Bicyclic compounds, intermediates thereof, methods of preparation and uses thereof

Abstract

This invention discloses a bicyclic compound, its intermediate, a preparation method, and its applications. Specifically, it discloses a compound as shown in Formula I, and its pharmaceutically acceptable salt or isotope. The compound of this invention exhibits good binding ability to amyloid protein, a short half-life, and good imaging effect. Furthermore, the compound of this invention can be used to prepare positron emission tomography (PET) agents and can be used for the early diagnosis of amyloid protein deposition-related diseases, such as Alzheimer's disease, and for monitoring the efficacy of drugs.

Description

Technical Field

[0001] This invention relates to a bicyclic compound, its intermediate, its preparation method, and its application. Background Technology

[0002] Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive loss of cognitive function and progressively increasing behavioral impairments. This progressive, irreversible brain dysfunction affects millions of lives and poses a devastating health burden worldwide. Significant progress has been made in deciphering its pathogenesis and developing new treatments over the past two decades. Pathological features of AD include β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau protein. Recent directions in the development of AD treatments focus on controlling the production, aggregation, and deposition of amyloid in the brain, as well as accelerating the metabolism of amyloid from the brain.

[0003] Non-invasive detection of amyloid deposition in the brain has been used to develop anti-amyloid therapies. Direct imaging of amyloid in AD patients is useful for early diagnosis and treatment planning and evaluation. Therefore, compounds suitable for in vivo imaging of amyloid deposition in the human brain have been extensively developed. Among these compounds are monoclonal antibodies against Aβ, but these are not absorbed by the brain. Injection of an Aβ-peptide-putrescine-gadolinium copolymer into transgenic mice overexpressing Aβ amyloid has resulted in the observation of amyloid in the mouse brain on MRI. Amyloid deposition can also be non-invasively imaged and quantified using small molecules that readily penetrate the brain.

[0004] Imaging amyloid with small molecules is the most successful method to date. Some of the most promising compounds for imaging amyloid are derivatives of Congo red, thioflavone, stilbene, and FDDNP. Congo red and thioflavone derivatives have been used to stain brain tissue sections from AD patients and transgenic mice. Two compounds currently undergoing human clinical trials for F18 are Florbetapir from Eli Lilly and Flutemetamol from GE. Neither of these imaging agents exhibits the kinetic range shown by carbon-11 labeled PIB.

[0005] CN102532119A discloses a bicyclic compound of benzothiazole-aromatic ring or heteroaromatic ring-diamine, which has the following general formula structure and can be used as a positron emission tomography (PET) scanning agent. Effective management of Alzheimer's disease (AD) involves diagnosis, monitoring, treatment, and prevention.

[0006] Summary of the Invention

[0007] The technical problem this invention aims to solve is the limited variety of compounds available for amyloid imaging. To address this, this invention provides a bicyclic compound, its intermediate, a preparation method, and its applications. The compound of this invention exhibits good binding affinity to amyloid protein, a short half-life, and excellent imaging performance. Furthermore, the compound can be used to prepare positron emission tomography (PET) agents and can be used for the early diagnosis of amyloid deposition-related diseases, such as Alzheimer's disease, and for monitoring the efficacy of medications.

[0008] This invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt or isotope thereof,

[0009]

[0010] Rings A and B are independently C6 to C6. 10 Aromatic ring or 5- to 10-membered heteroaromatic ring; wherein the heteroatoms in the 5- to 10-membered heteroaromatic ring are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0011] R a -N(R) a-1 R a-2 ) or halogen;

[0012] R a-1 and R a-2 Independently, it is H or a C1-C6 alkyl group;

[0013] Or two adjacent R a Together with the connected atoms, they form 5- to 10-membered heterocyclic alkyl groups or 5- to 10-membered heteroaryl groups; wherein the heteroatoms in the 5- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0014] m is 1, 2, or 3;

[0015] R b Halogen, -N(R) b-1 R b-2 -O-(C1~C6 alkylene)OH, -(C1~C6 alkylene)o1OH, -CN, -C(=O)-OR c-1 -C(=O)-R c-2 -C(=O)-N(R) b-3 R b-4 -NO2, -OR d5- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the heteroatoms in the 5- to 10-membered heterocyclic alkyl and 5- to 10-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0016] R b-1 R b-2 R b-3 and R b-4 Independently H, C1-C6 alkyl, halogen-substituted C1-C6 alkyl or -(C1-C6 alkylene)o2OH;

[0017] Or R b-3 and R b-4 Together with the attached N atom, it forms a 5- to 10-membered heterocyclic alkyl group or a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heterocyclic alkyl group and the 5- to 10-membered heteroaryl group contain 1, 2 or 3 N atoms;

[0018] O1 and O2 are independently 0 or 1;

[0019] R c-1 and R c-2 Independently, it is a C1 to C6 alkyl group;

[0020] R d Halogen-substituted C1-C6 alkyl groups;

[0021] n is 1, 2, or 3.

[0022] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt or isotope compound; certain groups may be defined as follows, and other groups may be defined as in any of the preceding embodiments (hereinafter referred to as "in one embodiment").

[0023] In one embodiment, the isotopic compound is an F isotopic compound, such as F... 18 .

[0024] In one scheme, in ring A, C6 to C 10 The aromatic ring is a benzene ring or a naphthalene ring, for example, a benzene ring.

[0025] In one embodiment, in ring A, the 5- to 10-membered heteroaromatic ring is a 5- to 6-membered heteroaromatic ring, and the heteroatoms are independently selected from one or both of N and O, with the number of heteroatoms being independently one or two, preferably a pyridine ring, for example...

[0026] In one scheme, within ring B, C6 to C... 10 The aromatic ring is a benzene ring or a naphthalene ring, for example, a benzene ring.

[0027] In one embodiment, in ring B, the 5- to 10-membered heteroaromatic ring is a 5- to 6-membered heteroaromatic ring, and the heteroatom is independently selected from one or both of N and O, with the number of heteroatoms being independently one or two, preferably a pyridine ring, for example...

[0028] In one particular scheme, R a and R b In this context, the halogen is independently F, Cl, Br, or I.

[0029] In one particular scheme, R a-1 R a-2 R b-1 R b-2 R b-3 R b-4 R c-1 and R c-2 In this context, the C1-C6 alkyl group is independently a C1-C4 alkyl group, preferably methyl, ethyl, n-propyl or isopropyl, such as methyl or ethyl.

[0030] In a certain scheme, two adjacent R a In the formation of a 5- to 10-membered heterocyclic alkyl group together with the linked atoms, the 5- to 10-membered heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group, wherein the heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently one or two, preferably dioxolane or tetrahydropyrrole, for example

[0031] In a certain scheme, two adjacent R a In the formation of a 5- to 10-membered heteroaryl group together with the linked atoms, the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group, wherein the heteroatom is independently selected from one or two of N and O, and the number of heteroatoms is independently one or two, preferably imidazole, pyrrole, or pyrazolyl; for example

[0032] In one particular scheme, R b R b-1 R b-2 R b-3 and R b-4 In this context, the C1-C6 alkylene groups are C1-C4 alkylene groups, preferably -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2- or -C(CH3)2-, for example -CH2- or -CH2CH2-.

[0033] In one particular scheme, R bIn this context, the 5- to 10-membered heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group, wherein the heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently one or two, preferably morpholino; for example

[0034] In one particular scheme, R b In this context, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom is independently selected from one or two of N and O, and the number of heteroatoms is independently one or two, preferably pyrrole, imidazolyl, or oxazolyl, for example...

[0035] In one particular scheme, R b-3 and R b-4 In the formation of a 5- to 10-membered heterocyclic alkyl group together with the linked N atom, the 5- to 10-membered heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group containing 1 or 2 N atoms; preferably a tetrahydropyrrolyl group; for example

[0036] In one particular scheme, R b-3 and R b-4 Together with the connected N atom, they form a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group containing 1 or 2 N atoms.

[0037] In one particular scheme, R b-1 R b-2 R b-3 R b-4 and R d In this context, the halogen substitution is independently fluorine substitution, chlorine substitution, bromine substitution, and iodine substitution; for example, fluorine substitution.

[0038] In one particular scheme, R b-1 R b-2 R b-3 R b-4 and R d In this context, the number of halogen substitutions is independently 1, 2, or 3, for example, 1.

[0039] In one scheme, ring B is C6~C 10 Aromatic ring.

[0040] In one embodiment, when ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring is... In one particular scheme, R a -N(R) a-1 R a-2 ).

[0041] In one particular scheme, R bHalogen, -CN or -C(=O)-N(R) b-5 R b-6 );

[0042] R b-5 and R b-6 It is independently H or C1 to C6 alkyl.

[0043] In one particular scheme, m is 1.

[0044] In a certain scheme, n is either 1 or 2.

[0045] In one particular scheme, R a for F, Cl, Br, or I.

[0046] In a certain scheme, two adjacent R a Formed together with the connected atoms

[0047] In one particular scheme, R b -F, -OH, -CN、 -CH2OH、 -NO2 or In one particular scheme, R b for 18 F.

[0048] In one embodiment, the compound represented by Formula I is the compound represented by Formula I-1. R 1 for

[0049] R 2 For H;

[0050] Or R 1 and R 2 Together with the connected atoms, they form 5- to 10-membered heterocyclic alkyl groups or 5- to 10-membered heteroaryl groups;

[0051] R 3 It is H or halogen;

[0052] Y 1 For CH or N;

[0053] R 4 It is H or halogen;

[0054] R 6 H, halogen, -N(R) 6-1 R 6-2), -O-(C1~C6 alkylene)OH, -(C1~C6 alkylene)o3OH, -CN, 5~10-membered heterocyclic alkyl or 5~10-membered heteroaryl;

[0055] O3 is 0;

[0056] R 6-1 and R 6-2 Independently, it can be H, C1-C6 alkyl, or -(C1-C6 alkylene)o4OH;

[0057] O4 is 1.

[0058] In one embodiment, the compound represented by Formula I is a compound represented by Formula I-2.

[0059] R 2 It is H or halogen;

[0060] Y 1 For CH or N;

[0061] R 5 Halogen, -(C1-C6 alkylene)o5OH, -N(R 5-1 R 5-2 -CN, -C(=O)-OR c-1 Or 5- to 10-membered heterocyclic alkyl groups;

[0062] O5 is 0;

[0063] R 5-1 and R 5-2 It is independently H or C1 to C6 alkyl.

[0064] In one embodiment, the compound represented by Formula I is a compound represented by Formulas I-3.

[0065] Y 1 For CH or N;

[0066] R 5 H, -C(=O)-OR c-1 -(C1~C6 alkylene)o6OH, -CN, -C(=O)-N(R) 5-3 R 5-4 );

[0067] O6 is 1;

[0068] R 5-3 and R 5-4 Independently, it is H or a C1-C6 alkyl group;

[0069] Or R5-3 and R 5-4 Together with the attached N atom, it forms a 5- to 10-membered heterocyclic alkyl group;

[0070] R 6 It can be H, halogen, or -CN.

[0071] In one embodiment, the compound represented by Formula I is a compound represented by Formulas I-4.

[0072] R 5 -C(=O)-N(R) 5-5 R 5-6 ), -N(R 5-7 R 5-8 ) or halogen;

[0073] R 5-5 R 5-6 R 5-7 and R 5-8 C1 to C6 alkyl groups that are independently substituted with H or halogens;

[0074] R 6 It can be H or -CN.

[0075] In one embodiment, the compound represented by Formula I is a compound represented by Formulas I-5. R 5 It can be H, -CN, or halogen;

[0076] R 6 It is a halogen or -CN.

[0077] In one embodiment, the compound represented by Formula I is a compound represented by Formulas I-6. R 2 It is H or halogen;

[0078] R 5 H, halogen, -OR d -NO2, -CN, or -(C1-C6 alkylene)o7OH;

[0079] O7 is 0;

[0080] R 6 For H, -CN, -C (=O) -OR c-1 -C(=O)-N(R) 6-3 R 6-4 -NO2, -C(=O)-R c-2 Or halogen;

[0081] R6-3 and R 6-4 It is independently H or C1 to C6 alkyl.

[0082] In one embodiment, the compound represented by Formula I is a compound represented by Formulas I-7. Y 2 For CH or N;

[0083] R 5 It is H or halogen;

[0084] R 6 -CN or -C(=O)-N(R) 6-5 R 6-6 );

[0085] R 6-5 and R 6-6 It is independently H or C1 to C6 alkyl.

[0086] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0087]

[0088]

[0089]

[0090]

[0091] The present invention also provides a compound as shown in Formula II or Formula III.

[0092]

[0093] In formula II,

[0094] R 2-2 It is H or -NO2;

[0095] R 5-2 For H, -NO2, -CN or In Equation III,

[0096] R 2-3 For H or

[0097] R 5-3 For H, -CN or In a particular scheme, the compound represented by Formula II or Formula III is any of the following compounds:

[0098]

[0099] The present invention also provides a method for preparing a compound as shown in Formula I, which is Scheme 1 or Scheme 2:

[0100] Scheme 1. When the compound shown in Formula I is the compound shown in Formula I-6-1, it includes the following steps: reacting the compound shown in Formula II with CsF to obtain the compound shown in Formula I-6-1.

[0101]

[0102] R 2-2 and R 5-2 The definition in is as described above;

[0103] R 2-1 For H or F;

[0104] R 5-1 It can be H, F, -OH or -CN.

[0105] Option 2. When the compound shown in Formula I is the compound shown in Formula I-6-1, it includes the following steps: reacting the compound shown in Formula III with CsF;

[0106]

[0107] R 2-3 and R 5-3 The definition in is as described above;

[0108] R 2-1 For H or F;

[0109] R 5-1 It can be H, F, -OH or -CN.

[0110] Option 1 or Option 2:

[0111] The reaction can be carried out in a solvent, which can be a strongly polar aprotic solvent, preferably dichloromethane or DMF, such as DMF;

[0112] The reaction temperature can be 120-150℃, for example, 120℃;

[0113] The molar ratio of the compound shown in Formula II to the CsF can be 1:(3-6), for example 1:5;

[0114] The molar ratio of the compound as shown in Formula III to the CsF can be 1:(3-6), for example 1:5;

[0115] The mass-to-volume ratio of the compound as shown in Formula II to the solvent can be 0.1-0.5 g / mL, for example, 0.5 g / mL;

[0116] The mass-to-volume ratio of the compound as shown in Formula III to the solvent can be 0.1-0.5 g / mL, for example, 0.5 g / mL.

[0117] The present invention provides a pharmaceutical composition comprising the compound shown in Formula I above, a pharmaceutically acceptable salt or isotopic compound thereof, and at least one pharmaceutical excipient.

[0118] The present invention also provides a positron emission tomography (PET) agent comprising the compound shown in Formula I above, a pharmaceutically acceptable salt thereof, an isotopic compound, or a pharmaceutical composition as described above.

[0119] This invention provides the use of the compound shown in Formula I, its pharmaceutically acceptable salt, isotopic compound, or pharmaceutical composition as described above, as a preparation of a positron emission tomography (PET) agent.

[0120] In one embodiment, the positron emission tomography (PET) agent is a PET agent used for Alzheimer's disease imaging.

[0121] In one embodiment, the positron emission tomography (PET) agent is a PET agent used for imaging diseases related to amyloid deposition.

[0122] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, and mesylate salts. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.

[0123] In structural fragments This means that the structural segment is connected to the rest of the molecule through this site.

[0124] The term "halogen" refers to F, Cl, Br, I, or 18 F.

[0125] The term "alkyl" refers to a straight-chain or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1–C4 or C1–C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, or isopropyl.

[0126] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group; that is, one hydrogen atom in the alkyl group is replaced, as defined above. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, etc.

[0127] The term "aromatic ring" refers to a ring with a specified number of carbon atoms (e.g., C6 to C7). 10 Aromatic rings are cyclic, unsaturated, monovalent hydrocarbon groups, which can be monocyclic or polycyclic (e.g., two). In the case of polycyclic rings, the monocyclic rings share two atoms and one bond, and each ring is aromatic. The aromatic rings are connected to the rest of the molecule through aromatic rings. Aromatic rings include, but are not limited to, benzene rings or naphthalene rings.

[0128] The term "heteroaromatic ring (group)" refers to a cyclic group having a specified number of ring atoms (e.g., 5–6 or 5–10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). The heteroaromatic ring (group) is linked to other segments of the molecule through an aromatic or non-aromatic ring. Heteroaromatic rings (groups) include, but are not limited to, pyrrole rings, imidazole rings, oxazole rings, or pyridine rings.

