; ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 169.44, 167.63, 158.80, 152.21, 137.46, 135.66, 133.05, 131.67, 130.02, 129, 14, 129.00, 127.92, 119.28, 117.11, 116.47, 101.61, 50.24, 38.13, 37.39, 33.32, 31.96;; MS-ERI: 448.4 (M+H) ⁺ .

[0379] RIP1-082

[0380] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.82 (s, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H ), 7.36-7.29 (m, 3H), 7.21 (d, J=7.3, 2H), 7.14 (d, J=2.4, 1H), 7.07 (d , J=7.2, 1H), 6.47 (d, J=3.0, 1H), 5.25 (s, 2H), 4.78-4.72 (m, 1H), 3.85 -3.80 (m, 4H), 3.46 (s, 3H), 2.79 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 171.11, 161.37, 138.86, 137.65, 135.64, 135.46, 131.49, 130.83, 129.90, 129, 09, 128.57, 128.10, 119.60, 118.55, 117.04, 116.38, 101.54, 56.57, 49.73, 38.66, 37.31, 33.27; MS-ERI: 446.4 (M+H) ⁺ .

[0381] RIP1-083

[0382] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.83 (s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.54 (s, 1H ), 7.37-7.28 (m, 7H), 7.22 (d, J=1.5, 1H), 7.21 (d, J=3.1, 2H), 7.16 (d , J=0.7, 1H), 7.15(s, 1H), 6.54(d, J=3.1, 1H), 5.32(s, 2H), 5.25(s, 2H ), 4.82-4.75 (m, 1H), 3.78 (dd, J=11.2, 6.9, 1H), 3.45 (s, 3H), 2.78 (t, J =11.2, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 171.18, 161.43, 138.92, 137.87, 136.76, 135.45, 135.23, 130.86, 130.83, 130, 12, 129.09, 129.07, 129.04, 128.54, 128.09, 126.97, 119.92, 118.49, 117.19, 116.52, 102.27, 56.53, 50.44, 49.70, 38.59, 37.36, 1.14; MS-ERI: 522.4 (M+H) ⁺ .

[0383] RIP1-084

[0384] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.15 (d, J=7.9, 1H), 7.88 (s, 1H), 7.61 (s, 1H), 7 .53 (s, 1H), 7.36-7.33 (m, 5H), 7.26-7.22 (m, 3H), 7.20 (d, J=3.0, 1H), 7 .15 (d, J=7.3, 2H), 6.53 (d, J=3.1, 1H), 5.51 (d, J=6.4, 2H), 5.32 (s, 2H), 4.83-4.76 (m, 1H), 3.78 (dd, J=11.2, 6.8, 1H), 3.47 (s, 3H), 2.85 (t, J=11.2, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.31, 159.09, 143.19, 138.04, 136.77, 135.15, 133.95, 130.82, 130.10, 129, 32, 129.10, 129.06, 128.26, 128.06, 126.96, 125.43, 119.94, 117.17, 116.48, 102.23, 54.53, 50.42, 49.49, 38.45, 37.32;; MS-ERI: 523.4 (M+H) ⁺ .

[0385] RIP1-085

[0386] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.85 (d, J=7.7, 1H), 7.61 (s, 1H), 7.54 (d, J=1, 1, 1H), 7.37-7.30 (m, 6H), 7.23-7.20 (m, 3H), 7.16 (d, J=7.6, 2H), 6.55 ( s, 1H), 6.27 (s, 1H), 5.33 (s, 2H), 4.79-4.73 (m, 1H), 4.08 (s, 2H), 3.79 (dd , J=11.3, 6.5, 1H), 3.47 (s, 3H), 2.81 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 173.96, 170.04, 158.28, 158.11, 137.89, 136.75, 135.36, 135.20, 130.91, 130, 15, 129.10, 128.99, 128.86, 128.10, 127.43, 126.98, 119.82, 117.20, 116.54, 102.27, 101.67, 50.45, 49.79, 38.26, 37.34, 33.26;; MS-ERI: 523.4 (M+H) ⁺ .

[0387] RIP1-086

[0388] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.18 (d, J=7.6, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 7 .53 (s, 1H), 7.37-7.33 (m, 5H), 7.30 (d, J=7.0, 1H), 7.26 (t, J=3.7, 2H) , 7.21 (d, J=3.1, 1H), 7.17 (d, J=7.4, 2H), 6.54 (d, J=3.1, 1H), 5.35 ( s, 2H), 5.33 (s, 2H), 4.86-4.80 (m, 1H), 3.87 (dd, J=11.1, 7.0, 1H), 3.47 ( s, 3H), 2.81 (t, J=11.1, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.34, 157.91, 156.99, 144.00, 137.84, 136.77, 135.22, 133.92, 130.85, 130, 11, 129.25, 129.08, 129.00, 128.31, 128.07, 127.00, 119.84, 117.19, 116.62, 102.23, 54.37, 50.43, 49.74, 38.48, 37.36; MS-ERI: 523.5 (M+H) ⁺ .

[0389] RIP1-087

[0390] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.00 (s, 1H), 7.95 (d, J=7.7, 1H), 7.62 (s, 1H), 7 .54 (s, 1H), 7.36-7.33 (m, 4H), 7.32 (s, 1H), 7.30-7.28 (m, 3H), 7.21 (d, J =3.1, 1H), 7.16 (d, J=7.2, 2H), 6.54 (d, J=3.1, 1H), 5.33 (s, 2H), 4.81 -4.75 (m, 1H), 4.10 (s, 2H), 3.79 (dd, J=11.0, 6.9, 1H), 3.48 (s, 3H), 2.83 (t, J=11.1, 1H); ¹³ C-NMR (126 MHz, CDCl ₃ ) δ 170.45, 163.02, 159.69, 141.37, 138.01, 136.78, 135.99, 135.20, 134.80, 130, 84, 130.13, 129.10, 128.91, 128.09, 127.90, 127.41, 126.97, 119.94, 117.18, 116.53, 102.26, 50.45, 49.41, 38.50, 37.29, 34.61; MS-ERI: 523.4 (M+H) ⁺ .

[0391] RIP1-088

[0392] ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.04 (d, J=7.9, 1H), 7.60 (s, 1H), 7.52 (s, 1H), 7 .47 (s, 1H), 7.44 (s, 1H), 7.36-7.31 (m, 6H), 7.19 (d, J=2.2, 1H), 7.15 (d , J=7.8, 2H), 7.13 (d, J=7.0, 2H), 6.53 (d, J=2.9, 1H), 5.32 (s, 2H), 5 .07 (s, 2H), 4.83-4.77 (m, 1H), 3.76 (dd, J=11.0, 6.8, 1H), 3.45 (s, 3H), 2 .84 (t, J=11.2, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 170.77, 161.52, 138.16, 137.13, 137.02, 136.80, 135.23, 135.12, 130.71, 130, 05, 129.20, 129.04, 128.66, 128.02, 127.56, 126.95, 122.43, 120.07, 117.13, 116.45, 102.20, 51.38, 50.39, 49.29, 38.59, 37.25; MS-ERI: 522.3 (M+H) ⁺ .

[0393] RIP1-089

[0394] ¹ H-NMR (400 MHz, CD ₃ OD_SPE) δ 8.30 (s, 1H), 8.00 (d, J=18.6 Hz, 1H), 7.75 (s, 1H), 7.26 (dd, J=18.8, 6.7 Hz, 5H), 6.33 (s, 1H), 4.66 (dd, J=11.7, 7.0 Hz, 1H), 4 .11 (s, 2H), 3.69-3.51 (m, 1H), 3.43 (s, 3H), 3.30 (dt, J=3.3, 1.6 Hz, 2H), 3.05 (t, J=11.5 Hz, 1H), ¹³ C-NMR (101 MHz, CD ₃ OD_SPE) δ 174.48 (s), 170.74 (s), 159.07 (s), 157.90 (s), 143.94 (s), 141.00 (s), 135.77 (s), 128.47 (s), 128.45 (s), 126.85 (s), 121 .08 (s), 49.89 (s), 36.95 (s), 36.10 (s), 32.22 (s). ERI: m/z 434.1 (M+H) ⁺ .

[0395] RIP1-090

[0396] ¹ H-NMR (400 MHz, CD ₃ OD_SPE) δ 8.30 (s, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.25 (dd, J =14.0, 6.9 Hz, 5H), 4.70 (dd, J=11.6, 6.9 Hz, 1H), 4.12 (s, 2H), 3.66 (dt, J= 16.1, 8.1 Hz, 1H), 3.44 (s, 3H), 3.05-2.96 (m, 1H). ERI: m/z 434.1 (M+H) ⁺ .

[0397] RIP1-091

[0398] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.95 (s, 1H), 7 .62 (s, 1H), 7.32 (dt, J=28.9, 5.7 Hz, 5H), 5.54 (s, 2H), 4.81-4.71 (m, 1H), 3.76 (dd, J=10.9, 7.1 Hz, 1H), 3.48 (s, 3H), 2.93 (t, J=11.3 Hz, 1H), ¹³ C-NMR ( 101 MHz, CDCl ₃ ) δ 170.35 (s), 159.33 (s), 159.26 (s), 143.32 (s), 142.62 (s), 142.59 (s), 140 .73 (s), 139.38 (s), 136.30 (s), 133.76 (s), 129.19 (s), 129.01 (s), 128.12 (s), 125, 65 (s), 121.87 (s), 121.19 (s), 112.26 (s), 63.44 (s), 54.43 (s), 38.09 (s), 37.12 (With). ERI: m/z 434.1 (M+H) ⁺ .

[0399] RIP1-092

[0400] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.2, 1.5 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H) , 8.08 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.6, 4.2 Hz, 1H), 7.24-7.15 (m, 5H), 4.77 (dd, J=10.5, 7.4 Hz, 1H), 4.09 (s, 2H), 3.87 (dd , J=11.4, 7.2 Hz, 1H), 3.46 (s, 2H), 3.38 (s, 3H), 3.03 (t, J=11.2 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 172.01, 158.15, 151.46, 149.38, 141.76, 135.89, 135.02, 131.82, 130.26, 128.87 , 128.80, 127.13, 127.06, 124.16, 122.32, 60.46, 50.79, 49.72, 39.25, 36.93, 33.20, MS (ERI): m/z 445.1 (M+H) ⁺ .

[0401] RIP1-093

[0402] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.19-8.13 (m, 2H), 8, 10 (dd, J=8.8, 0.5 Hz, 1H), 8.03 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.51 (dd, J = 8.6, 4.2 Hz, 1H), 7.39-7.34 (m, 3H), 7.29-7.25 (m, 2H), 5.37 (s, 2H), 4, 84 (dt, J=10.7, 7.4 Hz, 1H), 4.01 (dd, J=11.4, 7.2 Hz, 1H), 3.42 (s, 3H), 3.03 (t, J=11.1 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.94, 158.02, 156.69, 151.46, 149.52, 143.95, 141 .71, 135.07, 133.77, 131.71, 130.33, 129.20, 128.98, 128.24, 127.10, 124.19, 122.23, 54.34, 49.68 , 39.52, 36.90, MS (ERI): m/z 445.1 (M+H) ⁺ .

[0403] RIP1-094

[0404] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.1, 1.5 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H) , 8.05 (d, J=8.8 Hz, 1H), 7.99 (d, J=7.9 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7 .51-7.41 (m, 3H), 7.36-7.28 (m, 3H), 7.15-7.09 (m, 2H), 5.07 (s, 2H), 4.77 (dt, J=10.9, 7.5 Hz, 1H), 3.87 (dd, J=11.3, 7.1 Hz, 1H), 3.38 (s, 3H), 3.04 ( t, J=11.1 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 172.38, 161.63, 151.35, 149.45, 142.03, 137.07, 136, 74, 135.08, 135.07, 131.86, 130.06, 129.16, 128.66, 127.50, 127.19, 124.23, 122.54, 122.20, 51.35, 49.27, 39.62, 36.80, MS (ERI): m/z 444.1 (M+H) ⁺ .

[0405] RIP1-095

[0406] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.99 (dd, J=4.2, 1.6 Hz, 1H), 8.18 (dd, J=8.5, 0.6 Hz, 1H), 8.13-8.05 (m, 2H), 7.93 (d, J=8.7 Hz, 1H), 7.87 (s, 1H), 7.51 (dd, J = 8.6, 4.2 Hz, 1H), 7.38-7.34 (m, 3H), 7.27-7.22 (m, 2H), 5.53 (d, J=1.3 Hz, 2H), 4.79 (dt, J=10.9, 7.4 Hz, 1H), 3.42 (s, 3H), 3.07 (t, J=11.1 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.86, 159.14, 151.44, 149.50, 142.86, 141.91, 135.03, 133.75, 131.77, 130, 22, 129.28, 129.11, 128.22, 127.10, 125.42, 124.21, 122.25, 54.52, 49.45, 39.45, 36.86, MS (ERI) : m/z 445.1 (M+H) ⁺ .

[0407] RIP1-096

[0408] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.00 (dd, J=4.1, 1.5 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H) , 8.10 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.81 (d, J=7.4 Hz, 1H), 7 .52 (dd, J=8.6, 4.2 Hz, 1H), 7.35-7.18 (m, 5H), 6.26 (s, 1H), 4.75 (dt, J=10 .7, 7.3 Hz, 1H), 4.09 (s, 2H), 3.93 (dd, J=11.3, 7.1 Hz, 1H), 3.42 (s, 3H), 3 .03 (t, J=11.1 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.10, 171.58, 158.19, 157.97, 151.51, 149.51 141.74 135.18 135.01 131.70 130.36 128.93 128.75 127.39 127.03 124.18 122.30 101.58 49 .72, 39.27, 36.88, 33.18, MS (ERI): m/z 445.1 (M+H) ⁺ .

[0409] RIP1-097

[0410] ¹ H-NMR (400 MHz, MeOD) δ 8.80 (d, J=3.5 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 7.97 ( d, J=9.0 Hz, 1H), 7.61-7.51 (m, 2H), 7.25-7.07 (m, 5H), 4.95 (d, J=7.7 Hz , 1H), 4.63-4.52 (m, 1H), 4.45 (t, J=9.9 Hz, 1H), 4.14-3.97 (m, 2H), 3.32 ( s, 3H), ¹³ C-NMR (100 MHz, MeOD) δ 171.13, 149.77, 149.28, 145.94, 132.31, 130.26, 129.57, 128.49, 128, 36, 126.82, 125.23, 124.19, 121.90, 77.28, 49.09, 36.43, MS (ERI): m/z 429.1 (M+H) ⁺ .

[0411] RIP1-098

[0412] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.2, 1.6 Hz, 1H), 8.17-8.06 (m, 3H), 8, 02 (s, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.41-7.36 (m, 3H), 7.29 (dd, J=7.1, 2.4 Hz, 2H), 5.38 (s, 2H), 5.17 (dt, J=10.9, 7.5 Hz, 1H), 4.85 (dd, J=9.9, 7.6 Hz, 1H), 4.41-4.34 (m, 1H), 3.47 (s, 3H), ¹³ C- NMR (100 MHz, CDCl ₃ ) δ 170.89, 158.47, 156.57, 150.04, 149.22, 146.78, 143.98, 133.72, 131.10, 131.08, 129 .57, 129.22, 129.01, 128.27, 125.30, 124.07, 121.71, 78.16, 54.39, 48.95, 37.41, MS (ERI): m/ z 429.1 (M+H) ⁺ .

[0413] RIP1-099

[0414] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.94 (dd, J=4.1, 1.5 Hz, 1H), 8.12 (dd, J=20.9, 8.5 Hz, 2H), 7.94 (d, J=7.5 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.52-7.44 (m, 3H), 7.39-7.32 (m, 3H), 7.15 (dd, J=7.3, 1.9 Hz, 2H), 5.16-5.06 (m, 3H), 4.76 ( dd, J=9.9, 7.6 Hz, 1H), 4.44-4.34 (m, 1H), 3.46 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.28, 162.04, 149.96, 149.25, 146.77, 137.07, 135.05, 131.19, 130.96, 130.87, 130.27, 129.88, 129, 19, 128.70, 127.52, 126.58, 125.30, 124.43, 124.15, 123.92, 122.51, 121.61, 78.41, 51.39, 48.52, 37.33, MS (ERI): m/z 428.1 (M+H) ⁺ .

[0415] RIP1-100

[0416] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.19-8.13 (m, 1H), 8, 11 (d, J=9.1 Hz, 1H), 8.05 (d, J=7.4 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.49 (dd, J=8.6, 4.2 Hz, 1H), 7.40-7.34 (m, 3H), 7.29-7.24 (m, 3H) , 5.54 (d, J=4.1 Hz, 2H), 5.11 (dt, J=10.9, 7.5 Hz, 1H), 4.78 (dd, J=9.9, 7 .6 Hz, 1H), 4.40 (dd, J=10.8, 10.1 Hz, 1H), 3.47 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170, 80, 159.56, 150.04, 149.20, 146.78, 142.75, 133.71, 131.14, 131.00, 129.74, 129.31, 129.14, 128.26, 125.45, 125.24, 124.10, 121.70, 78.13, 54.55, 48.74, 37.40, MS (ERI): m/z 429.1 (M+H) ⁺ .

[0417] RIP1-101

[0418] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.2, 1.6 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H) , 8.12 (d, J=9.4 Hz, 1H), 7.75 (d, J=7.1 Hz, 1H), 7.59 (d, J=9.1 Hz, 1H), 7 .50 (dd, J=8.6, 4.2 Hz, 1H), 7.36-7.27 (m, 3H), 7.25-7.20 (m, 2H), 6.28 (s , 1H), 5.07 (dt, J=10.9, 7.4 Hz, 1H), 4.79 (dd, J=9.9, 7.6 Hz, 1H), 4.45-4, 32 (m, 1H), 4.10 (s, 2H), 3.47 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.17, 170.51, 158.63, 157 .86, 150.10, 149.17, 146.79, 135.16, 131.14, 131.06, 129.57, 128.94, 128.77, 127.40, 125.19, 124.05 , 121.75, 101.59, 49.03, 37.41, 33.20, 29.33, MS (ESI): m/z 429.1 (M+H) ⁺ .

[0419] RIP1-102

[0420] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 8.59 (d, J=6.0 Hz, 1H), 8.22 (d, J=7, 7 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.59 (d, J=5.9 Hz , 1H), 7.25-7.18 (m, 5H), 4.77 (dt, J=10.8, 7.5 Hz, 1H), 4.11 (s, 2H), 3.90 ( dd, J=11.3, 7.1 Hz, 1H), 3.40 (s, 3H), 3.07 (t, J=11.1 Hz, 1H), ¹³ C-NMR (101 MHz, CDCl ₃ ) δ 171.58, 153.09, 144.48, 140.90, 135.87, 133.17, 131.66, 131.47, 129.76, 128.89, 128.83, 128.29 , 127.17, 116.00, 100.00, 77.25, 49.55, 39.17, 36.59, 33.25, MS (ERI): m/z 445.0 (M+H) ⁺ .

[0421] RIP1-103

[0422] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.34 (s, 1H), 8.64 (d, J=5.9 Hz, 1H), 8.18 (d, J=7, 5 Hz, 1H), 8.04 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.60 (d, J=5.9 Hz, 1H), 7.41-7.33 (m, 3H), 7.27 (d, J=5.2 Hz, 2H), 5.37 (s, 2H) , 4.91-4.78 (m, 1H), 4.02 (dd, J=11.3, 7.1 Hz, 1H), 3.43 (s, 3H), 3.06 (t, J =11.1 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.60, 158.03, 156.64, 153.19, 144.62, 143.97, 140.85, 133 .73, 133.21, 131.64, 131.47, 129.79, 129.21, 129.00, 128.24, 128.23, 115.91, 54.36, 49.55, 39.37 , 36.56, MS (ERI): m/z 445.0 (M+H) ⁺ .

[0423] RIP1-104

[0424] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.33 (s, 1H), 8.62 (d, J=5.9 Hz, 1H), 8.02 (d, J=7, 8 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.61 (d, J=5.9 Hz , 1H), 7.46 (d, J=13.1 Hz, 2H), 7.39-7.30 (m, 3H), 7.18-7.09 (m, 2H), 5.09 ( s, 2H), 4.79 (dt, J=10.9, 7.4 Hz, 1H), 3.91 (dd, J=11.2, 7.0 Hz, 1H), 3.41 (s , 3H), 3.09 (t, J=11.1 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 172.03, 161.63, 153.10, 144.56, 141, 18 137.06 136.75 135.05 133.20 131.72 131.53 129.77 129.18 128.69 128.00 127.49 122.53 116.02, 51.37, 49.12, 39.52, 36.45, MS (ERI): m/z 444.1 (M+H) ⁺ .

[0425] RIP1-105

[0426] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.33 (s, 1H), 8.63 (d, J=6.0 Hz, 1H), 8.13 (d, J=7, 7 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.89-7.81 (m, 2H), 7.61 (d, J=6.0 Hz, 1H) , 7.40-7.33 (m, 3H), 7.27-7.22 (m, 2H), 5.53 (d, J=1.8 Hz, 2H), 4.79 (dt, J =10.9, 7.3 Hz, 1H), 3.92 (dd, J=11.3, 7.0 Hz, 1H), 3.43 (s, 3H), 3.10 (t, J= 11.1 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.53, 159.16, 153.16, 144.66, 142.83, 141.07, 133.73, 133, 16, 131.61, 131.50, 129.78, 129.30, 129.13, 128.22, 128.11, 125.42, 115.95, 54.54, 49.29, 39.33, 36.52, MS (ERI): m/z 445.1 (M+H) ⁺ .

[0427] RIP1-106

[0428] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.34 (s, 1H), 8.65 (d, J=6.0 Hz, 1H), 7.98-7.94 (m, 1H), 7.87-7.80 (m, 2H), 7.61 (d, J=6.0 Hz, 1H), 7.35-7.27 (m, 3H), 7.24-7 .19 (m, 2H), 6.26 (s, 1H), 4.75 (dt, J=10.9, 7.3 Hz, 1H), 4.09 (s, 2H), 3.94 ( dd, J=11.3, 7.1 Hz, 1H), 3.42 (s, 3H), 3.06 (t, J=11.1 Hz, 1H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.13, 171.24, 158.20, 157.94, 153.21, 144.73, 140.90, 135.17, 133.13, 131.53, 131.45, 129.78 , 128.93, 128.76, 128.23, 127.40, 115.88, 101.57, 49.56, 39.14, 36.54, 33.18, MS (ERI): m/z 445 ,0 (M+H) ⁺ .

[0429] RIP1-107

[0430] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.11 (d, J=5, 3 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.58 (d, J=6.0 Hz, 1H), 7.43 (d, J=8.7 Hz , 1H), 7.25-7.16 (m, 5H), 5.06 (s, 1H), 4.75 (dd, J=9.7, 7.7 Hz, 1H), 4.40 ( t, J=10.5 Hz, 1H), 4.12 (s, 2H), 3.45 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.42, 158.63, 152.90, 152.36, 143.92, 135.85, 132.00, 129.55, 129.07, 128.89, 128.83, 127.20, 127.18, 123.58, 115, 79, 77.93, 48.81, 37.08, 33.24, MS (ERI): m/z 429.1 (M+H) ⁺ .

[0431] RIP1-108

[0432] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.10 (d, J=7, 2 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.43-7.34 (m, 3H), 7.32-7.27 (m, 2H), 5.38 (s, 2H), 5, 14 (dt, J=10.9, 7.4 Hz, 1H), 4.86 (dd, J=9.9, 7.5 Hz, 1H), 4.45-4.37 (m, 1H) , 3.48 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.55, 158.49, 156.55, 153.04, 152.36, 144.16, 143.97, 133.69, 131.99, 129.46, 129.24, 129.06, 129.04, 128.28, 127.25, 123.64, 115.67, 78.14, 54.42, 48, 83, 37.05, MS (ERI): m/z 429.1 (M+H) ⁺ .

[0433] RIP1-109

[0434] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.22 (s, 1H), 8.52 (d, J=6.0 Hz, 1H), 7.89 (m, 2H), 7 .53 (d, J=5.9 Hz, 1H), 7.40 (dd, J=9.4, 6.4 Hz, 3H), 7.28-7.22 (m, J=8.8 Hz, 3H), 7.12-7.05 (m, 2H), 5.10-4.98 (m, 2H), 4.70 (dd, J=9.8, 7.5 Hz, 1H) , 4.34 (t, J=10.5 Hz, 1H), 3.39 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.95, 162.06, 152.96, 152.39, 144.04, 137.10, 136.67, 135.04, 132.06, 129.35, 129.25, 129.19, 128.70, 127.52, 127.21, 123, 61, 122.56, 115.78, 78.39, 51.39, 48.38, 36.97, MS (ESI): m/z 428.0 (M+H) ⁺ .

