Aromatic sulfonamide compound as well as preparation method and application thereof

Abstract

The invention relates to an aromatic sulfonamide compound as well as a preparation method and application thereof. The aromatic sulfonamide compound has the structural characteristics as shown in the formula (I). The aromatic sulfonamide compound has relatively high P2X4 receptor antagonistic activity and can be used for treating hyperalgesia.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical compound technology, and in particular to an aromatic sulfonamide compound, its preparation method, and its application. Background Technology

[0002] Pain can be caused by various acute and chronic diseases or injuries, such as cancer and arthritis. In addition, various clinical scenarios, such as surgery, endoscopy, and trauma, can also cause pain. There are also some relatively complex types of pain, such as neuropathic pain and complex regional pain syndromes. Pain has become a serious health problem. According to a survey of 46,394 people in multiple countries published in the European Journal of Pain, 19% of the respondents experienced chronic pain of intensity 5 or higher lasting more than 6 months, of which 66% experienced moderate pain (NRS = 5-7) and 34% experienced severe pain (NRS = 8-10).

[0003] For different degrees of pain, appropriate analgesics or a combination of non-pharmacological methods can be used for pain management. Currently, there are three main categories of effective pain relievers: non-opioid analgesics, opioid (narcotic) analgesics, and adjunctive analgesics. In 2021, The Lancet showed that the first-line treatment for neuropathic pain is antidepressants and antiepileptic drugs, while the first-line treatment for non-neuropathic pain is nonsteroidal anti-inflammatory drugs (NSAIDs).

[0004] Of the three classes of analgesics mentioned above, non-opioid analgesics (primarily NASID) are less addictive than opioids, but their analgesic effect is weaker, exhibiting a ceiling effect, and due to their side effects, they are not suitable for long-term systemic administration. Opioids achieve analgesia by acting on opioid receptors, exhibiting strong analgesic effects and are clinically used for various moderate to severe pain. However, their use is greatly limited by side effects including sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Although opioids remain the first-line drugs for treating moderate to severe pain, overuse of opioids for pain treatment has led to an opioid abuse crisis. Therefore, new analgesics or treatment strategies are needed to curb the ongoing opioid epidemic.

[0005] Besides being a major energy source for cellular metabolism, extracellular adenosine triphosphate (ATP) is also an important neurotransmitter that modulates pain perception by activating the nociceptive afferent pathway mediated by P2 purine receptors located in DRG sensory neurons. Purine receptors are classified into two main families based on molecular structure, transduction mechanism, and pharmacological properties: P2Y- and P2X-purine receptors. P2X-purine receptors are a family of ATP-gated cation channels, including six homopolymers: P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7, and three heteropolymers: P2X2 / 3, P2X4 / 6, and P2X1 / 5. Among ionotropic receptors, P2X receptors have emerged as potential targets for central nervous system diseases such as epilepsy, ischemia, chronic pain, anxiety, multiple sclerosis, and neurodegenerative diseases over the past decade. Hyperpolarized activated cyclic nucleotide-gated channels and purinergic P2X receptors play key roles in pain sensitivity induced by nerve injury.

[0006] Currently, among all P2X receptor subtypes, spinal microglia activity mediated by P2X4Rs plays a crucial role in the induction of neuropathic pain, making it a potential therapeutic target for neuropathic pain. A groundbreaking report in 2003 on the mechanism of neuropathic pain induction demonstrated that spinal microglia are activated after PNI (percutaneous neuronal infarction) and overexpress P2X4R in these cells. Animals with P2X4R gene knockout or inhibition exhibited milder hyperalgesia symptoms in neuropathic abnormalities, indicating the important role of P2X4 receptors in the development and progression of neuropathic pain. Selecting microglia's P2X4Rs as a therapeutic target for neuropathic pain has unique advantages: in cases of peripheral nerve injury leading to hyperalgesia, P2X4R blockers do not affect normal pain signals and are only used to treat cases where P2X4Rs in activated microglia are significantly enhanced. In other words, P2X4 receptor antagonists have enormous potential for the treatment of hyperalgesia. Summary of the Invention

[0007] Based on this, this application provides an aromatic sulfonamide compound, its preparation method, and its application. This aromatic sulfonamide compound exhibits high P2X4 receptor antagonistic activity and can be used to treat hyperalgesia.

[0008] In a first aspect, this application provides an aromatic sulfonamide compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt thereof, wherein the aromatic sulfonamide compound has the structural features shown in formula (I):

[0009]

[0010] in,

[0011] R 1 H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-10 ring atoms, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5 to 20-membered heteroaryl groups or combinations thereof, wherein the heteroaryl and heterocycloalkyl groups each contain at least one heteroatom selected from nitrogen, oxygen or sulfur;

[0012] R 2 Independently, it can be H, halogen, hydroxyl, nitro, cyano, carboxyl, aldehyde, amide, ester, -C(O)-C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-10 ring atoms, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5- to 20-membered heteroaryl groups or combinations thereof, wherein the heteroaryl and heterocyclic groups each contain at least one heteroatom selected from nitrogen, oxygen or sulfur, and optionally, the heterocyclic or aryl group may share two carbon atoms with the substituted benzene ring to form a fused ring;

[0013] n can be 0, 1, 2, 3, 4, or 5.

[0014] A second aspect of this application provides a method for preparing the aromatic sulfonamide compounds described in the first aspect, comprising the following steps:

[0015] Compound E was reacted with compound 1 to prepare compound F;

[0016] The aromatic sulfonamide compound was prepared by subjecting compound F to an amino deprotection reaction.

[0017] Compound E is

[0018] Compound 1 is

[0019] Compound F is

[0020] A third aspect of this application provides a pharmaceutical composition comprising the aromatic sulfonamide compound of the first aspect or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, isotopic compound, crystal form, nitride, solvate, solvate of a pharmaceutically acceptable salt, and at least one pharmaceutical excipient.

[0021] A fourth aspect of this application provides the use of the aromatic sulfonamide compounds of the first aspect or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic compounds, crystal forms, nitrides, solvates, solvates of pharmaceutically acceptable salts, or pharmaceutical compositions of the third aspect in the preparation of medicaments for treating diseases related to or mediated by P2X4 receptor activity.

[0022] Studies have found that the aforementioned aromatic sulfonamide compounds have good antagonistic activity against P2X4 receptors and can be used as P2X4 antagonists, which is beneficial for the development of drugs for the treatment of neuropathic and inflammatory pain. Attached Figure Description

[0023] Figure 1 Bar chart showing the analgesic rate-dose correlation of compounds 4, 11, 43, and the positive control in a formalin-induced pain model in rats. Detailed Implementation

[0024] The aromatic sulfonamide compounds, their preparation methods, and applications described in this application are further illustrated below with specific embodiments. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0026] In this application, terms such as "first aspect," "second aspect," and "third aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," and "third," etc., serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0027] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0028] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0029] Unless otherwise specified, the percentage content mentioned in this application refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0030] Unless otherwise specified, all percentage concentrations mentioned in this application refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0031] Unless otherwise specified, the temperature parameters in this application may be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows for temperature fluctuations within the precision range controlled by the instrument.

[0032] In this application, room temperature generally refers to 4℃~30℃, and more preferably 20±5℃.

[0033] Unless otherwise stated, the numerical ranges described in this specification and claims correspond to at least each specific integer value described herein. For example, the numerical range "1-20" corresponds to each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-20", namely 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. It should be understood that when describing substituents herein, "more than" in the context of "one, two, or more" should refer to an integer of S, such as 3, 4, 5, 6, 7, 8, 9, or 10. The term "a plurality of" refers to an integer of 22, such as 2, 3, 4, 5, etc.

[0034] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentic acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002)

[0035] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0036] As described above, the terms "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances formed by combining the compounds of the present invention with 1, substances prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, or substances formed with a stoichiometric or non-stoichiometric solvent.

[0037] The term "stereoisomer" refers to isomers of molecules that have the same order of interconnection of atoms or groups of atoms but different spatial arrangements, such as cis-trans isomers, optical isomers, or trans-blocked isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.). They can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.

[0038] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of a single atom between two positions in a molecule. For example, acetone and 1-propen-2-ol can interconvert through the rapid movement of hydrogen atoms to the oxygen and α-carbon.

[0039] The term "isotopic compound" refers to a compound in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl). The isotopic compounds of the present invention can generally be prepared according to the methods described herein by replacing non-isotopic labeled reagents with isotopically labeled reagents.

[0040] The term "crystal form" refers to the strict periodic arrangement of ions or molecules in three-dimensional space in a defined manner, with a regular repetition pattern at certain intervals. Due to the different periodic arrangements, multiple crystal forms can exist, which is the phenomenon of polymorphism.

[0041] The term "nitrogen oxide" refers to the oxidation of one or more nitrogen atoms to form N-oxides when a compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th ed., Jerry March, pages).

[0042] Unless otherwise stated, any abbreviations for protecting groups, amino acids and other compounds used in this invention shall be the commonly used and recognized abbreviations, or refer to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11:942-944).

[0043] "alkyl" refers to straight-chain and branched saturated aliphatic hydrocarbon groups. "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably C16. 1-3 Alkyl; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and their various branched isomers.

[0044] "Cycloalkyl" and "cycloalkyl ring" are used interchangeably, both referring to saturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon groups that can be fused with aryl or heteroaryl groups. "C 3-8 "Cycloalkyl" refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. Preferably C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0045] The terms "heterocyclic alkyl" and "heterocyclic alkyl ring" are used interchangeably, both referring to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, which may be fused with an aryl or heteroaryl group. "3- to 10-membered heterocyclic alkyl" refers to a monocyclic cyclic hydrocarbon group having 3 to 10 ring atoms, wherein 1, 2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, preferably a 4- to 8-membered heterocyclic alkyl. More preferably, it is a 3- to 6-membered heterocyclic alkyl having 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Even more preferably, it is a 4- to 6-membered heterocyclic alkyl having 4 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur.

[0046] "Aryl" and "aromatic ring" are used interchangeably, both referring to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system. This group can be fused with cycloalkyl, heterocyclic alkyl, or heteroaryl rings. "C" 6-20 "Aryl" refers to a monocyclic or bicyclic aryl group having 6 to 20 carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, etc.

[0047] The terms "heteroaryl" and "heteroaryl ring" are used interchangeably, both referring to a 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) of monocyclic, bicyclic, or polycyclic forms having a ring carbon atom and a ring heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In this invention, heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl, heterocycloalkyl, or aromatic rings. "5 to 20-membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl having 5 to 20 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms. "5- to 6-membered heteroaryl" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. Non-limiting examples include thiophene, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrole, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridinyl, triazinyl, and tetraazinyl. "8 to 10-membered heteroaryl" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. Non-limiting examples include indole, isoindole, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzooxadiazolyl, benzothiazolyl, and benzoisothiazolyl. Azolyl, benzothiadiazolyl, indazinyl, purine, pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthidyl, 1,7-naphthidyl, 1,6-naphthidyl, 1,5-naphthidyl, pteridyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. "Heteroatom" refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. "Alkoxy" refers to -O-alkyl, where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, etc.

[0048] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0049] "Halogenated" means that one or more hydrogen atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) in a group are replaced by halogens.

[0050] "Amino" refers to NH2, "cyano" refers to CN, "hydroxy" refers to -OH, "nitro" refers to NO2, "carbonyl" refers to =O, "carboxyl" refers to -C(O)OH, and "acetyl" refers to -C(O)CH3.

[0051] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5 hydrogen atoms independently substituted by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms independently substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0052] Unless otherwise defined, when more than one identical substituent group exists in the general formula of this invention, the group may be the same or different, and may be of a distinct kind. For example, in the structure shown in formula (I), when n is 2, the two R... 2 They can be the same or different, and each can be an independent category.