[0129] The term "heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 5-6 or 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), and is monocyclic. Heterocyclic alkyl groups are attached to the rest of the molecule via carbon atoms or heteroatoms. Heterocyclic alkyl groups include, but are not limited to: wait.

[0130] The term "one or more" refers to 1, 2 or 3.

[0131] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0132] The reagents and raw materials used in this invention are all commercially available.

[0133] The positive and progressive effects of this invention are as follows: the compounds of this invention have good binding ability to β-amyloid protein; their clogD7.4 are all below 3.6, and their short half-life is beneficial for eliminating the influence of background during the development process, resulting in good development effect. The compounds of this invention can be used to prepare positron emission tomography (PET) agents and can be used for the early diagnosis of amyloid protein deposition-related diseases, such as Alzheimer's disease, and for tracking the efficacy of drugs. Attached Figure Description

[0134] Figure 1 Autoradiography of brain tissue sections from human AD patients. Detailed Implementation

[0135] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0136] For experimental methods in the following examples where specific conditions are not specified, follow conventional methods and conditions, or select according to the product instructions.

[0137]

[0138] Phenol derivatives numbering and structure

[0139]

[0140]

[0141] Numbering and Structure of Alkyne Derivatives

[0142]

[0143]

[0144] Example 1: Preparation of compound J03

[0145]

[0146] General synthesis steps: 1.0 mmol Using 2 mL of 48% HI as solvent, the reaction mixture was reacted at 95 °C for 20 min at 120 W until complete. The reaction mixture was neutralized with NaHCO3 and separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography.

[0147] Compound J03, yield 76%, 1 H NMR (400MHz; CDCl3), δ11.3(s,1H,OH), 8.68(s,1H,Ar-H), 6.70(s,1H,Ar-H).

[0148] Example 2: Preparation of compound J05

[0149]

[0150] General synthesis steps: 1.0 mmol Using 2 mL of 48% HI as solvent, the reaction mixture was reacted at 95 °C for 20 min at 120 W until complete. The reaction mixture was neutralized with NaHCO3 and separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography.

[0151] Compound J05, yield 44%, 1 H NMR (400MHz; CDCl3), δ11.5(s,1H,OH), 8.65(s,1H,Ar-H), 6.73(s,1H,Ar-H).

[0152] Example 3 Preparation of compound J06

[0153]

[0154] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0155] Compound J06, yield 56%, 1 H NMR (400MHz; CDCl3), δ9.12(s,1H,Ar-H), 7.61(s,1H,Ar-H), 11.5(brs,1H,Ar-OH), 3.81(s,3H,OCH3).

[0156] Example 4: Preparation of compound J08

[0157]

[0158] General synthesis steps: 1.0 mmol Two equivalents of NIS were used, with acetic acid as the solvent. The reaction mixture was stirred at 85°C for 5 h until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0159] Compound J08, yield 54%. 1H NMR (400MHz; CDCl3), δ9.80(s,1H,OH),7.87(s,1H,Ar-H),8.71(s,1H,Ar-H).

[0160] Example 5: Preparation of compound J09

[0161]

[0162] General synthesis steps: 1.0 mmol Two equivalents of NIS were used, with acetic acid as the solvent. The reaction mixture was stirred at 85°C for 5 h until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0163] Compound J09, yield 47%, 1 H NMR (400MHz; CDCl3), δ9.60 (s, 1H, OH), 7.40-7.50 (m, 2H, Ar-H).

[0164] Example 6 Preparation of compound J10

[0165]

[0166] General synthesis steps: 1.0 mmol Two equivalents of NIS were used, with acetic acid as the solvent. The reaction mixture was stirred at 85°C for 5 h until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0167] Compound J10, yield 59%, 1 H NMR (400MHz; CDCl3), δ11.50(s,1H,OH),8.91(s,1H,Ar-H),8.34(s,1H,Ar-H).

[0168] Example 7 Preparation of compound J11

[0169]

[0170] General synthesis steps: 1.0 mmol Two equivalents of NIS were used, with acetic acid as the solvent. The reaction mixture was stirred at 85°C for 5 h until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0171] Compound J11, yield 61%, 1H NMR (400MHz; CDCl3), δ9.50 (s, 1H, OH), 8.01 (d, 3 J HH =8.5Hz, 1H, Ar-H), 7.84(d, 3 J HH =8.5Hz, 1H, Ar-H).

[0172] Example 8 Preparation of compound J14

[0173]

[0174] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0175] Compound J14, yield 81%, 1 H NMR (400MHz; CDCl3), δ7.72(d, 3 J HF =8.2Hz, 1H, Ar-H), 6.90(d, 3 J HH =5.1Hz,1H,Ar-H),11.4(brs,1H,Ar-OH).

[0176] Example 9 Preparation of compound J16

[0177]

[0178] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0179] Compound J16, yield 58%, 1 H NMR (400MHz; CDCl3), δ7.80 (s, 1H, Ar-H), 7.70 (d, 3 J HH =8.2Hz, 1H, Ar-H), 6.74(d, 3 J HH =8.2Hz,1H,Ar-H),11.7(brs,1H,Ar-OH).

[0180] Example 10 Preparation of compound J17

[0181]

[0182] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0183] Compound J17, yield 55%, 1 H NMR (400MHz; CDCl3), δ9.12(s,1H,Ar-H), 7.61(s,1H,Ar-H), 11.5(brs,1H,Ar-OH).

[0184] Example 11 Preparation of compound J20

[0185]

[0186] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0187] Compound J20, yield 83%, 1 H NMR (400MHz; CDCl3), δ7.65(s,1H,Ar-H), 6.12(s,1H,Ar-H), 11.5(brs,1H,Ar-OH).

[0188] Example 12 Preparation of compound J22

[0189]

[0190] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0191] Compound J22, yield 42%, 1 H NMR (400MHz; CDCl3), δ7.50(s,1H,Ar-H), 6.15(s,1H,Ar-H), 11.6(brs,2H,Ar-OH).

[0192] Example 13 Preparation of compound J23

[0193]

[0194] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0195] Compound J23, yield 43%, 1 H NMR (400MHz; CDCl3), δ8.02(s,1H,Ar-H), 7.51(s,1H,Ar-H), 11.6(brs,1H,Ar-OH).

[0196] Example 14 Preparation of compound J24

[0197]

[0198] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with trifluoroacetic acid as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0199] Compound J24, yield 48%, 1 H NMR(400MHz; CDCl3), δ7.89(d, 3 J HH =8.5Hz,1H,Ar-H),7.29(s,1H,Ar-H),7.31(d, 3 J HH =8.5Hz,1H,Ar-H),11.4(brs,1H,Ar-OH).

[0200] Example 15 Preparation of compound J25

[0201]

[0202] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with trifluoroacetic acid as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0203] Compound J25, yield 51%,1 H NMR(400MHz; CDCl3), δ3.83(s,3H,CH3),6.89(d, 3 J HF =8.0Hz,1H,Ar-H),8.20(s,1H,Ar-H),11.3(brs,1H,Ar-OH).

[0204] Example 16 Preparation of compound J26

[0205]

[0206] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with trifluoroacetic acid as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0207] Compound J26, yield 48%, 1 H NMR(400MHz; CDCl3), δ2.53(s,3H,CH3),6.81(d, 3 J HF =8.0Hz, 1H, Ar-H), 8.13(d, 3 J HH =5.0Hz,1H,Ar-H),11.5(brs,1H,Ar-OH).

[0208] Example 17 Preparation of compound J27

[0209]

[0210] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with trifluoroacetic acid as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0211] Compound J27, yield 55%, 1 H NMR (400MHz; CDCl3), δ2.47(s,3H,CH3),8.01(s,1H,Ar-H),7.68(d, 3 J HH =8.6Hz, 1H, Ar-H), 6.14(d, 3 J HH =8.6Hz,1H,Ar-H),11.2(brs,1H,Ar-OH).

[0212] Example 18 Preparation of compound J28

[0213]

[0214] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with trifluoroacetic acid as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0215] Compound J28, yield 53%, 1 H NMR (400MHz; CDCl3), δ8.15(d, 3 J HF =8.0Hz, 1H, Ar-H), 7.18(d, 4 J HF =5.0Hz,1H,Ar-H),14.2(brs,1H,Ar-OH).

[0216] Example 19 Preparation of compounds H08b-H10b

[0217]

[0218] The general synthetic steps for compounds H08b-H10b are as follows: 1.0 mmol of substrate H08a-H10a is dissolved in 3 mL of formic acid. 3.0 equimolar amounts of methanesulfonyl chloride are added dropwise to the reaction mixture in liquid form. The reaction is carried out in acetonitrile at room temperature for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the substrate. The reaction mixture is separated in ethyl acetate and saturated brine. The organic solvent phase is dried in magnesium sulfate. The solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography.

[0219] Compound H08b, yield 58%, 1 H NMR (400MHz; CDCl3), δ10.3(s,1H,NH),8.55(s,1H,CHO),7.70(m,1H,ArH),7.56(m,1H,Ar-H),7.32(d, 3 J HH =8.6Hz,1H,Ar-H),3.88(s,1H,CCH).

[0220] Compound H09b, yield 76%. 1H NMR (400MHz; CDCl3), δ12.1(s,1H,NH),8.57(s,1H,CHO),8.25(m,1H,Ar-H),7.58(d, 3 J HH =8.6Hz,1H,Ar-H),4.10(s,1H,CCH).

[0221] Compound H10b, yield 69%, 1 H NMR (400MHz; CDCl3), δ12.0(s,1H,NH),8.59(s,1H,CHO),8.35(s,1H,Ar-H),7.83(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.49(d, 3 J HH =8.6Hz,1H,Ar-H),4.07(s,1H,CCH).

[0222] Example 20 Preparation of compounds H08c-H10c

[0223]

[0224] The general synthetic steps for compounds H08c-H10c are as follows: 1.0 mmol of substrate H08b-H10b is dissolved in 3 mL of DMF, 1.2 equivalents of KN(TMS)2, and 1.5 equivalents of iodomethane. The solution is added dropwise to the reaction mixture in liquid form and reacted at room temperature for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the substrate. The reaction mixture is separated in ethyl acetate and saturated brine. The organic solvent phase is dried in magnesium sulfate. The solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography.

[0225] Compound H08c, yield 53%. 1 H NMR (400MHz; CDCl3), δ8.55(s,1H,CHO),7.70(m,1H,ArH),7.54(m,1H,Ar-H),7.32(d, 3 J HH =8.6Hz,1H,Ar-H), 3.78(s,1H,CCH), 3.29(s,3H,CH3).

[0226] Compound H09c, yield 56%, 1 H NMR (400MHz; CDCl3), δ8.47(s,1H,CHO),8.29(m,1H,Ar-H),7.57(d, 3 J HH=8.6Hz,1H,Ar-H), 4.07(s,1H,CCH), 3.35(s,3H,CH3).

[0227] Compound H10c, yield 49%, 1 H NMR (400MHz; CDCl3), δ8.52(s,1H,CHO),8.33(s,1H,Ar-H), 7.84(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.41(d, 3 J HH =8.6Hz,1H,Ar-H), 4.07(s,1H,CCH), 3.30(s,3H,CH3).

[0228] Example 21 Preparation of compounds H08d-H10d

[0229]

[0230] The general synthetic steps for compounds H08d-H10d are as follows: 1.0 mmol of substrate H08c-H10c is dissolved in 3 mL of 1 M KOH methanol solution and reacted at room temperature for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the substrate. The reaction mixture is separated in ethyl acetate and saturated brine. The organic solvent phase is dried in magnesium sulfate. The solvent is removed by vacuum drying, and the crude product is separated by silica gel column chromatography.

[0231] Compound H08d, yield 99%, 1 H NMR(400MHz; CDCl3), δ7.35(m,1H,Ar-H),7.24(s,1H,NH),6.72(d, 3 J HH =8.6Hz, 1H, Ar-H), 6.41(d, 3 J HH =8.6Hz,1H,Ar-H),4.08(s,1H,CCH),2.64(s,3H,CH3).

[0232] Compound H09d, yield 96%, 1 H NMR(400MHz; CDCl3), δ8.03(m,1H,Ar-H),7.61(s,1H,NH),6.70(d, 3 J HH =8.6Hz,1H,Ar-H), 4.10(s,1H,CCH), 2.79(s,3H,CH3).

[0233] Compound H10d, yield 91%,1 H NMR (400MHz; CDCl3), δ8.23(s,1H,Ar-H),7.60(m,2H,NH+Ar-H),6.58(d, 3 J HH =8.6Hz,1H,Ar-H),4.09(s,1H,CCH),2.85(s,3H,CH3).

[0234] Example 22 Preparation of compounds H12a and H15a

[0235]

[0236] General synthesis steps: 1.0 mmol 1.2 equivalents of NIS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0237] Compound H12a, yield 76%, 1 H NMR (400MHz; CDCl3), δ5.80 (s, 2H, NH2), 7.51 (d, 3 J HH =8.5Hz, 1H, Ar-H), 7.21(d, 3 J HH =8.5Hz, 1H, Ar-H).

[0238] Compound H15a, yield 84%, 1 H NMR (400MHz; CDCl3), δ4.80 (s, 2H, NH2), 7.57 (d, 3 J HH =8.5Hz, 1H, Ar-H), 7.01(d, 3 J HH =8.5Hz, 1H, Ar-H).

[0239] Example 23 Preparation of compound H14a

[0240]

[0241] General synthesis steps: 1.0 mmol 1.2 equivalents of NBS were used, with acetonitrile as the solvent. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0242] Compound H14a, yield 44%,1 H NMR (400MHz; CDCl3), δ5.80 (s, 2H, NH2), 7.97 (d, 3 J HH =8.5Hz, 1H, Ar-H), 7.91(d, 3 J HH =8.5Hz, 1H, Ar-H).

[0243] Example 24 Preparation of compounds H12b, H14b, and H15b

[0244]

[0245] General synthesis steps: 1.0 mmol 1.2 equivalent 0.2 equivalents of CuI and 0.2 equivalents of (Ph3P)2PdCl2 were added, and acetonitrile was used as the solvent. The reaction mixture was heated to 100°C and stirred until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography.

[0246] Compound H12b, yield 41%, 1 H NMR (400MHz; CDCl3), δ5.80 (s, 2H, NH2), 7.49 (d, 3 J HH =8.5Hz, 1H, Ar-H), 7.11(d, 3 J HH =8.5Hz,1H,Ar-H),0.08(s,9H).

[0247] Compound H14b, yield 39%, 1 H NMR (400MHz; CDCl3), δ5.82 (s, 2H, NH2), 7.76 (d, 3 J HH =8.5Hz, 1H, Ar-H), 7.70(d, 3 J HH =8.5Hz,1H,Ar-H),0.08(s,9H).

[0248] Compound H15b, yield 57%, 1 H NMR (400MHz; CDCl3), δ4.80 (s, 2H, NH2), 7.21 (d, 3 J HH =8.5Hz, 1H, Ar-H), 7.09(d, 3 J HH=8.5Hz,1H,Ar-H),0.08(s,9H).

[0249] Example 25 Preparation of compounds H12c, H14c, and H15c

[0250]

[0251] General synthesis steps: 1.0 mmol Five equivalents of KOH (5M aqueous solution) were added, and ethanol was used as the solvent. The reaction mixture was stirred until the reaction was complete. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed by vacuum drying, and the crude product was separated by silica gel column chromatography.

[0252] Compound H12c, yield 95%, 1 H NMR(400MHz; CDCl3), δ4.10(s,1H,CH),5.80(s,2H,NH2),7.11(d, 3 J HH =7.5Hz, 1H, Ar-H), 7.50(d, 3 J HH =7.5Hz, 1H, Ar-H).

[0253] Compound H14c, yield 85%, 1 H NMR(400MHz; CDCl3), δ4.07(s,1H,CH),5.81(s,2H,NH2),7.69(d, 3 J HH =7.5Hz, 1H, Ar-H), 7.76(d, 3 J HH =7.5Hz, 1H, Ar-H).

[0254] Compound H15c, yield 90%, 1 H NMR (400MHz; CDCl3), δ4.11(s,1H,CH),4.80(s,2H,NH2),7.17(d, 3 J HH =7.5Hz, 1H, Ar-H), 7.26(d, 3 J HH =7.5Hz, 1H, Ar-H).