[0435] RIP1-110

[0436] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 8.60 (d, J=5.9 Hz, 1H), 8.07 (d, J=7, 1 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 7.61 (d, J=5.9 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.42-7.33 (m, 3H), 7.29-7.22 (m, 2H), 5.65-5.46 (m, 2H ), 5.10 (dt, J=10.9, 7.4 Hz, 1H), 4.78 (dd, J=9.6, 7.7 Hz, 1H), 4.43 (t, J= 10.5 Hz, 1H), 3.48 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.47, 159.59, 153.00, 152.33, 144.13, 142 .70, 133.71, 132.02, 129.37, 129.31, 129.23, 129.15, 128.25, 127.22, 125.47, 123.55, 115.73, 78.10 , 54.56, 48.60, 37.04, MS (ERI): m/z 429.1 (M+H) ⁺ .

[0437] RIP1-111

[0438] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 7.99 (d, J=8, 7 Hz, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.47 (d, J=8.7 Hz , 1H), 7.36-7.28 (m, 3H), 7.25-7.20 (m, 2H), 6.28 (s, 1H), 5.05 (dt, J=11.0 , 7.3 Hz, 1H), 4.80 (dd, J=9.9, 7.4 Hz, 1H), 4.40 (dd, J=10.8, 10.1 Hz, 1H), 4 .10 (s, 2H), 3.48 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.21, 170.18, 158.65, 157.82, 153.04, 152 .30, 144.20, 135.15, 131.97, 129.50, 129.07, 128.95, 128.78, 127.41, 127.23, 123.51, 115.67, 101.57 , 77.88, 48.89, 37.05, 33.20, MS (ERI): m/z 429.1 (M+H) ⁺ .

[0439] RIP1-112

[0440] ¹ H-NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.29 (s, 1H), 7.43-7.01 (m, 9H), 6.27 (s , 1H), 4.79 (d, J=9.3 Hz, 1H), 4.49-4.16 (m, 2H), 4.05 (s, 2H), 3.44 (s, 3H) , MS (ERI): m/z 417.1 (M+H) ⁺ . MS (ERI): m/z 417.1 (M+H) ⁺ .

[0441] RIP1-113

[0442] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.04 (d, J=91.0 Hz, 1H), 8.08 (d, J=17.6 Hz, 4H), 7.44 -7.35(m, 5H), 6.94(s, 1H), 6.46(s, 1H), 5.36(s, 2H), 4.72(s, 2H), 4.19( s, 1H), 3.37 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.92, 168.71, 158.53, 156.72, 150.46, 150.11, 146.25, 135.34, 133.81, 129.20, 128.96, 128.28, 125.99, 119.43, 105.15, 103.10, 57.00, 54.33, 49, 26, 36.36, MS (ESI): m/z 417.1 (M+H) ⁺ .MS (ESI): m/z 417.1 (M+H) ⁺ .

[0443] RIP1-114

[0444] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.42-7.37 (m, 3H), 7.31-7.25 (m, 3H), 7.19-7.16 (m, 1H), 7.14 (s, 1H), 7.08 (dd, J=7.3, 1.9 Hz, 2H), 6.47-6.44 (m, 1H), 5.02 (s, 2H), 4.99 (dd, J=7.5, 3.6 Hz, 1H), 4.59 (dd, J=9.7, 7.5 Hz, 1H), 4.15 (dd, J=11.0, 9.8 Hz, 1H), 3.43 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.49, 168.24, 160.97, 145.31, 135.99, 134.09, 133.06, 129.08, 128.90, 128.14 127.62, 126.49, 124.60, 124.15, 121.32, 113.94, 103.45, 101.71, 50.32, 47.74, 35.24, 34.91, MS (ERI): m/z 416.1 (M+H) ⁺ . MS (ERI): m/z 416.1 (M+H) ⁺ .

[0445] RIP1-115

[0446] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 1H), 8.15-8.01 (m, 2H), 7.96-7.82 (m, 2H), 7.45-7.31 (m, 5H), 6.96 (d, J=6.5 Hz, 1H), 6.45 (s, 1H), 5.26 (s, 1H), 5.08 (dd, J=16.4, 8.7 Hz, 2H), 4.65 (s, 2H), 3.37 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.88 159.57 150.15 146.56 142.94 135.17 133.78 129.29 129.10 128.25 125.36 119.51 118.72 104 .95, 102.90, 99.99, 57.17, 54.51, 49.02, 36.52, MS (ERI): m/z 417.1 (M+H) ⁺ . MS (ERI): m/z 417.1 (M+H) ⁺ .

[0447] RIP1-116

[0448] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.77 (d, J=6.4 Hz, 2H), 7.38-7.29 (m, 5H), 6.96 (d, J=6.4 Hz, 1H), 6.46 (d, J=4.3 Hz, 1H), 6.31 (d, J=5.0 Hz, 1H) , 6.28 (d, J=3.0 Hz, 1H), 5.13-4.97 (m, 2H), 4.31 (t, J=6.7 Hz, 1H), 4.09 ( s, 2H), 3.38 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.04, 168.59, 158.61, 150.13, 146.45, 135.23, 130.95, 128.93, 128.79, 127.38, 126.20, 122.97, 119.48, 118.68, 114.00, 104.97, 101.55, 65.61, 57, 20, 49.22, 33.19, MS (ERI): m/z 417.1 (M+H) ⁺ . MS (ERI): m/z 417.1 (M+H) ⁺ .

[0449] RIP1-119

[0450] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J=7.2 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J=2, 2 Hz, 1H), 7.43 (s, 1H), 7.40-7.34 (m, 4H), 7.31-7.27 (m, 2H), 6.77 (dd, J=2 .2, 0.8 Hz, 1H), 5.37 (s, 2H), 5.10 (dt, J=11.1, 7.4 Hz, 1H), 4.77 (dd, J=9, 8, 7.5 Hz, 1H), 4.25 (dd, J=11.0, 9.9 Hz, 1H), 3.49 (s, 3H); MS-ERI: m/z 418.0 (M+H) ⁺ .

[0451] RIP1-120

[0452] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, J=7.3 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.47 (d, J=4.2 Hz, 2H), 7.41 (s, 1H), 7.38-7.28 (m, 4H), 7.14 (d, J=5.8 Hz, 2H) , 6.75 (s, 1H), 5.09 (s, 2H), 5.07-4.98 (m, 1H), 4.71-4.63 (m, 1H), 4.25 (t , J=10.5 Hz, 1H), 3.47 (s, 3H); MS-ERI: m/z 417.0 (M+H) ⁺ .

[0453] RIP1-121

[0454] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J=7.2 Hz, 1H), 7.89 (s, 1H), 7.67 (d, J=2, 2 Hz, 1H), 7.43 (s, 1H), 7.41-7.33 (m, 4H), 7.28-7.24 (m, 2H), 6.77 (dd, J=2 .1, 0.8 Hz, 1H), 5.54 (d, J=3.3 Hz, 2H), 5.06 (dt, J=11.1, 7.4 Hz, 1H), 4.69 (dd, J=9.7, 7.5 Hz, 1H), 4.27 (dd, J=11.1, 9.9 Hz, 1H), 3.49 (s, 3H); MS-ERI: m/z 418.1 (M+H) ⁺ .

[0455] RIP1-122

[0456] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J=6.9 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.44 (s, 1H), 7.42-7.34 (m, 6H), 6.77 (dd, J=2.2, 0.9 Hz, 1H), 5.81 (s, 2H), 5, 09 (dt, J=11.0, 7.3 Hz, 1H), 4.78 (dd, J=9.8, 7.5 Hz, 1H), 4.26 (dd, J=11.0, 9.9 Hz, 1H), 3.50 (s, 3H); MS-ERI: m/z 419.1 (M+H) ⁺ .

[0457] RIP1-123

[0458] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J=6.8 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.44 (s, 1H), 7.39-7.29 (m, 6H), 6.77 (dd, J=2.2, 0.9 Hz, 1H), 5.05 (dt, J=11.0 , 7.3 Hz, 1H), 4.77 (dd, J=9.8, 7.5 Hz, 1H), 4.28 (s, 2H), 4.24 (dd, J=11.0, 9.9 Hz, 1H), 3.50 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 207.1, 179.5, 168.2, 163.1, 155.7, 153.0, 147.6, 146.8, 132.6, 132, 1, 129.1, 129.0, 128.0, 125.1, 115.3, 106.4, 106.0, 49.4, 36.4, 33.0, 31.0; MS-ERI: m/z 419.1 (M+H) ⁺ .

[0459] RIP1-124

[0460] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J=7.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J=0.5 Hz, 1H), 7.10 (d, J=7.8 Hz, 2H), 6.99 (d, J=8.0 Hz , 2H), 6.76 (dd, J=2.2, 0.9 Hz, 1H), 6.48 (s, 1H), 5.06 (dt, J=11.1, 7.4 Hz, 1H), 4.72 (dd, J=9.7, 7.5 Hz, 1H), 4.24 (dd, J=11.1, 9.8 Hz, 1H), 3.92 (s, 2H ), 3.71 (s, 3H), 3.48 (s, 3H), 2.31 (s, 3H); MS-ERI: m/z 445.1 (M+H) ⁺ .

[0461] RIP1-125

[0462] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.45 (s, 1H), 7 .40-7.36 (m, 1H), 7.35-7.28 (m, 5H), 6.78 (d, J=1.3 Hz, 1H), 4.99 (t, J=8 .9 Hz, 1H), 4.73 (dd, J=9.8, 7.5 Hz, 1H), 4.31-4.21 (m, 3H), 3.49 (s, 3H); MS-ERI: m/z 419.1 (M+H) ⁺ .

[0463] RIP1-126

[0464] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.76 (d, J=6.9 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.43 (s, 1H), 7.38-7.27 (m, 4H), 7.23 (d, J=6.9 Hz, 2H), 6.77 (d, J=1.4 Hz, 1H) , 6.29 (s, 1H), 5.01 (dt, J=11.1, 7.2 Hz, 1H), 4.71 (dd, J=9.7, 7.5 Hz, 1H), 4.24 (dd, J=10.9, 10.0 Hz, 1H), 4.10 (s, 2H), 3.48 (s, 3H); MS-ERI: m/z 419.0 (M+H) ⁺ .

[0465] RIP1-127

[0466] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J=7.2 Hz, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.48 (d, J=9.5 Hz, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.29-7.21 (m, 4H), 6.82 (dd, J=2.1, 0.8 Hz, 1H), 5.10 (dt, J=10.9, 7.3 Hz, 1H), 4.71 (dd, J=9.7, 7.6 Hz , 1H), 4.35-4.25 (m, 1H), 4.17 (s, 2H), 3.51 (s, 3H); MS-ERI: m/z 418.0 (M+H) ⁺ .

[0467] RIP1-128

[0468] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.87 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.8 Hz, 1H), 8.08 (d, J=7.1 Hz, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.42-7.36 (m, 3H), 7.31-7.27 (m, 2H), 5.39 (s, 2H), 5.18 (dt, J=11.3, 7.3 Hz, 1H), 4.84 (dd , J=9.8, 7.4 Hz, 1H), 4.35 (dd, J=11.2, 9.9 Hz, 1H), 3.61 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.5, 158.5, 156.5, 151.4, 145.4, 145.2, 144.0, 142.0, 141.0, 140, 0, 133.7, 129.3, 129.1, 128.3, 122.6, 121.6, 76.4, 54.4, 49.1, 36.3; MS-ERI: m/z 430.0 (M+H) ⁺ .

[0469] RIP1-129

[0470] ¹ H-NMR (400 MHz, DMSO) δ 8.94 (dd, J=5.1, 1.8 Hz, 2H), 8.19 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.98 (d, J=1.1 Hz, 1H), 7.92 (s, 2H), 7.89 (s, 1H), 7.76 (s, 1H ), 7.40-7.27 (m, 3H), 5.26 (s, 2H), 4.98-4.87 (m, 1H), 4.66-4.56 (m, 1H), 4.51 (dd, J=9.8, 7.6 Hz, 1H), 3.72 (s, 3H); ¹³ C-NMR (100 MHz, DMSO) δ 169.3, 163.1, 162.0, 151.6, 146.2, 146.2, 141.4, 140.8, 140.7, 139.4 , 138.3, 137.6, 137.5, 136.1, 132.8, 129.3, 129.2, 128.5, 128.4, 128.2, 128.2, 126.8, 123 .4, 122.7, 120.8, 76.0, 51.5, 50.3, 36.0; MS-ERI: m/z 429.0 (M+H) ⁺ .

[0471] RIP1-130

[0472] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.84 (d, J=5.5 Hz, 2H), 8.05 (d, J=6.9 Hz, 1H), 8.00 -7.85 (m, 3H), 7.43-7.23 (m, 5H), 5.54 (s, 2H), 5.14 (dt, J=11.2, 7.2 Hz, 1H ), 4.82-4.70 (m, 1H), 4.38 (t, J=10.6 Hz, 1H), 3.60 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.4, 159.6, 151.5, 145.4, 145.1, 142.7, 141.9, 141.0, 140.2, 133, 7, 129.3, 129.2, 128.3, 125.5, 122.5, 121.4, 76.4, 54.6, 48.9, 36.3; MS-ERI: m/z 430.0 (M+H) ⁺ .

[0473] RIP1-131

[0474] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.88 (d, J=7.4 Hz, 2H), 8.11 (d, J=6.6 Hz, 1H), 7.94 (d, J=16.3 Hz, 2H), 7.43-7.34 (m, 5H), 5.81 (s, 2H), 5.18 (dt, J=11.3, 7.2 Hz, 1H), 4.88-4.79 (m, 1H), 4.37 (t, J=10.6 Hz, 1H), 3.61 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.1, 159.3, 156.1, 151.3, 145.5, 145.2, 142.0, 141.0, 139.8, 132, 3, 129.4, 129.2, 128.7, 122.7, 121.6, 76.1, 57.6, 49.3, 36.3; MS-ERI: m/z 431.0 (M+H) ⁺ .

[0475] RIP1-132

[0476] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.85 (d, J=7.3 Hz, 2H), 8.00 (d, J=6.9 Hz, 1H), 7.93 (d, J=16.7 Hz, 2H), 7.39-7.28 (m, 5H), 5.12 (dt, J=11.3, 7.2 Hz, 1H), 4.82 ( dd, J=9.8, 7.4 Hz, 1H), 4.34 (dd, J=11.1, 10.1 Hz, 1H), 4.28 (s, 2H), 3.60 (s , 3Н); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 179.7, 167.9, 162.9, 155.8, 151.3, 145.6, 145.3, 142.0, 141.0, 139, 7, 132.6, 129.1, 129.0, 128.0, 122.8, 121.6, 76.0, 49.4, 36.3, 33.0; MS-ERI: m/z 431.1 (M+H) ⁺ .

[0477] RIP1-133

[0478] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.83 (d, J=6.8 Hz, 2H), 7.91 (d, J=16.9 Hz, 2H), 7.74 (d, J=7.1 Hz, 1H), 7.09 (d, J=7.7 Hz, 2H), 6.98 (d, J=7.8 Hz, 2H), 6.47 (s , 1H), 5.13 (dt, J=11.3, 7.2 Hz, 1H), 4.77 (dd, J=9.4, 7.5 Hz, 1H), 4.33 (t, J=10.6 Hz, 1H), 3.91(s, 2H), 3.71(s, 3H), 3.59(s, 3H), 2.30(s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.0, 161.7, 151.6, 145.3, 145.1, 144.0, 143.4, 141.9, 141.0, 140, 3, 136.6, 133.5, 129.5, 128.3, 122.5, 121.4, 106.9, 80.1, 65.6, 48.8, 37.1, 36.2, 31.5, 21.0; MS-ERI: m/z 457.1 (M+H) ⁺ .

[0479] RIP1-134

[0480] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.86 (d, J=6.4 Hz, 2H), 8.06 (d, J=6.7 Hz, 1H), 7.94 (d, J=16.9 Hz, 2H), 7.39-7.27 (m, 5H), 5.07 (dt, J=11.3, 7.1 Hz, 1H), 4.83- 4.74 (m, 1H), 4.37 (t, J=10.6 Hz, 1H), 4.26 (s, 2H), 3.61 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 167.8, 167.5, 158.4, 152.7, 151.2, 145.6, 145.3, 142.0, 141.0, 139, 7, 132.8, 129.1, 128.9, 127.9, 122.8, 121.6, 75.8, 49.5, 36.4, 31.9; MS-ERI: m/z 431.1 (M+H) ⁺ .

[0481] RIP1-135

[0482] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.82 (d, J=6.8 Hz, 2H), 8.13 (d, J=7.3 Hz, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.19 (d, J=13.4 Hz, 5H), 5.09 (dt, J=11.3, 7.4 Hz, 1H) , 4.75-4.66 (m, 1H), 4.40-4.30 (m, 1H), 4.11 (s, 2H), 3.56 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.4, 162.7, 158.7, 151.4, 145.4, 145.2, 141.9, 140.9, 140.0, 135, 8, 128.8, 128.8, 127.1, 122.6, 121.4, 76.2, 49.1, 36.3, 33.1; MS-ERI: m/z 430.1 (M+H) ⁺ .

[0483] RIP1-136

[0484] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 8.18 (d, J=6.2 Hz, 1H), 7.81 (s, 1H), 7 .61 (s, 1H), 7.41-7.35 (m, 3H), 7.34-7.28 (m, 2H), 5.42 (s, 2H), 5.10-4.96 (m, 1H), 4.86 (s, 1H), 4.32 (t, J=10.4 Hz, 1H), 3.52 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.3, 158.8, 156.3, 144.5, 133.4, 129.3, 128.4, 76.4, 54.6, 49, 6, 36.5; MS-ERI: m/z 419.0 (M+H) ⁺ .

[0485] RIP1-137

[0486] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J=7.5 Hz, 1H), 7.65 (s, 1H), 7.58-7.47 (m, 3H), 7.40-7.31 (m, 3H), 7.20-7.13 (m, 2H), 5.12 (s, 2H), 5.07-4.97 (m, 1H) , 4.73 (dd, J=9.8, 7.5 Hz, 1H), 4.35-4.26 (m, 1H), 3.50 (s, 3H); MS-ERI: m/z 418.1 (M+H) ⁺ .

[0487] RIP1-138

[0488] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J=7.1 Hz, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7 .57 (s, 1H), 7.43-7.32 (m, 3H), 7.31-7.27 (m, 2H), 5.55 (s, 2H), 5.05 (dt, J =14.7, 7.3 Hz, 1H), 4.76-4.67 (m, 1H), 4.31 (t, J=10.5 Hz, 1H), 3.51 (s, 3H) ; MS-ERI: m/z 419.1 (M+H) ⁺ .

[0489] RIP1-139

[0490] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J=6.6 Hz, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 7 .45-7.32 (m, 5H), 5.83 (s, 2H), 5.08 (dt, J=11.1, 7.1 Hz, 1H), 4.86-4.75 (m , 1H), 4.30 (t, J=10.5 Hz, 1H), 3.53 (s, 3H); MS-ERI: m/z 420.0 (M+H) ⁺ .

[0491] RIP1-140

[0492] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.81 (s, 1H), 7.61 (s, 1H), 7.41-7.28 ( m, 5H), 5.03 (s, 1H), 4.85-4.67 (m, 1H), 4.31 (s, 2H), 4.30-4.25 (m, 1H), 3 .54 (s, 3H); MS-ERI: m/z 420.0 (M+H) ⁺ .

[0493] RIP1-141

[0494] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J=7.1 Hz, 1H), 7.75-7.45 (d, J=47.5 Hz, 2H) , 7.10 (d, J=7.9 Hz, 2H), 7.00 (d, J=7.9 Hz, 2H), 6.52 (s, 1H), 5.01 (dt, J= 14.3, 7.2 Hz, 1H), 4.80 (dd, J=9.7, 7.4 Hz, 1H), 4.34-4.24 (m, 1H), 3.94 (s , 2H), 3.75 (s, 3H), 3.50 (s, 3H), 2.31 (s, 3H); MS-ERI: m/z 446.1 (M+H) ⁺ .

[0495] RIP1-142

[0496] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.84 (d, J=7.0 Hz, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 7 .36-7.27 (m, 3H), 7.25-7.19 (m, 2H), 6.31 (s, 1H), 5.02 (dt, J=11.2, 7.2 Hz , 1H), 4.73 (dd, J=9.7, 7.5 Hz, 1H), 4.34-4.23 (m, 1H), 4.11 (s, 2H), 3.53 ( s, 3H); MS-ERI: m/z 419.0 (M+H) ⁺ .

[0497] RIP1-143

[0498] ¹ H-NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 8.13-7.56 (m, 2H), 7.37-7.10 (m, 6H), 4 .86 (d, J=9.8 Hz, 1H), 4.63-4.29 (m, 2H), 4.13 (s, 2H), 3.39 (s, 3H); MS-ERI: m/z 419.0 (M+H) ⁺ .

[0499] RIP1-145

[0500] 26.9 mg, 73% yield, ¹ H-NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.59 (br, 1H), 8.44 (s, 1H), 8.18 (s, 1H), 7.52 (s, 1H), 7.48-7.25 (m, 5H), 5.54 (s, 2H), 5.05-4.84 (m, 1H), 4.80-4.64 (m, 1H), 4.63-4.44 (m, 1H), 3.56 (s, 3H), 3.45 (s, 3H), ¹³ C- NMR (100 MHz, CDCl ₃ ) δ 168.48, 160.64, 158.47, 156.53, 154.79, 147.83, 147.60, 143.99, 136.34, 133.73, 129 .22, 129.01, 128.27, 121.13, 120.88, 119.66, 77.27, 54.39, 48.96, 36.14, 34.24, MS-ERI m/z 460 ,1 (M+H) ⁺ .

[0501] RIP1-146

[0502] 27.6 mg, 75% yield, ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.12-8.00 (m, 2H), 7.97 (s, 1H), 7.39 ( s, 1H), 7.17-7.03 (m, 5H), 5.03-4.85 (m, 1H), 4.68-4.52 (m, 1H), 4.32-4, 20 (m, 1H), 4.04 (s, 2H), 3.52 (s, 3H), 3.41 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.34, 160.62, 158.75, 154.74, 147.71, 147.67, 136.33, 135.91, 128.83, 128.73, 127.05, 120.91, 120.87, 119, 61, 76.51, 48.97, 36.14, 34.30, 33.04, MS-ERI m/z 460.1 (M+H) ⁺ .

[0503] RIP1-147

[0504] 25.3 mg, 69% yield, ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 8.05 (s, 1H), 7.93 (br, J= 7.2 Hz, 1H), 7.51-7.44 (m, 3H), 7.39-7.32 (m, 3H), 7.18-7.10 (m, 2H), 5.10 (s, 2H), 5.09-5.01 (m, 1H), 4.76-4.68 (m, 1H), 4.39-4.30 (m, 1H), 3.61 (s , 3H), 3.51 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.88, 162.02, 160.69, 154.95, 147.69, 147.44, 137 .08, 136.72, 136.68, 135.06, 129.19, 128.70, 127.53, 122.53, 120.97, 120.74, 119.56, 51.38, 48.52 , 36.03, 34.23, MS-ERI m/z 459.1 (M+H) ⁺ .

[0505] RIP1-148

[0506] MS-ERI: m/z 429.1 (M+H) ⁺ .

[0507] RIP1-149

[0508] ¹ H-NMR (400 MHz, CDCl ₃ +CD ₃ OD) δ 8.76 (dd, J=4.2, 1.6 Hz, 1H), 8.08 (dd, J=8.2 , 1.6 Hz, 1H), 7.46 (d, J=9.1 Hz, 1H), 7.36 (dd, J=8.2, 4.3 Hz, 1H), 7.29-7 .18 (m, 6H), 4.98 (dd, J=8.5, 2.4 Hz, 1H), 4.70 (dd, J=11.2, 2.4 Hz, 1H), 4, 30 (dd, J=11.2, 8.7 Hz, 1H), 4.09 (s, 2H); MS-ERI: m/z 415.1 (M+H) ⁺ .

[0509] RIP1-150

[0510] MS-ERI: m/z 430.0 (M+H) ⁺ .

[0511] RIP1-153

[0512] ¹ H-NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.75 (s, 1H), 7.42-7.23 (m, 5H), 4.90-4 .80 (m, 1H), 4.65 (t, J=10.7 Hz, 1H), 4.48-4.40 (m, 1H), 4.37 (s, 2H), 3.42 ( s, 3H); ¹³ C-NMR (100 MHz, DMSO) δ 168.3, 167.9, 158.8, 153.5, 148.6, 136.0, 134.4, 129.4, 129.3, 127.8 , 110.3, 107.4, 75.1, 49.7, 36.4, 31.2; MS-ERI: m/z 420.0 (M+H) ⁺ .

[0513] RIP1-156

[0514] 13.1 mg, 33% yield, ¹ H-NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.13 (s, 1H), 7.48 (s, 1H), 7.45-7.31 (m, 1H), 7.17-7.03 (m, 2H), 4.88 (dt, J=11.6, 7.7 Hz, 1H), 4.70 ( t, J=10.7 Hz, 1H), 4.48 (dd, J=9.7, 7.6 Hz, 1H), 4.14 (s, 2H), 3.50 (s, 3H), 3.40 (s, 3H), MS-ERI m/z 496.0 (M+H) ⁺ .