[0053] It indicates a connection with other atoms.

[0054] In this invention, when no linking site is specified in the group, it means that any linkable site in the group is selected as the linking site.

[0055] In some examples of this application, an aromatic sulfonamide compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt thereof is provided, wherein the aromatic sulfonamide compound has the structural features shown in formula (I):

[0056]

[0057] in,

[0058] R 1 H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-10 ring atoms, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5 to 20-membered heteroaryl groups or combinations thereof, wherein the heteroaryl and heterocycloalkyl groups each contain at least one heteroatom selected from nitrogen, oxygen or sulfur;

[0059] R 2Independently, it can be H, halogen, hydroxyl, nitro, cyano, carboxyl, aldehyde, amide, ester, -C(O)-C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-10 ring atoms, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5- to 20-membered heteroaryl groups or combinations thereof, wherein the heteroaryl and heterocyclic groups each contain at least one heteroatom selected from nitrogen, oxygen or sulfur, and optionally, the heterocyclic or aryl group may share two carbon atoms with the substituted benzene ring to form a fused ring;

[0060] n can be 0, 1, 2, 3, 4, or 5.

[0061] In some of these examples, R 1 for

[0062] Among them, R 1-1 For substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5 to 20 heteroaryl groups or combinations thereof.

[0063] In some of these examples, R 1-1 C 6-10 aryl, with one or more R b Replacement C 6-10 aryl, 5-10 heteroaryl, with one or more R b Substituted 5-10 heteroaryl groups or combinations thereof; said R b Independent of H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen-substituted C 1-6 Alkyl, C 1-6 Alkoxy, nitro, carbonyl, cyano, or hydroxyl.

[0064] Without limitation, the number of heteroatoms in the heteroaryl group is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S.

[0065] In some of these examples, the R 1-1 It is one of the following groups:

[0066]

[0067] Where p is 0, 1, 2, 3, 4 or 5.

[0068] In some of these examples, the R bIndependently, it is H, halogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, or cyclobutyl.

[0069] In some of these examples, R 1 for

[0070] Among them, R 1-2 For substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5 to 20 heteroaryl groups or combinations thereof.

[0071] In some of these examples, R 1-2 C is either replaced by one or more Rc or not replaced. 1-6 Alkyl groups, C groups substituted with one or more Rc groups, or C groups that are not substituted 3-8 Cycloalkyl, 3- to 10-membered heterocyclic alkyl groups substituted with or unsubstituted with one or more Rc groups, C-membered heterocyclic alkyl groups substituted with or unsubstituted with one or more Rc groups 6-20 Aryl, 5- to 20-membered heteroaryl groups substituted or unsubstituted with Rc, or combinations thereof; wherein Rc is independently H, halogen, or C. 1-3 Alkyl, C 3-10 Cycloalkyl, halogen-substituted C 1-3 Alkyl, C 1-3 alkoxy, carbonyl, at least one C 1-3 Alkyl-substituted amino, cyano, hydroxyl, C 6-10 Aryl, -OC 6-10 Aryl or -C(O)-5 to 10 heteroaryl groups.

[0072] Without limitation, the heteroaryl or heterocycloalkyl group has one, two or three heteroatoms, which are selected from one or more of N, O and S.

[0073] In some of these examples, the R 1-2 It is one of the following groups:

[0074]

[0075] Where m is 0, 1, 2, 3, 4 or 5.

[0076] In some of these examples, the R c Independently, it can be H, halogen, methyl, ethyl, propyl, cyano, -O-Ph, -N(CH3)2, methoxy, ethoxy, propoxy, trifluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclobutyl, phenyl, or

[0077] In some of these examples, R 2 Independently, it can be H, halogen, hydroxyl, nitro, carbonyl, cyano, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 1-6 alkylthio groups, halogenated C 1-6 Alkylthio, C 3-6 Cycloalkyl groups, heterocyclic groups containing 3-10 ring atoms, or substituted or unsubstituted C4 groups. 6-20 Aryl group, optionally, the heterocyclic group or aryl group may share two carbon atoms with the substituted benzene ring to form a fused ring.

[0078] In some of these examples, R 2 Independently, it can be H, halogen, hydroxyl, nitro, carbonyl, cyano, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 1-6 alkylthio groups, halogenated C 1-6 Alkylthio, C 3-6 Cycloalkyl groups, heterocyclic groups containing 3-10 ring atoms, or those with R d C substituted or unsubstituted 6-20 Aryl; the R d For H and C 1-6 Alkoxy group, optionally, the heterocyclic or aryl group may share two carbon atoms with the substituted benzene ring to form a fused ring.

[0079] Without limitation, the heterocyclic group may contain 1, 2 or 3 heteroatoms, which may be selected from one or more of N, O and S.

[0080] In some of these examples, R 2 Independently, it can be H, halogen, hydroxyl, nitro, carbonyl, cyano, -C(O)-CH3, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, methoxy, ethoxy, propoxy, butoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, fluorobutoxy, methylthio, ethylthio, propylthio, butylthio, fluoromethylthio, fluoroethylthio, fluoropropylthio, fluorobutylthio.

[0081] Without limitation, the aromatic sulfonamide compound has a structure shown in any of the following formulas:

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] A second aspect of this application provides a method for preparing the aromatic sulfonamide compounds described in the first aspect, comprising the following steps:

[0089] Compound E was reacted with compound 1 to prepare compound F;

[0090] The aromatic sulfonamide compound was prepared by subjecting compound F to an amino deprotection reaction.

[0091] Compound E is

[0092] Compound 1 is Understandably, compound 1 is The reaction is carried out in the presence of the reagent bis(trichloromethyl) carbonate (BTC);

[0093] Compound F is

[0094] In some of these examples, the preparation of compound E includes the following steps:

[0095] Compound D was reduced to prepare compound E;

[0096] Compound D is

[0097] In some of these examples, compound D is prepared by method 1, method 2, or method 3.

[0098] Where R 1 for Method 1;

[0099] When R 1 for And R 1-2 For substituted or unsubstituted C 6-20 Method 2 for use with aryl, substituted or unsubstituted 5 to 20-membered heteroaryl groups;

[0100] When R 1 for And R 1-2 For substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Method 3 is used when the cycloalkyl, substituted or unsubstituted 3 to 10-membered heterocycloalkyl groups are used.

[0101] Furthermore, Method 1 includes the following steps:

[0102] Compound C is reacted with compound VII or compound IX to prepare compound D1;

[0103] Compound C is

[0104] Compound VII is R 1-1 -Bpin, where Bpin represents pinacol boryl ester;

[0105] Compound IX is R 1-1 -B(OH)2;

[0106] Compound D1 is

[0107] In some of these examples, the steps of reacting compound C with compound VII or compound IX include:

[0108] In a solvent, in the presence of a base and a catalyst, compound C undergoes a coupling reaction with either compound VII or compound IX. Further, method 2 includes the following steps:

[0109] Compound C was reacted with compound III to prepare compound D2;

[0110] Compound C is

[0111] Compound II is IR 1-2 -OH;

[0112] Compound D2 is

[0113] In some of these examples, the steps for reacting compound C with compound III include:

[0114] In a solvent, in the presence of a base, compound C undergoes a substitution reaction with compound III.

[0115] Furthermore, method 3 includes the following steps:

[0116] Compound C was hydrolyzed to prepare compound V;

[0117] Compound V was reacted with compound VI to prepare compound D3;

[0118] Compound C is

[0119] Compound V is

[0120] Compound VI is R 1-2 -X, where X represents halogen;

[0121] Compound D3 is

[0122] In some of these examples, the steps involved in hydrolyzing compound C include:

[0123] In a solvent, under the presence of a base, compound C undergoes a hydrolysis reaction.

[0124] In some of these examples, compound V is subjected to a substitution reaction with compound VI.

[0125] Understandably, R 1-1 or R 1-2 Same or different, as defined above independently of each other.

[0126] In some of these examples, the preparation of compound C includes the following steps:

[0127] Compound A is reacted with compound B to prepare compound C;

[0128] Compound A is

[0129] Compound B is DMBNH2.

[0130] Other examples of this application provide a pharmaceutical composition comprising an aromatic sulfonamide compound as described above, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, isotopic compound, crystal form, nitride, solvate, a solvate of a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0131] "Pharmaceutical excipients" refer to pharmaceutically acceptable materials, compositions, or carriers, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be "pharmaceutically acceptable" in the sense that it is compatible with other components in the formulation and harmless to the patient. "Pharmaceutical acceptable" means those ligands, materials, compositions, and / or dosage forms that are suitable for administration to the patient within the bounds of reasonable medical judgment and that are proportionate to a reasonable benefit / risk ratio.

[0132] Other examples of this application provide the use of aromatic sulfonamide compounds as described above, or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic compounds, crystal forms, nitrides, solvates, solvates of pharmaceutically acceptable salts, or pharmaceutical compositions as described above, in the preparation of medicaments for treating diseases associated with or mediated by P2X4 receptor activity. Further, the diseases associated with or mediated by P2X4 receptor activity include pain, such as neuropathic pain or hyperalgesia.

[0133] As used herein, "drug" includes any agent, compound, composition, or mixture that provides physiological and / or pharmacological effects in vivo or in vitro, and often provides beneficial effects. The scope of the physiological and / or pharmacological effects produced by the "drug" in vivo is not particularly limited; it may have systemic effects or only local effects. The activity of the "drug" is not particularly limited; it may be an active substance that can interact with other substances or an inert substance that does not interact with other substances.

[0134] Other examples of this application provide the use of aromatic sulfonamide compounds as described above, or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic compounds, crystal forms, nitrides, solvates, solvates of pharmaceutically acceptable salts, or pharmaceutical compositions as described above, in the preparation of P2X4 receptor antagonists.

[0135] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0136] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0137] The abbreviations in the embodiments of this invention are illustrated below:

[0138] ACN: Acetonitrile;

[0139] EA: Ethyl acetate;

[0140] PPh3: triphenylphosphine;

[0141] THF: Tetrahydrofuran;

[0142] TEA: Triethylamine;

[0143] TFA: Trifluoroacetic acid;

[0144] DCM: Dichloromethane (Methylene chloride);

[0145] DMSO: Dimethyl sulfoxide;

[0146] EtOH: Ethyl Alcohol;

[0147] DMBNH2: 2,4-Dimethoxybenzylamine;

[0148] BTC: Three Light Gases;

[0149] Bpin: Pinaryl boron ester.

[0150] Compound preparation examples

[0151] General experimental procedure:

[0152]

[0153] General procedure GP 1:

[0154] Compound A (10.8 g, 42.2 mmol) was dissolved in 108 mL of DCM, and NaHCO3 (7.09 g, 84.4 mmol) and DMB amine (7.05 g, 42.2 mmol) were added sequentially. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC plate. After the reaction was completed, the reaction solution was concentrated using a rotary evaporator, and then water (75 mL) and EA (75 mL) were added to the system, respectively. The mixture was stirred at room temperature for 10 min. The mixture was filtered, and the chlorine filter cake was dried overnight in a vacuum dryer at 40 °C.

[0155]

[0156] General procedure GP 2.1:

[0157] Compound C (1.29 mmol, 1.0 eq) was dissolved in 5 ml of ACN, and Cs₂CO₃ (1.29 mmol, 1.0 eq) and the corresponding phenolic substance (compound II, R) were added sequentially. 1-2 -OH)(1.29 mmol, 1.0 eq). The reaction was carried out overnight at 100 °C under argon protection. The reaction was monitored by TLC plate. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filter cake was washed three times with water, the filtrate was concentrated and 5 ml of DCM was added. The mixture was stirred at room temperature for 10 min, filtered, and the filter cakes were combined and dried overnight at 40 °C in a vacuum dryer.