[0255] Example 26 Preparation of compounds H11d-H13d, H15d

[0256]

[0257] The general synthetic steps for compounds H11d-H13d,H15d are as follows: 1.0 mmol of substrate H11c-H13c,H15c is dissolved in 3 mL of formic acid. 3.0 equimolar amounts of methanesulfonyl chloride are added dropwise to the reaction mixture in liquid form. The reaction is carried out in acetonitrile at room temperature for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the substrate. The reaction mixture is separated in ethyl acetate and saturated brine. The organic solvent phase is dried in magnesium sulfate. The solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography.

[0258] Compound H11d, yield 89%, 1 H NMR(400MHz; CDCl3), δ9.9(s,1H,NH),8.55(s,1H,CHO),7.59(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.35(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.19(d, 3 J HF =8.0Hz,1H,Ar-H),3.89(s,1H,CCH).

[0259] Compound H12d, yield 73%. 1 H NMR(400MHz; CDCl3), δ9.1(s,1H,NH),8.50(s,1H,CHO),8.41(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.14(d, 3 J HH =8.6Hz,1H,Ar-H),4.10(s,1H,CCH).

[0260] Compound H13d, yield 78%. 1 H NMR(400MHz; CDCl3), δ9.0(s,1H,NH),8.51(s,1H,CHO),8.09(s,1H,ArH),8.04(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.00(d, 3 J HH =8.6Hz,1H,Ar-H),4.08(s,1H,CCH).

[0261] Compound H15d, yield 67%. 1 H NMR(400MHz; CDCl3), δ9.2(s,1H,NH),8.53(s,1H,CHO),8.21(d,3 J HH =8.6Hz, 1H, Ar-H), 7.19(d, 3 J HH =8.6Hz,1H,Ar-H),4.10(s,1H,CCH).

[0262] Example 27 Preparation of compounds H11e-H13e,H15e

[0263]

[0264] The general synthetic steps for compounds H11e-H13e,H15e are as follows: 1.0 mmol of substrates H11d-H13d, H15d are dissolved in 3 mL of DMF, 1.2 equivalents of KN(TMS)2, and 1.5 equivalents of iodomethane. The solutions are added dropwise in liquid form to the reaction mixture and reacted at room temperature for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the substrates. The reaction mixture is separated in ethyl acetate and saturated brine. The organic solvent phase is dried in magnesium sulfate. The solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography.

[0265] Compound H11e, yield 45%, 1 H NMR (400MHz; CDCl3), δ8.46(s,1H,CHO),7.58(m,1H,Ar-H),7.39(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.15(d, 3 J HF =8.0Hz,1H,Ar-H), 3.84(s,1H,CCH), 3.30(s,3H,CH3).

[0266] Compound H12e, yield 78%, 1 H NMR (400MHz; CDCl3), δ8.45 (s, 1H, CHO), 8.39 (d, 3 J HH =8.6Hz, 1H, Ar-H), 7.07(d, 3 J HH =8.6Hz,1H,Ar-H),4.10(s,1H,CCH),2.75(s,3H,CH3).

[0267] Compound H13e, yield 61%, 1 H NMR (400MHz; CDCl3), δ8.50(s,1H,CHO),8.07(s,1H,Ar-H),8.03(d, 3 J HH=8.6Hz, 1H, Ar-H), 6.99(d, 3 J HH =8.6Hz,1H,Ar-H),4.08(s,1H,CCH),2.75(s,3H,CH3).

[0268] Compound H15e, yield 52%, 1 H NMR(400MHz; CDCl3), δ8.49(s,1H,CHO),8.24(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.18(d, 3 J HH =8.6Hz,1H,Ar-H),4.10(s,1H,CCH),2.75(s,3H,CH3).

[0269] Example 28 Preparation of compounds H11-H13,H15

[0270]

[0271] The general synthetic steps for compounds H11-H13,H15 are as follows: 1.0 mmol of substrate H11e-H13e,H15e is dissolved in 3 mL of 1 M KOH methanol solution and reacted at room temperature for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the substrate. The reaction mixture is separated in ethyl acetate and saturated brine. The organic solvent phase is dried in magnesium sulfate. The solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography.

[0272] Compound H11, yield 92%, 1 H NMR (400MHz; CDCl3), δ7.15(d, 3 J HH =8.6Hz,1H,Ar-H),7.00(s,1H,Ar-H),6.60(d, 3 J HH =8.6Hz,1H,Ar-H),6.70(s,1H,NH),3.80(s,1H,CCH),2.59(s,3H,CH3).

[0273] Compound H12, yield 97%, 1 H NMR(400MHz; CDCl3), δ7.45(m,1H,Ar-H),7.04(d, 3 J HH =8.6Hz,1H,Ar-H),6.00(brs,1H,NH),4.10(s,1H,CCH),2.71(s,3H,CH3).

[0274] Compound H13, yield 89%, 1 H NMR (400MHz; CDCl3), δ7.60 (s, 1H, Ar-H), 7.03 (d, 3 J HH =8.6Hz, 1H, Ar-H), 6.95(d, 3 J HH =8.6Hz,1H,Ar-H),5.80(s,1H,NH),4.08(s,1H,CCH),2.65(s,3H,CH3).

[0275] Compound H15, yield 95%, 1 H NMR (400MHz; CDCl3), δ7.20(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.14(d, 3 J HH =8.6Hz,1H,Ar-H),4.07(s,1H,CCH),2.70(s,3H,CH3).

[0276] Example 29 Preparation of compound H14

[0277]

[0278] The general synthetic steps for compound H14 are as follows: 1.0 mmol of substrate H14c was dissolved in 3 mL of DMF, 1.2 equivalents of KN(TMS)2, and 1.5 equivalents of iodomethane. The solution was added dropwise to the reaction mixture in liquid form and reacted at room temperature for 3 hours, during which the solution color changed from pale yellow to deep red. LC-MS analysis showed complete disappearance of the substrate. The reaction mixture was separated in ethyl acetate and saturated brine. The organic solvent phase was dried in magnesium sulfate. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography.

[0279] Compound H14, yield 41%, 1 H NMR(400MHz; CDCl3), δ7.70(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.68(d, 3 J HH =8.6Hz,1H,Ar-H),5.97(s,1H,NH),4.05(s,1H,CCH),2.70(s,3H,CH3).

[0280] Example 30 Preparation of compound H16

[0281]

[0282] The general synthetic steps for compound H16 are as follows: 1.0 mmol of substrate H15 is dissolved in 3 mL of DMF, 1.2 equivalents of PhSe-SePh, and 0.2 equivalents of CuI. The mixture is reacted at 120°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the substrate. The reaction mixture is separated in ethyl acetate and saturated brine. The organic solvent phase is dried in magnesium sulfate. The solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography.

[0283] Compound H16, yield 38%, 1 H NMR (400MHz; CDCl3), δ7.33-7.36(m,5H,Ph),7.12(d, 3 J HH =8.6Hz, 1H, Ar-H), 6.91(d, 3 J HH =8.6Hz,1H,Ar-H),5.92(s,1H,NH),4.15(s,1H,CCH),2.63(s,3H,CH3).

[0284] Example 31 Preparation of compound P01

[0285]

[0286] The general synthetic steps for compound P01 are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of 3-iodopyridin-4-ol, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The reaction mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.02% TA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0287] Compound P01, yield 34%, 1 H NMR(400MHz; CDCl3), δ2.65(s,3H,CH3),6.51(d, 3 J HH =8.6Hz,2H,Ar-H),6.51(s,1H,Ar-H),7.22(s,1H,NH),7.31(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.54(d, 3 J HH =8.6Hz, 2H, Ar-H), 8.40(d, 3J HH =8.6Hz,1H,Ar-H),8.52(s,1H,Ar-H).

[0288] Example 32 Preparation of compound PO2

[0289]

[0290] The general synthetic steps for compound PO2 are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J01, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0291] Compound PO2, yield 52%, 1 H NMR(400MHz; CDCl3), δ2.61(s,3H,CH3),6.55(d, 3 J HH =8.6Hz,2H,Ar-H),6.50(s,1H,Ar-H),7.20(s,1H,NH),7.25(m,1H,Ar-H),7.58(d, 3 J HH =8.6Hz, 2H, Ar-H), 8.45(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0292] Example 33 Preparation of compound PO3

[0293]

[0294] The general synthetic steps for compound PO3 are as follows: 1.0 mmol of substrate HO2, 1.2 equivalents of J01, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that HO2 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0295] Compound PO3, yield 35%, 1H NMR(400MHz; CDCl3), δ2.79(s,3H,CH3),6.51(s,1H,Ar-H),6.80(d, 3 J HH =8.6Hz,1H,Ar-H),7.25(m,1H,Ar-H),7.60(s,1H,NH),7.68(d, 3 J HH =8.6Hz,1H,Ar-H),8.40(s,1H,Ar-H),8.48(s,1H,Ar-H).

[0296] Example 34 Preparation of compound Pa

[0297]

[0298] The general synthetic steps for compound Pa are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J03, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0299] Compound Pa, yield 52%, 1 H NMR(400MHz; CDCl3), δ2.64(s,3H,CH3),6.51(d, 3 J HH =8.6Hz,2H,Ar-H),6.53(s,1H,Ar-H),7.21(s,1H,NH),7.53(d, 3 J HH =8.6Hz,2H,Ar-H),7.73(s,1H,Ar-H),8.55(s,1H,Ar-H).

[0300] Example 35 Preparation of compound PO4

[0301]

[0302] The general synthetic steps for compound PO4 are as follows: 1.0 mmol of substrate Pa was dissolved in ethanolamine and reacted under microwave at 120 °C for 30 min at 70 W and 250 psi, until the solution color changed from pale yellow to deep red. LC-MS analysis showed that Pa completely disappeared. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, and Phase B was 0.025% TFA acetonitrile solution. The reaction mixture was then reacted with 10-30% B for 0-30 min, and the solvent was removed under vacuum.

[0303] Compound PO4, yield 83%, 1 H NMR(400MHz; CDCl3), δ2.64(s,3H,CH3),3.43(t, 3 J HH =7.4Hz, 2H, CH2N), 3.62(t, 3 J HH =7.4Hz,2H,CH2O),4.70(s,1H,OH),6.53(d, 3 J HH =8.6Hz,2H,Ar-H),6.57(s,1H,Ar-H),6.62(s,1H,Ar-H),7.23(s,1H,NH),7.51(d, 3 J HH =8.6Hz,2H,Ar-H),8.07(s,1H,Ar-H),8.35(s,1H,NH).

[0304] Example 36 Preparation of compound P05

[0305]

[0306] The general synthetic steps for compound P05 are as follows: 1.0 mmol of substrate Pa was dissolved in ethylene glycol, and 2 mL of KOtBu, 1 M, THF solution was added. The mixture was microwaved at 120 °C for 30 min at 70 W and 250 psi, and the solution color changed from pale yellow to deep red. LC-MS analysis showed that Pa completely disappeared. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% TFA aqueous solution, and phase B was 0.025% TFA acetonitrile solution, 10-30% B, for 0-30 min, and the solvent was dried under vacuum.

[0307] Compound P05, yield 87%, 1 H NMR(400MHz; CDCl3), δ2.62(s,3H,CH3),3.65(t, 3 J HH =7.4Hz, 2H, CH2N), 4.22(t, 3 JHH =7.4Hz,2H,CH2O),4.90(s,1H,OH),5.79(s,1H,Ar-H),6.49(d, 3 J HH =8.6Hz,2H,Ar-H),6.54(s,1H,Ar-H),7.21(s,1H,NH),7.54(d, 3 J HH =8.6Hz,2H,Ar-H),7.65(s,1H,Ar-H).

[0308] Example 37 Preparation of compound P06

[0309]

[0310] The general synthetic steps for compound P06 are as follows: 1.0 mmol of substrate Pa was dissolved in 2 mL of KOH, 1M H2O solution. The reaction mixture was microwaved at 120 °C for 30 min at 70 W and 250 psi, and the solution color changed from pale yellow to deep red. LC-MS analysis showed that Pa completely disappeared. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% TFA aqueous solution, and phase B was 0.025% TFA acetonitrile solution. The reaction mixture was incubated with 10-30% B solution for 0-30 min, and the solvent was removed under vacuum.

[0311] Compound P06, yield 57%, 1 H NMR(400MHz; CDCl3), δ2.60(s,3H,CH3),6.47(d, 3 J HH =8.6Hz,2H,Ar-H),6.51(s,1H,Ar-H),7.20(s,1H,NH),7.50(d, 3 J HH =8.6Hz,2H,Ar-H),7.63(s,1H,Ar-H),11.5(brs,1H,Ar-OH).

[0312] Example 38 Preparation of compound P07

[0313]

[0314] The general synthetic steps for compound P07 are as follows: 1.0 mmol of substrate Pa was dissolved in 2 mL of 40% methylamine aqueous solution. The reaction was carried out under microwave at 100 °C for 60 min at 70 W and 250 psi, during which the solution color changed from pale yellow to deep red. LC-MS analysis showed that Pa completely disappeared. After filtration, the reaction mixture was directly separated by HPLC. Phase A was 0.025% TFA aqueous solution, and Phase B was 0.025% TFA acetonitrile solution. The reaction mixture was then incubated with 10-30% B solution for 0-30 min, and the solvent was removed under vacuum.

[0315] Compound P07, yield 77%, 1 H NMR(400MHz; CDCl3), δ2.65(s,3H,CH3),2.71(s,3H,CH3),6.49(d, 3 J HH =8.6Hz,2H,Ar-H),6.53(s,1H,Ar-H),6.70(s,1H,Ar-H),7.22(s,1H,NH),7.54(d, 3 J HH =8.6Hz,2H,Ar-H),7.60(s,1H,NH),8.13(s,1H,Ar-H).

[0316] Example 39 Preparation of compound P08

[0317]

[0318] The general synthetic steps for compound P08 are as follows: 1.0 mmol of substrate Pa and 5.0 equivalences of Morphine are dissolved in 2 mL of DMF. The reaction mixture is microwaved at 120 °C for 30 min at 70 W and 250 psi, until the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pa has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then incubated with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0319] Compound P08, yield 45%, 1 H NMR(400MHz; CDCl3), δ2.68(s,3H,CH3),3.70(m,8H,CH2),6.53(d, 3 J HH =8.6Hz,2H,Ar-H),6.51(s,1H,Ar-H),6.72(s,1H,Ar-H),7.24(s,1H,NH),7.51(d, 3 J HH=8.6Hz,2H,Ar-H),8.07(s,1H,Ar-H).

[0320] Example 40 Preparation of compound P09

[0321]

[0322] The general synthetic steps for compound P09 are as follows: 1.0 mmol of substrate Pa, 5.0 equivalents of pyrrole, and 5.0 equivalents of Cs₂CO₃ are dissolved in 2 mL of DMF. The reaction mixture is microwaved at 120 °C for 30 min at 70 W and 250 psi, and the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pa has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated with 10-30% B solution for 0-30 min, and the solvent is removed under vacuum.

[0323] Compound P09, yield 45%, 1 H NMR (400MHz; CDCl3), δ2.63(s,3H,CH3),6.29(m,2H,Ar-H),6.50(d, 3 J HH =8.6Hz,2H,Ar-H),6.53(s,1H,Ar-H),7.26(m,3H,NH+ArH),7.50(s,1H,Ar-H),7.59(d, 3 J HH =8.6Hz,2H,Ar-H),8.77(s,1H,Ar-H).

[0324] Example 41 Preparation of compound P10

[0325]

[0326] The general synthetic steps for compound P10 are as follows: 1.0 mmol of substrate Pa, 5.0 equivalents of imidazole, and 5.0 equivalents of Cs₂CO₃ are dissolved in 2 mL of DMF. The reaction mixture is microwaved at 120 °C for 30 min at 70 W and 250 psi, and the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pa has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0327] Compound P10, yield 67%, 1 H NMR(400MHz; CDCl3), δ2.66(s,3H,CH3),6.53(d,3 J HH =8.6Hz,2H,Ar-H),6.57(s,1H,Ar-H),7.28(s,1H,ArH),7.26(s,1H,NH),7.15(m,2H,Ar-H),7.48(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.54(d, 3 J HH =8.6Hz,2H,Ar-H),8.37(s,1H,Ar-H).

[0328] Example 42 Preparation of compound P11

[0329]

[0330] The general synthetic steps for compound P11 are as follows: 1.0 mmol of substrate Pa, 5.0 equivalents of boric acid, 5.0 equivalents of Cs₂CO₃, and 0.1 equivalents of Pd[P(tBu)₃]₂ are dissolved in 2 mL of MeCN. The reaction mixture is microwaved at 80 °C for 30 min at 50 W and 250 psi, and the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pa has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated with 10-30% B solution for 0-30 min, and the solvent is removed under vacuum.