[0515] RIP1-157

[0516] 11.0 mg, 27% yield, ¹ H-NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.48 (s, 1H), 7.23 (t, J=8.5 Hz, 2H), 4.89 (dt, J=11.4, 7.6 Hz, 1H), 4.70 (t , J=10.7 Hz, 1H), 4.49 (dd, J=9.5, 7.7 Hz, 1H), 4.11 (s, 2H), 3.51 (s, 3H), 3 .40 (s, 3H), MS-ERI m/z 514.0 (M+H) ⁺ .

[0517] RIP1-158

[0518] 5.4 mg, 21% yield, ¹ H-NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 8.20 (s, 1H), 7.54 (s, 1H), 7.37 (dd, J=8.2, 5.7 Hz, 2H), 7.22 (t, J=8.7 Hz, 2H), 4.96 (dt, J=11.5, 7, 7 Hz, 1H), 4.76 (t, J=10.7 Hz, 1H), 4.56 (dd, J=9.5, 7.7 Hz, 1H), 4.18 (s, 2H) , 3.57 (s, 3H), 3.46 (s, 3H), ¹³ C-NMR (100 MHz, DMSO) δ 168.75, 160.43, 154.61, 149.50, 147.72, 136.72, 131.04, 130.95, 120.69, 120.44, 119.66, 115.89, 115.68, 75.91, 49.05, 35.86, 34.13, MS- ERI m/z 478.1 (M+H) ⁺ .

[0519] RIP1-159

[0520] 6.4 mg, 25% yield, ¹ H-NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.46 (s, 1H), 8.19 (s, 1H), 7.54 (s, 1H), 7.43 (dd, J=14.3, 7.6 Hz, 1H), 7.23-7.09 (m, 3H), 4.97 (dt, J= 11.4, 7.7 Hz, 1H), 4.76 (t, J=10.7 Hz, 1H), 4.56 (dd, J=9.5, 7.8 Hz, 1H), 4, 22 (s, 2H), 3.57 (s, 3H), 3.47 (s, 3H), ¹³ C-NMR (100 MHz, DMSO) δ 168.75, 163.85, 161.43, 160, 42, 154.61, 149.49, 147.72, 136.71, 131.01, 130.92, 130.12, 125.28, 125.25, 120.68, 120.43, 119.65, 116.08, 115.86, 114.13, 113.93, 99.99, 75.91, 49.06, 35.86, 34.13, MS-ERI m/z 478.1 (M+H) ⁺ .

[0521] RIP1-160

[0522] 8.0 mg, 21% yield, ¹ H-NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.48 (s, 1H), 7.38-7.27 (m, 2H), 7.24-7.13 (m, 2H), 4.90 (dt, J=11.5, 7.7 Hz, 1H), 4.70 (t, J=10.7 Hz, 1H), 4.49 (dd, J=9.7, 7.6 Hz, 1H), 4.15 (s, 2H), 3.51 (s, 3H), 3.40 (s, 3H), ¹³ C-NMR (100 MHz, DMSO) δ 168.74, 161.97, 160.42, 159.54, 154.60, 149 .48, 147.71, 136.71, 131.75, 131.71, 129.58, 129.50, 125.06, 125.02, 120.67, 120.43, 119.65, 115.92 , 115.70, 75.90, 49.05, 35.85, 34.13, ESI MS m/z 478.0 (M+H) ⁺ .

[0523] RIP1-161

[0524] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 8.59 (d, J=6.0 Hz, 1H), 8.08 (d, J=5, 8 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.46 (d, J=8.8 Hz , 1H), 7.22 (td, J=8.3, 4.1 Hz, 1H), 6.95-6.82 (m, 2H), 5.13-5.01 (m, 1H), 4.78 (dd, J=9.8, 7.5 Hz, 1H), 4.48-4.37 (m, 1H), 4.21 (s, 2H), 3.46 (s, 3H) ; MS-ERI: m/z 465.0 (M+H) ⁺ .

[0525] RIP1-162

[0526] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 7.99 (d, J=8, 8 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 6.73-6.64 (m, 2H) , 5.06 (dd, J=10.9, 7.5 Hz, 1H), 4.78 (dd, J=9.9, 7.5 Hz, 1H), 4.46-4.37 (m , 1H), 4.15 (s, 2H), 3.47 (s, 3H); MS-ERI: m/z 483.0 (M+H) ⁺ .

[0527] RIP1-163

[0528] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.29 (s, 1H), 8.59 (d, J=6.0 Hz, 1H), 8.10 (s, 1H), 7 .99 (d, J=8.8 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.29 -7.18 (m, 2H), 7.06 (t, J=7.3 Hz, 1H), 7.00 (t, J=9.1 Hz, 1H), 5.14-5.02 ( m, 1H), 4.79 (dd, J=9.9, 7.5 Hz, 1H), 4.46-4.37 (m, 1H), 4.19 (s, 2H), 3.47 (s, 3H); MS-ERI: m/z 447.0 (M+H) ⁺ .

[0529] RIP1-164

[0530] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 8.59 (d, J=6.0 Hz, 1H), 8.11 (d, J=7, 3 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.46 (d, J=8.8 Hz , 1H), 7.22 (dd, J=8.3, 5.4 Hz, 2H), 6.94 (t, J=8.6 Hz, 2H), 5.06 (dt, J=11, 0, 7.4 Hz, 1H), 4.77 (dd, J=9.9, 7.5 Hz, 1H), 4.45-4.38 (m, 1H), 4.11 (s, 2H ), 3.46 (s, 3H); MS-ERI: m/z 447.0 (M+H) ⁺ .

[0531] RIP1-165

[0532] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.30 (s, 1H), 8.60 (d, J=6.0 Hz, 1H), 8.12 (s, 1H), 7 .99 (d, J=8.8 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.25 -7.21(m, 1H), 7.05(d, J=7.5Hz, 1H), 7.01-6.89(m, 2H), 5.13-5.01(m, 1H ), 4.79 (dd, J=9.8, 7.6 Hz, 1H), 4.43 (t, J=10.5 Hz, 1H), 4.15 (s, 2H), 3.48 (s, 3H); MS-ERI: m/z 447.0 (M+H) ⁺ .

[0533] RIP1-166

[0534] ¹ H-NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.10 (s, 1H), 7.75 (s, 1H), 7.46-7.32 (m , 1H), 7.19-7.02 (m, 2H), 4.85 (dt, J=11.1, 7.6 Hz, 1H), 4.65-4.57 (m, 1H), 4.41 (dd, J=9.8, 7.8 Hz, 1H), 4.14 (s, 2H), 3.42 (s, 3H); MS-ERI: m/z 455.0 (M+H) ⁺ .

[0535] RIP1-167

[0536] ¹ H-NMR (400 MHz, DMSO) δ 8.53 (d, J=6.4 Hz, 1H), 8.10 (d, J=13.8 Hz, 1H), 7.74 ( s, 1H), 7.35-7.27 (dd, J=8.6, 5.6 Hz, 3H), 7.21-7.10 (m, 3H), 4.86 (dd, J= 10.8, 6.8 Hz, 1H), 4.64-4.54 (m, 1H), 4.42 (dd, J=9.8, 7.8 Hz, 1H), 4.30 (dd , J=14.2, 7.1 Hz, 1H), 4.12 (s, 2H), 3.42 (s, 3H); MS-ERI: m/z 437.0 (M+H) ⁺ .

[0537] RIP1-168

[0538] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.99-8.91 (m, 1H), 8.28-7.99 (m, 3H), 7.57 (d, J=9 .0 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (td, J=8.2, 4.1 Hz, 1H), 6.88 (t, J=7.7 Hz, 2H), 5.15-5.03 (m, 1H), 4.76 (dd, J=9.8, 7.8 Hz, 1H), 4.40 ( t, J=10.4 Hz, 1H), 4.20 (s, 2H), 3.45 (s, 3H); MS-ERI: m/z 465.0 (M+H) ⁺ .

[0539] RIP1-169

[0540] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.95 (dd, J=4.2, 1.5 Hz, 1H), 8.22-8.02 (m, 3H), 7, 57 (d, J=9.0 Hz, 1H), 7.50 (dd, J=8.5, 4.2 Hz, 1H), 6.65 (t, J=8.0 Hz, 2H), 5.07 (dd, J=10.8, 7.7 Hz, 1H), 4.76 (dd, J=9.9, 7.6 Hz, 1H), 4.39 (t, J=10, 4 Hz, 1H), 4.13 (s, 2H), 3.46 (s, 3H); MS-ERI: m/z 483.0 (M+H) ⁺ .

[0541] RIP1-170

[0542] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.93 (dd, J=4.2, 1.5 Hz, 1H), 8.26-8.00 (m, 3H), 7, 57 (d, J=9.1 Hz, 1H), 7.49 (dd, J=8.6, 4.2 Hz, 1H), 7.25-7.12 (m, 2H), 7.04 -6.98 (m, 1H), 6.97-6.91 (t, 1H), 5.17-5.04 (m, 1H), 4.76-4.70 (m, 1H), 4 .39 (t, J=10.5 Hz, 1H), 4.15 (s, 2H), 3.45 (s, 3H); MS-ERI: m/z 447.0 (M+H) ⁺ .

[0543] RIP1-171

[0544] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.13 (t, J=9.2 Hz, 3H) , 7.58 (d, J=9.0 Hz, 1H), 7.50 (dd, J=8.5, 4.3 Hz, 1H), 7.24-7.18 (m, 2H), 6.98-6.91 (m, 2H), 5.09 (dd, J=10.6, 7.7 Hz, 1H), 4.77 (dd, J=9.9, 7.6 Hz, 1H), 4.43-4.36 (m, 1H), 4.11 (s, 2H), 3.46 (s, 3H); MS-ERI: m/z 447.0 (M+H) ⁺ .

[0545] RIP1-172

[0546] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.13 (t, J=9.7 Hz, 3H) , 7.58 (d, J=9.0 Hz, 1H), 7.50 (dd, J=8.5, 4.2 Hz, 1H), 7.22 (td, J=7.9, 6 .1 Hz, 1H), 7.04-7.00 (m, 1H), 6.98-6.87 (m, 2H), 5.09 (dd, J=10.8, 7.7 Hz, 1H), 4.77 (dd, J=9.9, 7.6 Hz, 1H), 4.43-4.36 (m, 1H), 4.13 (s, 2H), 3.46 (s , 3Н); MS-ERI: m/z 447.0 (M+H) ⁺ .

[0547] RIP1-173

[0548] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.44 (s, 1H), 7 .38 (d, J=9.0 Hz, 1H), 6.77 (dd, J=2.2, 0.8 Hz, 1H), 6.74-6.65 (m, 2H), 5, 07-4.97 (m, 1H), 4.70 (dd, J=9.8, 7.5 Hz, 1H), 4.27 (dd, J=11.0, 9.9 Hz, 1H) , 4.14 (s, 2H), 3.49 (s, 3H); MS-ERI: m/z 470.1 (M-H) ^- ,

[0549] RIP1-174

[0550] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.44 (s, 1H), 7 .36 (s, 1H), 7.22 (dd, J=8.4, 5.4 Hz, 2H), 6.94 (t, J=8.7 Hz, 2H), 6.80-6, 75 (m, 1H), 5.04 (dd, J=10.7, 7.8 Hz, 1H), 4.68 (dd, J=9.7, 7.6 Hz, 1H), 4.31 -4.22 (m, 1H), 4.10 (s, 2H), 3.48 (s, 3H); MS-ERI: m/z 436.0 (M+H) ⁺ .

[0551] RIP1-175

[0552] 15.1 mg, 40% yield, ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.83 (d, J=6.8 Hz, 1H), 8.37 (d, J=5, 4 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.53 (s, 1H), 7.43 (s, 1H), 7.34 (t, J= 7.5 Hz, 2H), 7.17 (d, J=7.1 Hz, 1H), 7.00 (d, J=7.7 Hz, 2H), 6.88 (d, J=3, 1 Hz, 1H), 5.05-4.91 (m, 1H), 4.73-4.65 (m, 1H), 4.30 (t, J=10.6 Hz, 1H), 3, 55 (s, 3H), 3.46 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 168.69, 166.13, 163.72, 160.66, 154.87, 153, 72, 151.23, 150.15, 147.76, 147.53, 136.56, 130.35, 125.76, 120.95, 120.79, 119.62, 114.53, 110.66, 76.79, 49.21, 36.05, 34.24, MS-ERI m/z 472.0 (M+H) ⁺ .

[0553] RIP1-176

[0554] MS-ERI: m/z 496.0 (M+H) ⁺ .

[0555] RIP1-177

[0556] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.84 (d, J=7.2 Hz, 1H), 8.80-8.70 (m, 2H), 8.38 (d, J=5.6Hz, 1H), 7.87(s, 1H), 7.83(s, 1H), 7.52(d, J=2.4Hz, 1H), 7.34(t, J=7.9 Hz, 2H), 7.16 (d, J=7.4 Hz, 1H), 6.99 (d, J=7.8 Hz, 2H), 6.88 (dd, J= 5.6, 2.5 Hz, 1H), 5.06 (dt, J=11.4, 7.3 Hz, 1H), 4.71 (dd, J=9.7, 7.4 Hz, 1H ), 4.37-4.25 (m, 1H), 3.54 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 167.68, 165.10, 162.70, 152, 68, 150.50, 150.17, 149.11, 144.33, 144.08, 140.90, 139.98, 139.17, 129.31, 124.72, 121.43, 120.34, 119.74, 113.51, 109.64, 75.37, 48.31, 35.13, ESI MS m/z 442.1 (M+H) ⁺ .

[0557] RIP1-178

[0558] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.22 (s, 1H), 8.84 (d, J=7.3 Hz, 1H), 8.52 (d, J=6, 0 Hz, 1H), 8.38 (d, J=5.6 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.53 (d, J=6.0 Hz , 1H), 7.50 (d, J=2.5 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.33 (t, J=7.9 Hz, 2H ), 7.16 (t, J=7.4 Hz, 1H), 6.98 (d, J=7.7 Hz, 2H), 6.88 (dd, J=5.6, 2.5 Hz , 1H), 5.01 (dt, J=11.0, 7.4 Hz, 1H), 4.73 (dd, J=9.8, 7.5 Hz, 1H), 4.40-4, 32 (m, 1H), 3.41 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.73, 166.11, 163.76, 153.70, 153.01, 152, 34, 151.23, 150.16, 144.12, 132.01, 130.34, 129.38, 129.28, 127.21, 125.76, 123.52, 120.77, 115.73, 114.50, 110.64, 78.13, 49.03, 36.98, MS-ERI m/z 441.0 (M+H) ⁺ .

[0559] RIP1-179

[0560] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.87 (d, J=2.9 Hz, 1H), 8.82 (d, J=7.4 Hz, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.06 (dd, J=17.3, 8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7 .42 (dd, J=8.5, 4.2 Hz, 1H), 7.33 (t, J=7.8 Hz, 2H), 7.16 (t, J=7.4 Hz, 1H) , 6.98 (d, J=7.8 Hz, 2H), 6.88 (dd, J=5.5, 2.4 Hz, 1H), 5.03 (dt, J=10.8, 7 .6 Hz, 1H), 4.72 (dd, J=9.7, 7.7 Hz, 1H), 4.34 (t, J=10.4 Hz, 1H), 3.40 (s, 3H ), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.03, 165.07, 162.70, 152.66, 150.24, 149.10, 148.99, 148.16, 145.72, 130.09, 129.96, 129.30, 128.75, 124.71, 124.16, 123.05, 120.65, 119.73, 113.46, 109.59, 77.11, 48, 13, 36.30, MS-ERI m/z 441.1 (M+H) ⁺ .

[0561] RIP1-180

[0562] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.89 (d, J=7.4 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.46-7.35 (m, 4H), 7.25-7.21 ( m, 1H), 7.10-7.04 (m, 2H), 6.94 (dd, J=5.6, 2.5 Hz, 1H), 6.77 (dd, J=2.2, 0.8 Hz, 1H), 5.05 (dt, J=11.1, 7.4 Hz, 1H), 4.72 (dd, J=9.7, 7.5 Hz, 1H), 4, 28 (dd, J=11.1, 9.8 Hz, 1H), 3.50 (s, 3H); MS-ERI: m/z 430.0 (M+H) ⁺ .

[0563] RIP1-181

[0564] ¹ H-NMR (400 MHz, DMSO) δ 8.96-8.76 (m, 1H), 8.52 (d, J=5.4 Hz, 1H), 7.99 (s, 1H ), 7.66 (s, 1H), 7.44 (t, J=7.7 Hz, 2H), 7.30-7.20 (m, 2H), 7.15 (d, J=7, 9 Hz, 2H), 4.87-4.69 (m, 1H), 4.54-4.24 (m, 2H); MS-ERI: m/z 431.0 (M+H) ⁺ .

[0565] RIP1-182

[0566] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 8.05 (br, J=7.4 Hz, 1H), 7.51 (s, 1H), 7 .38 (s, 1H), 7.16-7.01 (m, 5H), 4.97 (dd, J=17.4, 7.3 Hz, 1H), 4.62-4.52 (m , 1H), 4.24-4.15 (m, 1H), 4.01 (s, 2H), 3.39 (s, 3H), MS-ERI m/z 419.1 (M+H) ⁺ .

[0567] RIP1-183

[0568] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 8.08 (br, J=6.7 Hz, 1H), 7.62 (s, 1H), 7 .49 (s, 1H), 7.22 (dd, J=14.7, 7.4 Hz, 1H), 6.89 (t, J=7.6 Hz, 2H), 5.05 (dd, J=18.0, 7.5 Hz, 1H), 4.73-4.65 (m, 1H), 4.33-4.25 (m, 1H), 4.20 (s, 2H), 3 .49 (s, 3H), MS-ERI m/z 455.1 (M+H) ⁺ .

[0569] RIP1-184

[0570] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.17 (s, 1H), 8.11 (br, J=7.2 Hz, 1H), 7.61 (s, 1H), 7 .49 (s, 1H), 6.63 (t, J=7.8 Hz, 2H), 5.10-4.97 (m, 1H), 4.71-4.60 (m, 1H), 4.36-4.25 (m, 1H), 4.11 (s, 2H), 3.48 (s, 3H), MS-ERI m/z 473.1 (M+H) ⁺ .

[0571] RIP1-185

[0572] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 8.06 (br, J=6.1 Hz, 1H), 7.53 (s, 1H), 7 .41 (s, 1H), 7.13-7.00 (m, 2H), 6.86-6.73 (m, 2H), 5.02-4.88 (m, 1H), 4.65 -4.50 (m, 1H), 4.28-4.14 (m, 1H), 3.99 (s, 2H), 3.40 (s, 3H), MS-ERI m/z 437.1 (M+H) ⁺ .

[0573] RIP1-186

[0574] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.87 (d, J=7.4 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 7.63 (s, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.49 (s, 1H), 7.41 (t, J=7, 9 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.8 Hz, 2H), 6.95 (dd, J=5.6, 2.5 Hz, 1H), 5.06 (dt, J=11.2, 7.5 Hz, 1H), 4.73 (dd, J=9.7, 7.6 Hz, 1H), 4, 36-4.25 (m, 1H), 3.51 (s, 3H), ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.10, 166.13, 163.72, 154.11, 153, 71, 151.29, 150.13, 147.81, 147.17, 138.69, 135.07, 130.35, 125.76, 120.79, 114.50, 114.15, 110.66, 105.77, 77.46, 49.32, 36.15, MS-ERI m/z 431.1 (M+H) ⁺ .

[0575] RIP1-187

[0576] MS-ERI m/z 446.1 (M+H) ⁺ .

[0577] RIP1-188

[0578] MS-ERI m/z 458.1 (M+H) ⁺ .

[0579] RIP1-189

[0580] ¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.92 (d, J=7.2 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.32 (s, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.46 (s, 1H), 7.40 (t, J=7.9 Hz, 2H), 7.26 -7.23 (m, 2H), 7.22 (s, 1H), 7.06 (d, J=7.6 Hz, 2H), 6.94 (dd, J=5.6, 2.5 Hz, 1H), 6.54 (s, 1H), 5.09-5.03 (m, 1H), 4.71 (dd, J=9.6, 7.5 Hz, 1H), 4.24 (dd, J=11.0, 9.8 Hz, 1H), 3.51 (s, 3H); MS-ERI: 429.45 [M+H] ⁺ .

[0581] RIP1-190

[0582] ¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.92 (d, J=7.2 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.60 (s, 2H), 7.41 (t, J=7.9 Hz, 2H), 7.31 (s, 1H), 7.26-7.22 (m, 1H), 7.06 (d, J=7.9 Hz, 2H), 6.95 (dd, J=5.3, 2.2 Hz, 1H), 5.10-5.03 (m, 1H), 4.69 (dd, J = 9.6, 7.5 Hz, 1H), 4.32-4.26 (m, 1H), 3.52 (s, 3H); MS-ERI: 430.40 [M+H] ⁺ .

[0583] RIP1-193

[0584] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.95 (dd, J=4.2, 1.5 Hz, 1H), 8.72 (d, J=1.3 Hz, 1H) , 8.48 (d, J=2.6 Hz, 1H), 8.13 (dd, J=13.3, 8.7 Hz, 2H), 7.65-7.62 (m, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.53-7.44 (m, 2H), 7.40-7.33 (m, 2H), 7.17 (t, J= 7.4 Hz, 1H), 7.01 (d, J=7.7 Hz, 2H), 5.11 (dt, J=10.8, 7.3 Hz, 1H), 4.82 (dd, J=9.9, 7.6 Hz, 1H), 4.43-4.35 (m, 1H), 3.47 (s, 3H); MS-ERI: m/z 441.1 (M+H) ⁺ .

[0585] RIP1-194

[0586] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.94 (d, J=2.9 Hz, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.16 -8.05(m, 2H), 7.83-7.73(m, 2H), 7.61-7.45(m, 4H), 7.32(t, J=7.4Hz, 1H ), 7.26-7.22 (m, 2H), 7.03 (dd, J=7.7, 1.3 Hz, 1H), 5.05 (dt, J=11.0, 7.6 Hz, 1H), 4.72 (dd, J=9.8, 7.6 Hz, 1H), 4.29 (dd, J=10.9, 10.0 Hz, 1H), 3.44 (s , 3Н); MS-ERI: m/z 441.0 (M+H) ⁺ .

[0587] RIP1-195

[0588] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.00-8.94 (m, 1H), 8.28 (d, J=5.2 Hz, 1H), 8.15 (t, J=8.8 Hz, 2H), 7.61 (d, J=9.0 Hz, 1H), 7.52 (dd, J=8.6, 4.2 Hz, 1H), 7.46- 7.34 (m, 3H), 7.28 (dd, J=5.2, 1.3 Hz, 1H), 7.26-7.20 (t, J=7.4 Hz, 2H), 7 .13 (d, J=7.6 Hz, 2H), 5.10 (dt, J=10.8, 7.2 Hz, 1H), 4.88 (dd, J=9.9, 7.6 Hz, 1H), 4.42-4.33 (m, 1H), 3.50 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.0, 164.6, 164.5, 153.6, 150.2, 149.2, 148.7, 146.8, 144.2, 131, 3, 131.0, 129.8, 129.4, 125.2, 124.0, 121.8, 121.3, 115.6, 109.6, 78.1, 49.6, 37.5; MS-ERI: m/z 441.0 (M+H) ⁺ .

[0589] RIP1-196

[0590] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.95 (dd, J=4.1, 1.5 Hz, 1H), 8.74 (d, J=7.5 Hz, 1H) , 8.35 (d, J=2.5 Hz, 1H), 8.19-8.08 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.59 ( d, J=9.1 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.44-7.37 (m, 2H), 7.28 (dd , J=8.6, 2.8 Hz, 1H), 7.25-7.19 (m, 1H), 7.09-7.03 (m, 2H), 5.13 (dt, J=11 .0, 7.6 Hz, 1H), 4.80 (dd, J=9.9, 7.6 Hz, 1H), 4.41 (dd, J=10.9, 10.0 Hz, 1H) , 3.48 (s, 3H); MS-ERI: m/z 441.0 (M+H) ⁺ .

[0591] RIP1-197

[0592] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (d, J=3.0 Hz, 1H), 8.89 (d, J=7.4 Hz, 1H), 8.47 (d, J=5.6 Hz, 1H), 8.14 (dd, J=15.2, 8.8 Hz, 2H), 7.59 (d, J=9.1 Hz, 1H), 7 .54 (d, J=2.5 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.14-7.07 (m, 2H), 7. 07-7.00 (m, 2H), 6.94 (dd, J=5.6, 2.5 Hz, 1H), 5.10 (dt, J=10.9, 7.5 Hz, 1H) , 4.79 (dd, J=9.8, 7.6 Hz, 1H), 4.47-4.37 (m, 1H), 3.48 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.1, 166.2, 163.7, 158.9, 151.4, 150.2, 150.1, 149.5, 149.2, 146, 8, 131.1, 131.0, 129.8, 125.2, 124.1, 122.4, 122.3, 121.7, 117.2, 116.9, 114.3, 110.3, 78.2, 49.2, 37.4; MS-ERI: m/z 459.1 (M+H) ⁺ .