[0158] General procedure GP 2.2:

[0159] KOH (6.45 mmol, 5.0 eq) was dissolved in 10 mL of H₂O and allowed to dissolve completely at 20-40 °C. Compound C (1.29 mmol, 1.0 eq) was slowly added, and the reaction was carried out at 120-140 °C for 6 h under argon protection. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, the pH was adjusted to 1-3 with 1 M hydrochloric acid solution, and the mixture was stirred at room temperature for 10 min. The mixture was then filtered, and the filter cake was dried overnight at 40 °C in a vacuum dryer. The filter cake (0.78 mmol, 1.0 eq) was dissolved in 3 mL of ACN, and the corresponding aliphatic halides (compounds VI, R) were added sequentially. 1-2 The reaction mixture was prepared by reacting X (1.16 mmol, 1.5 eq) and Cs₂CO₃ (1.55 mmol, 2.0 eq) at 80 °C overnight under argon protection. The reaction was monitored by TLC plate. After the reaction was completed, the reaction solution was cooled to room temperature. The mixture was extracted twice with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to obtain compound D.

[0160] General procedure GP 2.3:

[0161] Compound C (1.29 mmol, 1.0 eq) was dissolved in 5 ml of n-propanol, and the corresponding boric acid or borate ester compound (compound VII or compound IX, R) was added sequentially. 1-1 -Bpin or R 1-1 -B(OH)2 (1.94 mmol, 1.5 eq), PPh3 (0.13 mmol, 0.1 eq), and the catalyst bis(triphenylphosphine)palladium dichloride (CAS: 13965-03-2, 0.13 mmol, 0.1 eq) were added, and argon gas was purged for 5 min. K2CO3 (2.58 mmol, 2.0 eq) was added, and the reaction was carried out at 110 °C for 3 h under argon protection. The reaction was monitored by TLC plate. After the reaction was completed, the reaction solution was cooled to room temperature and extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Compound D was separated by column chromatography (petroleum ether:ethyl acetate = 2:1, v / v).

[0162]

[0163] General procedure GP 3:

[0164] Compound D (0.64 mmol, 1.0 eq) was dissolved in 6 mL of a 5:1 mixture of ethanol and water. Reduced iron powder (7.74 mmol, 12.0 eq) and NH₄Cl (7.74 mmol, 12.0 eq) were added sequentially. The reaction was carried out at 100 °C for 4 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was cooled to room temperature and extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound E. No further purification was required; the reaction proceeded directly to the next step.

[0165]

[0166] General procedure GP 4.1:

[0167] Compound E (0.64 mmol, 1.0 eq) was dissolved in 3 mL of THF, and TEA (1.29 mmol, 2.0 eq) was added. After the addition was complete, the temperature was lowered to 0 °C, and the corresponding isocyanate compound dissolved in 1 mL of THF was added dropwise under argon protection. 0.96 mmol (1.5 eq). After addition, the mixture was heated to room temperature and reacted overnight. The reaction was monitored by TLC plate. After the reaction was completed, the mixture was extracted twice with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. Compound F was obtained by column chromatography (petroleum ether:ethyl acetate = 2:1, v / v).

[0168] General procedure GP 4.2:

[0169] BTC (0.1 mmol, 1.0 eq) was dissolved in 3 ml of THF, cooled to -10°C, and then, under argon protection, aniline compounds dissolved in 1 ml of THF were added dropwise. 0.3 mmol (3.0 eq) and TEA (0.2 mmol, 2.0 eq) were added, and the mixture was heated to room temperature for 30 min. Compound E (0.3 mmol, 3.0 eq) was dissolved in 1 mL of THF and added dropwise to the above system, and the mixture was reacted at room temperature for 2 h. The reaction was monitored by TLC plate. After the reaction was completed, saturated NaHCO3 solution was added to quench the reaction. The mixture was extracted twice with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to obtain compound F.

[0170]

[0171] General procedure GP 5:

[0172] Compound F (0.3 mmol, 1.0 eq) was dissolved in 3 mL of DCM, and 2 mL of TFA was added dropwise with stirring. The reaction was carried out at room temperature for 2 h under argon protection. The reaction was monitored by TLC plate, and after the reaction was completed, saturated NaHCO3 solution was added to quench the reaction. The mixture was extracted twice with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to obtain compound G.

[0173] Compound 1:

[0174]

[0175] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and 2-isocyano-1,3-dimethylbenzene (0.20 g, 1.34 mmol) were converted into compound 1 and purified by silica gel column chromatography. A pale yellow solid (45 mg, 0.11 mmol, 5.3% yield in 5 steps) was obtained.

[0176] LC-MS(ESI)[M+H] + :446.1.Retention time:2.012min.HPLC purity=100.00%.

[0177] 1 H NMR(400MHz,Chloroform-d)δ9.14-9.07(m,1H),8.09(d,J=2.7Hz,1H),7.75(s,1H),7.61(dd,J=8 .9,2.7Hz,1H),7.36(m,3H),7.19-7.12(m,1H),7.10-7.02(m,5H),6.98-6.92(m,1H),2.20(s,7H).

[0178] Compound 2:

[0179]

[0180] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and 2-(methylthio)phenyl isocyanate (0.21 g, 1.34 mmol) were converted into compound 2 and purified by silica gel column chromatography. A pale yellow solid (50 mg, 0.11 mmol, 5.3% yield in 5 steps) was obtained.

[0181] LC-MS(ESI)[M+H] + :463.9.Retention time:2.088min.HPLC purity=100.00%.

[0182] 1 H NMR(400MHz,Chloroform-d)δ9.74(s,1H),8.16(s,1H),8.09(s,1H),7.93(d,J=8.2Hz,1H),7. 64(m,1H),7.44-7.33(m,4H),7.26-7.13(m,2H),7.11-7.01(m,3H),6.97(m,1H),2.43(s,3H).

[0183] Compound 3:

[0184]

[0185] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 1,3-dichloro-2-isocyanobenzene (0.12 g, 0.67 mmol) were converted into compound 3 and purified by silica gel column chromatography. A white solid (20 mg, 0.04 mmol, 5-step yield 1.9%) was obtained.

[0186] LC-MS(ESI)[M+H] + :485.9.Retention time:2.013min.HPLC purity=100.00%.

[0187] 1 H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.25(s,1H),8.11(d,J=2.7Hz,1H),7.61(dd,J=8.9,2.7Hz, 1H),7.53(d,J=8.1Hz,2H),7.40-7.29(m,4H),7.18-7.14(m,1H),7.09-7.03(m,2H),6.99-6.92(m,1H).

[0188] Compound 4:

[0189]

[0190] Following the general synthetic procedure GP1, GP2.1, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and 2-ethoxyphenyl isocyanate (0.22 g, 1.34 mmol) were converted into compound 4 and purified by silica gel column chromatography. A white solid (60 mg, 0.13 mmol, 5-step yield 6.2%) was obtained.

[0191] LC-MS(ESI)[M+H] + :462.0.Retention time:2.135min.HPLC purity=98.40%.

[0192] 1 H NMR(400MHz,Chloroform-d)δ9.90(s,1H),8.19-8.04(m,3H),7.64(dd,J=8.8,2.7Hz,1 H),7.39(m,4H),7.18(m,2H),7.07(m,2H),7.03-6.94(m,2H),4.12(m,2H),1.99(m,3H).

[0193] Compound 5:

[0194]

[0195] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.30 g, 0.67 mmol) and 2,6-diisopropylphenyl isocyanate (0.20 g, 1.00 mmol) were converted to compound 5 and purified by silica gel column chromatography. A pale yellow solid (30 mg, 0.06 mmol, 2.8% yield in 5 steps) was obtained.

[0196] LC-MS(ESI)[M+H] + :502.0.Retention time:2.232min.HPLC purity=100.00%.

[0197] 1 H NMR(400MHz,Chloroform-d)δ9.13(s,1H),8.10(d,J=2.7Hz,1H),7.67(s,1H),7.62-7.57(m,1H),7.35(m,3H),7. 28-7.22(m,1H),7.15(m,3H),7.08-7.02(m,2H),6.95(dd,J=8.3,2.4Hz,1H),3.16(m,2H),1.14(d,J=6.9Hz,12H).

[0198] Compound 6:

[0199]

[0200] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 3,4-dimethoxyphenyl isocyanate (0.12 g, 0.66 mmol) were converted into compound 6 and purified by silica gel column chromatography. A yellow solid (20 mg, 0.04 mmol, 5-step yield 2.0%) was obtained.

[0201] LC-MS(ESI)[M+H] + :477.9Retention time:1.934min.HPLC purity=100.00%.

[0202] 1 H NMR (400MHz, Chloroform-d) δ8.93 (s, 1H), 8.53 (s, 1H), 8.08 (d, J = 2.7Hz, 1H), 7.59 (dd, J = 8.9, 2.8Hz, 1H), 7.42-7. 35(m,3H),7.23-7.15(m,2H),7.09-7.04(m,2H),6.96(dd,J=8.3,2.4Hz,1H),6.87(m,2H),3.73(s,3H),3.70(s,3H).

[0203] Compound 7:

[0204]

[0205] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and 4-methoxy-2-tolyl isocyanate (0.22 g, 1.34 mmol) were converted into compound 7 and purified by silica gel column chromatography. A pale yellow solid (50 mg, 0.11 mmol, 5.3% yield in 5 steps) was obtained.

[0206] LC-MS(ESI)[M+H] + :461.8.Retention time:1.996min.HPLC purity=95.79%.

[0207] 1 H NMR(400MHz,Chloroform-d)δ9.32(s,1H),8.10(d,J=2.7Hz,1H),7.98(s,1H),7.60(dd,J=8.8,2.7Hz,1H),7.47(m,1H),7.36 (m,3H),7.16(d,J=7.9Hz,1H),7.08-7.03(m,2H),6.95(d,J=8.1Hz,1H),6.78(m,1H),6.72(m,1H),3.71(s,3H),2.20(s,4H).

[0208] Compound 8:

[0209]

[0210] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 3,4-(methylenedioxy)phenyl isocyanate (0.11 g, 0.67 mmol) were converted into compound 8 and purified by silica gel column chromatography. A white solid (10 mg, 0.02 mmol, 5-step yield 1.03%) was obtained.

[0211] LC-MS(ESI)[M+H] + :461.9.Retention time:1.979min.HPLC purity=100.00%.

[0212] 1H NMR(400MHz,Chloroform-d)δ9.20(s,1H),8.85(s,1H),8.07(d,J=2.7Hz,1H),7.58(dd,J=9.0,2.7Hz,1H),7.42-7.31( m,3H),7.23-7.13(m,2H),7.09-7.03(m,2H),6.95(dd,J=8.4,2.3Hz,1H),6.82(m,1H),6.79-6.73(m,1H),5.96(s,2H).

[0213] Compound 9:

[0214]

[0215] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and 2-methoxyphenyl isocyanate (0.20 g, 1.34 mmol) were converted into compound 9 and purified by silica gel column chromatography. A pale yellow solid (40 mg, 0.09 mmol, 4.2% yield in 5 steps) was obtained.

[0216] LC-MS(ESI)[M+H] + :447.9.Retention time:2.063min.HPLC purity=100.00%.

[0217] 1 H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.24(s,1H),8.16-8.08(m,2H),7.62(dd,J=8.8,2.7Hz,1H),7.45 -7.36(m,3H),7.19(d,J=8.0Hz,1H),7.12-7.07(m,2H),7.04(m,1H),6.97(m,2H),6.91(m,1H),3.89(s,3H).

[0218] Compound 10:

[0219]

[0220] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-methoxyphenol (0.08 mg, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-methoxyphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.45 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.68 mmol) were converted into compound 10 and purified by silica gel column chromatography. A yellow solid (20 mg, 0.04 mmol, 5-step yield 2.1%) was obtained.