[0331] Compound P11, yield 53%, 1 H NMR(400MHz; CDCl3), δ2.62(s,3H,CH3),6.50(d, 3 J HH =8.6Hz,2H,Ar-H),6.51(s,1H,Ar-H),7.12(d, 3 J HH =8.6Hz,1H,Ar-H),7.26(s,1H,NH),7.52(m,3H,Ar-H),8.24(s,1H,Ar-H),8.83(s,1H,Ar-H).

[0332] Example 43 Preparation of compound P12

[0333]

[0334] The general synthetic steps of compound P12 are as follows: 1.0 mmol of substrate Pa, 5.0 equivalents of K4[Fe(CN)6], 5.0 equivalents of Cs2CO3, and 0.1 equivalents of Pd[P(tBu)3]2 are dissolved in 2 mL of MeCN. The reaction mixture is microwaved at 100 °C for 30 min at 80 W and 250 psi, and the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pa has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated with 10-30% B solution for 0-30 min, and the solvent is removed under vacuum.

[0335] Compound P12, yield 73%, 1 H NMR(400MHz; CDCl3), δ2.65(s,3H,CH3),6.53(d, 3 J HH =8.6Hz,2H,Ar-H),6.57(s,1H,Ar-H),7.26(s,1H,NH),7.54(d, 3 J HH =8.6Hz,2H,Ar-H), 8.28(s,1H,Ar-H), 9.03(s,1H,Ar-H).

[0336] Example 44 Preparation of compound P13

[0337]

[0338] The general synthetic steps for compound P13 are as follows: 1.0 mmol of substrate H03, 1.2 equivalents of J02, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that the H03 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0339] Compound P13, yield 82%, 1 H NMR (400MHz; CDCl3), δ6.01(s,2H,CH2),6.50(s,1H,Ar-H),7.04(d, 3 J HH =8.6Hz,1H,Ar-H),7.27-7.35(m,3H,Ar-H),8.51(s,1H,Ar-H).

[0340] Example 45 Preparation of compound P14

[0341]

[0342] The general synthetic steps for compound P14 are as follows: 1.0 mmol of substrate H04, 1.2 equivalents of J02, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H04 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0343] Compound P14, yield 61%, 1 H NMR (400MHz; CDCl3), δ6.54(s,1H,Ar-H),7.25(m,1H,Ar-H),7.74(d, 3 J HH =8.6Hz,1H,Ar-H),8.01(s,1H,Ar-H),8.15(m,2H,Ar-H),8.53(s,1H,Ar-H),12.2(s,1H,NH).

[0344] Example 46 Preparation of compound P15

[0345]

[0346] The general synthetic steps for compound P15 are as follows: 1.0 mmol of substrate H05, 1.2 equivalents of J02, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H05 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0347] Compound P15, yield 78%, 1 H NMR(400MHz; CDCl3), δ6.58(m,2H,Ar-H),7.04(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.24(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.73(d, 3 J HH=8.6Hz,1H,Ar-H),7.85(s,1H,Ar-H),7.96(d, 3 J HH =8.6Hz,1H,Ar-H),8.51(s,1H,Ar-H),10.2(s,1H,NH).

[0348] Example 47 Preparation of compound P16

[0349]

[0350] The general synthetic steps for compound P16 are as follows: 1.0 mmol of substrate H06, 1.2 equivalents of J02, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H06 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0351] Compound P16, yield 83%, 1 H NMR (400MHz; CDCl3), δ6.51(s,1H,Ar-H),7.23(m,1H,Ar-H),7.71(d, 3 J HH =8.6Hz,1H,Ar-H),8.18-8.20(m,2H,Ar-H),8.45-8.52(m,2H,Ar-H),12.6(s,1H,NH).

[0352] Example 48 Preparation of compound P17

[0353]

[0354] The general synthetic steps for compound P17 are as follows: 1.0 mmol of substrate H07, 1.2 equivalents of J02, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H07 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0355] Compound P17, yield 41%, 1H NMR(400MHz; CDCl3), δ2.99(t, 3 J HH =7.0Hz,2H,CH2),3.51(t, 3 J HH =7.0Hz,2H,CH2),5.98(s,1H,NH),6.50(s,1H,Ar-H),6.82(d, 3 J HH =8.6Hz,1H,Ar-H),7.24(m,1H,Ar-H),7.42(d, 3 J HH =8.6Hz,1H,Ar-H),7.69(s,1H,Ar-H),8.42(s,1H,Ar-H).

[0356] Example 49 Preparation of compound P18

[0357]

[0358] The general synthetic steps for compound P18 are as follows: 1.0 mmol of substrate H08, 1.2 equivalents of J02, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H08 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0359] Compound P18, yield 86%, 1 H NMR(400MHz; CDCl3), δ2.62(s,3H,CH3),6.24(d, 3 J HH =8.6Hz,1H,Ar-H),6.53(s,1H,Ar-H),6.94(m,1H,Ar-H),7.25-7.30(m,2H,Ar-H+NH),7.61(d, 3 J HH =8.6Hz,1H,Ar-H),8.41(s,1H,Ar-H).

[0360] Example 50 Preparation of compound M01

[0361]

[0362] The general synthetic steps for compound M01 are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J04, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0363] Compound M01, yield 57%, 1 H NMR(400MHz; CDCl3), δ2.64(s,3H,CH3),6.47(d, 3 J HH =8.6Hz,2H,Ar-H),6.52(s,1H,Ar-H),7.26-7.30(m,2H,Ar-H),7.54(d, 3 J HH =8.6Hz,1H,Ar-H),8.44(s,1H,Ar-H).

[0364] Example 51 Preparation of compound MO2

[0365]

[0366] The general synthetic steps for compound MO2 are as follows: 1.0 mmol of substrate H02, 1.2 equivalents of J04, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H02 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0367] Compound M02, yield 65%, 1 H NMR(400MHz; CDCl3), δ2.85(s,3H,CH3),6.55(s,1H,Ar-H),6.80(d, 3 J HH =8.6Hz,1H,Ar-H),7.24(m,1H,Ar-H),7.54(s,1H,NH),7.74(d, 3 J HH =8.6Hz,1H,Ar-H),8.44-8.48(m,2H,Ar-H).

[0368] Example 52 Preparation of compound M03

[0369]

[0370] The general synthetic steps for compound M03 are as follows: 1.0 mmol substrate M02, 1.2 equivalence NCS, in acetonitrile, reacted at 60 °C for 3 h, the solution color changing from pale yellow to deep red. LC-MS detection showed complete disappearance of M02. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, Phase B was 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0371] Compound M03, yield 87%, 1 H NMR (400MHz; CDCl3), δ2.81(s,3H,CH3),6.52(s,1H,Ar-H),7.25(m,1H,Ar-H),7.64(s,1H,NH),8.04(s,1H,Ar-H),8.42(s,1H,Ar-H),8.57(s,1H,Ar-H).

[0372] Example 53 Preparation of compound M04

[0373]

[0374] The general synthetic steps for compound M04 are as follows: 1.0 mmol substrate M02, 1.2 equivalents of NBS, in acetonitrile, reacted at 60 °C for 3 h, the solution color changing from pale yellow to deep red. LC-MS detection showed complete disappearance of M02. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, Phase B was 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0375] Compound M04, yield 73%, 1 H NMR (400MHz; CDCl3), δ2.87(s,3H,CH3),6.50(s,1H,Ar-H),7.28(m,1H,Ar-H),7.68(s,1H,NH),8.24(s,1H,Ar-H),8.48(s,1H,Ar-H),8.66(s,1H,Ar-H).

[0376] Example 54 Preparation of compound M05

[0377]

[0378] The general synthetic steps for compound M04 are as follows: 1.0 mmol substrate M02, 1.2 equivalence NIS, in acetonitrile, reacted at 60 °C for 3 h, the solution color changing from pale yellow to deep red. LC-MS detection showed complete disappearance of M02. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, Phase B was 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0379] Compound M05, yield 57%, 1 H NMR (400MHz; CDCl3), δ2.84(s,3H,CH3),6.49(s,1H,Ar-H),7.23(m,1H,Ar-H),7.62(s,1H,NH),8.18(s,1H,Ar-H),8.40(s,1H,Ar-H),8.51(s,1H,Ar-H).

[0380] Example 55 Preparation of compound Ma

[0381]

[0382] The general synthetic steps for compound Ma are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J05, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0383] Compound Ma, yield 87%. 1 H NMR(400MHz; CDCl3), δ2.65(s,3H,CH3),6.49(d, 3 J HH =8.6Hz,2H,Ar-H),6.54(s,1H,Ar-H),7.22(s,1H,NH),7.51(d, 3 J HH =8.6Hz,2H,Ar-H),7.74(s,1H,Ar-H),8.58(s,1H,Ar-H).

[0384] Example 56 Preparation of compound M06

[0385]

[0386] The general synthetic steps for compound M06 are as follows: 1.0 mmol of substrate Ma, 5.0 equivalents of KOH, 1 M, in methanol, reacted at 100 °C for 3 hours, the solution color changing from pale yellow to deep red. LC-MS showed complete disappearance of the substrate. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, Phase B was 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0387] Compound M06, yield 76%, 1 H NMR (400MHz; CDCl3), δ2.63(s,3H,CH3),6.50-6.57(m,3H,Ar-H),6.64(s,1H,Ar-H),7.27(s,1H,NH),7.54(d, 3 J HH =8.6Hz,2H,Ar-H),7.70(s,1H,Ar-H),11.5(s,1H,OH).

[0388] Example 57 Preparation of compound M07

[0389]

[0390] The general synthetic steps for compound M07 are as follows: 1.0 mmol of substrate Ma is added to an aqueous solution of methylamine at 40% concentration and reacted at 100°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that Ma has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated with 10-30% B solution for 0-30 min, and the solvent is removed under vacuum.

[0391] Compound M07, yield 54%, 1 H NMR(400MHz; CDCl3), δ2.65(s,3H,CH3),2.81(s,3H,CH3),6.45(d, 3 J HH =8.6Hz,2H,Ar-H),6.52(s,1H,Ar-H),6.67(s,1H,Ar-H),7.23(s,1H,NH),7.54(d, 3 J HH =8.6Hz,2H,Ar-H),7.62(s,1H,NH),8.07(s,1H,Ar-H).

[0392] Example 58 Preparation of compound M08

[0393]

[0394] The general synthetic steps for compound M08 are as follows: 1.0 mmol substrate Ma, 5.0 equivalences of Morphine, 2 mL DMF, reacted at 100 °C for 3 h, the solution color changed from pale yellow to deep red. LC-MS detection showed that Ma completely disappeared. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, Phase B was 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0395] Compound M08, yield 42%. 1 H NMR (400MHz; CDCl3), δ2.63(s,3H,CH3),3.70(m,8H,CH2),6.51-6.56(m,3H,Ar-H),6.62(s,1H,Ar-H),7.23(s,1H,NH),7.57(d, 3 J HH =8.6Hz,2H,Ar-H),8.12(s,1H,Ar-H).

[0396] Example 59 Preparation of compound M09

[0397]

[0398] The general synthetic steps of compound M09 are as follows: 1.0 mmol of substrate Pa, 5.0 equivalents of K₄[Fe(CN)₆], 5.0 equivalents of Cs₂CO₃, and 0.1 equivalents of Pd[P(tBu)₃]₂ are dissolved in 2 mL of MeCN. The reaction mixture is microwaved at 100 °C for 30 min at 80 W and 250 psi, and the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pa has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0399] Compound M09, yield 54%, 1 H NMR(400MHz; CDCl3), δ2.62(s,3H,CH3),6.50(d, 3 J HH =8.6Hz,2H,Ar-H),6.56(s,1H,Ar-H),7.24(s,1H,NH),7.53(d, 3 J HH =8.6Hz,2H,Ar-H),8.23(s,1H,Ar-H),8.94(s,1H,Ar-H).

[0400] Example 60 Preparation of compound M10

[0401]

[0402] The general synthetic steps for compound M10 are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J06, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0403] Compound M10, yield 87%, 1 H NMR(400MHz; CDCl3), δ2.70(s,3H,CH3),3.97(s,3H,CH3),6.47(d, 3 J HH =8.6Hz,2H,Ar-H),6.57(s,1H,Ar-H),7.28(s,1H,NH),7.58(d, 3 J HH =8.6Hz,2H,Ar-H),8.53(s,1H,Ar-H),9.08(s,1H,Ar-H).

[0404] Example 61 Preparation of compound O01

[0405]

[0406] The general synthetic steps for compound O01 are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J07, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0407] Compound O01, yield 84%, 1 H NMR (400MHz; CDCl3), δ1.23(t, 3 J HH =7.2Hz,3H,CH3),2.64(s,3H,NCH3),4.30(q,3 J HH =7.2Hz, 2H, CH2), 6.49(d, 3 J HH =8.6Hz,2H,Ar-H),6.52(s,1H,Ar-H),7.20(s,1H,NH),7.52(d, 3 J HH =8.6Hz,2H,Ar-H),8.31(s,1H,Ar-H),9.10(s,1H,Ar-H).

[0408] Example 62 Preparation of compound Oa

[0409]

[0410] The general synthetic steps for compound Oa are as follows: 1.0 mmol of substrate O01 is dissolved in 2 mL of KOH methanol solution (1 M), and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS detection shows that O01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0411] Compound Oa, yield 94%, 1 H NMR(400MHz; CDCl3), δ2.60(s,3H,NCH3),6.44(d, 3 J HH =8.6Hz,2H,Ar-H),6.50(s,1H,Ar-H),7.17(s,1H,NH),7.51(d, 3 J HH =8.6Hz,2H,Ar-H),8.11(s,1H,Ar-H),8.83(s,1H,Ar-H),12.0(s,1H,CO2H).

[0412] Example 63 Preparation of compound Ob

[0413]

[0414] The general synthetic steps for compound Ob are as follows: 1.0 mmol of substrate Oa is dissolved in 2 mL of SOCl2 and reacted at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. The solvent is then removed by vacuum to obtain a dark brown solid, which is used directly in the next reaction.

[0415] Example 64 Preparation of compound O02

[0416]

[0417] The general synthetic steps for compound O02 are as follows: 1.0 mmol of substrate Ob is added to 2 mL of NaBH4 and 1 M pyridine solution, and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is incubated with 10-30% B for 0-30 min, and the solvent is then removed under vacuum.

[0418] Compound O02, yield 91%, 1 H NMR (400MHz; CDCl3), δ2.64(s,3H,NCH3),4.65(s,2H,CH2O),5.20(s,1H,OH),6.49(d, 3 J HH =8.6Hz,2H,Ar-H),6.52(s,1H,Ar-H),7.21(s,1H,NH),7.53(d, 3 J HH =8.6Hz,2H,Ar-H),7.92(s,1H,Ar-H),8.50(s,1H,Ar-H).

[0419] Example 65 Preparation of compound O03

[0420]

[0421] The general synthetic steps for compound O03 are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J08, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0422] Compound O03, yield 47%, 1 H NMR(400MHz; CDCl3), δ2.61(s,3H,NCH3),6.54(d, 3 J HH =8.6Hz,2H,Ar-H),6.58(s,1H,Ar-H),7.25(s,1H,NH),7.59(d, 3 J HH =8.6Hz,2H,Ar-H),8.43(s,1H,Ar-H),9.26(s,1H,Ar-H).

[0423] Example 66 Preparation of compound Oc

[0424]

[0425] The general synthetic steps for compound Oc are as follows: 1.0 mmol of substrate H02, 1.2 equivalents of J07, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H02 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0426] Compound Oc, yield 59%. 1 H NMR(400MHz; CDCl3), δ1.33(t, 3 J HH =7.2Hz,3H,CH3),2.84(s,3H,NCH3),4.33(q, 3 J HH =7.2Hz,2H,CH2),6.57(s,1H,Ar-H),6.85(d, 3 J HH =8.6Hz,1H,Ar-H),7.24(s,1H,NH),7.82(d, 3 J HH =8.6Hz,1H,Ar-H),8.37(s,1H,Ar-H),8.49(s,1H,Ar-H),9.09(s,1H,Ar-H).

[0427] Example 67 Preparation of compound Od

[0428]

[0429] The general synthetic steps for compound Od are as follows: 1.0 mmol of substrate Oc is dissolved in 2 mL of KOH methanol solution (1 M), and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS detection shows that Oc has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is incubated with 10-30% B solution for 0-30 min, and the solvent is then removed under vacuum.