[0593] RIP1-198

[0594] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (d, J=2.8 Hz, 1H), 8.90 (d, J=7.5 Hz, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.14 (dd, J=17.1, 8.8 Hz, 2H), 7.59 (d, J=9.1 Hz, 1H), 7 .54 (d, J=2.5 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.24-7.18 (dd, J=14.4 , 7.0, 4.4 Hz, 1H), 7.07-6.99 (m, 3H), 5.10 (dt, J=11.0, 7.5 Hz, 1H), 4.79 ( dd, J=9.9, 7.6 Hz, 1H), 4.41 (dd, J=10.8, 10.0 Hz, 1H), 3.48 (s, 3H); MS-ERI: m/z 477.0 (M+H) ⁺ .

[0595] RIP1-199

[0596] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.1, 1.4 Hz, 1H), 8.72 (d, J=4.8 Hz, 1H) , 8.60 (d, J=7.4 Hz, 1H), 8.18-8.09 (m, 2H), 7.69 (d, J=4.8 Hz, 1H), 7.59 ( d, J=9.0 Hz, 1H), 7.54-7.48 (m, 3H), 7.37-7.32 (m, 1H), 7.28-7.24 (m, 2H) , 5.08 (dt, J=10.9, 7.5 Hz, 1H), 4.77 (dd, J=9.9, 7.6 Hz, 1H), 4.37 (dd, J=10 .8, 10.0 Hz, 1H), 3.47 (s, 3H); MS-ERI: m/z 442.0 (M+H) ⁺ .

[0597] RIP1-200

[0598] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (d, J=2.9 Hz, 1H), 8.91 (d, J=7.5 Hz, 1H), 8.27 (d, J=5.6 Hz, 1H), 8.14 (dd, J=19.8, 8.8 Hz, 2H), 7.59 (d, J=9.1 Hz, 1H), 7 .54 (d, J=2.0 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.35 (t, J=7.8 Hz, 2H) , 7.21-7.11 (m, 3H), 6.92 (dd, J=5.6, 2.3 Hz, 1H), 6.24 (s, 1H), 5.12 (dt, J =11.0, 7.6 Hz, 1H), 4.82-4.75(m, 1H), 4.46-4.38(m, 1H), 3.48(s, 3H); MS-ERI: m/z 440.0 (M+H) ⁺ .

[0599] RIP1-201

[0600] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.1, 1.4 Hz, 1H), 8.79 (d, J=7.4 Hz, 1H) , 8.68 (t, J=1.4 Hz, 1H), 8.20-8.09 (m, 2H), 7.95 (d, J=1.5 Hz, 2H), 7.60 ( d, J=9.0 Hz, 1H), 7.51 (dd, J=8.6, 4.2 Hz, 1H), 7.42-7.30 (m, 2H), 7.18-7 .10 (m, 3H), 5.12 (dt, J=10.9, 7.5 Hz, 1H), 4.87-4.76 (m, 1H), 4.41 (dd, J=10 .8, 10.0 Hz, 1H), 3.49 (s, 3H); MS-ERI: m/z 440.0 (M+H) ⁺ .

[0601] RIP1-202

[0602] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.97 (dd, J=4.2, 1.5 Hz, 1H), 8.81 (d, J=7.1 Hz, 1H) , 8.61 (d, J=4.8 Hz, 1H), 8.19-8.10 (m, 2H), 7.68 (d, J=7.7 Hz, 2H), 7.61 ( d, J=9.0 Hz, 1H), 7.51 (dd, J=8.6, 4.2 Hz, 1H), 7.46 (t, J=7.9 Hz, 2H), 7, 37 (d, J=4.8 Hz, 1H), 7.34 (s, 1H), 7.14 (t, J=7.4 Hz, 1H), 5.08 (dt, J=10.9 , 7.4 Hz, 1H), 4.84 (dd, J=9.9, 7.6 Hz, 1H), 4.45-4.34 (m, 1H), 3.51 (s, 3H) ; MS-ERI: m/z 441.0 (M+H) ⁺ .

[0603] RIP1-203

[0604] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.90 (d, J=7.5 Hz, 1H) , 8.48 (d, J=5.6 Hz, 1H), 8.19-8.14 (m, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.59 ( d, J=9.1 Hz, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7, 26-7.13 (m, 4H), 6.97 (dd, J=5.6, 2.5 Hz, 1H), 5.10 (dt, J=11.0, 7.5 Hz, 1H) , 4.79 (dd, J=9.9, 7.6 Hz, 1H), 4.41 (dd, J=10.9, 10.0 Hz, 1H), 3.48 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.1, 165.6, 163.6, 151.4, 150.2, 150.1, 149.2, 146.8, 131.1, 131, 0, 129.8, 127.3, 127.2, 125.3, 125.27, 124.1, 123.5, 121.7, 117.7, 117.5, 113.8, 109.7, 78.2, 49.2, 37.4; MS-ERI: m/z 459.0 (M+H) ⁺ .

[0605] RIP1-204

[0606] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.2, 1.6 Hz, 1H), 8.90 (d, J=7.5 Hz, 1H) , 8.50 (d, J=5.6 Hz, 1H), 8.18-8.14 (m, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.60 ( dd, J=5.7, 3.3 Hz, 2H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.37 (td, J=8.3, 6, 6 Hz, 1H), 7.01-6.93 (ddd, J=10.0, 6.9, 2.1 Hz, 2H), 6.86 (dd, J=8.2, 2.1 Hz , 1H), 6.80 (dt, J=9.4, 2.3 Hz, 1H), 5.11 (dt, J=11.0, 7.6 Hz, 1H), 4.80 (dd, J=9.9, 7.6 Hz, 1H), 4.42 (dd, J=10.8, 10.0 Hz, 1H), 3.48 (s, 3H); MS-ERI: m/z 459.0 (M+H) ⁺ .

[0607] RIP1-205

[0608] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.2, 1.6 Hz, 1H), 8.91 (d, J=7.5 Hz, 1H) , 8.54 (d, J=5.6 Hz, 1H), 8.19-8.15 (m, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.61 ( dd, J=9.0, 5.8 Hz, 2H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.04 (dd, J=5.6, 2, 5 Hz, 1H), 6.71 (tt, J=8.8, 2.3 Hz, 1H), 6.65-6.57 (m, 2H), 5.11 (dt, J=10.9 , 7.5 Hz, 1H), 4.81 (dd, J=9.9, 7.6 Hz, 1H), 4.42 (dd, J=10.8, 10.0 Hz, 1H), 3 .49 (s, 3H); MS-ERI: m/z 477.0 (M+H) ⁺ .

[0609] RIP1-206

[0610] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H) , 7.32-7.21 (m, 2H), 7.12-7.01 (m, 2H), 5.1-5.02 (m, 1H), 4.71 (dd, J=9, 8, 7.7 Hz, 1H), 4.33-4.25(m, 1H), 4.19(s, 2H), 3.50(s, 3H); MS-ERI: m/z 437.0 (M+H) ⁺ .

[0611] RIP1-207

[0612] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.78 (d, J=5.5 Hz, 2H), 8.04 (s, 1H), 7.88 (s, 1H), 7 .83 (s, 1H), 7.35-7.22 (m, 1H), 7.15 (s, 1H), 6.94-6.84 (m, 2H), 5.10-4.97 (m, 1H), 4.75-4.64 (m, 1H), 4.33-4.26 (m, 1H), 4.04 (s, 2H), 3.52 (s, 3H); MS-ERI: m/z 448.0 (M+H) ⁺ .

[0613] RIP1-208

[0614] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.81-8.72 (m, 2H), 7.88 (s, 1H), 7.82 (s, 1H), 7.17- 7.06 (m, 2H), 6.92 (dt, J=18.1, 8.1 Hz, 2H), 5.09-4.97 (m, 1H), 4.72-4.58 ( m, 1H), 4.33-4.22 (m, 1H), 4.09 (s, 2H), 3.51 (s, 3H), MS-ERI m/z 448.1 (M+H) ⁺ .

[0615] RIP1-209

[0616] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.91-8.78 (m, 2H), 7.95 (s, 1H), 7.89 (s, 1H), 7.19 ( dd, J=13.9, 7.5 Hz, 1H), 7.06-6.79 (m, 3H), 5.17-5.01 (m, 1H), 4.78-4.67 ( m, 1H), 4.43-4.30 (m, 1H), 4.12 (s, 2H), 3.59 (s, 3H), MS-ERI m/z 448.1 (M+H) ⁺ .

[0617] RIP1-210

[0618] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.96 (dd, J=4.2, 1.5 Hz, 1H), 8.91 (d, J=7.5 Hz, 1H) , 8.52 (t, J=3.9 Hz, 2H), 8.46 (d, J=2.4 Hz, 1H), 8.20-8.07 (m, 2H), 7.64- 7.56 (m, 2H), 7.54-7.47 (m, 1H), 7.46-7.34 (m, 2H), 7.00 (dd, J=5.6, 2.6 Hz, 1H), 5.11 (dt, J=10.9, 7.5 Hz, 1H), 4.80 (dd, J=9.9, 7.6 Hz, 1H), 4.42 (dd , J=10.8, 10.1 Hz, 1H), 3.48 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.0, 165.4, 163.4, 151.6, 150.5, 150.5, 150.1, 149.2, 146.9, 146, 8, 143.1, 131.1, 131.0, 129.7, 128.1, 125.2, 124.6, 124.1, 121.7, 114.6, 110.5, 78.1, 49.2, 37.4; MS-ERI: m/z 442.0 (M+H) ⁺ .

0619] RIP1-211

[0620] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.82 (br, J=6, 9 Hz, 1H), 7.60 (s, 1H), 7.44 (s, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.22 (d, J=7, 5 Hz, 1H), 4.99-4.88 (m, 1H), 4.74-4.65 (m, 1H), 4.29-4.18 (m, 1H), 3.46 (s , 3H), MS-ERI m/z 421.0 (M+H) ⁺ .

[0621] RIP1-212

[0622] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.88 (br, J=7.4 Hz, 1H), 8.65-8.47 (m, 3H), 8.17 (s, 1H), 7.64 (s, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.61-7.52 (m, 2H), 7.50 (s, 1H), 7.04 (dd, J=5.5, 2.5 Hz, 1H), 5.06 (dt, J=11.1, 7.5 Hz, 1H), 4.74 (dd, J=9, 8, 7.6 Hz, 1H), 4.36-4.27 (m, 1H), 3.52 (s, 3H), MS-ERI m/z 432.0 (M+H) ⁺ .

[0623] RIP1-213

[0624] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J=7.3 Hz, 1H), 8.74 (s, 1H), 8.10 (s, 1H), 7 .58 (s, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.38 (t, J=7.9 Hz, 2H), 7.23 (t, J= 7.5 Hz, 1H), 7.07 (d, J=7.9 Hz, 2H), 4.99 (dt, J=11.1, 7.5 Hz, 1H), 4.69 (dd, J=9.7, 7.7 Hz, 1H), 4.29-4.18 (m, 1H), 3.45 (s, 3H), MS-ERI m/z 432.0 (M+H) ⁺ .

[0625] RIP1-214

[0626] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.91 (d, J=7.2 Hz, 1H), 8.88-8.82 (m, 2H), 8.57-8, 43 (m, 3H), 7.95 (s, 1H), 7.91 (s, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.48-7.33 (m , 2H), 7.01 (dd, J=5.5, 2.5 Hz, 1H), 5.13 (dt, J=11.4, 7.3 Hz, 1H), 4.79 (dd, J=9.7, 7.4 Hz, 1H), 4.39 (dd, J=11.2, 10.0 Hz, 1H), 3.62 (s, 3H), MS-ERI m/z 443 ,0 (M+H) ⁺ .

[0627] RIP1-215

[0628] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.81-8.76 (m, 2H), 8.75 (s, 1H), 7.89 ( s, 1H), 7.86 (s, 1H), 7.49 (s, 1H), 7.38 (t, J=7.8 Hz, 2H), 7.23 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.9 Hz, 2H), 5.06 (dt, J=11.4, 7.2 Hz, 1H), 4.74 (dd, J=9 .6, 7.4 Hz, 1H), 4.39-4.23 (m, 1H), 3.55 (s, 3H), MS-ERI m/z 443.0 (M+H) ⁺ .

[0629] RIP1-217

[0630] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 8.14 (s, 1H), 7.66 (s, 1H), 7.43 (s, 1H) , 7.18 (dd, J=14.0, 7.6 Hz, 1H), 7.03-6.83 (m, 3H), 5.02 (dd, J=18.1, 7.4 Hz , 1H), 4.74-4.62 (m, 1H), 4.36-4.24 (m, 1H), 4.12 (s, 2H), 3.49 (s, 3H), MS- ERI m/z 437.1 (M+H) ⁺ .

[0631] RIP1-218

[0632] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 8.04 (d, J=6.9 Hz, 1H), 7.59 (s, 1H), 7 .38 (s, 1H), 7.28-7.19 (m, 5H), 5.03-4.92 (m, 1H), 4.70-4.60 (m, 1H), 4.26 -4.18 (m, 1H), 4.09 (s, 2H), 3.42 (s, 3H), MS-ERI m/z 419.0 (M+H) ⁺ .

[0633] RIP1-219

[0634] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.59 (s, 1H), 7 .37 (s, 1H), 7.18-7.10 (m, 2H), 7.03-6.86 (m, 2H), 4.97 (dt, J=11.0, 7.5 Hz , 1H), 4.70-4.57 (m, 1H), 4.28-4.17 (m, 1H), 4.10 (s, 2H), 3.42 (s, 3H), MS- ERI m/z 437.0 (M+H) ⁺ .

[0635] RIP1-220

[0636] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.12-8.04 (m, 2H), 7.56 (s, 1H), 7.42 (s, 1H), 7.29- 7.13 (m, 5H), 4.92 (dt, J=11.0, 7.4 Hz, 1H), 4.65-4.55 (m, 1H), 4.28-4.19 ( m, 1H), 4.03 (s, 3H), 3.96 (s, 2H), 3.43 (s, 3H), MS-ERI m/z 433.0 (M+H) ⁺ .

[0637] RIP1-221

[0638] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.80 (d, J=7.5 Hz, 1H), 8.41 (d, J=5.0 Hz, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.25-7.20 (m, 2H), 7.15 ( dd, J=8.2, 4.4 Hz, 2H), 7.10-7.03 (m, 2H), 5.02 (dt, J=11.2, 7.6 Hz, 1H), 4 .67 (dd, J=9.7, 7.6 Hz, 1H), 4.29-4.18 (m, 1H), 3.94 (s, 2H), 3.42 (s, 3H), MS-ERI m/z 429.1 (M+H) ⁺ .

[0639] RIP1-222

[0640] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 8.06 (d, J=7.3 Hz, 1H), 7.54 (s, 1H), 7 .41 (s, 1H), 7.13 (dd, J=14.1, 7.5 Hz, 1H), 6.97-6.77 (m, 3H), 4.97 (dd, J=18 .3, 7.7 Hz, 1H), 4.68-4.52 (m, 1H), 4.23 (t, J=10.5 Hz, 1H), 4.05 (s, 2H), 3 .41 (s, 3H), MS-ERI m/z 437.1 (M+H) ⁺ .

[0641] Example 2: Synthesis of Compound RIP1-018

[0642]

[0643] The compound RIP1-015 (13 mg, 0.03 mmol) was placed in a 25 ml one-neck flask, then DCM (5 ml), one drop of acetic anhydride and two drops of TEA were added and the reaction was carried out at room temperature for 30 minutes until the reaction is complete as shown by TLC. The solvent was removed under reduced pressure and the residue was extracted with EA, washed with deionized water and saturated NaCl and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by reverse phase column chromatography and lyophilized to give RIP1-018: white solid, 10 mg (70.7%).

[0644] RIP1-018: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.87 (s, 1H), 8.17 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.70 (s, 1H), 7.38-7.29 (m, 3H), 7.27-7.23 (m, 2H), 6.32 (s, 1H), 4.82 -4.72 (m, 1H), 4.12 (s, 2H), 3.86 (dd, J=11.1, 6.8 Hz, 1H), 3.51 (s, 3H), 3. 01-2.94 (m, 1H), 2.85 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 174.1, 171.0, 169.7, 158.2, 158.1, 142.3, 139.1, 137.4, 135.3, 129, 8, 129.0, 128.9, 127.5, 127.5, 122.5, 116.7, 101.7, 49.5, 37.7, 37.4, 33.3, 23.0, MS-ERI: m/z 476.1 (M+H) ⁺ .

[0645] Example 3: Synthesis of Compound II-1

[0646] NaNO ₃ (11.33 g) and H ₂ SO ₄ (100 ml) were added to the reaction flask with a volume of 500 ml, stirred and cooled to 0°C in an ice bath. Compound 1-1 (20.00 g) was dissolved in H ₂ SO ₄ (120 ml) and a solution of 1-1 in H ₂ SO ₄ was slowly added dropwise to the reaction flask. After completion of the addition, the reaction was continued at 0° C. for 1 h, and then the reaction solution was poured into ice water (1 L), stirred for 0.5 h, and filtered. The filter cake was washed with water until neutral. The filter cake was suspended, washed with EtOH/H ₂ O (7:3) (80 ml) for 0.5 h and filtered. The filter cake was dried to give crude product 2-1 (18.83 g, 74% yield).

[0647] 2-1 (9.10 g), N-Boc-L-cysteine (13.24 g) and NaHCO ₃ (5.67 g) were added sequentially to the reaction flask, then EtOH (200 ml) was added and the reaction at 70° C. for 8 hours. After completion of the reaction, the reaction solution was cooled with stirring, and a large amount of precipitate was formed. Added H ₂ O (100 ml) and stirred for another 0.5 h until complete precipitation. After filtration, the filter cake was suspended, washed with H ₂ O (500 ml) for 0.5 h and filtered. The filter cake was dried to give crude product 3-1 (17.5 g, 95% yield). ¹ H-NMR (500 MHz, DMSO-d6) δ=11.60 (s, 1H), 8.27 (s, 1H), 7.56 (d, J=8.4, 1H), 6.96 (s, 1H), 4.34-4.28 (m, 1H), 3.70 (s, 3H), 3.58 (dd, J=13.0, 3.8, 1H), 3.31 (dd, J=12.8, 10.8, 1H), 1.37 (s, 9H); ¹³ C-NMR (125 MHz, DMSO-d6) δ 181.47, 170.82, 160.37, 155.35, 153.15, 149.16, 139.90, 122.60, 114.61, 107 .90, 78.81, 52.43, 51.51, 33.36, 28.04; MS-ERI m/z 424.1 (M-N) ^- .

[0648] 3-1 (10.00 g) was placed in a 250 ml reaction flask, then THF (80 ml) was added and stirred until complete dissolution. Then the solution was cooled to -10°C and a solution of BH ₃ in THF (1 mol/l, 40 ml) was slowly added to the reaction solution. After completion of the addition, the reaction solution was warmed to room temperature and reacted for 2 hours, and then transferred to 50° C. and reacted for 15 minutes. After cooling to 0°C the reaction was stopped by slow addition of H ₂ O (10 ml), stirred for 0.5 h and evaporated on a rotary evaporator to remove most of the THF. The residue was taken up in ethyl acetate and extracted with water. The ethyl acetate layer was dried and rotary evaporated to dryness to give a crude product, which was separated by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 1:5) to give 4-1 (6.6 g, 71% yield). ¹ H-NMR (500 MHz, CD ₃ OD) δ=8.40 (s, 1H), 7.59 (s, 1H), 7.43 (d, J=3.2, 1H), 6.63 (d, J=3.1, 1H), 4.39 (dd, J=8.3, 5.0, 1H), 3.68 (s, 3H), 3.49 (dd, J=13, 8, 5.0, 1H), 3.26 (dd, J=13.8, 8.5, 1H), 1.39 (s, 9H); ¹³ C-NMR (125 MHz, CD ₃ OD) δ 172.95, 157.70, 143.95, 140.05, 129.85, 127.13, 125.92, 120.12, 113.10, 104 .46, 80.86, 61.53, 52.89, 28.61, 14.46; MS-ERI m/z 394.1, 433.4 (M-N) ^- _.

[0649] 4-1 (3.00 g) was placed in a 100 ml reaction flask and THF (30 ml) was added until complete dissolution. DIEA (1.27 g) and Boe anhydride (2.07 g) were added successively with stirring. The reaction solution was heated to 50° C. and reacted overnight. After completion of the reaction, the reaction solution was cooled to room temperature, rotary evaporated to dryness, and extracted with ethyl acetate and water. The ethyl acetate phase was collected, dried and evaporated to dryness on a rotary evaporator. The residue was separated by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:8) to give Compound 5-1 (3.57 g, 95% yield). MS-ERI m/z 496.3 (M+H) ⁺ .

[0650] 5-1 (3.50 g) was placed in a 100 ml reaction flask and THF (20 ml) was added until complete dissolution. Lithium hydroxide monohydrate (0.89 g) and H ₂ O (10 ml) were added and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was adjusted to pH 4-5 using 1 mol/l HCl in an ice bath, evaporated on a rotary evaporator to remove most of the THF and was extracted with ethyl acetate and water. The organic phase was collected, dried and rotary evaporated to dryness to give crude product 6-1.

[0651] To the crude product 6-1 was added methanol (30 ml) until complete dissolution and sparged three times with argon. Under an argon atmosphere, Pd-C (0.75 g) was added, and then hydrogen was added with stirring, and the reaction was carried out at 25°C for 24 hours. After completion of the reaction, the reaction solution was filtered through diatomite to remove Pd-C, and the filtrate was evaporated to dryness on rotary evaporator to obtain the crude product 7-1.

[0652] Anhydrous THF (200 ml) was added to the crude product 7-1 until complete dissolution. DIEA (2.01 g) was added and cooled to 0° C. with stirring. HATU (5.37 g) was added slowly, and after completion of the addition, the reaction solution was warmed to room temperature and reacted overnight. Added H ₂ O (10 ml) and stirred for 0.5 h, and most of the THF was removed by evaporation on a rotary evaporator. The residue was extracted with ethyl acetate and water. The ethyl acetate layer was collected, dried and evaporated to dryness on a rotary evaporator. The residue was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1) to give 8-1 (1.85 g, total yield in three steps 60%).

[0653] 8-1 (1.80 g) was placed in a 100 ml reaction flask and DMF (15 ml) was added until complete dissolution. Added cesium carbonate (1.76 g) and cooled to -5°With stirring. Then iodomethane (0.68 g) was slowly added. After completion of the addition, the reaction solution was warmed to room temperature and reacted for 3 hours at room temperature. After the completion of the reaction, H ₂ O (60 ml) was slowly added to the reaction solution, whereby a large amount of precipitate was formed. After completion of the addition, the reaction solution was stirred for 0.5 h and filtered. The filter cake was collected and dried to give 1.63 g (1.63 g, 88% yield). ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.42 (s, 1H), 8.31 (s, 1H), 7.64 (d, J=3.5, 1H), 7.32 ( s, 1H), 6.51 (d, J=3.6, 1H), 5.65 (d, J=7.7, 1H), 4.47-4.41 (m, 1H), 3, 81 (dd, J=11.0, 6.7, 1H), 2.87 (t, J=11.4, 1H), 1.69 (s, 9H), 1.38 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 172.51, 154.70, 149.32, 134.71, 133.57, 132.01, 128.14, 122.58, 122.02, 116, 02, 106.92, 80.16, 50.40, 39.06, 38.74, 28.39, 28.26; MS-ERI m/z 448.2 (M+H) ⁺ .

[0654] Example 4: Synthesis of Compound II-2

[0655] 4-1 (3 g) was placed in a 100 ml reaction flask and THF (20 ml) was added until complete dissolution. Lithium hydroxide monohydrate (0.96 g) and H ₂ O (10 ml) were added and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was adjusted to pH 4-5 using 1 mol/l HCl in an ice bath, evaporated on a rotary evaporator to remove most of the THF and was extracted with ethyl acetate and water. The organic phase was collected, dried and rotary evaporated to dryness to give crude product 5-2. MS-ERI: Calc. for C ₁₆ H ₁₉ N ₃ O ₆ S (M): 381.1, found by MS-ERI m/z 380.0433.4 (M-H) ^- .

[0656] Methanol (30 ml) was added to the crude product 5-2 until complete dissolution and sparged with argon three times. Pd-C (0.81 g) was added under an argon atmosphere, then hydrogen was added with stirring, and the reaction was carried out at 25°C for 24 h. evaporator to obtain a crude product 6-2. MS-ERI m/z 352.1 (M+H) ⁺ .

[0657] Anhydrous THF (200 ml) was added to the crude product 6-2 until complete dissolution. DIEA (2.15 g) was added and cooled to 0°C with stirring. HATU (5.77 g) was added slowly, warmed to room temperature and reacted overnight. Added H ₂ O (10 ml) and stirred for 0.5 h, and most of the THF was removed by evaporation on a rotary evaporator. The residue was extracted with ethyl acetate and water. The ethyl acetate layer was collected, dried and rotary evaporated to dryness. The residue was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1) to give 7-2 (1.43 g, 57% overall yield over three steps). MS-ERI m/z 334.1 (M+H) ⁺ .