[0221] LC-MS(ESI)[M+H] + :458.0Retention time:2.056min.HPLC purity=100.00%.

[0222] 1 H NMR(400MHz,Chloroform-d)δ9.67(s,1H),8.13(d,J=7.8Hz,1H),8.10-8.04(m,2H),7.61(dd,J=8.8,2.7Hz,1H),7.39-7.24(m,3H),6.96( m,4H),6.74(dd,J=8.4,2.5Hz,1H),6.67(d,J=2.6Hz,1H),6.60(d,J=8.1Hz,1H),4.15(q,J=6.9Hz,2H),3.75(s,3H),1.43(t,J=6.9Hz,3H).

[0223] Compound 11:

[0224]

[0225] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and 2-trifluoromethylphenyl isocyanate (0.25 g, 1.34 mmol) were converted into compound 11 and purified by silica gel column chromatography. A grayish-white solid (46 mg, 0.09 mmol, 5-step yield 4.2%) was obtained.

[0226] LC-MS(ESI)[M+H] + :486.0.Retention time:2.101min.HPLC purity=100.00%.

[0227] 1 H NMR(400MHz,Chloroform-d)δ9.69(s,1H),8.13-8.05(m,2H),7.96(d,J=8.2Hz,1H),7.75-7.61(m, 3H),7.41(d,J=4.7Hz,3H),7.31(t,J=7.7Hz,1H),7.19(m,1H),7.10(m,2H),6.99(d,J=8.3Hz,1H).

[0228] Compound 12:

[0229]

[0230] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.19 g, 0.45 mmol) and phenyl 3-cyanoisocyanate (0.10 g, 0.68 mmol) were converted into compound 12 and purified by silica gel column chromatography. A white solid (17 mg, 0.04 mmol, 5-step yield 2.1%) was obtained.

[0231] LC-MS(ESI)[M+H] + :442.8.Retention time:2.007min.HPLC purity=100.00%.

[0232] 1 H NMR(400MHz,Chloroform-d)δ9.19(s,1H),9.04(s,1H),8.10(d,J=2.6Hz,1H),7.97(s,1H),7.74-7.68(m,1H),7.61(dd,J=9. 0,2.7Hz,1H),7.49(t,J=7.9Hz,1H),7.46-7.35(m,4H),7.18(d,J=8.0Hz,1H),7.12-7.06(m,2H),6.97(dd,J=8.4,2.4Hz,1H).

[0233] Compound 13:

[0234]

[0235] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-methylphenol (0.07 mg, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-methylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.17 g, 0.40 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.60 mmol) were converted into compound 13 and purified by silica gel column chromatography. A white solid (20 mg, 0.04 mmol, 5-step yield 2.1%) was obtained.

[0236] LC-MS(ESI)[M+H] + :442.0.Retention time:2.129min.HPLC purity=100.00%.

[0237] 1H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.12(m,J=7.9,1.7Hz,1H),8.05(q,J=1.6Hz,2H),7.59(m,J=8.9,2. 7Hz,1H),7.35-7.22(m,3H),7.03-6.81(m,7H),4.13(q,J=6.9Hz,2H),2.29(s,3H),1.41(dd,J=7.6,6.3Hz,3H).

[0238] Compound 14:

[0239]

[0240] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-ethylphenol (0.08 mg, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-ethylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.45 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.68 mmol) were converted into compound 14 and purified by silica gel column chromatography. A pale yellow solid (15 mg, 0.03 mmol, 5-step yield 1.6%) was obtained.

[0241] LC-MS(ESI)[M+H] + :456.1.Retention time:2.186min.HPLC purity=100.00%.

[0242] 1 H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.12(m,1H),8.05(m,2H),7.59(dd,J=8.9,2.7Hz,1H),7. 35-7.22(m,3H),7.03-6.81(m,7H),4.13(q,J=6.9Hz,2H),2.29(s,3H),1.41(dd,J=7.6,6.3Hz,3H).

[0243] Compound 15:

[0244]

[0245] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and o-tolyl isocyanate (0.18 g, 1.34 mmol) were converted into compound 15 and purified by silica gel column chromatography. A pale pink solid (41 mg, 0.10 mmol, 4.5% yield in 5 steps) was obtained.

[0246] LC-MS(ESI)[M+H] + :431.8.Retention time:2.041min.HPLC purity=100.00%.

[0247] 1 H NMR(400MHz,Chloroform-d)δ9.33(s,1H),8.08(d,J=2.7Hz,1H),7.92(s,1H),7.80(d,J=8.0Hz,1H),7. 62(dd,J=8.9,2.7Hz,1H),7.37(m,3H),7.22-7.11(m,3H),7.10-7.04(m,2H),6.96(m,2H),2.24(s,3H).

[0248] Compound 16:

[0249]

[0250] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-cyanophenol (0.08 mg, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-cyanophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.46 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.68 mmol) were converted into compound 16 and purified by silica gel column chromatography. A yellow solid (27 mg, 0.06 mmol, 5-step yield 2.8%) was obtained.

[0251] LC-MS(ESI)[M+H] + :452.9.Retention time:2.022min.HPLC purity=100.00%.

[0252] 1 H NMR(400MHz,Chloroform-d)δ9.74(s,1H),8.14-8.04(m,3H),7.66(dd,J=8.7,2.7Hz,1H),7.56(m,2H),7.47-7.39 (m,3H),7.32(m,1H),7.11(d,J=8.8Hz,1H),7.01(m,1H),6.90(m,2H),4.13(q,J=6.9Hz,2H),1.41(t,J=6.9Hz,3H).

[0253] Compound 17:

[0254]

[0255] Following the general synthetic procedure GP1, GP2.1, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.14 g, 0.33 mmol) and phenyl 3-acetyl isocyanate (0.08 g, 0.50 mmol) were converted into compound 17 and purified by silica gel column chromatography. A white solid (10 mg, 0.02 mmol, 5-step yield 1.0%) was obtained.

[0256] LC-MS(ESI)[MH] + :459.9.Retention time:1.963min.HPLC purity=98.88%.

[0257] 1H NMR(400MHz,Chloroform-d)δ9.22(s,1H),9.09(s,1H),8.11(d,J=2.7Hz,1H),8.08(m,1H),7.68(m, 1H),7.63-7.57(m,2H),7.46-7.35(m,4H),7.17(m,1H),7.09-7.05(m,2H),6.96(m,1H),2.55(s,3H).

[0258] Compound 18:

[0259]

[0260] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and 2-nitrophenyl isocyanate (0.22 g, 1.34 mmol) were converted to compound 18 and purified by silica gel column chromatography. A yellow solid (30 mg, 0.06 mmol, 5-step yield 3.1%) was obtained.

[0261] LC-MS(ESI)[M+H] + :462.9.Retention time:2.154min.HPLC purity=100.00%.

[0262] 1 H NMR(400MHz,Chloroform-d)δ10.16(s,1H),9.63(s,1H),8.33-8.28(m,1H),8.10(m,2H),7.74-7 .64(m,2H),7.44-7.36(m,3H),7.25-7.16(m,2H),7.12-7.07(m,2H),6.98(dd,J=8.4,2.4Hz,1H).

[0263] Compound 19:

[0264]

[0265] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.32 g, 0.71 mmol) and 3,4-difluorophenyl isothiocyanate (0.16 g, 1.07 mmol) were converted into compound 19 and purified by silica gel column chromatography. A brown solid (22 mg, 0.05 mmol, 5-step yield 2.3%) was obtained.

[0266] LC-MS(ESI)[M+H] + :453.9.Retention time:2.404min.HPLC purity=100.00%.

[0267] 1 H NMR(400MHz,Chloroform-d)δ9.09(s,1H),8.91(s,1H),8.08(d,J=2.7Hz,1H),7.66(m,1H),7.60(dd ,J=8.9,2.7Hz,1H),7.44-7.29(m,4H),7.16(m,2H),7.11-7.04(m,2H),6.97(dd,J=8.3,2.3Hz,1H).

[0268] Compound 20:

[0269]

[0270] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.30 g, 0.67 mmol) and o-chlorophenyl isocyanate (0.15 g, 1.00 mmol) were converted into compound 20 and purified by silica gel column chromatography. A pale yellow solid (9 mg, 0.02 mmol, 0.9% yield in 5 steps) was obtained.

[0271] LC-MS(ESI)[M+H] + :451.9.Retention time:2.103min.HPLC purity=100.00%.

[0272] 1 H NMR (400MHz, Chloroform-d): 1 H NMR (400MHz, DMSO) δ9.75(s,1H),8.32(s,1H),8.17(d,J=8.3Hz,1H),8.11(d,J=2.7Hz,1H),7.64(dd,J=8.8,2.8Hz,1H),7.48(d,J=8 .0Hz,1H),7.41(d,J=6.9Hz,3H),7.32(t,J=7.8Hz,1H),7.19(dd,J=7.7,1.9Hz,1H),7.14-7.05(m,3H),6.99(dd,J=8.3,2.4Hz,1H).

[0273] Compound 21:

[0274]

[0275] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.27 g, 0.60 mmol) and o-fluorophenyl isocyanate (0.12 g, 0.90 mmol) were converted into compound 21 and purified by silica gel column chromatography. A pale yellow solid (22 mg, 0.05 mmol, 5-step yield 2.3%) was obtained.

[0276] LC-MS(ESI)[MH] + :435.8.Retention time:2.041min.HPLC purity=100.00%.

[0277] 1H NMR (400MHz, Chloroform-d): δ9.37(s,1H),8.53(s,1H),8.17-8.07(m,2H),7.58(dt,J=9.0,2.2Hz,1H),7.44- 7.35(m,3H),7.24(dd,J=11.6,8.2Hz,1H),7.15(dd,J=17.9,8.3Hz,2H),7.11-7.06(m,2H),7.05-6.95(m,2H).

[0278] Compound 22:

[0279]

[0280] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.40 g, 0.89 mmol) and 1-naphthyl isocyanate (0.23 g, 1.34 mmol) were converted into compound 22 and purified by silica gel column chromatography. A yellow solid (43 mg, 0.09 mmol, 4.4% yield in 5 steps) was obtained.

[0281] LC-MS(ESI)[M+H] + :467.9.Retention time:2.09min.HPLC purity=100.00%.

[0282] 1 H NMR (400MHz, Chloroform-d) δ9.36 (s, 1H), 8.77 (s, 1H), 8.18-8.08 (m, 2H), 7.98 (d, J = 7.5Hz, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.66 (dd, J = 8. 9,2.1Hz,2H),7.57(m,2H),7.49(m,1H),7.45-7.34(m,3H),7.18(dd,J=8.0,1.8Hz,1H),7.12-7.06(m,2H),6.98(dd,J=8.4,2.3Hz,1H).

[0283] Compound 23:

[0284]

[0285] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-chlorophenol (0.07 ml, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.30 g, 0.67 mmol) and o-fluorophenyl isocyanate (0.17 g, 1.00 mmol) were converted into compound 23 and purified by silica gel column chromatography. A pale pink solid (26 mg, 0.06 mmol, 5-step yield 2.6%) was obtained.

[0286] LC-MS(ESI)[MH] + :469.9.Retention time:2.135min.HPLC purity=93.66%.

[0287] 1 H NMR(400MHz,Chloroform-d)δ9.68(s,1H),8.13(dd,J=8.0,1.8Hz,1H),8.10-8.04(m,2H),7.61(dd,J=8.8, 2.6Hz,1H),7.37-7.24(m,3H),6.99-6.85(m,3H),6.73(d,J=8.9Hz,1H),6.66(m,1H),6.60(d,J=8.1Hz,1H).