[0430] Compound Od, yield 97%. 1H NMR(400MHz; CDCl3), δ2.86(s,3H,NCH3),6.53(s,1H,Ar-H),6.80(d, 3 J HH =8.6Hz,1H,Ar-H),7.67(s,1H,NH),7.75(d, 3 J HH =8.6Hz,1H,Ar-H),8.13(s,1H,Ar-H),8.39(s,1H,Ar-H),8.87(s,1H,Ar-H),12.5(s,1H,CO2H).

[0431] Example 68 Preparation of compound Oe

[0432]

[0433] The general synthetic steps for compound Oe are as follows: 1.0 mmol of substrate Od is dissolved in 2 mL of SOCl2 and reacted at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. The solvent is then removed by vacuum to obtain a dark brown solid, which is used directly in the next reaction.

[0434] Example 69 Preparation of compound O04

[0435]

[0436] The general synthetic steps for compound O04 are as follows: 1.0 mmol of substrate Oe is added to 2 mL of concentrated ammonia solution (28%), and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. 10-30% B is added, and the reaction is carried out for 0-30 min, after which the solvent is dried.

[0437] Compound O04, yield 93%, 1 H NMR(400MHz; CDCl3), δ2.81(s,3H,NCH3),6.54(s,1H,Ar-H),6.79(d, 3 J HH =8.6Hz,1H,Ar-H),7.28(s,1H,NH),7.78-7.80(m,3H,2NH+Ar-H),8.35(s,1H,Ar-H),8.48(s,1H,Ar-H),9.04(s,1H,Ar-H).

[0438] Example 70 Preparation of compound O05

[0439]

[0440] The general synthetic steps for compound O05 are as follows: 1.0 mmol of substrate Oe is added to 2 mL of 40% methylamine aqueous solution, and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. 10-30% B is added, and the reaction is carried out for 0-30 min, after which the solvent is dried.

[0441] Compound O05, yield 97%, 1 H NMR (400MHz; CDCl3), δ2.80(s,3H,NCH3),2.83(s,3H,NCH3),6.57(s,1H,Ar-H),6.85(d, 3 J HH =8.6Hz,1H,Ar-H),7.68(s,1H,NH),7.75(d, 3 J HH =8.6Hz,1H,Ar-H),8.20(s,1H,NH),8.33(s,1H,Ar-H),8.41(s,1H,Ar-H),9.09(s,1H,Ar-H).

[0442] Example 71 Preparation of compound O06

[0443]

[0444] The general synthetic steps for compound O06 are as follows: 1.0 mmol of substrate Oe, 5 equivalents of dimethylamine, 2 mL of DMF, and reaction at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. 10-30% B is added, and the reaction is carried out for 0-30 min, after which the solvent is dried.

[0445] Compound O06, yield 90%, 1 H NMR (400MHz; CDCl3), δ2.81(s,3H,NCH3),2.89(s,3H,NCH3),2.94(s,3H,NCH3),6.51(s,1H,Ar-H),6.80(d, 3 J HH =8.6Hz,1H,Ar-H),7.60(s,1H,NH),7.71(d, 3 J HH =8.6Hz,1H,Ar-H),8.29(s,1H,Ar-H),8.47(s,1H,Ar-H),9.00(s,1H,Ar-H).

[0446] Example 72 Preparation of compound O07

[0447]

[0448] The general synthetic steps for compound O07 are as follows: 1.0 mmol of substrate Oe, 5 equivalents of diethylamine, 2 mL of DMF, and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. 10-30% B is added, and the reaction is carried out for 0-30 min, after which the solvent is dried.

[0449] Compound O07, yield 94%, 1 H NMR(400MHz; CDCl3), δ1.20(t, 3 J HH =7.0Hz,6H,CH3),2.80(s,3H,NCH3),3.21(q, 3 J HH =7.0Hz,4H,CH2),6.53(s,1H,Ar-H),6.81(d, 3 J HH =8.6Hz,1H,Ar-H),7.63(s,1H,NH),7.74(d, 3 J HH =8.6Hz,1H,Ar-H),8.32(s,1H,Ar-H),8.41(s,1H,Ar-H),8.97(s,1H,Ar-H).

[0450] Example 73 Preparation of compound O08

[0451]

[0452] The general synthetic steps for compound O08 are as follows: 1.0 mmol of substrate Oe, 5 equivalents of cyclopentanediol, 2 mL of DMF, and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. 10-30% B is added, and the reaction is carried out for 0-30 min, after which the solvent is dried.

[0453] Compound O08, yield 91%, 1 H NMR (400MHz; CDCl3), δ1.97(m,4H,CH2),2.84(s,3H,NCH3),3.52(m,4H,CH2),6.55(s,1H,Ar-H),6.85(d,3 J HH =8.6Hz,1H,Ar-H),7.65(s,1H,NH),7.78(d, 3 J HH =8.6Hz,1H,Ar-H),8.35(s,1H,Ar-H),8.48(s,1H,Ar-H),8.99(s,1H,Ar-H).

[0454] Example 74 Preparation of compound O09

[0455]

[0456] The general synthetic steps for compound O09 are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J09, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0457] Compound O09, yield 58%, 1 H NMR(400MHz; CDCl3), δ2.65(s,3H,CH3),6.47(d, 3 J HH =8.6Hz, 2H, Ar-H), 6.51(d, 3 J HH =8.6Hz,1H,Ar-H),7.26-7.29(m,2H,Ar-H+NH),7.55(d, 3 J HH =8.6Hz,2H,Ar-H),8.11(m,1H,Ar-H).

[0458] Example 75 Preparation of compound O10

[0459]

[0460] The general synthetic steps for compound O10 are as follows: 1.0 mmol of substrate H02, 1.2 equivalents of J09, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0461] Compound O10, yield 47%, 1 H NMR (400MHz; CDCl3), δ2.84(s,3H,CH3),6.51(s,1H,Ar-H),6.87(d, 3 J HH =8.6Hz,1H,Ar-H),7.21(m,1H,Ar-H),7.60(s,1H,NH),7.72(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.11(d, 3 J HH =8.6Hz,1H,Ar-H),8.41(s,1H,Ar-H).

[0462] Example 76 Preparation of compound Q01

[0463]

[0464] The general synthetic steps for compound Q01 are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J10, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0465] Compound Q01, yield 64%, 1 H NMR(400MHz; CDCl3), δ2.61(s,3H,CH3),6.44(d, 3 J HH =8.6Hz,2H,Ar-H),6.52(s,1H,Ar-H),7.20(s,1H,NH),7.51(d, 3 J HH=8.6Hz,1H,Ar-H),8.42(s,1H,Ar-H),9.25(s,1H,Ar-H).

[0466] Example 77 Preparation of compound Q02

[0467]

[0468] The general synthetic steps for compound Q02 are as follows: 1.0 mmol of substrate H05, 1.2 equivalents of J11, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H05 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0469] Compound Q02, yield 64%, 1 H NMR(400MHz; CDCl3), δ6.52(m,2H,Ar-H),7.01(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.73(d, 3 J HH =8.6Hz,1H,Ar-H),7.85(s,1H,Ar-H),7.90(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.14(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.22(d, 3 J HH =8.6Hz,1H,Ar-H),10.2(s,1H,NH).

[0470] Example 78 Preparation of compound Pha

[0471]

[0472] The general synthetic steps for compound Pha are as follows: 1.0 mmol of substrate H01, 1.2 equivalents of J12, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0473] Compound Pha, yield 52%. 1 H NMR(400MHz; CDCl3), δ2.62(s,3H,CH3),3.81(s,3H,CH3),6.46(d, 3 J HH =8.6Hz,2H,Ar-H),7.09(s,1H,Ar-H),7.25(s,1H,NH),7.55(d, 3 J HH =8.6Hz, 2H, Ar-H), 7.90(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.16(d, 3 J HH =8.6Hz,1H,Ar-H),8.31(s,1H,Ar-H).

[0474] Example 79 Preparation of compound Phb

[0475]

[0476] The general synthetic steps for compound Phb are as follows: 1.0 mmol of substrate Pha is dissolved in 2 mL of KOH methanol solution (1 M), and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS detection shows that Pha has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is incubated with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0477] Compound Phb, yield 52%, 1 H NMR(400MHz; CDCl3), δ2.60(s,3H,CH3),6.43(d, 3 J HH =8.6Hz,2H,Ar-H),7.02(s,1H,Ar-H),7.21(s,1H,NH),7.51(d, 3 JHH =8.6Hz, 2H, Ar-H), 7.93(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.32(d, 3 J HH =8.6Hz,1H,Ar-H),8.51(s,1H,Ar-H).

[0478] Example 80 Preparation of compound Phc

[0479]

[0480] The general synthetic procedure for compound Phb is as follows: 1.0 mmol of substrate Phb is dissolved in 2 mL of SOCl2 and reacted at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. The reaction mixture is then dried under vacuum and used directly.

[0481] Example 81 Preparation of compound Ph01

[0482]

[0483] The general synthetic steps for compound Ph01 are as follows: 1.0 mmol of substrate Phc is added to 5.0 equivalents of Cs₂CO₃ and 5.0 equivalents of FC₂H₄NH₂·HCl, dissolved in 2 mL of acetonitrile. The reaction mixture is reacted at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0484] Compound Ph01, yield 52%, 1 H NMR(400MHz; CDCl3), δ2.64(s,3H,CH3),3.32(dt, 3 J HF =25Hz, 3 J HH =7.1Hz,2H,CH2),4.35(dt, 3 J HF =46Hz, 3 J HH =7.1Hz, 2H, CH2), 6.46(d, 3 J HH =8.6Hz,2H,Ar-H),7.12(s,1H,Ar-H),7.25(s,1H,NH),7.54(d, 3 J HH =8.6Hz, 2H, Ar-H), 7.99(d,3 J HH =8.6Hz, 1H, Ar-H), 8.12(d, 3 J HH =8.6Hz,1H,Ar-H),8.30(s,1H,Ar-H),8.44(s,1H,NH).

[0485] Example 82 Preparation of compound Phd

[0486]

[0487] The general synthetic steps for compound Phd are as follows: 1.0 mmol of substrate H01a, 1.2 equivalents of J13, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H01a has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0488] Compound Phd, yield 39%, 1 H NMR (400MHz; CDCl3), δ1.41(s,9H,CH3),3.28(s,3H,CH3),7.17(s,1H,Ar-H),7.59(d, 3 J HH =8.6Hz,1H,Ar-H),7.73-7.84(m,5H,Ar-H),8.27(s,1H,Ar-H).

[0489] Example 83 Preparation of compound Phe

[0490]

[0491] The general synthetic steps for compound Phe are as follows: 1.0 mmol of substrate Phd and 0.5 equimolar CuCl are added to the reaction solution in solid form. The mixture is then reacted in 2 mL of ethanolamine at 105 °C for 12 h, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that Phd has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is incubated with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0492] Compound Phe, yield 38%, 1H NMR(400MHz; CDCl3), δ1.40(s,9H,CH3),3.21(s,3H,CH3),3.51(t, 3 J HH =7.1Hz,2H,CH2),3.59(t, 3 J HH =7.1Hz,2H,CH2),4.90(s,1H,OH),6.58(d, 3 J HH =8.6Hz,1H,Ar-H),7.10(s,1H,Ar-H),7.49(s,1H,Ar-H),7.74-7.84(m,5H,Ar-H),9.50(s,1H,NH).

[0493] Example 84 Preparation of compound Phf

[0494]

[0495] The general synthetic steps for compound Phf are as follows: 1.0 mmol of substrate Phe, 0.2 equivalents of imidazole, and 5.0 equivalents of triethylamine are added to 5 mL of CH₂Cl₂ at 0 °C. 2.0 equivalents of SOCl₂ are added, and the reaction proceeds for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of Phe. After filtration, the reaction mixture is directly separated by silica gel column chromatography. Phase A is hexane, and phase B is ethyl acetate. The chromatography cycle is 0-100% B, 0-30 min, and the solvent is removed under vacuum.

[0496] Compound Phf, yield 27%, 1 H NMR(400MHz; CDCl3), δ1.40(s,9H,CH3),3.21(m,5H,CH3+CH2),3.70(t, 3 J HH =7.1Hz, 2H, CH2), 6.58(d, 3 J HH =8.6Hz,1H,Ar-H),7.10(s,1H,Ar-H),7.49(s,1H,Ar-H),7.74-7.84(m,5H,Ar-H).

[0497] Example 85 Preparation of compound Phf

[0498]

[0499] The general synthetic steps for compound PhO2 are as follows: 1.0 mmol of substrate Phf and 5.0 equivalences of CsF are added to 5 mL of DMF and heated to 105 °C for 2 hours, during which the solution color changes from pale yellow to deep red. 50 mL of water is added, and the mixture is extracted with 3 × 50 mL of ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate. The solvent is removed to obtain the product.

[0500] Compound PhO2, yield 97%, 1 H NMR(400MHz; CDCl3), δ2.62(s,3H,CH3),3.21(dt, 2 J HF =46Hz, 3 J HH =7.1Hz, 2H, CH2), 4.29(dt, 3 J HF =25Hz, 3 J HH =7.1Hz, 2H, CH2), 6.55(d, 3 J HH =8.6Hz, 2H, Ar-H), 6.61(d, 3 J HH =8.6Hz,1H,Ar-H),7.10(s,1H,Ar-H),7.30(s,2H,NH),7.49(s,1H,Ar-H),7.53(d, 3 J HH =8.6Hz, 2H, Ar-H), 7.71(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0501] Example 86 Preparation of compound PhO3

[0502]

[0503] The general synthetic steps for compound PhO3 are as follows: 1.0 mmol of substrate HO1, 1.2 equivalents of J14, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that HO1 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0504] Compound PhO3, yield 79%, 1H NMR(400MHz; CDCl3), δ2.63(s,3H,CH3),6.46(d, 3 J HH =8.6Hz,2H,Ar-H),7.11(s,1H,Ar-H),7.22(s,1H,NH),7.50(s,1H,Ar-H),7.61(d, 3 J HH =8.6Hz,2H,Ar-H),7.98(s,1H,Ar-H).

[0505] Example 87 Preparation of compound Py21

[0506]

[0507] The general synthetic steps for compound Py21 are as follows: 1.0 mmol of substrate HO2, 1.2 equivalents of J15, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that HO2 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0508] Compound Py21, yield 67%, 1 H NMR(400MHz; CDCl3), δ2.81(s,3H,CH3),6.78(d, 3 J HH =8.6Hz,1H,Ar-H),7.11-7.14(m,2H,Ar-H),7.40(m,1H,Ar-H),7.51(d, 3 J HH =8.6Hz,1H,Ar-H),7.60(s,1H,NH),7.72(d, 3 J HH =8.6Hz,1H,Ar-H),8.39(s,1H,Ar-H).

[0509] Example 88 Preparation of compound Py22

[0510]

[0511] The general synthetic steps for compound Py22 are as follows: 1.0 mmol of substrate H02, 1.2 equivalents of J16, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that the H02 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0512] Compound Py22, yield 58%, 1 H NMR(400MHz; CDCl3), δ2.79(s,3H,CH3),6.76(d, 3 J HH =8.6Hz,1H,Ar-H),7.11(s,1H,Ar-H),7.63(m,2H,Ar-H),7.75(d, 3 J HH =8.6Hz,1H,Ar-H),7.91(s,1H,Ar-H),8.43(s,1H,Ar-H).

[0513] Example 89 Preparation of compound Py23

[0514]

[0515] The general synthetic steps for compound Py23 are as follows: 1.0 mmol of substrate H02, 1.2 equivalents of J17, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that the H02 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0516] Compound Py23, yield 71%, 1 H NMR(400MHz; CDCl3), δ2.86(s,3H,CH3),6.85(d, 3 J HH =8.6Hz,1H,Ar-H),7.18(s,1H,Ar-H),7.64(m,1H,Ar-H),7.70(s,1H,NH),7.84(d, 3 J HH=8.6Hz,1H,Ar-H),7.96(s,1H,Ar-H),8.49(s,1H,Ar-H).

[0517] Example 90 Preparation of compound Py24

[0518]

[0519] The general synthetic steps for compound Py24 are as follows: 1.0 mmol of substrate H2O2, 1.2 equivalents of J14, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H2O2 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0520] Compound Py24, yield 77%, 1 H NMR(400MHz; CDCl3), δ2.88(s,3H,CH3),6.87(d, 3 J HH =8.6Hz,1H,Ar-H),7.19(s,1H,Ar-H),7.65(d, 3 J HH =8.6Hz,1H,Ar-H),7.71(s,1H,NH),7.87(d, 3 J HH =8.6Hz,1H,Ar-H),7.99(s,1H,Ar-H),8.52(s,1H,Ar-H).