[0658] 7-2 (1.40 g) was placed in a 100 ml reaction flask and DMF (15 ml) was added until complete dissolution. Added cesium carbonate (1.78 g) and then cooled to -5°With stirring. Then iodomethane (0.69 g) was slowly added, warmed to room temperature and reacted for 3 hours at room temperature. After completion of the reaction, H ₂ O (60 ml) was slowly added to the reaction solution, and a large amount of precipitate was formed. After completion of the addition, the reaction solution was stirred for 0.5 h and filtered. The filter cake was collected and dried to give II-2 (1.25 g, 86% yield). ¹ H-NMR (500 MHz, CDCl ₃ ) δ=7.59 (s, 1H), 7.51 (s, 1H), 7.12 (d, J=2.9, 1H), 6.46 ( d, J=2.6, 1H), 5.61 (d, J=7.6, 1H), 4.41-4.32 (m, 1H), 3.79 (s, 3H), 3. 68 (dd, J=11.0, 6.7, 1H), 3.45 (s, 3H), 2.75 (t, J=11.2, 1H), 1.36 (s, 9H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 171.13, 154.65, 137.94, 135.56, 131.37, 129.84, 119.70, 117.06, 116.16, 101, 52, 79.92, 50.78, 39.01, 37.11, 33.22, 28.40; MS-ERI m/z 362.1 (M+H) ⁺ .

[0659] Example 5: Synthesis of Compound II-3

[0660] NaNO ₃ (5100 mg, 60 mmol) was placed in a 500 ml reaction flask, and then concentrated sulfuric acid (60 ml) was added dropwise at 0°C. 6-Fluorindazole 1 (8167 mg, 60 mmol) was dissolved in concentrated sulfuric acid (60 ml), and then the resulting solution was slowly added dropwise to a solution of NaNO ₃ in concentrated sulfuric acid and the reaction was carried out at 0°C for 2.5 h until complete completion of the reaction, as shown by TLC. The reaction solution was poured into ice water (500 ml) and filtered through filter paper on a vacuum filter. The filtrate was extracted with EA. The organic phase was combined with the vacuum filtered solid, washed with saturated NaHCO ₃ and saturated NaCl, dried over Na ₂ SO ₄ , evaporated, and the residue was separated using column chromatography (DCM) to give a 2: pale yellow solid ( 3300 mg, 30.3%).

[0661] Compound 2 (144 9 mg, 8 mmol) was placed in a 250 ml reaction flask, and then Boc ₂ O (2095 mg, 9.6 mmol), DMAP (195 mg, 1.6 mmol) and THF ( 100 ml), and the reaction was carried out at room temperature for 2 h until the reaction was complete, as shown by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . After removal of the solvent under reduced pressure, the Boc-protected intermediate was obtained. The intermediate was used directly in the next step without purification. N-Boc-L-cysteine (2655 mg, 12 mmol) and Cs ₂ CO ₃ (7819 mg, 24 mmol) were placed in a 250 ml reaction flask, DMF (80 ml) was added at 0°C and the reaction was carried out for 15 min. Then, a solution of the Boc-protected intermediate obtained after the Reaction in DMF (20 ml) was slowly added dropwise, and the reaction was carried out overnight at 0°C until the reaction was completed, as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (DCM:MeOH=20:1) to give a 3: pale yellow solid 2400 mg (62.2%).

[0662] Compound 3 (2310 mg, 4.8 mmol) was placed in a 250 ml three-necked flask and sparged with argon three times. Pd/C (4000 mg, 10% wt.) and MeOH (150 ml) were added under argon, hydrogen was sparged three times, and the reaction was carried out for 8 hours under hydrogen atmosphere at room temperature until complete reaction was indicated by TLC. The reaction solution was filtered through diatomaceous earth on a vacuum filter. The solvent was removed under reduced pressure and the residue redissolved in DMF (40 ml). HATU (1825 mg, 4.8 mmol) and DIEA (1240 mg, 9.6 mmol) were added to the solution and reacted overnight at room temperature until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA:PE=1:2) to give a 4: off-yellow solid (800 mg, 38%).

[0663] 4 (434.5 mg, 1 mmol) was placed in a reaction flask, and then Cs ₂ CO ₃ (407.3 mg, 1.25 mmol) and DMF (40 ml) were added and the reaction was carried out at 0 ° C in within 10 min. Iodomethane (177.4 mg, 1.25 mmol) was slowly added dropwise to the solution and the reaction was carried out overnight at 0° C. until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:2) to give II-3: pale yellow solid (417 mg, 93%).

[0664] II-3: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 5.57 ( d, J=7.9 Hz, 1H), 4.34 (dt, J=11.5, 7.3 Hz, 1H), 3.69 (dd, J=11.0, 6.6 Hz, 1H ), 3.45 (s, 3H), 2.82 (t, J=11.3 Hz, 1H), 1.73 (s, 9H), 1.35 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.7, 154.6, 148.7, 141.8, 139.0, 138.0, 129.4, 126.9, 121.6, 116, 8, 85.9, 80.2, 50.6, 38.4, 37.2, 28.4, 28.2, ESI MS: m/z 471.1 (M+H) ⁺ .

[0665] Compound II-5 can be obtained according to the same synthesis method from 2 to II-3 in this example using Compound 8 as a starting material. Synthesis 8 was the same as described in Example 7.

[0666] II-5

[0667] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.49 (s, 1H), 7.58 (s, 1H), 5.57 (d, J=7.9 Hz, 1H), 4 .33 (dt, J=11.6, 7.3 Hz, 1H), 3.68 (dt, J=14.1, 7.1 Hz, 1H), 3.47 (s, 3H), 2, 84 (t, J=11.3 Hz, 1H), 1.72 (s, 9H), 1.36 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.6, 154.6, 148.0, 142.5, 140.5, 138.8, 131.1, 124.6, 122.0, 115, 6, 80.3, 50.5, 38.3, 37.2, 28.4, 28.2, ESI MS: m/z 505.1 (M+Na) ⁺ .

[0668] Example 6: Synthesis of Compound II-4

[0669] NaNO ₃ (5100 mg, 60 mmol) was placed in a 500 ml reaction flask, and then concentrated sulfuric acid (60 ml) was added dropwise at 0°C. 6-Fluorindazole 1 (8167 mg, 60 mmol) was dissolved in concentrated sulfuric acid (60 ml), and then the resulting solution was slowly added dropwise to a solution of NaNO ₃ in concentrated sulfuric acid and the reaction was carried out at 0°C for 2.5 h until the reaction is complete as shown by TLC. The reaction solution was poured into ice water (500 ml) and filtered through filter paper on a vacuum filter. The filtrate was extracted with EA. The organic phase was combined with the solid phase obtained after vacuum filtration, washed with saturated NaHCO ₃ and saturated NaCl, dried over Na ₂ SO ₄ , evaporated, and the residue was separated using column chromatography (DCM) to obtain 2: pale yellow solid (3300 mg, 30.3%).

[0670] Compound 2 (1086.8 mg, 6 mmol) was placed in a 250 ml reaction flask, Cs ₂ CO ₃ (2443 mg, 7.5 mmol) was added, and then DMF (40 ml) was added at 0 ° C and the reaction was carried out for 15 min. SEMC1 (1.33 ml, 7.5 mmol) was then slowly added dropwise and the reaction was carried out for 4 h at room temperature until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:8) to give a 5: pale yellow solid (900 mg, 48.2%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J=6.9 Hz, 1H), 8.18 (s, 1H), 7.42 (d, J=10.7 Hz, 1H), 5.72 (s, 2H), 3.62-3.51 (m, 2H), 0.93-0.86 (m, 2H), -0.06 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 154.8 (d, J=262.1 Hz), 140.8 (d, J=11.5 Hz), 134.0 (d, J=10, 9 Hz), 136.3, 121.0, 120.0, 98.3 (d, J=26.1 Hz), 78.5, 67.2, 17.8, -1.4.

[0671] N-Boc-L-serine (1026.1 mg, 5 mmol) and NaH (400 mg, 10 mmol, 60% by weight) were placed in a 250 ml reaction flask and sparged with argon three times. DMF (50 ml) was added under argon atmosphere at 0° C. and the reaction was carried out for 15 min. A solution of 5 (778.5 mg, 2.5 mmol) in DMF (10 ml) was then slowly added dropwise and the reaction was carried out overnight at 0° C. until the reaction was complete as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, then extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (DCM:MeOH=20:1) to give a 6: pale yellow solid (473 mg, 38.1%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 5.73-5.60 (m, 2H ), 5.58-5.47 (m, 1H), 4.70-4.59 (m, 1H), 4.58-4.49 (m, 1H), 4.17-4.09 (m , 1H), 3.60-3.48 (m, 2H), 3.45 (s, 3H), 0.96-0.85 (m, 2H), -0.08 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.4, 155.1, 150.0, 138.2, 134.0, 132.2, 121.9, 115.3, 103.1, 80, 3, 78.0, 66.6, 49.9, 36.4, 28.3, 17.7, -1.4.

[0672] Compound 6 (450 mg, 0.9062 mmol) was placed in a 100 ml three-necked flask and sparged with argon three times. Pd/C (600 mg, 10% by weight) and MeOH (30 ml) were added under argon atmosphere, hydrogen was sparged three times and the reaction was carried out for 4 h under hydrogen atmosphere at room temperature until the reaction was complete as indicated by TLC. The reaction solution was filtered through diatomaceous earth on a vacuum filter. The solvent was removed under reduced pressure and the residue redissolved in DMF (20 ml). HATU (380.2 mg, 1 mmol) and DIEA (234 mg, 1.81 mmol) were added to the solution and reacted overnight at room temperature until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA:PE=1:2) to give a brown solid 7 (260 mg, 64%).

[0673] Cs ₂ CO ₃ (226.6 mg, 0.6955 mmol) and DMF (20 mL) were added to 7 and reacted at 0°C for 10 min. Iodomethane (98.7 mg, 0.6955 mmol) was slowly added dropwise to the solution and the reaction was carried out overnight at 0° C. until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:2) to give II-4: brown solid (202 mg, 75.3%).

[0674] II-4: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 5.72- 5.62 (m, 2H), 5.54 (d, J=7.2 Hz, 1H), 4.65 (dt, J=11.2, 7.3 Hz, 1H), 4.53 (dd , J=9.5, 7.4 Hz, 1H), 4.18-4.08 (m, 1H), 3.57-3.49 (m, 2H), 3.45 (s, 3H), 1.36 (s, 9H), 0.95-0.86 (m, 2H), -0.06 (s, 9H); ¹³ C-NMR (101 MHz, CDCl ₃ ) δ 169, 4, 155.1, 150.0, 138.2, 133.96, 132.2, 121.9, 115.3, 103.1, 80, 3, 78.0, 66.6, 49.9, 36.4, 28.3, 17.7, -1.4.

[0675] Compound II-6 can be obtained according to the same synthesis method from 2 to II-4 in this example using Compound 8 as starting material. Synthesis 8 was carried out as described in Example 7.

[0676] II-6

[0677] ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.48 (s, 1H), 7.32 (s, 1H), 5.65-5.58 (m, 2H), 5.50 ( d, J=7.1 Hz, 1H), 4.65 (dt, J=11.3, 7.2 Hz, 1H), 4.55 (dd, J=9.5, 7.3 Hz, 1H ), 4.21-4.12 (m, 1H), 3.62-3.54 (m, 2H), 3.49 (s, 3H), 1.38 (s, 9H), 0.97- 0.88 (m, 2H), -0.02 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.2, 155.1, 151.0, 139.3, 134.1, 133.1, 119.1, 114.0, 103.6, 80, 2, 78.1, 77.3, 66.9, 49.8, 36.3, 28.2, 17.7, -1.4.

[0678] Example 7: Synthesis of Compound 8

[0679] Compound 2 (2000 mg, 11 mmol) was placed in a 250 ml reaction flask, and then EtOH (50 ml) and NaOCl (20 ml, 55 mmol) were added and the reaction was carried out overnight at room temperature until the reaction was complete as shown by TLC. The reaction was acidified with 1N HCl, extracted with EA, washed with deionized water and saturated NaCl and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:4) to give 8: pale yellow solid (2000 mg, 84.3%).

[0680] 8: ¹ H-NMR (400 MHz, CD ₃ OD_SPE) δ 8.41 (d, J=6.9 Hz, 1H), 7.42 (d, J=11.1 Hz, 1H); ¹³ C-NMR (101 MHz, CD ₃ OD_SPE) δ 156.2 (d, J=260.0 Hz), 143.4 (d, J=12.2 Hz), 137.7, 135.2 (d , J=11.6 Hz), 120, 2, 116, 8, 99, 8 (d, J=26.4 Hz).

[0681] Example 8: Synthesis of Compound II-7

[0 682] NaNO ₃ (5100 mg, 60 mmol) was placed in a 500 ml reaction flask, and then concentrated sulfuric acid (60 ml) was added dropwise at 0°C. 4-Fluoro-2-hydroxyacetophenone 9 (9248 mg, 60 mmol) was dissolved in concentrated sulfuric acid (60 ml), and then the resulting solution was slowly added dropwise to a solution of NaNO ₃ in concentrated sulfuric acid and the reaction was carried out at 0°C for 2.5 h until the reaction is complete, as shown by TLC. The reaction solution was poured into ice water (500 ml) and filtered through filter paper on a vacuum filter. The filtrate was extracted with EA. The organic phase was combined with the solid phase obtained by vacuum filtration, washed with saturated NaHCO ₃ and saturated NaCl, dried over Na ₂ SO ₄ , evaporated, and the residue was separated using column chromatography (EA:PE=1:20) to obtain 10: pale -yellow solid (4570 mg, 38.2%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 13.02 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 6.83 (d, J=12.2 Hz, 1H), 2.72 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 203.2, 168.5 (d, J=14.5 Hz), 161.9, 159.2, 130.6, 116.0 (d, J= 2.5 Hz), 107.6 (d, J=23.0 Hz), 26.9.

[0683] CuBR ₂ (1898 mg, 8.5 mmol) was placed in a 250 ml reaction flask, then ethyl acetate (50 ml) was added and heated under reflux. A solution of 10 (995.7 mg, 5 mmol) in chloroform (50 ml) was added to the reaction solution, and the reaction was carried out at reflux for 2-4 hours. The green color of the reaction liquid disappeared, and a lime-colored solid was formed. Most of 10 reacted as indicated by TLC. The solid was filtered through diatomaceous earth on a vacuum filter. The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:20-1:10) to give an 11: brown solid (833 mg, 60%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J=7.3 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.41 (d, J=10.6 Hz, 1H), 6.90 (dd, J=2.2, 0.7 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 156.8 (d, J=12.4 Hz), 155.3, 152.7, 148.6 (d, J=3.7 Hz), 123, 6 (d, J=2.1 Hz), 119.2 (d, J=1.8 Hz), 107.3 (d, J=1.2 Hz), 101.5 (d, J=25, 8 Hz).

[0684] Compound 11 (5004 mg, 18 mmol) was placed in a 500 ml reaction flask, THF (180 ml) was added, and then DIEA (3 ml, 18 mmol) was slowly added and the reaction was carried out for 4 5 min at room temperature until the reaction is complete as shown by TLC. NaBH ₄ (2723 mg, 72 mmol) was added to the solution and the reaction was carried out for 8 h at room temperature until the reaction was complete as shown by TLC. The reaction was stopped by slow addition of methanol. The solvent was removed under reduced pressure and the residue was redissolved in MeOH (50 ml). Then 4N HCl (25 ml) was added and heated to 75°C for 3 h until the reaction was complete as shown by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:10) to give a 12: yellow solid (1200 mg, 36.8%).

[0685] N-Boc-L-cysteine (2660 mg, 12 mmol) and Cs ₂ CO ₃ (7819 mg, 24 mmol) were placed in a 250 ml reaction flask, DMF (40 ml) was added at 0°C and the reaction was carried out within 15 min. A solution of 12 (1086 mg, 6 mmol) in DMF (10 mL) was then slowly added dropwise and the reaction was carried out at 0°C for 24 h until the reaction was complete as shown by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was separated by column chromatography (DCM:MeOH=20:1) to give 13: pale yellow solid 2780 mg (quant.). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 6.75 ( d, J=1.9 Hz, 1H), 5.70 (s, 1H), 4.50 (s, 1H), 3.60-3.49 (m, 1H), 3.35 (s, 1H ), 1.35 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 175.1, 157.2, 155.9, 147.8, 143.5, 132.4, 124.9, 119.7, 110.4, 107, 1, 80.5, 53.5, 36.1, 28.4, MS-ERI: m/z 383.1 (M+H) ⁺ .

[0686] Compound 13 (956 mg, 2.5 mmol) was placed in a 100 ml reaction flask and Fe (698 mg, 12.5 mmol) and NH ₄ Cl (267 mg, 5 mmol) were added. Then EtOH (24 ml) and H ₂ O (6 ml) were added and the reaction was carried out at 50°C for 4 h until the reaction was complete, as indicated by TLC. The reaction solution was filtered through diatomaceous earth. The solvent was removed under reduced pressure and the residue redissolved in DMF (60 ml). HATU (950 mg, 2.5 mmol) and DIE (0.83 ml, 5 mmol) were added to the solution and reacted overnight at room temperature until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA:PE=1:3) to give a tan solid 14 (500 mg, 59.8%).

[0687] 14 (1500 mg, 4.5 mmol) was placed in a reaction flask, and then Cs ₂ CO ₃ (1759 mg, 5.4 mmol) and DMF (60 ml) were added and the reaction was carried out at 0°C for 10 min. Iodomethane (766.5 mg, 5.4 mmol) was slowly added dropwise to the solution and the reaction was carried out overnight at 0° C. until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:4) to give II-7: white solid 1320 mg (84.2%).

[0688] II-7: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.78 (s, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.52 (s, 1H), 6.77 (d, J=1.3 Hz, 1H), 5.58 (d, J=7.8 Hz, 1H), 4.37 (dt, J=11.3, 7.5 Hz, 1H), 3.70 (dd, J=11.1, 6.7 Hz, 1H), 3.44 (s, 3H), 2.79 (t, J=11.2 Hz, 1H), 1.37 (s, 9H); ¹³ C-NMR (101 MHz, CDCl ₃ ) δ 171.0, 154.6, 153.1, 147.4, 141.4, 129.6, 123.3, 118.1, 117.4, 106, 7, 80.0, 50.7, 39.0, 37.0, 28.4.

[0689] Example 9: Synthesis of Compound II-8

[0690] NaNO ₃ (2520 mg, 30 mmol) was placed in a 500 ml reaction flask, and then concentrated sulfuric acid (30 ml) was added dropwise at 0°C. 6-Fluorobenzimidazole 15 (29 mg, 30 mmol) was dissolved in concentrated sulfuric acid (30 ml), and then the resulting solution was slowly added dropwise to a solution of NaNO ₃ in concentrated sulfuric acid and the reaction was carried out at 0°C for 2.5 h until the reaction is complete as shown by TLC. The reaction solution was poured into ice water (500 ml) and adjusted to basic pH with saturated NaCO ₃ solution. The reaction solution was extracted with EA and dried over Na ₂ SO ₄ . Removal of the solvent under reduced pressure gave a brown solid powder, which was used directly in the next reaction without purification by column chromatography.

[0691] Compound 16 (2300 mg, 12.7 mmol) was placed in a 50 ml reaction flask, Cs ₂ CO ₃ (5200 mg, 15.9 mmol) was added, and then DMF (20 ml) was added at 0 ° C and the reaction was carried out for 15 min. SEMCl (2.8 ml, 15.9 mmol) was then slowly added dropwise and the reaction was carried out for 4 h at room temperature until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with saturated NaCl and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:8) to give a pair of isomers 17 and 17' in a ratio of approximately 1:1, which could not be separated by column chromatography: pale yellow solid substance (900 mg).

[0692] N-Boc-L-cysteine (284 mg, 1.3 mmol) and Cs ₂ CO ₃ (837 mg, 2.6 mmol) were placed in a 50 ml reaction flask, and then DMF (10 ml) was added at room temperature and reacted for 15 min. A solution of mixed 17 and 17' in DMF (2 ml) was then slowly added dropwise and the reaction was carried out overnight at room temperature until the reaction was complete as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (DCM:MeOH=10:1) to give an isomer pair of Compounds 18 and 18': a pale yellow solid (140.6 mg, 86%).

[0693] Compounds 18 and 18' (330 mg, 0.64 mmol) were placed in a 250 ml three-neck flask and sparged with argon three times. Fe powder (180 mg, 3.2 mmol), NH ₄ Cl (172.2 mg, 3.2 mmol), ethanol (12.5 ml) and deionized water (10 ml) were added under an argon atmosphere and the reaction was carried out with heating at reflux for 3 h until the reaction is complete, as shown by TLC. The reaction solution was filtered through diatomaceous earth on a vacuum filter and dried over anhydrous Na ₂ SO ₄ . After removal of the solvent under reduced pressure, the crude product was obtained as a pair of isomers 19 and 19'.

[0694] To a solution of Compounds 19 and 19' in DMF was added HATU (293 mg, 0.8 mmol) and DIEA (181 mg, 1.4 mmol) and the reaction was carried out overnight at room temperature until the reaction was complete, as was shown by TLC. The reaction solution was extracted with EA, washed with deionized water and then with saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA:PE=1:2) to give a pair of isomers 20 and 20': an off-yellow solid (240 mg, 38%).

[0695] Compounds 20 and 20' (240 mg, 0.52 mmol) were placed in a reaction flask, and then Cs ₂ CO ₃ (202 mg, 0.62 mmol) and DMF (10 ml) were added and the reaction was carried out at 0 ° C for 10 min. Iodomethane (88 mg, 0.62 mmol) was slowly added dropwise to the solution and the reaction was carried out overnight at 0° C. until the reaction was complete as shown by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was separated using column chromatography (EA:PE=1:2) to obtain a pair of isomers II-8 and II-8': pale yellow solid (120 mg, 93%). Then, after removing the protecting group from the intermediates, the total intermediate was obtained for the final condensation reaction.

[0696] Data for II-8+II-8': ERI: m/z 479.2 (M+H) ⁺ .

[0697] Example 10: Synthesis of Compound II-9

[0698] Compound 21 (8 g) was added to a 250 ml one-necked flask equipped with a stirrer and dichloromethane (50 ml) was added until complete dissolution. Trifluoroacetic acid (12 ml) was added with stirring, and the reaction solution was stirred at room temperature for 1 hour, followed by rotary evaporation to remove dichloromethane and trifluoroacetic acid. The residue was extracted with water (80 ml), adjusted to pH 8-9 and then extracted with ethyl acetate. The organic phase was collected, extracted with brine, dried over anhydrous sodium sulfate, filtered on a vacuum filter and evaporated to dryness on a rotary evaporator to obtain Compound 22 as a brown solid (5.8 g). MS-ERI t/z ( ⁷⁹ Br) 271.0 and ( ⁸¹ Br) 273.0 (M+H) ⁺ .

[0699] Compound 22 (5.5 g), N,N-diisopropylethylamine (3.93 g) and trifluoroacetic anhydride (5.75 g) were added sequentially to a 250 ml one-necked flask equipped with a stirrer, then dichloromethane (50 ml ) until complete dissolution and stirred at room temperature for 8 hours. After completion of the reaction, the reaction solution was extracted with water (50 ml). The dichloromethane layer was collected, extracted with brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, evaporated to dryness on a rotary evaporator, and the residue was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=7:1) with obtaining Compound 23 (7.30 g, 98% yield). MS-ERI m/z ( ⁷⁹ Br) 367.1 and ( ⁸¹ Br) 369.1 (M+H) ⁺ .

[0700] Trifluoroacetic anhydride (60 ml) was added to a 250 ml two-necked flask equipped with a thermometer and stirrer and cooled to -30°C. Compound 23 (7 g) was added and dissolved with stirring. Concentrated nitric acid (1.4 g) was slowly added dropwise, and then the reaction was continued for 4 hours, while the temperature was maintained at -10°C or lower. After completion of the reaction, the reaction solution was poured into ice water (300 ml) and thoroughly stirred. A large amount of solid formed, which was filtered off on a vacuum filter. The filter cake was washed with water until neutral, collected and dried to give Compound 24 as a yellow solid (7.70 g, 96% yield). MS-ERI m/z ( ⁷⁹ Br) 411 and ( ⁸¹ Br) 413 (M) ⁺ .

[0701] Compound 24 (7 g), iron powder (7.6 g), saturated aqueous ammonium chloride solution (100 ml) and ethanol (100 ml) were added sequentially to a 250 ml single-necked flask equipped with a stirrer, heated to 90° C and reacted for 5 hours. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed three times with dichloromethane (150 ml). The filtrate was collected and rotary evaporated to remove most of the ethanol and dichloromethane. The remaining liquid was adjusted to pH 8-9 with saturated sodium carbonate and extracted three times with dichloromethane (300 ml). The organic phase was collected, washed once, respectively, with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and the residue was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8:1) to give Compound 25 (4.02 g) as a white solid. Yield 62%; MS-ERI m/z ( ⁷⁹ Br) 382.1 and ( ⁸¹ Br) 384.0 (M+H) ⁺ .