[0288] Compound 24:

[0289]

[0290] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.04 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-(trifluoromethoxy)phenyl isocyanate (0.14 g, 0.67 mmol) were converted into compound 24 and purified by silica gel column chromatography. A pale pink solid (65 mg, 0.13 mmol, 5-step yield 11.1%) was obtained.

[0291] LC-MS(ESI)[M+H] + :501.8.Retention time:2.423.HPLC purity=98.32%.

[0292] 1 H NMR(400MHz,Chloroform-d)δ9.60(s,1H),8.46(s,1H),8.26(dd,J=8.3,1.8Hz,1H),8.11(d,J=2.6Hz,1H),7.64(dd ,J=9.0,2.7Hz,1H),7.47-7.33(m,5H),7.20(dd,J=7.9,1.9Hz,1H),7.16-7.08(m,3H),6.99(dd,J=8.4,2.4Hz,1H).

[0293] Compound 25:

[0294]

[0295] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.04 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-methoxy-4-trifluoromethylbenzene isocyanate (0.14 g, 0.67 mmol) were converted to compound 25 and purified by silica gel column chromatography. A pale pink solid (33 mg, 0.06 mmol, 5.5% yield in 5 steps) was obtained.

[0296] LC-MS(ESI)[MH] + :515.9.Retention time:2.266.HPLC purity=100.00%.

[0297] 1 H NMR(400MHz,Chloroform-d)δ9.75(s,1H),8.59-8.54(m,1H),8.51(s,1H),8.11(d,J=2.6Hz,1H),7.62(dd,J=8.9,2.7H z,1H),7.47-7.37(m,3H),7.37-7.32(m,1H),7.25-7.17(m,2H),7.10(m,2H),6.99(dd,J=8.3,2.4Hz,1H),3.99(s,3H).

[0298] Compound 26:

[0299]

[0300] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and p-isopropylphenol (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(4-isopropylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.66 mmol) were converted into compound 26 and purified by silica gel column chromatography. A pale pink solid (27 mg, 0.06 mmol, 4.9% yield in 5 steps) was obtained.

[0301] LC-MS(ESI)[M+H] + :470.0.Retention time:2.29.HPLC purity=96.27%.

[0302] 1 H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.13(d,J=7.8Hz,1H),8.09-8.03(m,2H),7.58(dd,J=9.0,2.7Hz,1H),7.36-7.24(m, 4H),7.00(m,3H),6.97-6.85(m,3H),4.14(q,J=6.9Hz,2H),2.91(h,J=6.9Hz,1H),1.43(t,J=6.9Hz,3H),1.21(d,J=6.9Hz,6H).

[0303] Compound 27:

[0304]

[0305] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and p-phenoxyphenol (0.07 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(4-phenoxyphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.39 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.59 mmol) were converted into compound 27 and purified by silica gel column chromatography. A yellow solid (18 mg, 0.03 mmol, 5-step yield 3.0%) was obtained.

[0306] LC-MS(ESI)[MH] + :518.0.Retention time:2.307.HPLC purity=96.57%.

[0307] 1 H NMR (400MHz, Chloroform-d) δ9.64 (s, 1H), 8.12 (dd, J = 7.8, 1.8 Hz, 1H), 8.08-8.02 (m, 2H), 7.59 (dd, J = 8. 9,2.7Hz,1H),7.37(m,4H),7.09(m,5H),7.03-6.85(m,6H),4.13(q,J=6.9Hz,2H),1.41(t,J=6.9Hz,3H).

[0308] Compound 28:

[0309]

[0310] Following the general synthetic procedure GP1, GP2.1, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chloro-4-fluorophenol (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chloro-4-fluorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.43 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.64 mmol) were converted to compound 28 and purified by silica gel column chromatography. A pale yellow solid (24 mg, 0.05 mmol, 5-step yield 4.3%) was obtained.

[0311] LC-MS(ESI)[M+H] + :479.8.Retention time:2.16.HPLC purity=97.91%.

[0312] 1 H NMR(400MHz,Chloroform-d)δ9.71(s,1H),8.11(d,J=7.8Hz,1H),8.09-8.04(m,2H),7.63(dd,J=8.8,2.7Hz,1H ),7.46-7.38(m,3H),7.25(m,1H),7.10-6.98(m,3H),6.90(m,2H),4.13(q,J=6.9Hz,2H),1.41(t,J=6.9Hz,3H).

[0313] Compound 29:

[0314]

[0315] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and phenol (0.03 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-phenoxy-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.48 mmol) and 2-ethoxyphenyl isocyanate (0.12 g, 0.72 mmol) were converted into compound 29 and purified by silica gel column chromatography. A pale yellow solid (15 mg, 0.04 mmol, 3.0% yield in 5 steps) was obtained.

[0316] LC-MS(ESI)[M+H] + :427.8.Retention time:2.054.HPLC purity=100.00%.

[0317] 1H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.12(dd,J=7.9,1.8Hz,1H),8.07-8.02(m,2H),7.59(dd,J=8.8,2.8Hz,1H),7.39(t,J=7.8Hz,2 H),7.33(s,2H),7.14(t,J=7.4Hz,1H),7.05(d,J=8.0Hz,2H),7.00(m,1H),6.97-6.84(m,3H),4.13(q,J=7.0Hz,2H),1.41(t,J=6.9Hz,3H).

[0318] Compound 30:

[0319]

[0320] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3,4-methylenedioxyphenol (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3,4-methylenedioxyphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.65 mmol) were converted into compound 30 and purified by silica gel column chromatography. A pale yellow solid (68 mg, 0.14 mmol, 5-step yield 12.3%) was obtained.

[0321] LC-MS(ESI)[M+H] + :472.0.Retention time:2.04.HPLC purity=96.88%.

[0322] 1H NMR(400MHz,Chloroform-d)δ9.62(s,1H),8.11(d,J=7.8Hz,1H),8.03(d,J=3.6Hz,2H),7.56(dd,J=8.8,2.7Hz,1H),7.30(s,2H),7.00(d,J=8.0H z,1H),6.89(dq,J=14.5,7.2Hz,4H),6.71(d,J=2.4Hz,1H),6.53(dd,J=8 .3,2.4Hz,1H),6.03(s,2H),4.12(q,J=6.9Hz,2H),1.41(t,J=6.9Hz,3H).

[0323] Compound 31:

[0324]

[0325] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2,3,5-trimethylphenol (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(2,3,5-trimethylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.65 mmol) were converted into compound 31 and purified by silica gel column chromatography. A white solid (66 mg, 0.14 mmol, 5-step yield 12.3%) was obtained.

[0326] LC-MS(ESI)[M+H] + :469.9.Retention time:2.261.HPLC purity=100.00%.

[0327] 1H NMR(400MHz,Chloroform-d)δ9.55(s,1H),8.11(dd,J=7.9,1.8Hz,1H),8.04(d,J=2.7Hz,1H),8.00(s,1H),7.47(dd,J=8.9,2.8Hz,1H),7.30(s,2H),6.99 (m,1H),6.94-6.83(m,3H),6.63(d,J=1.8Hz,1H),6.53(d,J=8.9Hz,1H),4.11 (q,J=7.0Hz,2H),2.22(d,J=13.3Hz,6H),2.03(s,3H),1.40(t,J=6.9Hz,3H).

[0328] Compound 32:

[0329]

[0330] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2-bromo-5-methylphenol (0.07 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(2-bromo-5-methylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.39 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.59 mmol) were converted into compound 32 and purified by silica gel column chromatography. A pale yellow solid (40 mg, 0.08 mmol, 6.6% yield in 5 steps) was obtained.

[0331] LC-MS(ESI)[M+H] + :519.8.Retention time:2.241.HPLC purity=95.71%.

[0332] 1H NMR(400MHz,Chloroform-d)δ9.62(s,1H),8.11(dd,J=7.9,1.8Hz,1H),8.06(d,J=2.7Hz,1H),8.02(s,1H),7.58-7.55(m,1H),7.53(dd,J=8.9,2.8Hz, 1H),7.32(s,2H),7.23-7.20(m,1H),7.02-6.94(m,2H),6.89(m,2H),6.67( d,J=8.9Hz,1H),4.12(q,J=6.9Hz,2H),2.31(s,3H),1.40(t,J=6.9Hz,3H).

[0333] Compound 33:

[0334]

[0335] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2-trifluoromethylphenol (0.06 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-trifluoromethylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.41 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.62 mmol) were converted into compound 33 and purified by silica gel column chromatography. A pale yellow solid (23 mg, 0.05 mmol, 4.0% yield in 5 steps) was obtained.

[0336] LC-MS(ESI)[M+H] + :495.9.Retention time:2.407.HPLC purity=97.38%.

[0337] 1 H NMR(400MHz,Chloroform-d)δ9.73(s,1H),8.15-8.06(m,3H),7.77(dd,J=8.0,1.6Hz,1H),7.64(m,2 H),7.36-7.24(m,3H),7.00(m,1H),6.97-6.84(m,4H),4.13(q,J=6.9Hz,2H),1.41(t,J=7.0Hz,3H).

[0338] Compound 34:

[0339]

[0340] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2-isopropyl-5-methylphenol (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(2-isopropyl-5-methylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.42 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.64 mmol) were converted into compound 34 and purified by silica gel column chromatography. A yellow solid (32 mg, 0.07 mmol, 5-step yield 5.7%) was obtained.

[0341] LC-MS(ESI)[M+H] + :484.0.Retention time:2.533.HPLC purity=100.00%.

[0342] 1 H NMR (400MHz, Chloroform-d) δ9.58 (s, 1H), 8.11 (dd, J = 7.8, 1.8Hz, 1H), 8.07- 8.00(m,2H),7.51(dd,J=8.9,2.8Hz,1H),7.34-7.25(m,3H),7.00(m,2H),6.8 9(m,2H),6.72-6.68(m,1H),6.62(d,J=8.9Hz,1H),4.12(q,J=6.9Hz,2H),3.2 0(p,J=6.9Hz,1H),2.23(s,3H),1.40(t,J=6.9Hz,3H),1.14(d,J=6.8Hz,6H).

[0343] Compound 35:

[0344]

[0345] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and tetrahydronaphthol (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-tetrahydronaphthoxy-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.43 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.64 mmol) were converted into compound 35 and purified by silica gel column chromatography. A white solid (51 mg, 0.10 mmol, 8.5% yield in 5 steps) was obtained.

[0346] LC-MS(ESI)[M+H] + :482.0.Retention time:2.498.HPLC purity=100.00%.

[0347] 1 H NMR(400MHz,Chloroform-d)δ9.56(s,1H),8.10(dd,J=7.9,1.8Hz,1H),8.05-7.98(m ,2H),7.49(dd,J=8.9,2.7Hz,1H),7.30(s,2H),7.12(t,J=7.8Hz,1H),7.01-6.82(m, 4H),6.72(dd,J=8.1,1.2Hz,1H),6.61(d,J=8.9Hz,1H),4.11(q,J=7.0Hz,2H),2.75( d,J=6.2Hz,2H),2.61(d,J=5.4Hz,2H),1.69(p,J=3.8Hz,4H),1.40(t,J=7.0Hz,3H).

[0348] Compound 36:

[0349]

[0350] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-dimethylaminophenol (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-dimethylaminophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.66 mmol) were converted into compound 36 and purified by silica gel column chromatography. A pale purple solid (57 mg, 0.12 mmol, 5-step yield 10.4%) was obtained.

[0351] LC-MS(ESI)[M+H] + :471.1.Retention time:2.311.HPLC purity=98.70%.