[0521] Example 91 Preparation of compound Py25

[0522]

[0523] The general synthetic steps for compound Py25 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J19, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0524] Compound Py25, yield 69%,1 H NMR (400MHz; CDCl3), δ2.65(s,3H,CH3),5.85(s,1H,NH),7.11(s,1H,Ar-H),7.22(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.64(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.71(d, 3 J HH =8.6Hz,1H,Ar-H),7.80(s,1H,Ar-H),7.95-8.05(m,2H,Ar-H).

[0525] Example 92 Preparation of compound Py26

[0526]

[0527] The general synthetic steps for compound Py26 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J14, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0528] Compound Py26, yield 62%, 1 H NMR (400MHz; CDCl3), δ2.65(s,3H,CH3),5.85(s,1H,NH),7.11(s,1H,Ar-H),7.22(d, 3 J HH =8.6Hz,1H,Ar-H),7.52(m,1H,Ar-H),7.80(s,1H,Ar-H),7.91(m,1H,Ar-H),8.00(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0529] Example 93 Preparation of compound Py27

[0530]

[0531] The general synthetic steps for compound Py27 are as follows: 1.0 mmol substrate Py26, 5.0 equivalents of FC2H4OH, and 3.0 equivalents of KN(TMS)2 (1M, THF) were added to THF and reacted at 60°C for 3 hours, during which the solution color changed from pale yellow to deep red. LC-MS analysis showed complete disappearance of Py26. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, and Phase B was 0.025% TFA acetonitrile solution, 10-30% B, for 0-30 min, with the solvent removed under vacuum.

[0532] Compound Py27, yield 53%, 1 H NMR(400MHz; CDCl3), δ2.59(s,3H,CH3),4.07(dt, 3 J HF =25Hz, 3 J HH =7.1Hz, 2H, CH2), 4.57(dt, 2 J HF =46Hz, 3 J HH =7.1Hz,2H,CH2),5.80(s,1H,NH),7.10(s,1H,Ar-H),7.25(d, 3 J HH =8.6Hz,1H,Ar-H),7.62(s,1H,Ar-H),7.82(s,1H,Ar-H),7.93(s,1H,Ar-H),8.05(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0533] Example 94 Preparation of compound Py28

[0534]

[0535] The general synthetic steps for compound Py28 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J30, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0536] Compound Py28, yield 51%, 1H NMR (400MHz; CDCl3), δ2.69(s,3H,CH3),3.83(s,3H,CH3),5.75(s,1H,NH),7.10(s,1H,Ar-H),7.21(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.61(d, 3 J HH =8.6Hz,1H,Ar-H),7.81(s,1H,Ar-H),8.04(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.20(d, 3 J HH =8.6Hz,1H,Ar-H),8.47(s,1H,Ar-H).

[0537] Example 95 Preparation of compound Py28a

[0538]

[0539] The general synthetic steps for compound Py28a are as follows: 1.0 mmol of substrate Py28 is dissolved in 2 mL of KOH methanol solution (1 M), and the reaction is carried out at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS detection shows that Py28 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0540] Compound Py28a, yield 73%, 1 H NMR (400MHz; CDCl3), δ2.60(s,3H,CH3),5.81(s,1H,NH),7.10(s,1H,Ar-H),7.25(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.70(d, 3 J HH =8.6Hz,1H,Ar-H),7.81(s,1H,Ar-H),7.99(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.42(d, 3 J HH =8.6Hz,1H,Ar-H),8.57(s,1H,Ar-H),12.5(s,1H,CO2H).

[0541] Example 96 Preparation of compound Py28b

[0542]

[0543] The general synthetic steps for compound Py28b are as follows: 1.0 mmol of substrate Py28a is dissolved in 2 mL of SOCl2 and reacted at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. The reaction mixture is then dried under vacuum and used directly.

[0544] Example 97 Preparation of compound Py29

[0545]

[0546] The general synthetic steps for compound Py29 are as follows: 1.0 mmol of substrate Py28b is added to 5.0 equivalents of Cs₂CO₃ and 5.0 equivalents of MeNH₂, dissolved in 2 mL of acetonitrile. The reaction mixture is reacted at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0547] Compound Py29, yield 44%, 1 H NMR (400MHz; CDCl3), δ2.62(s,3H,CH3),2.80(s,3H,CH3),5.82(s,1H,NH),7.12(s,1H,Ar-H),7.24(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.70(d, 3 J HH =8.6Hz,1H,Ar-H),7.81(s,1H,Ar-H),8.01(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.21(d, 3 J HH =8.6Hz,1H,Ar-H),8.26(s,1H,NH),8.40(s,1H,Ar-H).

[0548] Example 98 Preparation of compound Py30

[0549]

[0550] The general synthetic steps for compound Py30 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J18, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0551] Compound Py30, yield 41%, 1 H NMR (400MHz; CDCl3), δ2.72(s,3H,CH3),5.94(s,1H,NH),7.17(s,1H,Ar-H),7.32(d, 3 J HH =8.6Hz,1H,Ar-H),7.85(s,1H,Ar-H),7.91(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.07(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.40(d, 3 J HH =8.6Hz,1H,Ar-H),8.67(s,1H,Ar-H).

[0552] Example 99 Preparation of compound Py31

[0553]

[0554] The general synthetic steps for compound Py31 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J23, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0555] Compound Py31, yield 21%, 1 H NMR (400MHz; CDCl3), δ2.66(s,3H,CH3),5.84(s,1H,NH),7.13(s,1H,Ar-H),7.26(d, 3 JHH =8.6Hz,1H,Ar-H),7.80(s,1H,Ar-H),7.97(d, 3 J HH =8.6Hz,1H,Ar-H),8.27(s,1H,Ar-H),8.79(s,1H,Ar-H).

[0556] Example 100 Preparation of compound Py32

[0557]

[0558] The general synthetic steps for compound Py32 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J25, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0559] Compound Py32, yield 45%, 1 H NMR (400MHz; CDCl3), δ2.61(s,3H,CH3),3.83(s,3H,CH3),5.80(s,1H,NH),7.11(s,1H,Ar-H),7.22(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.45(d, 3 J HF =8.0Hz,1H,Ar-H),7.80(s,1H,Ar-H),8.05(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.41(d, 3 J HF =5.0Hz, 1H, Ar-H).

[0560] Example 101 Preparation of compound Py33

[0561]

[0562] The general synthetic steps for compound Py33 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J26, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0563] Compound Py33, yield 24%, 1 H NMR (400MHz; CDCl3), δ2.44(s,3H,CH3),2.63(s,3H,CH3),5.86(s,1H,NH),7.13(s,1H,Ar-H),7.25(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.41(d, 3 J HF =8.0Hz,1H,Ar-H),7.79(s,1H,Ar-H),8.01(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.31(d, 3 J HF =5.0Hz, 1H, Ar-H).

[0564] Example 102 Preparation of compound Py34

[0565]

[0566] The general synthetic steps for compound Py34 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J27, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0567] Compound Py34, yield 36%, 1 H NMR (400MHz; CDCl3), δ2.47(s,3H,CH3),2.66(s,3H,CH3),5.81(s,1H,NH),7.11(s,1H,Ar-H),7.21(d,3 J HH =8.6Hz, 1H, Ar-H), 7.61(d, 3 J HH =8.6Hz,1H,Ar-H),7.74(s,1H,Ar-H),8.04(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.11(d, 3 J HH =8.6Hz,1H,Ar-H),8.28(s,1H,Ar-H).

[0568] Example 103 Preparation of compound Py35

[0569]

[0570] The general synthetic steps for compound Py35 are as follows: 1.0 mmol of substrate H10, 1.2 equivalents of J29, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H10 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0571] Compound Py35, yield 18%, 1 H NMR (400MHz; CDCl3), δ2.73(s,3H,CH3),5.91(s,1H,NH),7.18(s,1H,Ar-H),7.31(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.65(d, 3 J HF =8.0Hz,1H,Ar-H),7.86(s,1H,Ar-H),8.09(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.67(d, 3 J HF =8.0Hz, 1H, Ar-H).

[0572] Example 104 Preparation of compound Pf01

[0573]

[0574] The general synthetic steps for compound Pf01 are as follows: 1.0 mmol of substrate H09, 1.2 equivalents of J18, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H09 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0575] Compound Pf01, yield 77%, 1 H NMR (400MHz; CDCl3), δ2.70(s,3H,CH3),5.90(s,1H,NH),7.11(s,1H,Ar-H),7.54(m,1H,Ar-H),7.89(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.17(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.41(d, 3 J HH =8.6Hz,1H,Ar-H),8.75(s,1H,Ar-H).

[0576] Example 105 Preparation of compound PfO2

[0577]

[0578] The general synthetic steps for compound PfO2 are as follows: 1.0 mmol of substrate H09, 1.2 equivalents of J17, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H09 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0579] Compound PfO2, yield 77%, 1 H NMR (400MHz; CDCl3), δ2.75(s,3H,CH3),5.93(s,1H,NH),7.13(s,1H,Ar-H),7.50-7.70(m,2H,Ar-H),7.85(s,1H,Ar-H),8.12(d, 3 J HH=8.6Hz, 1H, Ar-H).

[0580] Example 106 Preparation of compound PfO3

[0581]

[0582] The general synthetic steps for compound PfO3 are as follows: 1.0 mmol of substrate H12, 1.2 equivalents of J19, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H12 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0583] Compound PfO3, yield 69%, 1 H NMR (400MHz; CDCl3), δ2.65(s,3H,CH3),5.85(s,1H,NH),7.11(s,1H,Ar-H),7.67-7.70(m,2H,Ar-H),7.82(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.94(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.11(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0584] Example 107 Preparation of compound Pf04a

[0585]

[0586] The general synthetic steps for compound Pf04a are as follows: 1.0 mmol of substrate H12, 1.2 equivalents of J20, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H12 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0587] Compound Pf04a, yield 79%, 1H NMR (400MHz; CDCl3), δ2.64(s,3H,CH3),5.99(s,1H,NH),7.11(s,1H,Ar-H),7.62(m,1H,Ar-H),7.81(s,1H,Ar-H),8.09(d, 3 J HH =8.6Hz,1H,Ar-H),8.41(s,1H,Ar-H).

[0588] Example 108 Preparation of compound PfO4

[0589]

[0590] The general synthetic steps of compound PfO4 are as follows: 1.0 mmol of substrate PfO4a, 5.0 equivalents of K4[Fe(CN)6], 5.0 equivalents of Cs2CO3, and 0.1 equivalents of Pd[P(tBu)3]2 are dissolved in 2 mL of MeCN. The reaction mixture is microwaved at 100 °C for 30 min at 80 W and 250 psi, and the solution color changes from pale yellow to deep red. LC-MS detection shows that PfO4a has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated for 0–30 min, and the solvent is removed by vacuum drying.

[0591] Compound PfO4, yield 54%, 1 H NMR (400MHz; CDCl3), δ2.70(s,3H,CH3),5.95(s,1H,NH),7.10(s,1H,Ar-H),7.60(m,1H,Ar-H),8.07-8.15(m,3H,Ar-H).

[0592] Example 109 Preparation of compound Pf05a

[0593]

[0594] The general synthetic steps for compound Pf05a are as follows: 1.0 mmol of substrate H12, 1.2 equivalents of J21, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H12 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0595] Compound Pf05a, yield 88%,1 H NMR (400MHz; CDCl3), δ2.68(s,3H,CH3),5.98(s,1H,NH),7.12(s,1H,Ar-H),7.52(s,1H,Ar-H),7.63(d, 3 J HH =8.6Hz,1H,Ar-H),8.10-8.15(m,2H,Ar-H),10.1(s,1H,CHO),16.5(s,1H,OH).

[0596] Example 110 Preparation of compound Pf05

[0597]

[0598] The general synthetic steps for compound PfO5 are as follows: 1.0 mmol of substrate PfO5a, 5 equivalents of NH2-OSO3H, and 5 equivalents of triethylamine are reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the substrate. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0599] Compound Pf05, yield 88%, 1 H NMR (400MHz; CDCl3), δ2.67(s,3H,CH3),5.93(s,1H,NH),7.10(s,1H,Ar-H),7.51(s,1H,Ar-H),7.60(d, 3 J HH =8.6Hz,1H,Ar-H),7.72(s,1H,Ar-H),8.11(d, 3 J HH =8.6Hz,1H,Ar-H),10.5(s,1H,OH).

[0600] Example 111 Preparation of compound Pf06

[0601]

[0602] The general synthetic steps for compound PfO6 are as follows: 1.0 mmol of substrate H12, 1.2 equivalents of J24, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H12 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0603] Compound Pf06, yield 51%, 1 H NMR (400MHz; CDCl3), δ2.77(s,3H,CH3),6.05(s,1H,NH),7.10(s,1H,Ar-H),7.60(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.73(d, 3 J HH =8.6Hz,1H,Ar-H),7.91(s,1H,Ar-H),8.04(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.16(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0604] Example 112 Preparation of compound PfO3a

[0605]

[0606] The general synthetic steps for compound Pf03a are as follows: 1.0 mmol of substrate H14, 1.2 equivalents of J16, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H14 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0607] Compound Pf03a, yield 57%, 1 H NMR (400MHz; CDCl3), δ2.69(s,3H,CH3),5.96(s,1H,NH),7.12(s,1H,Ar-H),7.61(d, 3 J HH=8.6Hz, 1H, Ar-H), 7.74(d, 3 J HH =8.6Hz,1H,Ar-H),7.95(m,2H,Ar-H),8.71(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0608] Example 113 Preparation of compound PfO3b

[0609]

[0610] The general synthetic steps for compound PfO3b are as follows: 1.0 mmol of substrate PfO3a, 5.0 equivalents of Boc2O, and 5.0 equivalents of triethylamine are reacted in acetonitrile at 20°C for 3 hours, during which the solution color changes from pale yellow to deep yellow. LC-MS analysis shows that PfO3a has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0611] Compound Pf03b, yield 89%, 1 H NMR (400MHz; CDCl3), δ1.41(s,9H,CH3),2.64(s,3H,CH3),7.13(s,1H,Ar-H),7.65(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.76(d, 3 J HH =8.6Hz,1H,Ar-H),7.92(s,1H,Ar-H),8.73(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.91(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0612] Example 114 Preparation of compound Py26a

[0613]

[0614] The general synthetic steps for compound Py26a are as follows: 1.0 mmol of substrate H13, 1.2 equivalents of J23, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H13 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0615] Compound Py26a, yield 63%, 1 H NMR (400MHz; CDCl3), δ2.72(s,3H,CH3),5.86(s,1H,NH),7.17(s,1H,Ar-H),7.32(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.86(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.07(d, 3 J HH =8.6Hz,1H,Ar-H),8.27(s,1H,Ar-H),8.79(s,1H,Ar-H).

[0616] Example 115 Preparation of compound Py26b

[0617]

[0618] The general synthetic steps for compound Py26b are as follows: 1.0 mmol of substrate Py26a, 5.0 equivalents of Boc2O, and 5.0 equivalents of triethylamine are reacted in acetonitrile at 20°C for 3 hours, during which the solution color changes from pale yellow to deep yellow. LC-MS analysis shows that Py35a has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0619] Compound Py26b, yield 76%, 1 H NMR (400MHz; CDCl3), δ1.40(s,9H,CH3),2.66(s,3H,CH3),7.11(s,1H,Ar-H),8.02(d, 3 J HH =8.6Hz,1H,Ar-H),8.20-8.25(m,3H,Ar-H),8.81(s,1H,Ar-H).

[0620] Example 116 Preparation of compound Py26c

[0621]

[0622] The general synthetic steps for compound Py26c are as follows: 1.0 mmol of substrate H13, 1.2 equivalents of J20, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H13 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0623] Compound Py26c, yield 59%, 1 H NMR (400MHz; CDCl3), δ2.71(s,3H,CH3),5.81(s,1H,NH),7.13(s,1H,Ar-H),7.21(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,2H,Ar-H),7.99(d, 3 J HH =8.6Hz,1H,Ar-H),8.48(s,1H,Ar-H).

[0624] Example 117 Preparation of compound Py26d

[0625]

[0626] The general synthetic steps for compound Py26d are as follows: 1.0 mmol of substrate Py26c, 0.2 equivalents of CuI, and 3.0 equivalents of Ph2Se2 are reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that Py26c has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0627] Compound Py26d, yield 71%. 1H NMR (400MHz; CDCl3), δ2.74(s,3H,CH3),5.91(s,1H,NH),7.11(s,1H,Ar-H),7.30-7.35(m,6H,Ph+Ar-H),7.80-7.85(m,2H,Ar-H),8.00-8.05(m,2H,Ar-H).