[0702] Compound 25 (4 g) and N,N-diisopropylethylamine (1.83 g) were added sequentially to a 250 ml two-necked flask equipped with a thermometer and stirrer, and dichloromethane (40 ml) was added with stirring until complete dissolution. Then the reaction solution was cooled to -10°C. Acetyl chloride (1.06 g) was dissolved in dichloromethane (10 ml). A solution of acetyl chloride in dichloromethane was slowly added dropwise to the above reaction solution so that the temperature of the reaction solution during the addition remained at -5° C. or lower. Then, the reaction solution was slowly warmed to room temperature and left to react overnight. After completion of the reaction, water (50 ml) was poured into the reaction solution and extracted. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=4:1) to give Compound 26 as white solid (3.19 g). Yield 72%. ¹ H-NMR (500 MHz, CDCl ₃ ) δ=8.34 (s, 1H), 7.62 (s, 1H), 7.55 (d, J=6.3, 1H), 7.39 ( s, 1H), 4.88-4.82 (m, 1H), 4.70 (dd, J=9.8, 7.4, 1H), 4.22 (dd, J=10.9, 10 .1, 1H), 3.39 (s, 3H), 2.26 (s, 3H); ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 168.38, 167.73, 156.74 (q, J=38.4), 149.71, 135.40, 131.81, 126.45, 115 .78, 115.57 (k, J=287.6), 108.53, 77.41, 77.16, 7691, 7635, 4975, 3576, 2504; MS-ERI m/z 424.1 ( ⁷⁹ Br) and 426.1 ( ⁸¹ Br) (M+H) ⁺ .

[0703] Compound 26 (3 g) and anhydrous potassium carbonate (3 g) were added sequentially to a 100 ml single-necked flask equipped with a stirring element, and tetrahydrofuran (15 ml) and water (15 ml) were added until complete dissolution. The reaction solution was stirred overnight at room temperature. After completion of the reaction, Boe anhydride (2.31 g) was added to the reaction solution, and stirred at room temperature for 5 hours. The reaction solution was extracted with water (30 ml) and dichloromethane (30 ml). The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to dryness to give Compound 27 as a white solid (3 g, 99% yield). MS-ERI m/z ( ⁷⁹ Br) 428.0 and ( ⁸¹ Br) 429.9 (M+H) ⁺ .

[0704] CuI (19.0 mg, 0.1 mmol), N ¹ , N ² -bis (5-methyl-[1,1'-biphenyl]-2-yl) oxamide (42.0 mg, 0. 1 mmol), Compound 27 (0.856 g, 2 mmol) and K ₃ PO ₄ (0.424 g, 2 mmol) were added sequentially to a 10 ml Schlenk tube equipped with a stirrer. Then 25% aqueous ammonia (0.28 g) and DMSO (2 ml) were added successively by syringe to the Schlenk tube under argon atmosphere and the Schlenk tube was sealed. The reaction solution was heated to 60° C. and reacted for 2 to 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate (30 ml), and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was distilled under reduced pressure. The remaining residue was purified and separated by silica gel column chromatography (developing reagent: dichloromethane:methanol=30:1) to give Compound 28 as a brown solid (0.59 g, 81% yield). MS-ERI: Calc. for C ₁₇ H ₂₄ N ₄ O ₅ (M): 364.1, found by MS-ERI m/z 365.1 (M+H) ⁺ .

[0705] Compound 28 (1 g) was added to a 50 ml one-necked flask equipped with a stirring element, then acetic acid (15 ml) was added, heated to 80° C., and reaction was carried out for 1 hour. After completion of the reaction, the reaction solution was heated to room temperature, water (50 ml) was added and extracted with ethyl acetate. The organic phase was collected, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. The residue was separated and purified by silica gel column chromatography (developing reagent: dichloromethane:methanol=25:1) to give Intermediate II-9 as a pale yellow solid (0.74 g, 78% yield). ¹ H-NMR (400 MHz, CDCl ₃ ) δ=7.29 (s, 1H), 7.21 (s, 1H), 5.62 (d, J=7.3, 1H), 4.65- 4.56 (m, 1H), 4.51 (dd, J=9.4, 7.5, 1H), 4.14 (t, J=10.4, 1H), 3.38 (s, 3H ), 2.55 (s, 3H), 1.38 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.49, 155.56, 153.52, 149.54, 146.13, 136.19, 131.83, 109.50, 107.07, 80, 67, 77.84, 50.25, 36.20, 28.34, 14.94; MS-ERI m/z 347.0 (M+H) ⁺ ; ERI-MSVR Comput. for C ₁₇ H ₂₃ O ₄ N ₄ (M+H) ⁺ : 347, 1714, found: 347, 1717.

[0706] Example 11: Synthesis of Compound II-10

[0707] Compound 25 (4 g) and N,N-diisopropylethylamine (1.83 g) were added sequentially to a 250 ml two-neck flask equipped with a thermometer and stirrer, and then dichloromethane (40 ml) was added with stirring until complete dissolution. The reaction solution was cooled to -5°C. Acetyl chloride (1.29 g) was dissolved in dichloromethane (10 ml). A solution of acetyl chloride in dichloromethane was slowly added dropwise to the above reaction solution so that the temperature of the reaction solution remained at 0° C. or lower during the addition. Then, the reaction solution was slowly warmed to room temperature and reacted overnight. After completion of the reaction, water (50 ml) was poured into the reaction solution, and extraction was performed. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness on a rotary evaporator, and separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=4:1) to give Compound 29 as white solid (3.19 g, 67% yield), MS-ERI m/z 440.2 ( ⁷⁹ Br) and 442.2 ( ⁸¹ Br) (M+H) ⁺ .

[0708] Compound 29 (3 g) and anhydrous potassium carbonate (3 g) were added sequentially to a 100 ml single-necked flask equipped with a stirring element, and tetrahydrofuran (15 ml) and water (15 ml) were added until complete dissolution. The reaction solution was stirred overnight at room temperature. After completion of the reaction, Boe anhydride (2.30 g) was added to the reaction solution and stirred at room temperature for 5 hours. The reaction solution was extracted with water (30 ml) and dichloromethane (30 ml). The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to dryness to give Compound 30 as a white solid (3 g, 99% yield). MS-ERI m/z 465.8 ( ⁷⁹ Br) and 467.8 ( ⁸¹ Br) (M+Na) ⁺ .

[0709] CuI (19.0 mg, 0.1 mmol), N ¹ ,N ² -bis (5-methyl-[1,1'-biphenyl]-2-yl) oxamide (42.0 mg, 0. 1 mmol), Compound 30 (0.888 g, 2 mmol) and K ₃ PO ₄ (0.424 g, 2 mmol) were added sequentially to a 10 ml Schlenk tube equipped with a stirrer. Then 25% aqueous ammonia (0.28 g) and DMSO (2 ml) were added successively by syringe to the Schlenk tube under argon atmosphere and the Schlenk tube was sealed. The reaction solution was heated to 70° C. and reacted for 24 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate (30 ml), and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was distilled under reduced pressure. The residue was purified and separated by silica gel column chromatography (developing reagent: dichloromethane:methanol=30:1) to give Compound 31 as a brown solid (0.40 g, 53% yield). MS-ERI m/z 381.1 (M+H) ⁺ .

[0710] Compound 31 (1 g) was added to a 2 x 5 ml single-necked flask equipped with a stirring element, and then DMSO (10 ml) and potassium phosphate (1.67 g) were added, heated to 100 ° C and the reaction was carried out for 5 hours After completion of the reaction, the reaction solution was cooled to room temperature, water (50 ml) was added and extracted with ethyl acetate. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to dryness. The residue was separated and purified by silica gel column chromatography (developing reagent: dichloromethane:methanol=20:1) to give Compound II-10 as a pale yellow solid (0.69 g, 78% yield). ¹ H-NMR (500 MHz, CDCl ₃ ) δ=10.58 (s, 1H), 10.46 (s, 1H), 6.88 (s, 1H), 6.62 (s, 1H), 5 .72 (d, J=7.1, 1H), 4.64-4.59 (m, 1H), 4.58-4.50 (m, 1H), 4.21-4.09 (m, 1H), 3.32 (s, 3H), 1.44 (s, 9H); MS-ERI m/z 371.1.

[0711] Example 12: Synthesis of Compound II-11

[0712] Compound 25 (4 g) and N,N-diisopropylethylamine (1.83 g) were added sequentially to a 250 ml two-necked flask equipped with a thermometer and stirrer, and dichloromethane (40 ml) was added until complete dissolution with stirring. Then the reaction solution was cooled to -20°C. Trifluoroacetic anhydride (2.9 g) was dissolved in dichloromethane (10 ml). A solution of trifluoroacetic anhydride in dichloromethane was slowly added dropwise to the above reaction solution so that the temperature of the reaction solution remained at -10° C. or lower during the addition. Then, the reaction solution was slowly warmed to room temperature and reacted overnight. After completion of the reaction, water (50 ml) was poured into the reaction solution, and extraction was performed. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness on a rotary evaporator, and separated and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=4:1) to give Compound 32 as white solid (4.20 g). Yield 84%. MS-ERI m/z 475.8 ( ⁷⁹ Br) and 477.8 ( ⁸¹ Br) (MH) ^- .

[0713] CuI (19.0 mg, 0.1 mmol), N ¹ ,N ² -bis (5-methyl-[1,1'-biphenyl]-2-yl) oxamide (42.0 mg, 0. 1 mmol), Compound 32 (0.956 g, 2 mmol) and K ₃ PO ₄ (0.424 g, 2 mmol) were added sequentially to a 10 ml Schlenk tube equipped with a stirrer. Then 25% aqueous ammonia (0.28 g) and DMSO (2 ml) were sequentially added by syringe to the Schlenk tube under argon atmosphere and the Schlenk tube was sealed. The reaction was continued at room temperature for 24 hours. After completion of the reaction, acetic acid (5 ml) was added and stirred for another 8 hours. The reaction solution was diluted with ethyl acetate (40 ml) and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was distilled under reduced pressure. The residue was purified and separated by silica gel column chromatography (developing reagent: dichloromethane:methanol=30:1) to give Compound 33 as a brown solid (0.40 g, 51% yield). ¹ H-NMR (500 MHz, CDCl ₃ ) δ=10.39 (s, 1H), 7.75 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 4 .87-4.79 (m, 1H), 4.79-4.72 (m, 1H), 4.24 (t, J=9.0, 1H), 3.53 (s, 3H); MS-ERI m/z 397.0 (M+H) ⁺ .

[0714] Compound 33 (0.4 g) was added to a one-necked flask equipped with a stirrer, and tetrahydrofuran (4 ml) was added with stirring until complete dissolution. Anhydrous K ₂ CO ₃ (0.42 g) and H ₂ O (4 ml) were then added and stirred overnight at room temperature. After completion of the reaction, the reaction solution was extracted with ethyl acetate (15 ml) and H ₂ O (15 ml). The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate and rotary evaporated to dryness to give Compound II-11 (0.3 g, 99% yield). ¹ H-NMR (400 MHz, DMSO-d6) δ=7.74 (s, 1H), 7.45 (s, 1H), 4.28 (dd, J=9.9, 7.6, 1H) , 3.99 (dd, J=11.4, 10.1, 1H), 3.68 (dd, J=11.5, 7.6, 1H), 3.37 (s, 3H); MS-ERI m/z 301.3 (M+H) ⁺ .

[0715] Example 13: Synthesis of Compound II-14

[0716] NaNO ₃ (5.2 g, 61.1 mmol) was placed in a 500 ml reaction flask, and then concentrated sulfuric acid (60 ml) was added dropwise at 0°C. 6-Chloroquinoline (10.0 g, 61.1 mmol) was dissolved in concentrated sulfuric acid (60 ml), and then the resulting solution was slowly added dropwise to a solution of NaNO ₃ in concentrated sulfuric acid, and the reaction was carried out at 0°C for 2 h until complete completion of the reaction, as shown by TLC. The reaction solution was poured into ice water (500 ml) and filtered through filter paper on a vacuum filter. The filtrate was extracted with EA. The organic phase was combined with the solid phase obtained after vacuum filtration, washed with saturated NaHCO ₃ and saturated NaCl, dried over Na ₂ SO ₄ , evaporated, and the residue was separated using column chromatography (EA:PE=1:8) to obtain 35: pale -yellow solid (11.2 g, 88%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.01 (dd, J=4.2, 1.5 Hz, 1H), 8.19 (d, J=9.1 Hz, 1H), 8, 04 (d, J=8.6 Hz, 1H), 7.75 (d, J=9.1 Hz, 1H), 7.59 (dd, J=8.7, 4.2 Hz, 1H).

[0717] N-Boc-L-cysteine (3.5 g, 15.8 mmol) and Cs ₂ CO ₃ (10.3 g, 31.6 mmol) were placed in a 250 ml reaction flask, DMF (40 ml) was added ) and reacted for 15 min at 0°C. Then a solution of Compound 35 (2.2 g, 10.5 mmol) in DMF (20 ml) was slowly added dropwise and the reaction was carried out at 0°C for 24 h until the reaction was completed, as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (DCM:MeOH=20:1) to give a 36: pale yellow solid (4.2 g, quant.). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.83-8.67 (m, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.88 (d, J=8 .5 Hz, 1H), 7.74 (d, J=9.1 Hz, 1H), 7.34 (dd, J=8.7, 4.5 Hz, 1H), 5.74 (d, J =6.8 Hz, 1H), 4.74 (dd, J=6.3, 3.1 Hz, 1H), 3.99 (dd, J=15.0, 2.5 Hz, 1H), 3 .60 (dd, J=15.0, 3.6 Hz, 1H), 1.48 (s, 9H).

[0718] Compound 36 (2.0 g, 5.09 mmol) was placed in a 100 ml reaction flask and Fe (1.42 g, 25.4 mmol) and NH ₄ Cl (0.43 g, 8.14 mmol). Then EtOH (40 ml) and H ₂ O (10 ml) were added and the reaction was carried out at 50°C for 2 h until the reaction was complete, as indicated by TLC. The reaction solution was filtered through diatomaceous earth. The solvent was removed under reduced pressure and the residue redissolved in DMF (80 ml). HATU (2.3 g, 6.11 mmol) and DIEA (1.77 ml, 10.2 mmol) were added to the solution and the reaction was carried out at room temperature for 30 min until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA:PE=1:3) to give 37 as a pale yellow solid (1.2 g, 2-step yield: 68%).

[0719] Compound 37 (1.0 g, 2.9 mmol) was placed in a reaction flask, and then Cs ₂ CO ₃ (1.1 g, 3.48 mmol) and DMF (60 ml) were added and the reaction was carried out at 0 °C for 10 min. Iodomethane (494 mg, 3.48 mmol) was slowly added dropwise to the solution and the reaction was carried out at 0° C. for 3 h until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:4) to give Compound II-14: white solid (0.95 g, 91%). ¹ NMR (400 MHz, CDCl ₃ ) δ 8.98 (dd, J=4.2, 1.6 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.05 ( d, J=8.7 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.52 (dd, J=8.6, 4.2 Hz, 1H), 5, 59 (d, J=7.8 Hz, 1H), 4.38 (dt, J=10.6, 7.6 Hz, 1H), 3.82 (dd, J=11.2, 7.0 Hz , 1H), 3.39 (s, 3H), 2.91 (dd, J=19.8, 8.7 Hz, 1H), 1.36 (s, 9H). ¹³ C-NMR (100 MHz, CDCl ₃ δ 172.66, 154.45, 151.37, 149.42, 141.92, 134.89, 131.82, 130.13, 127.13, 124.21 , 122.23, 80.18, 50.78, 39.98, 36.76, 28.26.

[0720] Example 14: Synthesis of Compound II-15

[0721] N-Boc-L-serine (3.25 g, 15.8 mmol) and NaH (0.76 g, 31.65 mmol, 60 wt%) were placed in a 250 ml reaction flask and sparged with argon three times . Under an argon atmosphere, DMF (50 ml) ghb 0°C was added and the reaction was carried out for 30 min. Then a solution of 35 (2.2 g, 10.55 mmol) in DMF (10 ml) was slowly added dropwise and the reaction was carried out overnight at 0°C until the reaction was complete, as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (DCM:MeOH=20:1) to give a 38: pale yellow solid 2.1 g (53%). ¹ H-NMR (400 MHz, MeOD) δ 8.89 (m, 1H), 8.26 (d, J=9.1 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H ), 7.89 (d, J=9.0 Hz, 1H), 7.69 (m, 1H), 4.68 (s, 2H), 4.60 (s, 1H), 1.46 (s , 9H).

[0722] Compound 38 (1.92 g, 5.09 mmol) was placed in a 100 ml reaction flask and Fe (1.42 g, 25.4 mmol) and NH ₄ Cl (0.43 g, 8.14 mmol). Then EtOH (40 ml) and H ₂ O (10 ml) were added and the reaction was carried out at 50°C for 2 h until the reaction was complete, as indicated by TLC. The reaction solution was filtered through diatomaceous earth. The solvent was removed under reduced pressure and the residue redissolved in DMF (80 ml). HATU (2.3 g, 6.11 mmol) and DIEA (1.77 ml, 10.2 mmol) were added to the solution and the reaction was carried out at room temperature for 30 min until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA:PE=1:3) to give 37 as a pale yellow solid (1.1 g, 2-step yield: 66%).

[0723] Compound 39 (1.0 g, 3.04 mmol) was placed in a reaction flask, and then Cs ₂ CO ₃ (1.48 g, 4.56 mmol) and DMF (60 ml) were added and the reaction was carried out at 0 °C for 10 min. Iodomethane (518 mg, 3.65 mmol) was slowly added dropwise to the solution and the reaction was carried out at 0° C. for 3 h until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:4) to give Compound II-15: white solid (0.96 g, 92%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.90 (dd, J=4.1, 1.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 8, 04 (d, J=9.1 Hz, 1H), 7.51 (d, J=9.1 Hz, 1H), 7.46 (dd, J=8.6, 4.2 Hz, 1H), 5.54 (d, J=6.7 Hz, 1H), 4.73-4.59 (m, 2H), 4.31-4.20 (m, 1H), 3.41 (s, 3H) , 1.35 (s, 9H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.59, 154.95, 149.94, 149.15, 146.67, 131.16, 130.89, 129.73, 125.11, 124, 08, 121.63, 80.30, 78.72, 49.94, 37.26, 28.21.

[072 4] Example 15: Synthesis of Compound II-16

[0725] NaNO ₃ (5.2 g, 61.1 mmol) was placed in a 500 ml reaction flask, and then concentrated sulfuric acid (60 ml) was added dropwise at 0°C. 6-Chlorisoquinoline 40 (10.0 g, 61.1 mmol) was dissolved in concentrated sulfuric acid (60 ml), the resulting solution was slowly added dropwise to a solution of NaNO ₃ in concentrated sulfuric acid and the reaction was carried out at 0°C for 2 h until the reaction is complete as shown by TLC. The reaction solution was poured into ice water (500 ml) and filtered through filter paper on a vacuum filter. The filtrate was extracted with EA. The organic phase was combined with the solid phase obtained after vacuum filtration, washed with saturated NaHCO ₃ and saturated NaCl, dried over Na ₂ SO ₄ , evaporated, and the residue was separated using column chromatography (EA:PE=1:8) to obtain 41: pale -yellow solid (11.2 g, 88%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.36 (s, 1H), 8.73 (d, J=6.0 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.56 (d, J=6.0 Hz, 1H).

[0726] N-Boc-L-cysteine (3.5 g, 15.8 mmol) and Cs ₂ CO ₃ (10.3 g, 31.6 mmol) were placed in a 250 ml reaction flask, added with DMF (40 ml) and reacted for 15 min at 0°C. Then, a solution of Compound 41 (2.2 g, 10.5 mmol) in DMF (20 ml) was slowly added dropwise and the reaction was carried out at 0°C for 24 h until the reaction was completed, as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (DCM:MeOH=20:1) to give a 42: pale yellow solid (4.2 g, quant.). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.52 (s, 1H), 8.32 (d, J=6.3 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.44 (d, J=6.3 Hz, 1H), 5.69 (d, J=6.9 Hz, 1H) , 4.68 (m, 1H), 3.97 (d, J=14.7 Hz, 1H), 3.55 (dd, J=15.0, 4.4 Hz, 1H), 1.47 ( s, 9H).

[0727] Compound 42 (2.0 g, 5.09 mmol) was placed in a 100 ml reaction flask and Fe (1.42 g, 25.4 mmol) and NH ₄ Cl (0.43 g, 8.14 mmol). Then EtOH (40 ml) and H ₂ O (10 ml) were added and the reaction was carried out at 50°C for 2 h until the reaction was complete, as indicated by TLC. The reaction solution was filtered through diatomaceous earth. The solvent was removed under reduced pressure and the residue redissolved in DMF (80 ml). HATU (2.3 g, 6.11 mmol) and DIEA (1.77 ml, 10.2 mmol) were added to the solution and the reaction was carried out at room temperature for 30 min until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (EA:PE=1:3) to give 43 as a pale yellow solid (1.2 g, 2-step yield: 68%).

[0728] Compound 43 (1.0 g, 2.9 mmol) was placed in a reaction flask, then Cs ₂ CO ₃ (1.1 g, 3.48 mmol) and DMF (60 ml) were added and the reaction was carried out at 0 ° C for 10 min. Iodomethane (494 mg, 3.48 mmol) was slowly added dropwise to the solution and the reaction was carried out at 0° C. for 3 h until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:4) to give Compound II-16: white solid (0.95 g, 91%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.31 (s, 1H), 8.64 (d, J=6.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.62 (d, J=6.0 Hz, 1H), 5.63 (d, J=7.7 Hz, 1H) , 4.37 (m, 1H), 3.82 (dd, J=11.1, 7.0 Hz, 1H), 3.39 (s, 3H), 2.95 (dd, J=12.5 , 9.7 Hz, 1H), 1.35 (s, 9H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 172.29, 154.43, 153.10, 144.60, 141.08, 133.02, 131.67, 131.49, 129.73, 128, 01, 116.00, 80.25, 50.62, 39.84, 36.41, 28.26.

[0729] Example 16: Synthesis of Compound II-17

[0730] N-Boc-L-serine (3.25 g, 15.8 mmol) and NaH (0.76 g, 31.65 mmol, 60% by weight) were placed in a 250 ml reaction flask and sparged three times argon. Under an argon atmosphere, DMF (50 ml) was added at 0°C and the reaction was carried out for 30 min. A solution of 41 (2.2 g, 10.55 mmol) in DMF (10 ml) was then slowly added dropwise and the reaction was carried out overnight at 0° C. until the reaction was complete as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, then extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (DCM:MeOH=20:1) to give a 44: pale yellow solid (2.1 g, 53%).

[0731] Compound 44 (1.92 g, 5.09 mmol) was placed in a 100 ml reaction flask and Fe (1.42 g, 25.4 mmol) and NH ₄ Cl (0.43 g, 8.14 mmol). Then EtOH (40 ml) and H ₂ O (10 ml) were added and the reaction was carried out at 50°C for 2 h until the reaction was complete, as indicated by TLC. The reaction solution was filtered through diatomaceous earth. The solvent was removed under reduced pressure and the residue redissolved in DMF (80 ml). HATU (2.3 g, 6.11 mmol) and DIEA (1.77 ml, 10.2 mmol) were added to the solution and the reaction was carried out at room temperature for 30 min until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA:PE=1:3) to give 45 as a pale yellow solid (1.1 g, yield in 2 steps: 66%).

[0732] Compound 45 (1.0 g, 3.04 mmol) was placed in a reaction flask, and then Cs ₂ CO ₃ (1.48 g, 4.56 mmol) and DMF (60 ml) were added and the reaction was carried out at 0 °C for 10 min. Iodomethane (518 mg, 3.65 mmol) was slowly added dropwise to the solution and the reaction was carried out for 3 h at 0° C. until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was separated using column chromatography (EA:PE=1:4) to obtain Compound II-17: white solid (0.96 g, 92%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 8.60 (d, J=6.0 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 5.53 (d, J=6.2 Hz, 1H) , 4.76-4.60 (m, 2H), 4.36-4.25 (m, 1H), 3.44 (s, 3H), 1.38 (s, 9H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 171.24, 154.94, 152.95, 152.31, 144.12, 132.01, 129.26, 129.21, 127.13, 123, 44, 115.74, 80.40, 78.75, 49.79, 36.92, 28.23.

[0733] Example 17: Synthesis of Compound II-18

[0734] Compound 2-1 (9.48 g, 45.12 mmol) was dissolved in THF (90 ml) and BH ₃ (135.6 ml, 1 M in THF) was added at 0° C. under argon atmosphere. The reaction solution was warmed to room temperature and reacted for 2 hours until the reaction was complete as shown by TLC. 1 M HCl was added to stop the reaction, after which the reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the residue was separated by column chromatography (EA/PE=1:3) to obtain Compound 46 (6, 0 g, 74% yield.