[0352] 1 H NMR(400MHz,Chloroform-d)δ9.61(s,1H),8.11(dd,J=7.8,1.8Hz,1H),8.03(m, 2H),7.56(dd,J=8.9,2.8Hz,1H),7.26(s,2H),7.16(t,J=8.2Hz,1H),7.00(m,1H ),6.95-6.84(m,3H),6.51(dd,J=8.3,2.5Hz,1H),6.46(t,J=2.3Hz,1H),6.28(d d,J=7.9,2.2Hz,1H),4.12(q,J=7.0Hz,2H),2.88(s,6H),1.41(t,J=6.9Hz,3H).

[0353] Compound 37:

[0354]

[0355] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 4-cyclopropylphenol (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(4-cyclopropylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.66 mmol) were converted into compound 36 and purified by silica gel column chromatography. A pale purple solid (57 mg, 0.07 mmol, 6.4% yield in 5 steps) was obtained.

[0356] LC-MS(ESI)[M+H] + :467.9.Retention time:2.43.HPLC purity=98.42%.

[0357] 1 H NMR(400MHz,Chloroform-d)δ9.62(s,1H),8.11(dd,J=7.9,1.8Hz,1H),8.07-8.01(m,2H),7.55(dd,J=8.9,2.8Hz,1H),7.29(s,2H),7.12-7.06(m,2H),6. 99(m,1H),6.93(m,3H),6.90-6.83(m,2H),4.12(q,J=7.0Hz,2H),1.90(tt,J= 8.4,5.1Hz,1H),1.40(t,J=7.0Hz,3H),0.96-0.89(m,2H),0.66-0.59(m,2H).

[0358] Compound 38:

[0359]

[0360] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 5-hydroxyisoquinoline (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-N-(2,4-dimethoxybenzyl)-2-(isoquinoline-5-yloxy)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.43 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.64 mmol) were converted into compound 38 and purified by silica gel column chromatography. A pale purple solid (51 mg, 0.11 mmol, 5-step yield 9.1%) was obtained.

[0361] LC-MS(ESI)[MH] + :476.9.Retention time:1.753.HPLC purity=100.00%.

[0362] 1 H NMR(400MHz,Chloroform-d)δ9.69(s,1H),9.38(s,1H),8.53(d,J=5.9Hz,1H),8.17-8.09(m,2H),8.07-8.02(m,2H),7.94(d,J=8.2Hz,1H),7.65(t,J=7 .9Hz,1H),7.55(dd,J=8.9,2.8Hz,1H),7.48(s,2H),7.24(m,J=7.6Hz,1H),7 .00(m,1H),6.96-6.84(m,3H),4.12(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H).

[0363] Compound 39:

[0364]

[0365] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-phenylphenol (0.06 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 2-([1,1'-biphenyl]-3-acyloxy)-5-amino-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.41 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.61 mmol) were converted into compound 39 and purified by silica gel column chromatography. A white solid (12 mg, 0.02 mmol, 5-step yield 2.0%) was obtained.

[0366] LC-MS(ESI)[M+H] + :503.9.Retention time:2.487.HPLC purity=97.63%.

[0367] 1 H NMR(400MHz,Chloroform-d)δ9.67(s,1H),8.12(dd,J=7.9,1.8Hz,1H),8.08(d,J=2.7Hz,1H),8.05(s,1H),7.62(m,3H ),7.51-7.42(m,4H),7.41-7.32(m,4H),7.07-6.99(m,3H),6.90(m,2H),4.13(q,J=6.9Hz,2H),1.41(t,J=7.0Hz,3H).

[0368] Compound 40:

[0369]

[0370] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(2-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.67 mmol) were converted into compound 40 and purified by silica gel column chromatography. A yellow solid (65 mg, 0.14 mmol, 5-step yield 12.0%) was obtained.

[0371] LC-MS(ESI)[M+H] + :461.9.Retention time:2.385.HPLC purity=97.85%.

[0372] 1 H NMR(400MHz,Chloroform-d)δ9.69(s,1H),8.11(dd,J=7.8,1.8Hz,1H),8.09-8.03(m,2H),7.62(dd,J=8.9, 2.8Hz,1H),7.44-7.35(m,4H),7.07-6.98(m,4H),6.89(m,2H),4.12(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H).

[0373] Compound 41:

[0374]

[0375] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 4-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.67 mmol) were converted into compound 41 and purified by silica gel column chromatography. A pale yellow solid (64 mg, 0.14 mmol, 5-step yield 11.9%) was obtained.

[0376] LC-MS(ESI)[M+H] + :461.9.Retention time:2.357.HPLC purity=100.00%.

[0377] 1 H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.15-8.01(m,3H),7.57(m,2H),7.36(m,3H),7.23(m,1H),7.08(dd,J=8.2,1 .5Hz,1H),6.99(dd,J=8.1,1.6Hz,1H),6.89(m,2H),6.73(d,J=8.8Hz,1H),4.12(q,J=6.9Hz,2H),1.40(t,J=7.0Hz,3H).

[0378] Compound 42:

[0379]

[0380] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-trifluoromethylphenol (0.06 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-trifluoromethylphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.41 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.62 mmol) were converted into compound 42 and purified by silica gel column chromatography. A pale yellow solid (75 mg, 0.14 mmol, 5-step yield 11.9%) was obtained.

[0381] LC-MS(ESI)[M+H] + :495.8.Retention time:2.420.HPLC purity=96.93%.

[0382] 1H NMR(400MHz,Chloroform-d)δ9.75(s,1H),8.16-8.04(m,3H),7.66(dd,J=8.9,2.8Hz,1H),7.59(t,J=8.0Hz,1H),7.46(d,J=9.6Hz,3H),7.36(t,J=2 .1Hz,1H),7.25(dd,J=8.2,2.5Hz,1H),7.11(d,J=8.8Hz,1H),7.00(dd,J= 8.0,1.6Hz,1H),6.90(m,2H),4.13(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H).

[0383] Compound 43:

[0384]

[0385] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.11 g, 0.67 mmol) were converted into compound 43 and purified by silica gel column chromatography. A pale yellow solid (46 mg, 0.10 mmol, 8.6% yield in 5 steps) was obtained.

[0386] LC-MS(ESI)[M+H] + :459.9.Retention time:2.384.HPLC purity=98.77%.

[0387] 1 H NMR(400MHz,Chloroform-d)δ9.14(s,1H),8.11(d,J=2.7Hz,1H),7.74(s,1H),7.61(dd,J=8.9,2.7Hz,1H),7 .42-7.32(m,3H),7.19-7.02(m,6H),6.96(m,1H),2.58(q,J=7.5Hz,2H),2.20(s,3H),1.12(t,J=7.5Hz,3H).

[0388] Compound 44:

[0389]

[0390] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 4-fluorophenyl isocyanate (0.09 g, 0.67 mmol) were converted into compound 44 and purified by silica gel column chromatography. A pale yellow solid (80 mg, 0.18 mmol, 5-step yield 15.7%) was obtained.

[0391] LC-MS(ESI)[M+H] + :436.0.Retention time:2.286.HPLC purity=95.12%.

[0392] 1 H NMR (400MHz, Chloroform-d) δ9.09 (s, 1H), 8.81 (s, 1H), 8.10 (d, J = 2.8Hz, 1H), 7.60 (dd ,J=8.9,2.8Hz,1H),7.53-7.32(m,5H),7.22-7.04(m,5H),6.96(dd,J=8.2,2.4Hz,1H).

[0393] Compound 45:

[0394]

[0395] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-bromophenyl isocyanate (0.13 g, 0.67 mmol) were converted into compound 45 and purified by silica gel column chromatography. A white solid (85 mg, 0.18 mmol, 5-step yield 15.2%) was obtained.

[0396] LC-MS(ESI)[M+H] + :479.8.Retention time:2.319.HPLC purity=97.91%.

[0397] 1 H NMR(400MHz,Chloroform-d)δ9.79(s,1H),8.13(s,1H),8.11-8.04(m,2H),7.6 2(m,2H),7.46-7.30(m,4H),7.17(m,1H),7.12-7.05(m,2H),7.02-6.93(m,2H).

[0398] Compound 46:

[0399]

[0400] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-bromophenyl isocyanate (0.10 g, 0.67 mmol) were converted into compound 46 and purified by silica gel column chromatography. A white solid (53 mg, 0.12 mmol, 5-step yield 10.1%) was obtained.

[0401] LC-MS(ESI)[M+H] + :447.8.Retention time:2.239.HPLC purity=100.00%.

[0402] 1 H NMR(400MHz,Chloroform-d)δ8.94(s,1H),8.49(s,1H),8.08(d,J=2.8Hz,1H),7.59(dd,J=8.9,2.8Hz,1H),7.45-7.3 1(m,5H),7.17(dd,J=7.9,2.0Hz,1H),7.10-7.02(m,2H),6.96(dd,J=8.3,2.4Hz,1H),6.89-6.82(m,2H),3.71(s,3H).

[0403] Compound 47:

[0404]

[0405] Following the general synthetic procedure GP1, GP2.1, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3,5-dichlorophenol (0.06 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3,5-dichlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.41 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.62 mmol) were converted into compound 47 and purified by silica gel column chromatography. A yellow solid (38 mg, 0.14 mmol, 5-step yield 11.9%) was obtained.

[0406] LC-MS(ESI)[M+H] + :495.8.Retention time:2.486.HPLC purity=100.00%.

[0407] 1 H NMR(400MHz,Chloroform-d)δ9.78(s,1H),8.18-8.05(m,3H),7.68(dd,J=8.8,2.7Hz,1H),7.45(s,2H),7.33(t,J=1.9 Hz,1H),7.20(d,J=8.8Hz,1H),7.01(dd,J=10.0,1.8Hz,3H),6.90(m,2H),4.13(q,J=6.9Hz,2H),1.41(t,J=7.0Hz,3H).

[0408] Compound 48:

[0409]

[0410] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 4-(pyrrolidine-1-carbonyl)phenol (0.07 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-(pyrrolidine-1-carbonyl)phenoxy)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.10 g, 0.20 mmol) and 2-ethoxyphenyl isocyanate (0.05 g, 0.30 mmol) were converted into compound 48 and purified by silica gel column chromatography. A white solid (10 mg, 0.02 mmol, 5-step yield 1.7%) was obtained.

[0411] LC-MS(ESI)[M+H] + :509.0.Retention time:2.231.HPLC purity=99.37%.

[0412] 1 H NMR(400MHz,Chloroform-d)δ9.81(s,1H),8.19(s,1H),8.17-8.10(m,2H),7.77(dd,J=8.4,2.3Hz,1H),7.54-7.48(m,2H),7.45-7.39(m,2H),7.2 7-7.20(m,3H),7.01(dd,J=8.1,1.6Hz,1H),6.91(m,2H),4.14(q,J=7.0H z,2H),3.46(dt,J=12.1,6.4Hz,4H),1.85(m,4H),1.42(t,J=7.0Hz,3H).

[0413] Compound 49:

[0414]

[0415] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.66 mmol) were converted into compound 49 and purified by silica gel column chromatography. A white solid (35 mg, 0.08 mmol, 6.5% yield in 5 steps) was obtained.

[0416] LC-MS(ESI)[MH] + :459.8.Retention time:2.298.HPLC purity=100.00%.

[0417] 1 H NMR(400MHz,Chloroform-d)δ8.96(s,1H),8.50(s,1H),8.08(d,J=2.7Hz,1H),7.59(dd,J=8.8,2.7Hz,1H),7.45-7.30(m,5H),7. 17(dd,J=7.7,2.0Hz,1H),7.09-7.04(m,2H),6.99-6.93(m,1H),6.89-6.81(m,2H),3.97(q,J=6.9Hz,2H),1.30(t,J=6.9Hz,3H).

[0418] Compound 50:

[0419]

[0420] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.2 and GP5, the above intermediate (0.20 g, 0.44 mmol) and aniline (0.04 ml, 0.44 mmol) were converted into compound 50 and purified by silica gel column chromatography. A white solid (85 mg, 0.20 mmol, 5-step yield 17.4%) was obtained.