[0628] Example 118 Preparation of compound Py26e

[0629]

[0630] The general synthetic steps for compound Py26e are as follows: 1.0 mmol of substrate Py26d, 5 equivalents of Boc2O, in acetonitrile, reacted at 20°C for 3 hours, the solution color changing from pale yellow to deep red. LC-MS analysis showed complete disappearance of Py26d. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, Phase B was 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0631] Compound Py26e, yield 91%, 1 H NMR (400MHz; CDCl3), δ1.40(s,9H,CH3),2.67(s,3H,CH3),7.15(s,1H,Ar-H),7.30-7.35(m,5H,Ph),7.79(s,1H,Ar-H),8.00(s,1H,Ar-H),8.10(d, 3 J HH =8.6Hz,1H,Ar-H),8.30-8.35(m,2H,Ar-H).

[0632] Example 119 Preparation of compound Py26f

[0633]

[0634] The general synthetic steps for compound Py26f are as follows: 1.0 mmol of substrate Py26e, 5 equivalents of KHSO5 / K2S2O8, in acetonitrile, reacted at 60 °C for 3 h, the solution color changing from pale yellow to deep red. LC-MS analysis showed complete disappearance of Py26e. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, Phase B was 0.025% TFA acetonitrile solution, 10-30% B, 0-30 min, solvent dried under vacuum.

[0635] Compound Py26f, yield 63%, 1H NMR (400MHz; CDCl3), δ1.42(s,9H,CH3),2.69(s,3H,CH3),7.16(s,1H,Ar-H),7.35-7.40(m,5H,Ph),7.81(s,1H,Ar-H),8.05(s,1H,Ar-H),8.12(d, 3 J HH =8.6Hz,1H,Ar-H),8.35-8.40(m,2H,Ar-H).

[0636] Example 120 Preparation of compound Py26

[0637]

[0638] The general synthetic steps of the compound were as follows: 1.0 mmol of substrate Py26b and 5 equivalents of CsF were added to DMF and reacted at 120 °C for 3 h, during which the solution color changed from pale yellow to deep red. LC-MS analysis showed complete disappearance of the substrate. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, and Phase B was 0.025% TFA acetonitrile solution. The reaction mixture was then subjected to 10-30% B solution for 0-30 min, and the solvent was removed under vacuum.

[0639] Example 121 Preparation of compound Py26

[0640]

[0641] The general synthetic procedure for the compound was as follows: 1.0 mmol of substrate Py26f and 5 equimolar amounts of CsF were added to DMF and reacted at 120 °C for 3 h, during which the solution color changed from pale yellow to deep red. LC-MS analysis showed complete disappearance of the substrate. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, and Phase B was 0.025% TFA acetonitrile solution. The reaction mixture was then subjected to 10-30% B solution for 0-30 min, and the solvent was removed under vacuum.

[0642] Example 122 Preparation of compound Pf04a

[0643]

[0644] The general synthetic steps for compound Pf04a are as follows: 1.0 mmol of substrate H14, 1.2 equivalents of J20, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H14 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0645] Compound Pf04a, yield 61%, 1 H NMR (400MHz; CDCl3), δ2.74(s,3H,CH3),5.98(s,1H,NH),7.11(s,1H,Ar-H),7.82(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.91(d, 3 J HH =8.6Hz,1H,Ar-H),8.39(s,1H,Ar-H),8.74(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0646] Example 123 Preparation of compound Pf04b

[0647]

[0648] The general synthetic steps for compound PfO4b are as follows: 1.0 mmol of substrate PfO4a, 5.0 equivalents of K4[Fe(CN)6], 5.0 equivalents of Cs2CO3, and 0.1 equivalents of Pd[P(tBu)3]2 are dissolved in 2 mL of MeCN. The reaction mixture is microwaved at 100 °C for 30 min at 80 W and 250 psi, and the solution color changes from pale yellow to deep red. LC-MS analysis shows that PfO4a has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated for 0–30 min, and the solvent is removed under vacuum.

[0649] Compound Pf04b, yield 83%, 1 H NMR (400MHz; CDCl3), δ2.68(s,3H,CH3),5.91(s,1H,NH),7.09(s,1H,Ar-H),7.92(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.01(d,3 J HH =8.6Hz,1H,Ar-H),8.11(s,1H,Ar-H),8.72(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0650] Example 124 Preparation of compound Pf04c

[0651]

[0652] The general synthetic steps for compound PfO4c are as follows: 1.0 mmol of substrate PfO4b, 5.0 equivalents of Boc2O, and 5.0 equivalents of triethylamine are reacted in acetonitrile at 20°C for 3 hours, during which the solution color changes from pale yellow to deep yellow. LC-MS analysis shows that PfO4b has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0653] Compound Pf04c, yield 82%. 1 H NMR (400MHz; CDCl3), δ1.43(s,9H,CH3),2.69(s,3H,CH3),7.17(s,1H,Ar-H),8.11(s,1H,Ar-H),8.17(s,1H,Ar-H),8.83(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.98(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0654] Example 125 Preparation of compound Pf05a

[0655]

[0656] The general synthetic steps for compound Pf05a are as follows: 1.0 mmol of substrate H14, 1.2 equivalents of J21, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H14 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0657] Compound Pf05a, yield 61%, 1H NMR (400MHz; CDCl3), δ2.70(s,3H,CH3),5.91(s,1H,NH),7.15(s,1H,Ar-H),7.62(s,1H,Ar-H),7.91(d, 3 J HH =8.6Hz,1H,Ar-H),8.05(s,1H,Ar-H),8.79(d, 3 J HH =8.6Hz,1H,Ar-H),10.2(s,1H,CHO),16.4(s,1H,OH).

[0658] Example 126 Preparation of compound Pf05b

[0659]

[0660] The general synthetic steps for compound Pf05b are as follows: 1.0 mmol of substrate Pf05a, 5 equivalents of NH2-OSO3H, and 5 equivalents of triethylamine are reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pf05a has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0661] Compound Pf05b, yield 81%, 1 H NMR (400MHz; CDCl3), δ2.75(s,3H,CH3),5.99(s,1H,NH),7.11(s,1H,Ar-H),7.47(s,1H,Ar-H),7.72(s,1H,Ar-H),7.91(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.69(d, 3 J HH =8.6Hz,1H,Ar-H),11.5(s,1H,OH).

[0662] Example 127 Preparation of compound Pf05c

[0663]

[0664] The general synthetic steps for compound Pf05c are as follows: 1.0 mmol of substrate Pf05b, 5 equivalents of Cs₂CO₃, and 1.2 equivalents of chloromethyl ethyl ether are reacted in acetonitrile at 20 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pf05b has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0665] Compound Pf05c, yield 89%. 1 H NMR (400MHz; CDCl3), δ1.21(t, 3 J HH =7.1Hz,3H,CH3),2.70(s,3H,CH3),3.60(q, 3 J HH =7.1Hz,2H,OCH2),6.01-6.05(m,3H,OCH2O+NH),7.13(s,1H,Ar-H),7.67(s,1H,Ar-H),7.91-7.93(m,2H,Ar-H),8.73(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0666] Example 128 Preparation of compound Pf05d

[0667]

[0668] The general synthetic steps for compound Pf05d are as follows: 1.0 mmol of substrate Pf05c, 5 equivalents of Cs₂CO₃, and 5 equivalents of Boc₂O are reacted in acetonitrile at 20 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pf05c has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0669] Compound Pf05d, yield 78%. 1 H NMR (400MHz; CDCl3), δ1.21(t, 3 J HH =7.1Hz,3H,CH3),1.40(s,9H,CH3),2.70(s,3H,CH3),3.60(q, 3 J HH=7.1Hz,2H,OCH2),6.01-6.05(m,3H,OCH2O+NH),7.13(s,1H,Ar-H),7.67(s,1H,Ar-H),7.91-7.93(m,2H,Ar-H),8.73(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0670] Example 129 Preparation of compound Pf03c

[0671]

[0672] The general synthetic steps for compound PfO3c are as follows: 1.0 mmol of substrate H16, 1.2 equivalents of J19, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H16 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0673] Compound Pf03c, yield 57%. 1 H NMR (400MHz; CDCl3), δ2.77(s,3H,CH3),5.98(s,1H,NH),7.10(s,1H,Ar-H),7.19-7.26(m,6H,Ar-H),7.64(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.77(d, 3 J HH =8.6Hz,1H,Ar-H),7.91-7.97(m,2H,Ar-H).

[0674] Example 130 Preparation of compound Pf04d

[0675]

[0676] The general synthetic steps for compound PfO4d are as follows: 1.0 mmol of substrate H16, 1.2 equivalents of J20, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H16 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and Phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0677] Compound Pf04d, yield 69%, 1 H NMR (400MHz; CDCl3), δ2.70(s,3H,CH3),6.05(s,1H,NH),7.18(s,1H,Ar-H),7.24-7.30(m,6H,Ar-H),7.80(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.99(d, 3 J HH =8.6Hz,1H,Ar-H),8.37(s,1H,Ar-H).

[0678] Example 131 Preparation of compound Pf04e

[0679]

[0680] The general synthetic steps for compound PfO4e are as follows: 1.0 mmol of substrate PfO4d, 5.0 equivalents of K4[Fe(CN)6], 5.0 equivalents of Cs2CO3, and 0.1 equivalents of Pd[P(tBu)3]2 are dissolved in 2 mL of MeCN. The reaction mixture is microwaved at 100 °C for 30 min at 80 W and 250 psi, and the solution color changes from pale yellow to deep red. LC-MS analysis shows that PfO4d has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is 0.025% TFA aqueous solution, and phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then incubated for 0–30 min, and the solvent is removed under vacuum.

[0681] Compound Pf04e, yield 48%, 1 H NMR (400MHz; CDCl3), δ2.60(s,3H,CH3),5.87(s,1H,NH),7.04(s,1H,Ar-H),7.18-7.25(m,6H,Ar-H),7.99(d, 3 J HH=8.6Hz,1H,Ar-H),8.01(s,1H,Ar-H),8.11(s,1H,Ar-H).

[0682] Example 132 Preparation of compound Pf05e

[0683]

[0684] The general synthetic steps for compound Pf05e are as follows: 1.0 mmol of substrate H16, 1.2 equivalents of J21, 3.0 equivalents of triethylamine, and 0.5 equivalents of (Ph3P)2PdCl2 are added to the reaction solution in solid form. The mixture is reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that H16 has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC. Phase A is a 0.025% TFA aqueous solution, and phase B is a 0.025% TFA acetonitrile solution. The reaction mixture is then subjected to 10–30% B for 0–30 min, and the solvent is removed under vacuum.

[0685] Compound Pf05e, yield 56%, 1 H NMR(400MHz; CDCl3), δ2.61(s,3H,CH3),5.96(s,1H,NH),7.12(s,1H,Ar-H),7.18-7.25(m ,6H,Ar-H),7.52(s,1H,Ar-H),7.95-8.05(m,2H,Ar-H),10.1(s,1H,CHO),16.0(s,1H,OH).

[0686] Example 133 Preparation of compound Pf05f

[0687]

[0688] The general synthetic steps for compound Pf05f are as follows: 1.0 mmol of substrate Pf05e, 5 equivalents of NH2-OSO3H, and 5 equivalents of triethylamine are reacted in acetonitrile at 60 °C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pf05e has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0689] Compound Pf05f, yield 92%, 1H NMR (400MHz; CDCl3), δ2.67(s,3H,CH3),5.98(s,1H,NH),7.10(s,1H,Ar-H),7.19-7.27(m,6H,Ar-H),7.50(s,1H,Ar-H),7.75(s,1H,Ar-H),7.97(d, 3 J HH =8.6Hz,1H,Ar-H),11.0(s,1H,OH).

[0690] Example 134 Preparation of compound Pf05g

[0691]

[0692] The general synthetic steps for compound Pf05g are as follows: 1.0 mmol of substrate Pf05f, 5 equivalents of Cs₂CO₃, and 1.2 equivalents of chloromethyl ethyl ether are reacted in acetonitrile at 20°C for 3 hours, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows that Pf05f has completely disappeared. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0693] Compound Pf05g, yield 89%, 1 H NMR(400MHz; CDCl3), δ1.20(t, 3 J HH =7.1Hz,3H,CH3),2.68(s,3H,CH3),3.51(q, 3 J HH =7.1Hz,2H,OCH2),6.00-6.05(m,3H,OCH2O+NH),7.10(s,1H,Ar-H),7.20-7.25(m,6H,Ar-H),7.64(s,1H,Ar-H),7.90-7.95(m,2H,Ar-H).

[0694] Example 135 Preparation of compounds Pf03d, Pf04f, and Pf05h

[0695]

[0696] The general synthetic steps of the compound are as follows: 1.0 mmol substrate, 5 equivalents of Cs₂CO₃, and 1.2 equivalents of Boc₂O are reacted in acetonitrile at 20 °C for 3 h, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the starting material. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0697] Compound Pf03d, yield 78%. 1 H NMR (400MHz; CDCl3), δ1.41(s,9H,CH3),2.67(s,3H,CH3),7.12(s,1H,Ar-H),7.20-7.25(m,5H,Ar-H),7.67(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.72(d, 3 J HH =8.6Hz,1H,Ar-H),7.92(s,1H,Ar-H),8.01(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.26(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0698] Compound Pf04f, yield 85%, 1 H NMR(400MHz; CDCl3), δ1.43(s,9H,CH3),2.63(s,3H,CH3),7.11(s,1H,Ar-H), 7.20-7.25(m,5H,Ar-H),8.05-8.10(m,2H,Ar-H),8.12(s,1H,Ar-H),8.24(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0699] Compound Pf05h, yield 92%. 1 H NMR (400MHz; CDCl3), δ1.17(t, 3 J HH =7.1Hz,3H,CH3),1.41(s,9H,CH3),2.62(s,3H,CH3),3.54(q, 3 J HH=7.1Hz,2H,OCH2),6.00(s,2H,OCH2O),7.12(s,1H,Ar-H),7.20-7.25(m,5H,Ph),7.67(s,1H,Ar-H),7.95(s,1H,Ar-H),8.04(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.22(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0700] Example 136 Preparation of compounds PfO3e, PfO4g, and PfO5i

[0701]

[0702] The general synthetic steps of the compound are as follows: 1.0 mmol substrate, 5 equivalents of Cs₂CO₃, and 5 equivalents of KHSO₅ / K₂S₂O₈ are reacted in acetonitrile at 20 °C for 3 h, during which the solution color changes from pale yellow to deep red. LC-MS analysis shows complete disappearance of the starting material. After filtration, the reaction mixture is directly separated by HPLC: Phase A is 0.025% TFA aqueous solution, and Phase B is 0.025% TFA acetonitrile solution. The reaction mixture is then reacted with 10-30% B for 0-30 min, and the solvent is removed under vacuum.

[0703] Compound Pf03e, yield 67%. 1 H NMR (400MHz; CDCl3), δ1.42(s,9H,CH3),2.69(s,3H,CH3),7.16(s,1H,Ar-H),7.30-7.35(m,5H,Ar-H),7.69(d, 3 J HH =8.6Hz, 1H, Ar-H), 7.79(d, 3 J HH =8.6Hz,1H,Ar-H),7.95(s,1H,Ar-H),8.08(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.29(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0704] Compound Pf04g, yield 75%, 1H NMR(400MHz; CDCl3), δ1.41(s,9H,CH3),2.65(s,3H,CH3),7.14(s,1H,Ar-H), 7.30-7.35(m,5H,Ar-H),8.10-8.15(m,2H,Ar-H),8.17(s,1H,Ar-H),8.30(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0705] Compound Pf05i, yield 79%, 1 H NMR (400MHz; CDCl3), δ1.19(t, 3 J HH =7.1Hz,3H,CH3),1.43(s,9H,CH3),2.67(s,3H,CH3),3.57(q, 3 J HH =7.1Hz,2H,OCH2),6.05(s,2H,OCH2O),7.17(s,1H,Ar-H),7.30-7.35(m,5H,Ph),7.72(s,1H,Ar-H),7.98(s,1H,Ar-H),8.10(d, 3 J HH =8.6Hz, 1H, Ar-H), 8.32(d, 3 J HH =8.6Hz, 1H, Ar-H).