[0735] Compound 46 (6.0 g, 33.3 mmol) and NaH (1.68 g, 41.64 mmol) were mixed, dissolved in DMF (120 ml) at 0°C and maintained at this temperature during the reaction in within 30 min. SEMC1 (8.82 ml, 49.98 mmol) was then added and the reaction was carried out overnight until the reaction was complete as indicated by TLC. 1 M HCl was added to stop the reaction, then the reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the residue was separated by column chromatography (EA/PE=1:8) to obtain Compound 47 (8.22 g, yield 80%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J=7.2 Hz, 1H), 7.48-7.20 (m, 2H), 6.71 (dd, J=3 .4, 0.7 Hz, 1H), 5.50 (s, 2H), 3.52 (dd, J=8.6, 7.7 Hz, 2H), 0.97-0.92 (m, 2H), -0.00 (s, 9H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 155.46, 152.91, 140.01, 139.90, 132.89, 132.86, 125.77, 121.15, 121.14, 105, 86, 100.31, 100.05, 77.66, 67.93, 19.17, 0.00.

[0736] N-Boc-L-serine (4.96 g, 24.15 mmol) and t-BuOK (7.23 g, 64.5 mmol) were placed in a 250 ml reaction flask and sparged with nitrogen three times. DMF (50 ml) was added under argon atmosphere at 0° C. and the reaction was carried out for 30 min. A solution of 47 (5.0 g, 16.1 mmol) in DMF (30 mL) was then slowly added dropwise and the reaction was carried out overnight at 0° C. until the reaction was complete as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, then extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (DCM:MeOH=20:1) to give a 48: pale yellow solid (1.67 g, 21%).

[0737] Compound 48 (1.67 g) was dissolved in methanol (40 ml) and then Pd/C (167 mg) was added. The reaction was continued for 3 hours at room temperature under a hydrogen-containing atmosphere until the reaction was complete as indicated by TLC. Pd/C was removed by filtration through diatomaceous earth and the solvent was removed by distillation under reduced pressure. The obtained crude product was dissolved in DMF (40 ml), and then DIPEA and HATU were added and the reaction was carried out at room temperature for 1 h until the reaction was complete, as indicated by TLC. Water was then added and the system was extracted with ethyl acetate, evaporated, purified by flash column chromatography (EA/PE=1:3) to give Compound 49 (1.0 g, two-step yield: 66%).

[0738] Compound 49 (1.0 g, 2.23 mmol) was placed in a reaction flask and then Cs ₂ CO ₃ (1.09 g, 3.36 mmol) and DMF (20 ml) were added and the reaction was carried out at 0 ° C for 10 min. Iodomethane (380 mg, 2.68 mmol) was slowly added dropwise to the solution and the reaction was carried out at 0° C. for 3 h until the reaction was complete as indicated by TLC. The reaction solution was extracted with EA, washed with deionized water and saturated NaCl, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA:PE=1:8) to give Compound 50: white solid (0.96 g, 93%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.44 (s, 1H), 7.29 (s, 1H), 7.21 (d, J=3.2 Hz, 1H), 6.50 ( d, J=3.1 Hz, 1H), 5.57 (d, J=6.8 Hz, 1H), 5.50-5.39 (m, 2H), 4.70 (dt, J=11 .0, 7.3 Hz, 1H), 4.59 (dd, J=9.5, 7.5 Hz, 1H), 4.15 (dd, J=10.9, 9.8 Hz, 1H) , 3.54-3.47 (m, 5H), 1.41 (s, 9H), 1.00-0.91 (m, 2H), 0.00 (s, 9H). ¹³ C-NMR (100 Hz, CDCl ₃ ) δ 171.03, 156.49, 147.69, 136.09, 131.71, 130.81, 127.63, 116.59, 105.00, 103, 74, 81.39, 79.21, 77.27, 67.38, 51.47, 37.56, 29.65, 19.06, 0.00.

[0739] Under argon atmosphere, Compound 50 (0.9 g, 1.95 mmol) was dissolved in anhydrous THF (15 ml), and then a solution of TBAF (13.65 ml, 1 M in THF) was added and the reaction was carried out at 70 ° C for 4 hours. After completion of the reaction, THF was removed and water was added. The reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, evaporated and the residue was separated by flash column chromatography (EA/PE=1:3) to give Compound II-18 (210 mg, 33% yield). MS-ERI m/z 330.1 (M-N) ^- .

[0740] Example 18: Synthesis of Compound II-23

[0741] NaNO ₃ (5.1 g, 60 mmol) was placed in a 500 ml reaction flask, and then concentrated sulfuric acid (60 ml) was added dropwise at 0°C. 4-Fluoro-2-hydroxyacetophenone 9 (9.25 g, 60 mmol) was dissolved in concentrated sulfuric acid (60 ml), and then the resulting solution was slowly added dropwise to a solution of NaNO ₃ in concentrated sulfuric acid and the reaction was carried out at 0°C for 2.5 h until the reaction is complete, as shown by TLC. The reaction solution was poured into ice water (500 ml) and filtered through filter paper on a vacuum filter. The filtrate was extracted with ethyl acetate. The organic phase was mixed with the solid phase obtained after vacuum filtration, washed successively with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, evaporated, and the residue was separated using column chromatography (EA/PE=1:20) to obtain 10: pale yellow solid (4.9 g, 41%). Compound 10: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 13.02 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 6.83 (d, J=12, 2 Hz, 1H), 2.72 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 203.1, 168.4, 168.3, 161.8, 159.1, 130.5, 115.9, 115.9, 107.6, 107, 4, 26.8; MS-ERI: m/z 200.0 (M+H) ⁺ .

[0742] CuBr ₂ (1.9 g, 8.5 mmol) was placed in a 250 ml reaction flask, and then ethyl acetate (50 ml) was added and heated under reflux. A solution of 10 (1.0 g, 5 mmol) in chloroform (50 ml) was added to the reaction solution, and the reaction was carried out at reflux for 24 hours. The green color of the reaction liquid disappeared, and a lime-colored solid was formed. After conversion of most of 10, as shown by TLC, the reaction solution was filtered through diatomaceous earth on a vacuum filter. The solvent was removed under reduced pressure and the obtained crude product was dissolved in THF (180 ml). DIPEA (3.0 ml, 18 mmol) was added slowly and the reaction was carried out at room temperature for 4-5 minutes until the reaction was complete as indicated by TLC. NaBH ₄ was added to the system and the reaction was carried out at room temperature for 2 hours. After completion of the reaction, the reaction was stopped by slowly adding methanol, and then 4N HCl was added and the reaction was carried out overnight at 65°C. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. Separation by column chromatography (EA/PE=1:10) gave a 12: yellow solid (0.56 g, 62% yield over two steps). Compound 12: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J=7.3 Hz, 1H), 7.78 (d, J=2.3 Hz, 1H), 7.42 (d, J=10.6 Hz, 1H), 6.91 (dd, J=2.2, 0.7 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 156.8, 156.7, 155.2, 152.6, 148.5, 148.4, 123.5, 123.5, 119.1, 119, 1, 107.2, 107.2, 101.6, 101.3; MS-ERI: m/z 182.0 (M+H) ⁺ .

[0743] N-Boc-L-serine (453 mg, 2.2 mmol) and NaH (105.6 mg, 4.4 mmol) were placed in a 50 ml reaction flask, DMF (8 ml) was added at 0°C and reacted for 15 min. A solution of 12 (200 mg, 1.1 mmol) in DMF (2 ml) was then slowly added dropwise and the reaction was carried out for 4.5 h at 0° C. until the reaction was complete as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (DCM:MeOH=20:1) to give 1-23:350 mg, 86% yield.

[0744] Compound 1-23 (800 mg, 2.18 mmol) was placed in a 100 ml reaction flask and Fe powder (610 mg, 10.9 mmol) and NH ₄ Cl (233 mg, 4.36 mmol) were added. Then EtOH (24 ml) and H ₂ O (6 ml) were added and the reaction was carried out at 50°C for 4 h until the reaction was complete, as indicated by TLC. The reaction solution was filtered through diatomaceous earth. The solvent was removed under reduced pressure and the residue redissolved in DMF (30 ml). HATU (995 mg, 2.62 mmol) and DIPEA (1.52 ml, 8.72 mmol) were added to the solution and reacted overnight at room temperature until the reaction was complete as indicated by TLC. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (EA:PE=1:3) to give Compound 2-23 (380 mg, 2-step yield: 55%).

[0745] Compound 2-23 (380 mg, 1.2 mmol) was dissolved in DMF (10 mL) and Cs ₂ CO ₃ (584 mg, 1.8 mmol) was added. Iodomethane (203 mg, 1.43 mmol) was slowly added dropwise to the solution and the reaction was carried out at room temperature for 2 hours until the reaction was complete as indicated by TLC. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA/PE=1:4) to give II-23: white solid, 385 mg, 97% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J=2.2 Hz, 1H), 7.41 (s, 1H), 7.31 (s, 1H), 6.74 ( d, J=1.4 Hz, 1H), 5.51 (d, J=7.0 Hz, 1H), 4.65 (dt, J=11.0, 7.3 Hz, 1H), 4, 57 (dd, J=9.5, 7.4 Hz, 1H), 4.15 (dd, J=10.9, 9.7 Hz, 1H), 3.46 (s, 3H), 1.39 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.5, 155.1, 152.9, 147.7, 146.6, 132.7, 124.7, 115.2, 106.4, 105, 7, 80.2, 77.9, 50.0, 36.1, 28.2; MS-ERI: m/z 333.0 (M+H) ⁺ .

[074 6] Example 19: Synthesis of Compound II-24

[0747] Compound 1-24 (5.04 g, 40 mmol) was dissolved in pyridine (10 ml) and then TsCl (15.25 g, 80 mmol) dissolved in pyridine (25 ml) was slowly added dropwise, heated to 80°C and the reaction was carried out overnight until the reaction was complete, as shown by TLC. The reaction solution was cooled to room temperature, and 3N hydrochloric acid (150 ml) was added in an ice bath. A large amount of precipitate formed, which was stirred for 0.5 h and then filtered. The filter cake was a brownish solid. Received product 2-24 (17.4 g, yield: quantitative).

[0748] Compound 2-24 (20 g, 46.08 mmol) was dissolved in acetic acid (80 ml) and fuming nitric acid (4.8 ml) was added, heated to 60° C. and reacted for 2 h. After completion of the reaction, the reaction solution was filtered and then washed with ethanol (40 ml). Received Compound 3-24 as a white solid (15 g, 68% yield).

[0749] Compound 3-24 (13.4 g, 28 mmol) was added to a mixed system of concentrated sulfuric acid (30 ml) and water (3 ml), heated to 85°C and reacted for 1 hour. After cooling, the system poured slowly into ice water (300 ml) to form a solid. The solid was dissolved on slow heating, adjusted to pH 9 with aqueous ammonia and filtered. The filter cake was washed with water to give Compound 4-24 as a solid (4.2 g, 88% yield).

[0750] Compound 4-24 (4.2 g, 24.5 mmol) was dissolved in ethanol (120 ml) and oxaldehyde (40% in water, 5.67 ml) was added.

The system was heated to 90° C. and reacted for 1 hour until the reaction was complete as shown by TLC. The reaction solution was distilled under reduced pressure to remove ethanol, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the residue was separated by flash column chromatography (EA/PE=1:2) to obtain Compound 5-24 as a white solid (4 .46 g, 94% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.02-8.97 (m, 2H), 8.86 (d, J=7.5 Hz, 1H), 7.99 (d, J=10 .8 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 155.5, 152.9, 148.4, 146.7, 146.6, 145.3, 145.2, 138.71, 138.69, 128, 4, 116.9, 116.7; MS-ERI: m/z 194.0 (M+H) ⁺ .

[0751] N-Boc-L-serine (3.18 g, 15.54 mmol) and NaH (0.93 g, 23.31 mmol) were placed in a 250 ml reaction flask, DMF (40 ml) was added at 0 °С and the reaction was carried out for 15 min. Then a solution of Compound 5-24 (1.5 g, 7.77 mmol) in DMF (20 ml) was slowly added dropwise and the reaction was carried out for 3 h at 0° C. until the reaction was complete, as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (DCM:MeOH=20:1) to give 6-24 (2.0 g, 68% yield).

[0752] Compound 6-24 (2.43 g, 6.43 mmol) was placed in a 250 ml reaction flask and Fe powder (1.79 g, 32.14 mmol) and NH ₄ Cl (0.69 g, 12.86 mmol). Then EtOH (80 ml) and H ₂ O (20 ml) were added and the reaction was carried out at 50°C for 4 h until the reaction was complete, as indicated by TLC. The reaction solution was filtered through diatomaceous earth. The solvent was removed under reduced pressure and the residue redissolved in DMF (30 ml). HATU (2.93 g, 7.72 mmol) and DIPEA (3.32 g, 25.75 mmol) were added to the solution and reacted overnight at room temperature until the reaction was complete as indicated by TLC. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by flash column chromatography (EA:PE=1:3) to give Compound 7-24 (540 mg, 2-step yield: 25%).

[0753] Compound 7-24 (340 mg, 1.03 mmol) was dissolved in DMF (10 ml) and Cs ₂ CO ₃ (503 mg, 1.55 mmol) was added. Iodomethane (175 mg, 1.24 mmol) was slowly added dropwise to the solution, and the reaction was carried out at room temperature for 2 h until the reaction was complete as indicated by TLC. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (EA/PE=1:4) to give 11-24: white solid, 345 mg, 97% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.84 (d, J=1.8 Hz, 1H), 8.82 (d, J=1.8 Hz, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 4.73 (dt, J=11.3, 7.2 Hz, 1H), 4.65 (dd, J=9.5, 7.2 Hz, 1H ), 4.26 (dd, J=11.2, 9.7 Hz, 1H), 3.58 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.3, 155.0, 151.5, 145.3, 145.1, 141.9, 140.9, 140.2, 122.5, 121, 2, 80.5, 50.1, 36.1, 28.2; MS-ERI: m/z 345.0 (M+H) ⁺ .

[07 54] Example 20: Synthesis of Compound II-25

[0755] Intermediate 1-25 (4.4 g, 25.71 mmol) was dissolved in acetic acid (100 ml) and then sodium nitrite (3.85 g, 55.79 mmol) was added at 5°C. The temperature was maintained during the reaction for 10 min, while the conversion was complete. The reaction solution was rotary evaporated to remove acetic acid, extracted with ethyl acetate, and evaporated to give Compound 2-25 as a solid (4.37 g, 94% yield).

[0756] Compound 2-25 (4.0 g, 21.98 mmol) was dissolved in acetic acid (80 ml), and then K ₂ CO ₃ (6.07 g, 44 mmol) and SEMCl (5, 5 g, 33 mmol). The reaction was maintained at 0°C for 2 h, while the conversion was complete. The reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated and purified by column chromatography (EA/PE=1:6) to give Compound 3-25 (3.9 g, 57% yield).

[0757] N-Boc-L-serine (5.11 g, 25 mmol) and NaH (1.5 g, 37.5 mmol) were placed in a 250 ml reaction flask, DMF (60 ml) was added at 0°C and reacted for 15 min. Then a solution of Compound 3-25 (3.9 g, 12.5 mmol) in DMF (20 ml) was slowly added dropwise and the reaction was carried out for 2 h at 0°C until the reaction was completed, as indicated by TLC. The reaction solution was acidified with 0.2 M HCl, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (DCM:MeOH=20:1) to give Compound 4-25 as a yellow solid powder (4.4 g, 71% yield).

[0758] Compound 4-25 (4.3 g, 8.65 mmol) was dissolved in methanol (80 ml) and then 10% Pd/C (2.15 g) was added. Under an atmosphere of hydrogen, the reaction was continued for 4 hours at normal temperature under normal pressure until complete conversion of the crude product. The reaction solution was filtered through diatomaceous earth to remove Pd/C and evaporated to remove methanol. The obtained crude product was dissolved in DMF (30 ml) and then DIPEA (2.24 g, 17.3 mmol) and HATU (3.95 g, 10.38 mmol) were added and the reaction was carried out for 1 h with stirring at room temperature. temperature until the reaction is complete. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was separated by column chromatography (EA/PE=1:3) to give Compound 5-25 (1/7 g, 2-step yield: 44%).

[0759] Compound 5-25 (1/7 g, 3.79 mmol) was dissolved in DMF (40 ml) and Cs ₂ CO ₃ (1/85 g/5/68 mmol) was added. Iodomethane (0/59 g/4/17 mmol) was slowly added dropwise to the solution and the reaction was carried out at room temperature for 2 h until the reaction was complete / as shown by TLC. The reaction solution was extracted with ethyl acetate/washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and separated by flash column chromatography (EA/PE=1:4) to give 11-25: white solid 1.69 g, 96% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.49 (s, 1H), 5.98 (s, 2H), 5.60 (d, J=7.0 Hz, 1H), 4.69 (dt, J=11.2, 7.2 Hz, 1H), 4.60 (ddd, J=11.2, 7.4, 3.8 Hz, 1H), 4 .22 (dd, J=11.1, 9.7 Hz, 1H), 3.66-3.57 (m, 2H), 3.54 (s, 3H), 1.41 (s, 9H), 1.02-0.94 (m, 2H), 0.00 (s, 9H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.6, 156.5, 152.2, 144.8, 136.6, 132.7, 115.5, 104.8, 81.8, 68, 8, 51.3, 37.9, 29.7, 19.1, 0.0; MS-ERI: m/z 464.1 (M+H) ⁺ .

[0760] Example 21: Synthesis of Compound 11-19

[0761] N-Boc-L-Serine (9.80 g, 47.80 mmol) and NaH (3.80 g, 95.60 mmol) were added to a 500 ml reaction flask, then DMF (120 ml) was added and the reaction was carried out at 0°C for 30 min. 1-19 (5.00 g, 23.9 mmol) was dissolved in DMF (100 ml), then added dropwise slowly to the reaction solution, and the reaction was carried out at 0°C for 3.5 hours. After the reaction was completed, the reaction solution was washed saturated NaCl solution and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated to dryness on a rotary evaporator, and the residue was separated by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to obtain 2-19 (4.99 g, yield 53%). MS-ERI m/z 393.0 (M-N) ^- .

[0762] 2-19 (900 mg, 2.28 mmol) and Pd/C (900 mg) were added to a 100 ml reaction flask, and then methanol (20 ml) was added until complete dissolution. The reaction was continued for 5 hours at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through diatomaceous earth to remove Pd/C and evaporated to dryness on a rotary evaporator to remove the solvent to obtain crude 3-19. MS-ERI m/z 363.1 (M-N) ^- .

[0763] Crude 3-19, HATU (1.04 g, 2.74 mmol) and DIPEA (755 μl, 4.57 mmol) were added to a 100 ml reaction flask and then DMF (20 ml) was added to dissolve them . The reaction was continued overnight at 75°C. After completion of the reaction, the reaction solution was washed with a saturated NaCl solution and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated to dryness and separated by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to give 4-19 (155 mg, yield 19.6 %). MS-ERI m/z 347.0 (M+H) ⁺ .

[0764] 4-19 (400 mg, 1.16 mmol) and cesium carbonate (791 mg, 2.43 mmol) were added to a 100 ml reaction flask, followed by DMF (15 ml). After reacting at 0° C. for 10 minutes, iodomethane (152 μl, 2.43 mmol) was slowly added dropwise, and the reaction was carried out at 0° C. for 1 hour. After the reaction was completed, the reaction solution was washed with saturated NaCl solution and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated to dryness and separated by silica gel column chromatography (eluent: dichloromethane:methanol = 40:1) to give the final product 11-19 (275 mg, yield 64 %). MS-ERI m/z 375.1 (M+H) ⁺ .

[0765] Example 22: Synthesis of Compound 11-26

[0766] NaNO ₃ (2.73 g, 32.1 mmol) was placed in a 100 ml reaction flask, and then concentrated sulfuric acid (15 ml) was added dropwise at 0°C. Compound 1-26 (5.0 g, 30.6 mmol) was dissolved in concentrated sulfuric acid (15 ml), and then the resulting solution was slowly added dropwise to a solution of NaNO ₃ in concentrated sulfuric acid, and the reaction was carried out at 0°C for 3 h until the reaction is complete, as shown by TLC. The reaction solution was poured into ice water (150 ml), and a large amount of white precipitate was formed. The reaction solution was filtered through filter paper and the filter cake was washed 3 times with ice water and dried to give Compound 2-36 as a white solid powder (6.25 g, 98% yield). Compound 2-26: ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.01 (dd, J=4.3, 1.6 Hz, 1H), 8.25 (dd, J=8.4, 1 .6 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 7.61 (d, J=8.9 Hz, 1H), 7.56 (dd, J=8.4 , 4.3 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 153.1, 140.2, 135.9, 130.2, 127.4, 127.2, 125.8, 123.0; MS-ERI: m/z 209.0 (M+H) ⁺ .

[0767] N-Boc-L-serine (5.9 g, 28.8 mmol) and NaH (1.73 g, 43.1 mmol) were placed in a 250 ml reaction flask, DMF (40 ml) was added at 0 °С and the reaction was carried out for 15 min. Then a solution of Compound 2-26 (3.0 g, 14.4 mmol) in DMF (30 ml) was slowly added dropwise and the reaction was carried out overnight at 0°C. The reaction solution was acidified with 0.2 M HCl, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (DCM:MeOH=20:1) to give 3-26 as a yellow solid powder: 0.27 g, 5% yield.

[0768] Compound 3-26 (200 mg, 0.53 mmol) was dissolved in methanol (2 ml) and then 10% Pd/C (100 mg) was added. Under an atmosphere of hydrogen, the reaction was continued for 2 hours at normal temperature under normal pressure until complete conversion of the crude product. The reaction solution was filtered through diatomaceous earth to remove Pd/C and evaporated to remove methanol. The obtained crude product was dissolved in DMF (3 ml), then DIPEA (274.2 mg, 2.12 mmol) and HATU (3.95 g, 0.64 mmol) were added and the reaction was carried out for 1 h with stirring at room temperature until the reaction has been completed. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (EA/PE=1:3) to give Compound 4-26 (95 mg, 2-step yield: 54%). MS-ERI: m/z 330.0 (M+H) ⁺ .

[0769] Compound 4-26 (40 mg, 0.12 mmol) was dissolved in DMF (5 ml) and Cs ₂ CO ₃ (76 mg, 0.23 mmol) was added. Iodomethane (24.8 mg, 0.18 mmol) was slowly added dropwise to the solution and the reaction was carried out at room temperature for 2 h until the reaction was complete, as indicated by TLC. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and separated by flash column chromatography (EA/PE=1:4) to give 11-26: white solid, 40 mg, 95% yield. MS-ERI: m/z 344.0 (M+H) ⁺ .

[0770] Example 23: Synthesis of Compound 11-27

[0771] BMDA (5.27 g, 39.6 mmol) was dissolved in a solvent mixture of THF (15 ml) and n-hexane (60 ml) and then n-BuLi (24 ml, 1 M in hexane) was added at -25 °C. The temperature was maintained during the reaction for 30 minutes. Compound 1-27 (5.06 g, 36.0 mmol) was added and reacted at -25° C. for 30 min, n-BuLi (33.6 ml, 1 M in hexane) was added and reacted at 0° C for 2 hours. Then the system was cooled to -80°C, and then DMF (8.4 ml, 118.8 mmol) was added and the reaction was carried out at -80°C for 10 min, and then at 0°C in NH ₄ Cl (5.76 g, 118.8 mmol) and N ₂ H ₄ ⋅H ₂ O (4.2 ml, 68.36 mmol) were added and the reaction was carried out overnight at room temperature until complete completion of the reaction as shown by TLC. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated using column chromatography (EA/PE=2:1) to obtain Compound 2-27 (5.0 g, 85% yield).

[0772] Compound 2-27 (2 g, 12.15 mmol) was dissolved in concentrated sulfuric acid (40 ml) and then fuming nitric acid (3.83 g, 60.75 mmol) was added, heated to 90°C and the reaction was carried out for 2 h until complete conversion of the crude product. The reaction solution was cooled to room temperature, poured into ice water (150 ml), and adjusted to neutral pH with an aqueous ammonia solution. The reaction solution was extracted with ethyl acetate, evaporated, and the residue was separated by flash column chromatography (EA/PE=2:1) to give Compound 3-27 (2.28 g). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.66 (d, J=1.3 Hz, 1H), 9.55 (d, J=1.3 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H); MS-ERI: m/z 209.0 (M+H) ⁺ .

[0773] N-Boc-L-serine (2.94 g, 14.35 mmol) and NaH (1.15 g, 28.71 mmol) were placed in a 250 ml reaction flask, DMF (30 ml) was added at 0 °С and the reaction was carried out for 15 min. Then a solution of Compound 3-27 (2.0 g, 9.57 mmol) in DMF (20 ml) was slowly added dropwise and the reaction was carried out for 5 h at 0°C. The reaction solution was acidified with 0.2 M HCl, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (DCM:MeOH=10:1) to give Compound 4-27 as a yellow solid powder (2.8 g, 77% yield).