[0421] LC-MS(ESI)[M+H] + :417.9.Retention time:2.296.HPLC purity=100.00%.

[0422] 1 H NMR(400MHz,Chloroform-d)δ9.05(s,1H),8.72(s,1H),8.10(d,J=2.7Hz,1H),7.60(dd,J=8.9,2.7Hz,1H), 7.51-7.34(m,5H),7.28(t,J=7.8Hz,2H),7.17(dd,J=8.0,2.0Hz,1H),7.11-7.04(m,2H),7.02-6.93(m,2H).

[0423] Compound 51:

[0424]

[0425] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.2 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2,6-dibromoaniline (0.11 g, 0.44 mmol) were converted into compound 51 and purified by silica gel column chromatography. A white solid (22 mg, 0.04 mmol, 3.3% yield in 5 steps) was obtained.

[0426] LC-MS(ESI)[M+H] + :575.7.Retention time:2.321.HPLC purity=99.02%.

[0427] 1 H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.26(s,1H),8.13(d,J=2.7Hz,1H),7.72(d,J=8.0Hz,2H),7.62(dd ,J=8.9,2.7Hz,1H),7.42-7.32(m,3H),7.17(t,J=8.0Hz,2H),7.11-7.03(m,2H),6.96(dd,J=8.3,2.4Hz,1H).

[0428] Compound 52:

[0429]

[0430] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.2 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2,6-dibromo-4-isopropylaniline (0.13 g, 0.44 mmol) were converted into compound 52 and purified by silica gel column chromatography. A white solid (49 mg, 0.08 mmol, 6.8% yield in 5 steps) was obtained.

[0431] LC-MS(ESI)[M+H] + :619.6.Retention time:2.511.HPLC purity=98.76%.

[0432] 1 H NMR(400MHz,Chloroform-d)δ9.25(s,1H),8.17-8.10(m,2H),7.64-7.57(m,3H),7.40-7.31(m,3H),7.15( dd,J=8.0,2.0Hz,1H),7.09-7.03(m,2H),6.95(dd,J=8.3,2.4Hz,1H),2.92(m,1H),1.19(d,J=6.9Hz,6H).

[0433] Compound 53:

[0434]

[0435] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.2 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxy-4-fluoroaniline (0.07 g, 0.44 mmol) were converted into compound 53 and purified by silica gel column chromatography. A pale purple solid (33 mg, 0.07 mmol, 5-step yield 5.9%) was obtained.

[0436] LC-MS(ESI)[M+H] + :479.8.Retention time:2.416.HPLC purity=97.86%.

[0437] 1 H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.07(q,J=3.1Hz,2H),8.00(s,1H),7.63(dd,J=8.9,2.7Hz,1H),7.42-7.35(m,3H) ,7.17(m,1H),7.10-7.04(m,2H),7.00-6.92(m,2H),6.70(td,J=8.7,2.8Hz,1H),4.14(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H).

[0438] Compound 54:

[0439]

[0440] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and phenylboronic acid (0.04 mg, 0.36 mmol) were used as starting materials to synthesize 4-amino-N-(2,4-dimethoxybenzyl)-[1,1'-biphenyl]-2-sulfonamide intermediate without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.05 g, 0.12 mmol) and 2-ethoxyphenyl isocyanate (0.03 g, 0.19 mmol) were converted into compound 54 and purified by silica gel column chromatography. A white solid (5 mg, 0.01 mmol, 5-step yield 1.0%) was obtained.

[0441] LC-MS(ESI)[M+H] + :411.9.Retention time:2.313.HPLC purity=100.00%.

[0442] 1 H NMR (400MHz, Chloroform-d): δ9.80(s,1H),8.24-8.09(m,3H),7.77(dd,J=8.3,2.3Hz,1H),7.47-7.31(m,5H),7.24(d,J =8.3Hz,1H),7.13(s,2H),7.03(d,J=8.0Hz,1H),6.93(dt,J=21.5,7.5Hz,2H),4.16(q,J=7.0Hz,2H),1.50-1.39(m,3H).

[0443] Compound 55:

[0444]

[0445] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and pinacol ester of 4-methoxyphenylboronic acid (0.08 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 4-amino-N-(2,4-dimethoxybenzyl)-4'-methoxy-[1,1'-biphenyl]-2-sulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.05 g, 0.12 mmol) and 2-ethoxyphenyl isocyanate (0.03 g, 0.18 mmol) were converted into compound 55 and purified by silica gel column chromatography. A white solid (5 mg, 0.01 mmol, 5-step yield 1.0%) was obtained.

[0446] LC-MS(ESI)[M+H] + :441.9.Retention time:2.308.HPLC purity=94.93%.

[0447] 1 H NMR (400MHz, Chloroform-d): δ9.77(s,1H),8.23-8.09(m,3H),7.75(dt,J=8.4,1.9Hz,1H),7.37-7.29(m,2H),7.22(d,J =8.3Hz,1H),7.04(d,J=13.2Hz,3H),7.00-6.87(m,4H),4.16(q,J=6.9Hz,2H),3.80(d,J=1.4Hz,3H),1.49-1.39(m,3H).

[0448] Compound 56:

[0449]

[0450] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 1-methylindazole-4-boronic acid (0.06 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-N-(2,4-dimethoxybenzyl)-2-(1-methyl-1H-indazole-4-yl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.10 g, 0.22 mmol) and 2-ethoxyphenyl isocyanate (0.05 g, 0.33 mmol) were converted into compound 56 and purified by silica gel column chromatography. A white solid (15 mg, 0.03 mmol, 5-step yield 2.8%) was obtained.

[0451] LC-MS(ESI)[M+H] + :466.0.Retention time:2.228.HPLC purity=100.00%.

[0452] 1 H NMR(400MHz,Chloroform-d)δ9.83(s,1H),8.26-8.15(m,3H),7.80(dd,J=8.3,2.3Hz,1H),7.60(d,J=9.5Hz,2H),7.39(dd,J=8.4,7.0Hz,1H),7.32(d, J=8.3Hz,1H),7.16(d,J=7.0Hz,1H),7.09(s,2H),7.03(dd,J=8.0,1.6Hz,1 H), 6.92 (m, 2H), 4.15 (q, J = 7.0Hz, 2H), 4.07 (s, 3H), 1.44 (t, J = 7.0Hz, 3H).

[0453] Compound 57:

[0454]

[0455] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and pyrazole (0.02 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-N-(2,4-dimethoxybenzyl)-2-(1H-pyrazole-1-yl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.51 mmol) and 2-ethoxyphenyl isocyanate (0.13 g, 0.77 mmol) were converted into compound 57 and purified by silica gel column chromatography. A yellow solid (30 mg, 0.07 mmol, 6.4% yield in 5 steps) was obtained.

[0456] LC-MS(ESI)[M+H] + :402.0.Retention time:2.193.HPLC purity=100.00%.

[0457] 1 H NMR(400MHz,Chloroform-d)δ9.99(s,1H),8.25-8.08(m,4H),7.84(dd,J=8.6,2.5Hz,1H),7.78(d,J=1.9Hz,1H),7.57-7 .43(m,3H),7.04(dd,J=8.1,1.6Hz,1H),6.94(m,2H),6.51(t,J=2.1Hz,1H),4.16(q,J=7.0Hz,2H),1.44(t,J=7.0Hz,3H).

[0458] Compound 58:

[0459]

[0460] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 4-methyl-3-thiopheneboronic acid (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-methylthiophene-3-yl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.05 g, 0.12 mmol) and 2-ethoxyphenyl isocyanate (0.03 g, 0.18 mmol) were converted to compound 55 and purified by silica gel column chromatography. A white solid (5 mg, 0.01 mmol, 5-step yield 1.0%) was obtained.

[0461] LC-MS(ESI)[M+H] + :431.8.Retention time:2.353.HPLC purity=100.00%.

[0462] 1 H NMR(400MHz,Chloroform-d)δ9.86(s,1H),8.27-8.10(m,3H),7.75(dd,J=8.5,2.3Hz,1H),7.31(d,J=3.1Hz,1H),7. 17(d,J=8.3Hz,2H),7.03(d,J=8.0Hz,1H),6.99-6.86(m,3H),6.66(s,1H),4.16(q,J=7.0Hz,2H),2.06-1.93(m,6H).

[0463] Compound 59:

[0464]

[0465] Following the general synthetic procedure GP1, GP2.1, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 1-(difluoromethyl)pyrazole-4-boronic acid pinacol ester (0.09 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(1-(difluoromethyl)-1H-pyrazole-4-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.46 mmol) and 2-ethoxyphenyl isocyanate (0.12 g, 0.68 mmol) were converted into compound 59 and purified by silica gel column chromatography. A yellow solid (25 mg, 0.06 mmol, 5-step yield 4.7%) was obtained.

[0466] LC-MS(ESI)[M+H] + :451.9.Retention time:2.204.HPLC purity=94.36%.

[0467] 1 H NMR(400MHz,Chloroform-d)δ9.81(s,1H),8.41(d,J=2.6Hz,1H),8.25-8.09(m,3H),8.00(d,J=9.3Hz,1H),7.77(dd,J=8.4,2.4Hz,1H),7 .44(d,J=5.2Hz,3H),7.01(dd,J=8.0,1.7Hz,1H),6.91(dtd,J=21.6,7.5,1.7Hz,2H),4.14(q,J=7.0Hz,2H),1.41(td,J=7.0,2.5Hz,3H).

[0468] Compound 60:

[0469]

[0470] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3,4,5-trifluorophenylboronic acid (0.06 mg, 0.36 mmol) were used as starting materials to synthesize 4-amino-N-(2,4-dimethoxybenzyl)-3',4',5'-trifluoro-[1,1'-biphenyl]-2-sulfonamide intermediate without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethoxyphenyl isocyanate (0.11 g, 0.66 mmol) were converted into compound 60 and purified by silica gel column chromatography. A yellow solid (21 mg, 0.04 mmol, 5-step yield 3.8%) was obtained.

[0471] LC-MS(ESI)[M+H] + :465.9.Retention time:2.402.HPLC purity=100.00%.

[0472] 1 H NMR(400MHz,Chloroform-d)δ9.87(s,1H),8.23-8.10(m,3H),7.76(dd,J=8.4,2.3Hz,1H),7.37-7.23(m,5H), 7.01(dd,J=8.1,1.6Hz,1H), 6.91(dtd,J=22.9,7.5,1.7Hz,2H), 4.14(q,J=7.0Hz,2H), 1.42(t,J=7.0Hz,3H).

[0473] Compound 61:

[0474]

[0475] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and phenylboronic acid (0.04 mg, 0.36 mmol) were used as starting materials to synthesize a 4-amino-N-(2,4-dimethoxybenzyl)-[1,1'-biphenyl]-2-sulfonamide intermediate without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.50 mmol) and 2-ethoxyphenyl isocyanate (0.14 g, 0.75 mmol) were converted into compound 61 and purified by silica gel column chromatography. A yellow solid (78 mg, 0.18 mmol, 5-step yield 15.3%) was obtained.

[0476] LC-MS(ESI)[M+H] + :435.9.Retention time:2.323.HPLC purity=100.00%.

[0477] 1 H NMR (400MHz, Chloroform-d) δ9.74 (s, 1H), 8.24-8.07 (m, 2H), 7.96 (d, J = 8.2Hz, 1H), 7.79-7.61 (m, 3H), 7.44-7.13 (m, 9H).