[0706] Example 137 Preparation of compounds PfO3, PfO4, and PfO5

[0707]

[0708] The general synthetic procedure for the compound was as follows: 1.0 mmol of substrate, 5 equivalents of CsF, in DMF, reacted at 120 °C for 3 h, during which the solution color changed from pale yellow to deep red. LC-MS analysis showed complete disappearance of the substrate. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, and Phase B was 0.025% TFA acetonitrile solution, 10-30% B, reacted for 0-30 min, and the solvent was removed under vacuum.

[0709] Example 138 Preparation of compounds PfO3, PfO4, and PfO5

[0710]

[0711] The general synthetic procedure for the compound was as follows: 1.0 mmol of substrate, 5 equivalents of CsF, in DMF, reacted at 120 °C for 3 h, during which the solution color changed from pale yellow to deep red. LC-MS analysis showed complete disappearance of the substrate. After filtration, the reaction mixture was directly separated by HPLC: Phase A was 0.025% TFA aqueous solution, and Phase B was 0.025% TFA acetonitrile solution, 10-30% B, reacted for 0-30 min, and the solvent was removed under vacuum.

[0712] Example 139 Radiochemical Labeling Experiment

[0713] General synthetic steps: 2.0 mg precursors Pf03b, Py26b, Pf04c, Pf05d, Pf03f, Py26f, Pf04g, Pf05i, >3 eq K2CO3 + K222 reagent (potassium carbonate molar amount less than half that of K222), 0.5 mL DMF. Heat the reaction mixture to 90–150 °C and react for 10–30 min. Separate by HPLC and prepare as a radioactive reagent for use. Radioactivity yield (RCY): 10–60%.

[0714] The purity and specific activity of the radioactive reagent were determined by UV spectroscopy using conventional radioactive HPLC. Specific activity was determined by measuring the amount of radioactivity injected into the HPLC reagent; the number of moles of reagent was determined using a standard curve established from the absorption peaks of non-radioactive standard reagents. Specific activity was calculated as the ratio of the amount of radioactivity to the number of moles of reagent. The range of specific activity was 1–3 Ci / μmol.

[0715] Example 1

[0716] In vitro binding experiment

[0717] Human AD brain tissue homogenate was prepared in 1:500 PBS, 800 μL per tube. [3H]BTA-1 (deuterium-labeled BTA-1) concentration was diluted with ethanol from 1 mCi / mL stock solution to 1 μCi / 100 μL. Further dilution to 2.7 × 10⁻⁶ was performed. -2 μCi / 100μL, using 100μL per tube. "Cold" 6-OH-BTA-1 or other analyte (such as the compound shown in Formula I of this invention) is dissolved in dimethyl sulfoxide to give 1×10 -3 Solution M was prepared using dimethyl sulfoxide to produce 1×10⁻⁶ solutions. -4 Up to 1×10 -10 Solution M, 10 μL per tube. After assembling the three solutions, vortex the tubes and react at 37°C for 2 hours. Separate using a cell collector, and wash filter paper with PBS containing 10% ethanol. Place the filter paper in a 4 mL plastic bottle and add 2 mL of scintillation solution. Count the samples. Analyze the data using GraphPad to obtain the binding constant.

[0718] In the in vitro binding experiment, tritium-labeled BTA-1 was used as the labeling reagent. The binding constant Ki was determined by competitive binding experiments using non-radioactive 6-OH-BTA-1 (PIB) and the compound shown in Formula I of the present invention.

[0719] The binding constants Ki of the compounds of this invention are listed in Table 1:

[0720] Table 1.

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727] C logD 7.4 The value is the logarithm of the compound's solubility in n-butanol divided by its solubility in water. It represents the compound's hydrophilicity and lipophilicity, thus reflecting its half-life. In developer applications, clogD... 7.4 The smaller the value, the shorter the half-life, which is more conducive to eliminating the influence of background during the development process, and the better the development effect. As shown in Table 1, the compound clogD of this application... 7.4 All values ​​were below 3.6, significantly better than the comparative compound [3H]BTA-1, exhibiting better imaging performance and thus being more suitable for preparing positron emission tomography (PET) agents. As shown in Table 1, the Ki values ​​of the compounds in this application are low, indicating good binding ability to β-amyloid protein.

[0728] Example 2

[0729] Results of autoradiography studies of brain tissue sections from different locations in human AD patients are shown in [link to study]. Figure 1 The first row of the image shows tissue sections from AD patients developed using the radioactive compound Py26. The upper right image shows the autoradiography of AD patient brain tissue sections with 1 μM of non-radioactive 6-OH-BTA-1 (PIB) pre-positioning. The lower left and lower right rows of the second row show non-AD patients, developed using the radioactive compound Py26, with / without non-radioactive 6-OH-BTA-1 pre-positioning. The autoradiography of these brain tissue sections without pre-positioning agent is shown.

[0730]

[0731] from Figure 1 As can be seen above, the radiolabeled compound Py26 clearly reveals spots of amyloid protein deposition in the cerebral cortex. These spots no longer develop after pretreatment with 6-OH-BTA-1. Therefore, the compound represented by radiolabeled formula I exhibits characteristic visualization of amyloid protein deposition.

[0732] Conclusion: This invention describes the synthesis of a new class of radiolabeled compounds. These radiolabeled compounds exhibit characteristic absorption in brain slices from Alzheimer's disease (AD) patients, making them excellent contrast agents and potentially providing sensitive molecular probes for the early diagnosis of Alzheimer's disease.

Claims

1. A compound as shown in Formula I, or a pharmaceutically acceptable salt or isotope thereof, Rings A and B are independently C6 to C6. 10 Aromatic ring or 5- to 10-membered heteroaromatic ring; wherein the heteroatoms in the 5- to 10-membered heteroaromatic ring are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R a -N(R) a-1 R a-2 ) or halogen; R a-1 and R a-2 Independently, it is H or a C1-C6 alkyl group; Or two adjacent R a Together with the connected atoms, they form 5- to 10-membered heterocyclic alkyl groups or 5- to 10-membered heteroaryl groups; wherein the heteroatoms in the 5- to 10-membered heterocyclic alkyl groups and 5- to 10-membered heteroaryl groups are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; m is 1, 2, or 3; R b Halogen, -N(R) b-1 R b-2 -O-(C1~C6 alkylene)OH, -(C1~C6 alkylene)o1OH, -CN, -C(=O)-OR c-1 -C(=O)-R c-2 -C(=O)-N(R) b-3 R b-4 -NO2, -OR d 5- to 10-membered heterocyclic alkyl or 5- to 10-membered heteroaryl; wherein the heteroatoms in the 5- to 10-membered heterocyclic alkyl and 5- to 10-membered heteroaryl are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R b-1 R b-2 R b-3 and R b-4 Independently H, C1-C6 alkyl, halogen-substituted C1-C6 alkyl or -(C1-C6 alkylene)o2OH; Or R b-3 and R b-4 Together with the attached N atom, it forms a 5- to 10-membered heterocyclic alkyl group or a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heterocyclic alkyl group and the 5- to 10-membered heteroaryl group contain 1, 2 or 3 N atoms; O1 and O2 are independently 0 or 1; R c-1 and R c-2 Independently, it is a C1 to C6 alkyl group; R d Halogen-substituted C1-C6 alkyl groups; n is 1, 2, or 3.

2. The compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt or isotopic compound, characterized in that, It satisfies one or more of the following conditions: (1) The isotopic compound is an F isotopic compound, such as F 18 ; (2) In ring A, C6~C 10 The aromatic ring is a benzene ring or a naphthalene ring, for example, a benzene ring; (3) In ring A, the 5- to 10-membered heteroaromatic ring is a 5- to 6-membered heteroaromatic ring, and the heteroatom is independently selected from one or two of N and O, and the number of heteroatoms is independently one or two, preferably a pyridine ring, for example (4) In ring B, C6~C 10 The aromatic ring is a benzene ring or a naphthalene ring, for example, a benzene ring; (5) In ring B, the 5-10 membered heteroaromatic ring is a 5-6 membered heteroaromatic ring, the heteroatom is independently selected from one or two of N and O, and the number of heteroatoms is independently one or two, preferably a pyridine ring, for example (6)R a and R b In this context, the halogen is independently F, Cl, Br, or I; (7)R a-1 R a-2 R b-1 R b-2 R b-3 R b-4 R c-1 and R c-2 In this context, the C1-C6 alkyl group is independently a C1-C4 alkyl group, preferably methyl, ethyl, n-propyl or isopropyl, such as methyl or ethyl; (8) Two adjacent R a In the formation of a 5- to 10-membered heterocyclic alkyl group together with the linked atoms, the 5- to 10-membered heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group, wherein the heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently one or two, preferably dioxolane or tetrahydropyrrole, for example (9) Two adjacent R a In the formation of a 5- to 10-membered heteroaryl group together with the linked atoms, the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group, wherein the heteroatom is independently selected from one or two of N and O, and the number of heteroatoms is independently one or two, preferably imidazole, pyrrole, or pyrazolyl; for example (10)R b R b-1 R b-2 R b-3 and R b-4 In this context, the C1-C6 alkylene groups are C1-C4 alkylene groups, preferably -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2- or -C(CH3)2-, for example -CH2- or -CH2CH2-; (11)R b In this context, the 5- to 10-membered heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group, wherein the heteroatom is independently selected from one or both of N and O, and the number of heteroatoms is independently one or two, preferably morpholino; for example (12)R b In this context, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom is independently selected from one or two of N and O, and the number of heteroatoms is independently one or two, preferably pyrrole, imidazolyl, or oxazolyl, for example... (13)R b-3 and R b-4 In the formation of a 5- to 10-membered heterocyclic alkyl group together with the linked N atom, the 5- to 10-membered heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group containing 1 or 2 N atoms; preferably a tetrahydropyrrolyl group; for example (14)R b-3 and R b-4 Together with the connected N atom, they form a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group containing 1 or 2 N atoms; (15)R b-1 R b-2 R b-3 R b-4 and R d In this context, the halogen substitution is independently fluorine substitution, chlorine substitution, bromine substitution, and iodine substitution; for example, fluorine substitution; (16)R b-1 R b-2 R b-3 R b-4 and R d In this context, the number of halogen substitutions is independently 1, 2, or 3, for example, 1.

3. The compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt or isotopic compound, characterized in that, It satisfies one or more of the following conditions: (1) Ring B is C6~C 10 Aromatic rings; (2) When ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring is (3)R a -N(R) a-1 R a-2 ); (4)R b Halogen, -CN or -C(=O)-N(R) b-5 R b-6 ); R b-5 and R b-6 Independently, it is H or a C1-C6 alkyl group; (5) m is 1; (6) n is 1 or 2.

4. The compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt or isotopic compound, characterized in that, It satisfies one or more of the following conditions: (1)R a for F, Cl, Br, or I; (2) Two adjacent R a Formed together with the connected atoms (3)R b -F, -OH, -CN、 -CH2OH、 -NO2 or (4)R b for 18 F.

5. The compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt or isotopic compound, characterized in that, It satisfies one or more of the following conditions: (1) The compound shown in Formula I is the compound shown in Formula I-1 below. R 1 for R 2 For H; Or R 1 and R 2 Together with the connected atoms, they form 5- to 10-membered heterocyclic alkyl groups or 5- to 10-membered heteroaryl groups; R 3 It is H or halogen; Y 1 For CH or N; R 4 It is H or halogen; R 6 H, halogen, -N(R) 6-1 R 6-2 ), -O-(C1~C6 alkylene)OH, -(C1~C6 alkylene)o3OH, -CN, 5~10-membered heterocyclic alkyl or 5~10-membered heteroaryl; O3 is 0; R 6-1 and R 6-2 Independently, it can be H, C1-C6 alkyl, or -(C1-C6 alkylene)o4OH; O4 is 1; (2) The compound shown in Formula I is the compound shown in Formula I-2 below. R 2 It is H or halogen; Y 1 For CH or N; R 5 Halogen, -(C1-C6 alkylene)o5OH, -N(R 5-1 R 5-2 -CN, -C(=O)-OR c-1 Or 5- to 10-membered heterocyclic alkyl groups; O5 is 0; R 5-1 and R 5-2 Independently, it is H or a C1-C6 alkyl group; (3) The compound shown in Formula I is the compound shown in Formula I-3 below. Y 1 For CH or N; R 5 H, -C(=O)-OR c-1 -(C1~C6 alkylene)o6OH, -CN, -C(=O)-N(R) 5-3 R 5-4 ); O6 is 1; R 5-3 and R 5-4 Independently, it is H or a C1-C6 alkyl group; Or R 5-3 and R 5-4 Together with the attached N atom, it forms a 5- to 10-membered heterocyclic alkyl group; R 6 It can be H, halogen, or -CN; (4) The compound shown in Formula I is the compound shown in Formulas I-4 below. R 5 -C(=O)-N(R) 5-5 R 5-6 ), -N(R 5-7 R 5-8 ) or halogen; R 5-5 R 5-6 R 5-7 and R 5-8 C1 to C6 alkyl groups that are independently substituted with H or halogens; R 6 For H or -CN; (5) The compound shown in Formula I is the compound shown in Formulas I-5 below. R 5 It can be H, -CN, or halogen; R 6 Halogen or -CN; (6) The compound shown in Formula I is a compound shown in Formulas I-6. R 2 It is H or halogen; R 5 H, halogen, -OR d -NO2, -CN, or -(C1-C6 alkylene)o7OH; O7 is 0; R 6 For H, -CN, -C (=O) -OR c-1 -C(=O)-N(R) 6-3 R 6-4 -NO2, -C(=O)-R c-2 Or halogen; R 6-3 and R 6-4 Independently, it is H or a C1-C6 alkyl group; (7) The compound shown in Formula I is a compound shown in Formulas I-7. Y 2 For CH or N; R 5 It is H or halogen; R 6 -CN or -C(=O)-N(R) 6-5 R 6-6 ); R 6-5 and R 6-6 It is independently H or C1 to C6 alkyl.

6. The compound of formula I as claimed in claim 1, or its pharmaceutically acceptable salt or isotopic compound, characterized in that, The compound shown in Formula I is any of the following compounds:

7. A compound as shown in Formula II or Formula III, In formula II, R 2-2 It is H or -NO2; R 5-2 For H, -NO2, -CN or In Equation III, R 2-3 For H or R 5-3 For H, -CN or Preferably, the compound shown in Formula II or Formula III is any of the following compounds:

8. A method for preparing a compound as shown in Formula I according to any one of claims 1 to 6, wherein the method is Scheme 1 or Scheme 2: Scheme 1. When the compound shown in Formula I is the compound shown in Formula I-6-1, it includes the following steps: reacting the compound shown in Formula II with CsF to obtain the compound shown in Formula I-6-1. R 2-2 and R 5-2 The definition in claim 7 is as described in claim 7; R 2-1 For H or F; R 5-1 It can be H, F, -OH or -CN; Option 2. When the compound shown in Formula I is the compound shown in Formula I-6-1, it includes the following steps: reacting the compound shown in Formula III with CsF; R 2-3 and R 5-3 The definition in claim 7 is as described in claim 7; R 2-1 For H or F; R 5-1 It can be H, F, -OH or -CN; Preferably, in option 1 or option 2: The reaction can be carried out in a solvent, which is a strongly polar aprotic solvent, preferably dichloromethane or DMF, such as DMF; The reaction temperature is 120-150℃, for example, 120℃; The molar ratio of the compound as shown in Formula II to the CsF is 1:(3-6), for example 1:5; The molar ratio of the compound as shown in Formula III to the CsF is 1:(3-6), for example 1:5; The mass-to-volume ratio of the compound as shown in Formula II to the solvent is 0.1-0.5 g / mL, for example, 0.5 g / mL; The mass-to-volume ratio of the compound as shown in Formula III to the solvent is 0.1-0.5 g / mL, for example, 0.5 g / mL.

9. A pharmaceutical composition comprising a compound of Formula I as described in any one of claims 1 to 6, and a pharmaceutically acceptable salt or isotopic compound thereof, and at least one pharmaceutical excipient.

10. A positron emission tomography (PET) agent comprising a compound of formula I as described in any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, an isotopic compound, or a pharmaceutical composition as described in claim 9.

11. The use of a compound of Formula I as described in any one of claims 1 to 6, a pharmaceutically acceptable salt or isotopic compound thereof, or a pharmaceutical composition as described in claim 9 as a preparation of a positron emission tomography (PET) agent; Preferably, the positron emission tomography (PET) agent is a PET agent used for Alzheimer's disease imaging; Preferably, the positron emission tomography (PET) agent is a PET agent used for imaging diseases related to amyloid deposition.

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