[0774] Compound 4-27 (1.1 g, 3.18 mmol) was dissolved in methanol (20 ml) and then 10% Pd/C (1.1 g) was added. Under an atmosphere of hydrogen, the reaction was continued for 2 hours at normal temperature under normal pressure until complete conversion of the crude product. The reaction solution was filtered through diatomaceous earth to remove Pd/C and evaporated to remove methanol. The obtained crude product was dissolved in DMF (20 ml) and then DIPEA (1.23 g, 9.52 mmol) and HATU (1.45 g, 3.82 mmol) were added and the reaction was carried out for 1 h with stirring at room temperature. temperature until the reaction is complete. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by column chromatography (DCM/MeOH=20:1) to give Compound 5-27 (390 mg, 2-step yield: 38%). MS-ERI: m/z 331.0 (M+H) ⁺ .

[0775] Compound 5-27 (240 mg, 0.73 mmol) was dissolved in DMF (8 ml) and Cs ₂ CO ₃ (355 mg, 1.09 mmol) was added. Iodomethane (123 mg, 0.87 mmol) was slowly added dropwise to the solution and the reaction was carried out at room temperature for 2 h until the reaction was complete, as indicated by TLC. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was separated by flash column chromatography (DCM/MeOH = 1:20) to give 11-27: white solid, 120 mg, 48% yield. MS-ERI: m/z 345.0 (M+H) ⁺ .

[0776] Example 24: Synthesis of Compound 11-21

[0777] 1-21 (10 g, 63.65 mmol) and potassium carbonate (26.39 g, 190.96 mmol) were added to a 500 ml reaction flask, followed by DMF (300 ml). Allyl bromide (17 ml, 190.96 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours. After completion of the reaction, the reaction solution was washed with saturated NaCl solution and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated to dryness, and the residue was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain 2-21 (12.41 g , 99% yield. MS-ERI m/z 198.0 (M+H) ⁺ .

[0778] N-Boc-L-Serine (7.80 g, 38.06 mmol) and NaH (3.6 g, 88.81 mmol) were added to a 250 ml reaction flask and then DMF (100 ml) was added as a solvent. The reaction was continued at 0°C for 30 min. 2-21 (5.00 g, 25.37 mmol) was dissolved in DMF (50 ml), then added dropwise slowly to the reaction solution, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, the reaction solution was washed with a saturated NaCl and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated to dryness to give crude 3-21 (4.99 g, 53% yield). MS-ERI m/z 381.1 (M-N) ^- .

[0779] The entire crude product 3-21, reduced iron powder (7.1 g, 126.87 mmol) and ammonium chloride (2.2 g, 40.6 mmol) were added to a 250 ml reaction flask, and then ethanol was added /water (120 ml/30 ml). The reaction was carried out under reflux at 70° C. for 1 hour. After the reaction was completed, the reaction solution was filtered through diatomaceous earth to remove iron powder, and the filtrate was rotary evaporated to dryness to obtain crude 4-21. MS-ERI m/z 351.1 (M+H) ⁺ .

[0780] All crude 4-21, HATU (11.6 g, 30.44 mmol) and DIPEA (17 ml, 101.48 mmol) were added to a 250 ml reaction flask, and then THF (200 ml) was added as solvent. The reaction was continued at room temperature for 1 hour. After completion of the reaction, the reaction solution was rotary evaporated to remove THF, washed with saturated NaCl solution, and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated to dryness, and the residue was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8:1) to give 5-21 (4.00 g , yield 23.6%). MS-ERI m/z 333.1 (M-N) ^- .

[0781] 5-21 (2.85 g, 8.50 mmol) and cesium carbonate (4.14 g, 12.7 mmol) were added to a 250 ml reaction flask, and then DMF (85 ml) was added. The reaction was carried out at 0° C. for 30 min, and then iodomethane (635 μl, 10.2 mmol) was slowly added dropwise, and the reaction was carried out at 0° C. for 1 hour. After the reaction was completed, the reaction solution was washed with saturated NaCl solution and extracted ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and rotary evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give Compound 6-21 (2.90 g, 98% yield). MS-ERI m/z 347.2 (M-N)-.

[0782] 6-21 (2.90 g, 8.30 mmol) was added to a 250 ml reaction flask, and then dichloromethane (64 ml) and TFA (16 ml) were added. The reaction was continued at room temperature for 1 hour. After completion of the reaction, the reaction solution was rotary evaporated to remove the solvent, water (100 ml) was added, adjusted to pH 8-9 with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was evaporated to dryness on a rotary evaporator, trifluoroacetic anhydride (1.70 ml, 11.6 mmol) and DIPEA (2.1 ml, 12.4 mmol) were added and DCM (85 ml) was added as a solvent. The reaction was continued overnight at room temperature. After completion of the reaction, the reaction solution was rotary evaporated to remove the solvent, washed with saturated NaCl solution, and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 7-21 (2.65 g, 92.7% yield). MS-ERI m/z 345.0 (M+H) ⁺ .

[0783] 7-21 (2.65 g, 7.70 mmol) and trifluoroacetic anhydride (80 ml) were added to a 250 ml reaction flask and cooled to -30°C. Concentrated nitric acid (560 μl, 8.4 mmol) was slowly added dropwise, followed by reaction for 1 hour at a temperature controlled at -10° C. or lower. After completion of the reaction, the reaction solution was washed with water (100 ml), extracted with ethyl acetate, and evaporated to dryness on a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1) to give Compound 8-21 (2.70 g, 90.2% yield). MS-ERI m/z 390.0 (M+H) ⁺ .

[0784] 8-21 (2.70 g, 6.90 mmol), tetrakis(triphenylphosphine)-palladium (3.1 g, 2.7 mmol), tri-n-butyltin hydride (5.6 ml, 20, 8 mmol) and acetic acid (2.5 ml, 41.6 mmol) were added to a 250 ml reaction flask, and then DCM (70 ml) was added as solvent. The reaction was continued for 1 hour at room temperature. After completion of the reaction, the reaction solution was rotary evaporated to remove the solvent, washed with saturated NaCl solution, and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=3:1) to give Compound 9-21 (1.10 g, 45.7% yield) and side product 10-21 (849 mg, 38 yield). .6%). MS-ERI m/z 350.0 (M+H) ⁺ .

[0785] 9-21 (1.10 g, 3.10 mmol) and Pd/C (1.1 g) were added to a 100 ml reaction flask, and then methanol (35 ml) was added. The reaction was continued for 1 hour at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through diatomaceous earth to remove Pd/C. The filtrate was rotary evaporated to dryness to give 10-21 (860 mg, 87% yield). MS-ERI m/z 320.1 (M+H) ⁺ .

[0786] 10-21 (1.71 g, 5.36 mmol) and triethylorthoformate (100 mL) were added to a 250 mL reaction flask and reacted for 3 hours under reflux at 130°C. water (100 ml) was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and rotary evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=1:1) to give 11-21 (1.70 g, 98% yield). MS-ERI m/z 330.1 (M+H) ⁺ .

[0787] Example 25: Synthesis of Compound 11-29

[0788] 1-29 (10 g, 63.65 mmol) and potassium carbonate (26.39 g, 190.96 mmol) were added to a 500 ml reaction flask, followed by DMF (300 ml). Allyl bromide (17 ml, 190.96 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 hours. After completion of the reaction, the reaction solution was washed with saturated NaCl solution and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated to dryness, and the residue was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain 2-29 (12.30 g , 98% yield. MS-ERI m/z 198.0 (M+H) ⁺ .

[0789] N-Boc-L-Serine (7.80 g, 38.06 mmol) and NaH (3.6 g, 88.81 mmol) were added to a 250 ml reaction flask followed by DMF (100 ml) as a solvent. The reaction was continued at 0°C for 30 min. 2-29 (5.00 g, 25.37 mmol) was dissolved in DMF (50 ml), then slowly added dropwise to the reaction solution, and the reaction was carried out at 0°C for 1 hour. After the reaction was completed, the reaction solution was washed with a saturated NaCl and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated to dryness to give crude 3-29 (4.99 g, 53% yield). MS-ERI m/z 381.1 (M-N) ^- .

[0790] The entire crude product 3-29, reduced iron powder (7.1 g, 126.87 mmol) and ammonium chloride (2.2 g, 40.6 mmol) were added to a 250 ml reaction flask, and then ethanol was added /water (120 ml/30 ml). The reaction was carried out under reflux at 70° C. for 1 hour. After the completion of the reaction, the reaction solution was filtered through diatomaceous earth to remove iron powder, and the filtrate was evaporated to dryness on a rotary evaporator to obtain crude 4-29. MS-ERI m/z 353.1 (M+H) ⁺ .

[0791] All crude 4-29, HATU (11.6 g, 30.44 mmol) and DIPEA (17 ml, 101.48 mmol) were added to a 250 ml reaction flask, and then THF (200 ml) was added as solvent. The reaction was continued at room temperature for 1 hour. After completion of the reaction, the reaction solution was rotary evaporated to remove THF, washed with saturated NaCl solution, and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated to dryness, and the residue was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=8:1) to give 5-29 (1.50 g , yield 17.7%). MS-ERI m/z 333.2 (M-N) ^- .

[0792] 5-29 (1.97 g, 5.84 mmol) and cesium carbonate (2.85 g, 8.75 mmol) were added to a 250 ml reaction flask followed by DMF (50 ml). After reaction at 0° C. for 30 minutes, iodomethane (438 μl, 7.03 mmol) was slowly added dropwise, and the reaction was carried out at 0° C. for 1 hour. After completion of the reaction, the reaction solution was washed with saturated NaCl solution and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give Compound 6-29 (1.65 g, 81% yield). MS-ERI m/z 293.1 (M+H) ⁺ .

[0793] 6-29 (1.65 g, 4.70 mmol) was added to a 250 ml reaction flask followed by dichloromethane (40 ml) and TFA (10 ml). The reaction was continued at room temperature for 1 hour. After completion of the reaction, the reaction solution was rotary evaporated to remove the solvent, water (100 ml) was added, adjusted to pH 8-9 with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was evaporated to dryness on a rotary evaporator, trifluoroacetic anhydride (905 μl, 6.5 mmol) and DIPEA (1.17 ml, 7.10 mmol) were added and DCM (50 ml) was added as a solvent. The reaction was continued overnight at room temperature. After completion of the reaction, the reaction solution was rotary evaporated to remove the solvent, washed with saturated NaCl solution, and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 7-29 (1.60 g, 98.8% yield). MS-ERI m/z 345.0 (M+H) ⁺ .

[0794] 7-29 (1.50 g, 4.30 mmol) and trifluoroacetic anhydride (45 ml) were added to a 250 ml reaction flask and cooled to -30°C. Concentrated nitric acid (320 μl, 4.70 mmol ) was slowly added dropwise and the reaction was carried out for 1 hour at a temperature controlled at -10°C or lower. After completion of the reaction, the reaction solution was washed with water (100 ml), extracted with ethyl acetate, and rotary evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=6:1) to give Compound 8-29 (1.43 g, 85.6% yield). MS-ERI m/z 390.0 (M+H) ⁺ .

[0795] 8-29 (1.33 g, 3.4 mmol), tetrakis(triphenylphosphine)-palladium (1.16 g, 1.0 mmol), tri-n-butyltin hydride (2.74 ml, 10, 2 mmol) and acetic acid (1.22 ml, 20.5 mmol) were added to a 250 ml reaction flask, and then DCM (35 ml) was added as solvent. The reaction was continued for 1 hour at room temperature. After completion of the reaction, the reaction solution was rotary evaporated to remove the solvent, washed with saturated NaCl solution, and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1) to give 9-29 (800 mg, 67.4% yield) and product 10-29 (312 mg, 27.0%). MS-ERI m/z 349.9 (M+H) ⁺ .

[0796] 9-29 (0.80 g, 2.20 mmol) and Pd/C (0.80 g) were added to a 100 ml reaction flask followed by methanol (25 ml). The reaction was continued for 1 hour at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through diatomaceous earth to remove Pd/C. The filtrate was rotary evaporated to dryness to give 10-29 (636 mg, 90.6% yield). MS-ERI m/z 320.0 (M+H) ⁺ .

[0797] 10-29 (0.948 g, 2.97 mmol) and triethylorthoformate (50 mL) were added to a 250 mL reaction flask and reacted for 3 hours at reflux at 130°C. the solution was added with water (100 ml) and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 11-29 (0.900 g, 92.1% yield). MS-ERI m/z 330.0 (M+H) ⁺ .

[0798] Example 26: TNF-Induced Jurkat Programmed Cell Death (FADD ^-/- ) Inhibition Assay (IC ₅₀ )

[0799] RPMI-1640 medium (containing serum, 50 μl per well) was added to a white 96-well cell culture plate, and then 0.5 μl of an appropriate concentration of drug solution containing a compound according to this application or a control compound 7- Cl-O-Nec-l or GSK2982772 (7-Cl-O-Nec-l and GSK2982772 are known RIP1 kinase inhibitors), or 0.5 μl of 100% DMSO was added to each well. Two replicate wells were set up for each concentration of each compound.

[0800] Jurkat (FADD ^-/- ) cells (human peripheral blood T-cell leukemia cell line with FADD gene knockout) were cultured in vitro. After growth to logarithmic growth phase, cells were harvested and centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded, the cells were resuspended in fresh medium and adjusted to a density of 5×10 ⁵ /ml. The cell suspension was added to the culture plate containing the drug (40 μl per well). In the treatment groups, 10 μl of TNF (tumor necrosis factor, final concentration 10 ng/ml) diluted in cell culture medium was added to each well and incubated for 20 hours in a cell incubator (37°C, 5% CO ₂ ). Then, 50 µl of Cell Titer-Glo solution was added to each well and incubated at room temperature for 10 min. Then, luminescence was recorded on a BioTek plate analyzer to measure the intracellular ATP level. The effect of test compounds on inhibition of TNF-induced cell necrosis was calculated relative to the well with full activity and the background well (using the control untreated well with DMSO as 100% cell viability), and the half-maximal inhibitory concentration (IC ₅₀ ) of the compound was calculated using the statistical program Graphpad Prism. The result is shown in Table 1 below.

[0801] Example 27: ADP-Glo™ RIP1 Kinase Activity Inhibition Assay (Ki)

[0802] The human RIP1 gene was transduced into Sf-9 insect cells and the RIP1 protein was purified by Ni+ affinity chromatography followed by S-200 molecular sieve to remove protein multimers. The resulting RIP1 protein was stored at -70°C, and the activity of the RIP1 protein in autophosphorylation catalysis was determined using the ADP-Glo™ kinase activity assay kit (Promega) and the inhibitory activity of the drug against RIP1 kinase was determined.

[0803] The drug (compounds according to the present application and control compounds 7-Cl-O-Nec-l and GSK2982772) was dissolved in 100% DMSO and serially diluted 3-fold with a total of 11 concentration gradients, and a 100x solution was prepared . 100 nl compounds were transferred to a 384-well assay plate. Two replicate wells were set up for each concentration of each drug.

[0804] RIP1 enzyme solution and ATP solution were prepared in assay buffer (containing 50 mM HEPES, pH 7.5, 30 mM MgCl ₂ , 50 mM NaCl, 1 mM DTT, 0.02% CHAPS, and 0.5 mg/ml BSA). Then, 5 µl of the RIP1 enzyme solution (final concentration 50 nM) was added to the assay plate and incubated at room temperature for 1 h. 5 µl of the ATP solution (final concentration 10 µM) was added to the assay plate and incubated at room temperature for 4 h. Then 5 µl of the ADP-Glo reagent was added to the assay plate and incubated at room temperature for 60 min. 5 µl of the kinase assay solution was added to the assay plate and incubated at room temperature for 30 minutes. After reading the data on Envision, the degree of inhibition in each well was calculated relative to the well with full activity and the background well, and the Ki of the compound was calculated using GraphPad Prism 7 software (using the Morrison equation for curve fitting and Ki calculation). The results are presented in Table 1.

[0805]

[0806] As can be seen from Table 1, the compounds according to the present application can effectively inhibit the activity of RIP1 kinase.

[0807] Example 28: In Vivo Efficacy in the TNF-α-Induced Shock Test in Mice

[0808] C57BL/6 mice were purposely spayed and randomized into groups according to their body weight. Prepared 0.15 mg/ml TNF-α. Each mouse was injected with 200 μl of TNF-alpha (30 μg per mouse) into the tail vein. 15 minutes prior to TNF-α induction, the drug was administered according to body weight. At 0 hr, 1 hr, 2 hr, 4 hr, and 6 hr, the body temperature of the mouse was measured with a small animal thermometer and recorded, while the animal was observed during the test. After 6 hours, mice were sacrificed with CO ₂ . Experimental data were plotted using Graph Pad Prism 7 and expressed as mean ± standard error (Mean ± SEM). The area under the clinical score curve was analyzed using one-way analysis of variance. A p value <0.05 was considered a significant difference compared to the control group.

[0809] In FIG. 1 shows the body temperature of mice as a function of time after administration of RIP1-034 Compound of the present application to mice at different doses (10 mg/kg, 20 mg/kg and 30 mg/kg). The test shows that the administration of Compound RIP1-034 effectively inhibits the decrease in body temperature due to the systemic inflammatory response caused by TNF-α.

[0810] Example 29: Measurement of plasma concentration in mice after a single oral administration

[0811] An oral solution containing the RIP1-034 compound of the present application was prepared on the day of administration with an aqueous solution containing 0.5% MC/0.25% Tween 80. All animals were fasted overnight prior to administration, and 4 hours after administration, they were allowed to freely eat. Each group included three mice, and each mouse was orally administered a single dose of 10 mg/kg on the day of the experiment. Approximately 30 μl of whole blood was taken from the dorsal vein of the hind limb at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, transferred to an anticoagulation tube containing sodium heparin, and thoroughly mixed several times by turning over. The collected blood sample was centrifuged at 4° C. and 4000 g for 5 min to collect plasma, and the plasma sample was transferred to clean polyethylene microcentrifuge tubes and then stored in a freezer at -75±15° C. until analysis. The actual volume administered was calculated based on the body weight of the animal. All samples were analyzed by LC-MS/MS, and the concentration of the study drug in the samples was determined by the standard curve method. The plasma concentration of each mouse at each measurement time point after a single oral administration is shown in FIG. 2. The mean plasma concentration in a group of three mice at each measurement time point after a single oral administration is shown in FIG. 3.

[0812] This test shows that Compound RIP1-034 can reach the desired plasma concentration after oral administration.

Claims (80)

1. Compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X is O or S; the ring M has the structure

where ring A is selected from the group consisting of a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen and oxygen, and a 5-membered heterocyclyl containing 2 nitrogen heteroatoms; ring B is selected from the group consisting of a substituted or unsubstituted 6-membered aryl and a substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen and oxygen; where “substituted” refers to the substitution of 1 hydrogen atom in the group with a substituent selected from C ₁ -C ₆ alkyl; C is selected from the group consisting of substituted or unsubstituted 6-membered aryl, substituted or unsubstituted 6-membered heteroaryl containing 1 nitrogen heteroatom; where "substituted" refers to the substitution of 1-3 hydrogen atoms in the group Deputy selected from the group consisting of halogen and C ₁ -C ₆ alkyl; L is selected from the group consisting of O, NH, C ₁ -C ₆ alkylene; R ₁ is selected from the group consisting of H and C ₁ -C ₆ alkyl; R ₂ is selected from the group consisting of halogen, hydroxyl, oxo, benzyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ acyl; And m is 0 or 1; n is 1. 2. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X is O or S. 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen and oxygen, or a 5-membered heterocyclyl containing 2 nitrogen heteroatoms. 4. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a 6-membered heteroaryl containing 1 or 2 nitrogen heteroatoms. 5. The compound or pharmaceutically acceptable salt thereof according to claim 1, where ring B is a substituted or unsubstituted 6-membered aryl, substituted or unsubstituted 5-6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen and oxygen; where “substituted” refers to the substitution of 1 hydrogen atom in the group with a substituent selected from C ₁ -C ₆ alkyl. 6. The compound or its pharmaceutically acceptable salt according to claim 1, where C represents a substituted or unsubstituted 6-membered aryl or a substituted or unsubstituted 6-membered heteroaryl containing 1 nitrogen heteroatom; where "substituted" refers to the substitution of 1-3 hydrogen atoms in the group substituent selected from the group consisting of halogen and C ₁ -C ₆ alkyl. 7. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is O, NH, or C ₁ -C ₆ alkylene. 8. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is H. 9. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is unsubstituted C ₁ -C ₆ alkyl. 10. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has Formula (Ia):

(Ia). 11. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the Formula (Ib):

(IB) Where L is O or CH ₂ ; Z is N or CH; R ₃ is selected from halogen and C ₁ -C ₆ alkyl; And p is 0, 1, 2, or 3. 12. A compound or a pharmaceutically acceptable salt thereof according to claim 10 or 11, where the structural group represented by the formula

, is selected from the group consisting of:

13. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the Formula (Ic):

where ring A is a 6-membered heteroaryl containing 1-2 nitrogen heteroatoms. 14. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the Formula (Id):

Where ring A is an unsubstituted 6-membered heteroaryl containing 1-2 nitrogen heteroatoms; L is O or CH ₂ ; Z is N or CH; R ₃ is selected from the group consisting of halogen and unsubstituted C ₁ -C ₆ alkyl; And p is 0, 1, 2, or 3. 15. A compound or a pharmaceutically acceptable salt thereof according to claim 13 or 14, where the structural group represented by the formula

, is selected from the group consisting of:

16. A compound or pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, where ring B is a group selected from the group consisting of:

. 17. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:

18. The method of obtaining the compound according to claim 1,

where R ₄ represents -COOH or -COO-G ⁺ where G ⁺ is an alkali metal ion; when R is H, the method comprises: reacting a compound of Formula (II) with a compound of Formula (III) in an inert solvent in the presence of a condensing agent and a base to obtain a compound of Formula (I) according to claim 1; And when R is an amino protecting group selected from trifluoroacetyl and t-butoxycarbonyl (Boc), the method comprises: removing R from a compound of Formula (II) under acidic conditions and then reacting a compound of Formula (II) from which R has been removed with a compound of Formula (III) in an inert solvent in the presence of a condensing agent and a base to obtain a compound of Formula (I) according to claim 1. 19. A pharmaceutical composition for the treatment or prevention of diseases or disorders mediated by RIP1 kinase, comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier. 20. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by RIP1 kinase. 21. Use according to claim 20, wherein the RIP1 kinase-mediated diseases or disorders are selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, degenerative retinal disease, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, hepatitis B, hepatitis C, autoimmune hepatobiliary disease, primary sclerosis poisoning acetaminophen, hepatotoxicity, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of parenchymal organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granuloma, pulmonary sarcoidosis, Behçet's disease, interleukin-1-converting enzyme-associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, stroke, burns , burn shock, traumatic brain injury, atherosclerosis, cisplatin-induced kidney injury, acute kidney injury, pancreatitis, chronic kidney disease, acute respiratory distress syndrome, chronic obstructive pulmonary disease, Gaucher disease, Niemann-Pick disease, acute liver failure, cancer (eg, pancreatic cancer), bacterial infection, smoking-induced injury, cystic fibrosis, NF-κB key regulatory gene mutation, heme-oxidized ubiquitin ligase-1 IRP2 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, hemoblast malignancies neoplasms, malignant neoplasms of solid organs, influenza, staphylococcal infections, mycobacterial infections, lysosomal storage diseases, GM2 gangliosidosis, α-mannosidosis, aspartyl glucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon's disease, Fabry's disease, Farber's disease, fucosidosis , galactosialidosis, GM1 gangliosidosis, mucolipid accumulation, childhood free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostoses disease, Schindler's disease, Sull's disease, Tay-Sachs disease, Wolman's disease, Stevens-Johnson syndrome and toxic epidermal necrolysis. 22. A method of inhibiting RIP1 kinase in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1 or a pharmaceutical composition according to claim 19. 23. Intermediate of Formula (II):

Where: R is H or an amino protecting group selected from trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc); X is O or S; the ring M has the structure

where ring A is selected from the group consisting of a substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen and oxygen, and a 5-membered heterocyclyl containing 2 nitrogen heteroatoms; where the specified 5-membered heteroaryl is optionally substituted on the nitrogen heteroatom with R' selected from the group consisting of H, Boc, (C ₁ -C ₆ ) alkyl and benzyl; R ₁ is selected from the group consisting of H and C ₁ -C ₆ alkyl; R ₂ is selected from the group consisting of halogen, hydroxyl, oxo, benzyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ acyl; m is 0 or 1; And n is 1. 24. Intermediate according to claim 23, selected from the group consisting of:

where R' is selected from the group consisting of H, Boc, (C ₁ -C ₄ ) alkyl and benzyl.

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