[0478] Compound 62:

[0479]

[0480] Following the general synthetic procedure GP1, GP2.3, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-trifluoromethylphenylboronic acid (0.07 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 4-amino-N-(2,4-dimethoxybenzyl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-sulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.43 mmol) and 2-ethoxyphenyl isocyanate (0.10 g, 0.64 mmol) were converted into compound 62 and purified by silica gel column chromatography. A yellow solid (33 mg, 0.07 mmol, 5-step yield 5.9%) was obtained.

[0481] LC-MS(ESI)[M+H] + :480.0.Retention time:2.433.HPLC purity=100.00%.

[0482] 1H NMR(400MHz,Chloroform-d)δ9.84(s,1H),8.20(s,1H),8.14(dd,J=7.8,1.9Hz,2H),7.78(dd,J=8.4,2.3Hz,1H),7.73-7.65(m,3H),7.60(t,J=7.6Hz, 1H),7.38(s,2H),7.27(d,J=8.3Hz,1H),7.01(dd,J=8.1,1.6Hz,1H),6.91( dtd,J=22.0,7.5,1.7Hz,2H),4.14(q,J=7.0Hz,2H),1.42(t,J=6.9Hz,3H).

[0483] Compound 63:

[0484]

[0485] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and phenylboronic acid (0.04 mg, 0.36 mmol) were used as starting materials to synthesize 4-amino-N-(2,4-dimethoxybenzyl)-[1,1'-biphenyl]-2-sulfonamide intermediate without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.50 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.12 g, 0.75 mmol) were converted into compound 63 and purified by silica gel column chromatography. A yellow solid (5 mg, 0.01 mmol, 5-step yield 1.0%) was obtained.

[0486] LC-MS(ESI)[M+H] + :409.9.Retention time:2.274.HPLC purity=93.21%.

[0487] 1 H NMR (400MHz, Chloroform-d): δ9.17(s,1H),8.14(t,J=1.8Hz,1H),7.81(s,1H),7.73(dt,J=8.4,1.8Hz,1H),7.42-7.31(m ,5H),7.20(d,J=8.3Hz,1H),7.12(q,J=5.0Hz,3H),7.06(s,2H),2.61(q,J=7.5Hz,2H),2.24(s,3H),1.15(t,J=7.5Hz,3H).

[0488] Compound 64:

[0489]

[0490] Following the general synthetic procedure GP1, GP2.1, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 1-(difluoromethyl)pyrazole-4-boronic acid pinacol ester (0.09 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(1-(difluoromethyl)-1H-pyrazole-4-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.46 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.11 g, 0.69 mmol) were converted to compound 64 and purified by silica gel column chromatography. A white solid (30 mg, 0.07 mmol, 5.7% yield in 5 steps) was obtained.

[0491] LC-MS(ESI)[M+H] + :450.0.Retention time:2.456.HPLC purity=96.86%.

[0492] 1 H NMR(400MHz,Chloroform-d)δ9.19(s,1H),8.39(s,1H),8.14(d,J=2.3Hz,1H),7.98(d,J=6.0Hz,1H),7.87-7. 67(m,3H),7.45-7.33(m,3H),7.10(q,J=5.1Hz,3H),2.58(q,J=7.5Hz,2H),2.21(s,3H),1.13(t,J=7.5Hz,3H).

[0493] Compound 65:

[0494]

[0495] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and phenylboronic acid (0.04 mg, 0.36 mmol) were used as starting materials to synthesize a 4-amino-N-(2,4-dimethoxybenzyl)-[1,1'-biphenyl]-2-sulfonamide intermediate without further purification. Then, following the general synthetic steps GP4.2 and GP5, the above intermediate (0.20 g, 0.50 mmol) and 2,6-dibromo-4-isopropylaniline (0.15 g, 0.50 mmol) were converted into compound 65 and purified by silica gel column chromatography. A pale yellow solid (38 mg, 0.07 mmol, 5.7% yield in 5 steps) was obtained.

[0496] LC-MS(ESI)[M+H] + :567.1.Retention time:2.193.HPLC purity=95.12%.

[0497] 1 H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.24-8.14(m,2H),7.60(s,2H),7.41-7.30( m, 6H), 7.20 (d, J = 8.4Hz, 1H), 7.07 (s, 2H), 4.02 (q, J = 7.1Hz, 1H), 1.22 (d, J = 5.3Hz, 6H).

[0498] Compound 66:

[0499]

[0500] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 3-thiopheneboronic acid (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-N-(2,4-dimethoxybenzyl)-2-(thiophene-3-yl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.49 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.12 g, 0.74 mmol) were converted to compound 66 and purified by silica gel column chromatography. A white solid (22 mg, 0.05 mmol, 4.5% yield in 5 steps) was obtained.

[0501] LC-MS(ESI)[M+H]+ :415.8.Retention time:2.267.HPLC purity=95.94%.

[0502] 1 H NMR(400MHz,Chloroform-d)δ9.15(s,1H),8.12(d,J=2.3Hz,1H),7.77(s,1H),7.70(dd,J=8.4,2.3Hz,1H),7.56-7.50(m,2H),7.29(d,J =8.4Hz,1H),7.25(dd,J=4.8,1.5Hz,1H),7.10(q,J=4.9Hz,3H),7.05(s,2H),2.59(q,J=7.6Hz,2H),2.21(s,3H),1.13(t,J=7.5Hz,3H).

[0503] Compound 67:

[0504]

[0505] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 4-methyl-3-thiopheneboronic acid (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-methylthiophene-3-yl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.05 g, 0.12 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.03 g, 0.18 mmol) were converted to compound 67 and purified by silica gel column chromatography. A white solid (5 mg, 0.01 mmol, 5-step yield 1.0%) was obtained.

[0506] LC-MS(ESI)[MH] + :427.8.Retention time:2.3.HPLC purity=100.00%.

[0507] 1H NMR (400MHz, Chloroform-d): δ9.19(s,1H),8.14(d,J=2.3Hz,1H),7.79(s,1H),7.70(dd,J=8.4,2.3Hz,1H),7. 29(d,J=3.2Hz,1H),7.20-7.07(m,5H),6.81(s,2H),2.61(q,J=7.5Hz,2H),2.23(s,3H),1.15(t,J=7.5Hz,3H).

[0508] Compound 68:

[0509]

[0510] Following the general synthetic procedure GP1, GP2.3, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 1-cyclopropylpyrazole-4-boronic acid pinacol ester (0.08 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(1-cyclopropyl-1H-pyrazole-3-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.47 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.11 g, 0.70 mmol) were converted to compound 68 and purified by silica gel column chromatography. A yellow solid (28 mg, 0.06 mmol, 5-step yield 5.4%) was obtained.

[0511] LC-MS(ESI)[MH] + :440.0.Retention time:2.152.HPLC purity=97.56%.

[0512] 1 H NMR(400MHz,Chloroform-d)δ9.10(s,1H),8.09(d,J=2.4Hz,1H),7.99(s,1H),7.74(s,1H),7.70-7.62(m,2H),7.35(d,J=8.4Hz,1H),7. 17-7.06(m,5H),3.72(m,1H),2.58(q,J=7.5Hz,2H),2.20(s,3H),1.12(t,J=7.5Hz,3H),1.06(dd,J=5.1,2.6Hz,2H),1.00-0.92(m,2H).

[0513] Compound 69:

[0514]

[0515] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and pinacol ester of 2-methylphenylboronic acid (0.08 mg, 0.36 mmol) were used as starting materials to synthesize 4-amino-N-(2,4-dimethoxybenzyl)-2'-methyl-[1,1'-biphenyl]-2-sulfonamide intermediate without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.05 g, 0.12 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.03 g, 0.18 mmol) were converted into compound 69 and purified by silica gel column chromatography. A yellow solid (5 mg, 0.01 mmol, 5-step yield 1.0%) was obtained.

[0516] LC-MS(ESI)[M+H] + :423.9.Retention time:2.353.HPLC purity=100.00%.

[0517] 1 H NMR (400MHz, Chloroform-d): 1 H NMR (400MHz, DMSO) δ9.17(s,1H),8.15(t,J=1.9Hz,1H),7.79(s,1H),7.75-7.68(m,1H),7.24(d,J= 6.6Hz,2H),7.20-7.03(m,6H),6.89(s,2H),2.61(q,J=7.5Hz,2H),2.24(s,3H),1.19-1.12(m,3H).

[0518] Compound 70:

[0519]

[0520] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2-fluorophenylboronic acid (0.05 mg, 0.36 mmol) were used as starting materials to synthesize 4-amino-N-(2,4-dimethoxybenzyl)-2'-fluoro-[1,1'-biphenyl]-2-sulfonamide intermediate without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.48 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.12 g, 0.72 mmol) were converted to compound 70 and purified by silica gel column chromatography. A white solid (50 mg, 0.12 mmol, 5-step yield 10.0%) was obtained.

[0521] LC-MS(ESI)[M+H] + :428.0.Retention time:1.966.HPLC purity=100.00%.

[0522] 1 H NMR(400MHz,Chloroform-d)δ9.19(s,1H),8.14(d,J=2.2Hz,1H),7.79(s,1H),7.70(dd,J=8.3,2.3Hz,1H),7.38(qd,J=6 .4,2.6Hz,1H),7.30(td,J=7.6,1.7Hz,1H),7.23-7.07(m,8H),2.59(q,J=7.5Hz,2H),2.22(s,3H),1.13(t,J=7.5Hz,3H).

[0523] Compound 71:

[0524]

[0525] Following the general synthetic procedure GP1, GP2.1, and GP3, compounds 2-chloro-5-nitrobenzenesulfonyl chloride (0.54 g, 2.11 mmol), 2,4-dimethoxybenzylamine (0.36 g, 2.11 mmol), and 3-methoxyphenol (0.08 mg, 0.65 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(3-methoxyphenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.45 mmol) and 2-chlorophenyl isocyanate (0.10 g, 0.68 mmol) were converted into compound 71 and purified by silica gel column chromatography. A yellow solid (20 mg, 0.04 mmol, 5-step yield 2.1%) was obtained.

[0526] LC-MS(ESI)[M+H] + :447.8.Retention time:2.280min.HPLC purity=98.61%.

[0527] 1 H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.27(s,1H),8.15(dd,J=8.3,1.6Hz,1H),8.06(d,J=2.7Hz,1H),7.60-7.55(m,1H),7.45(dd,J=8.0, 1.5Hz,1H),7.37-7.25(m,4H),7.07-6.95(m,2H),6.72(dd,J=8.1,2.5Hz,1H),6.64(t,J=2.4Hz,1H),6.58(dd,J=8.1,2.3Hz,1H),3.73(s,3H).

[0528] Compound 72:

[0529]

[0530] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(2-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.11 g, 0.67 mmol) were converted to compound 72 and purified by silica gel column chromatography. A yellow solid (55 mg, 0.12 mmol, 5-step yield 10.2%) was obtained.

[0531] LC-MS(ESI)[M+H] + :459.9.Retention time:2.296.HPLC purity=96.95%.

[0532] 1 H NMR(400MHz,Chloroform-d)δ9.03(s,1H),8.09(d,J=2.7Hz,1H),7.69(s,1H),7.58(dd,J=8.0,1.6Hz,1H),7.53(dd,J=8.9,2.7Hz,1H),7. 41-7.27(m,3H),7.22(td,J=7.7,1.6Hz,1H),7.15-7.02(m,4H),6.72(d,J=8.9Hz,1H),2.63-2.55(m,2H),2.20(s,3H),1.18-1.07(m,4H).

[0533] Compound 73:

[0534]

[0535] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2-chlorophenol (0.07 ml, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(2-chlorophenoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.44 mmol) and 2-chlorophenyl isocyanate (0.10 g, 0.67 mmol) were converted into compound 73 and purified by silica gel column chromatography. A yellow solid (54 mg, 0.12 mmol, 5-step yield 10.2%) was obtained.

[0536] LC-MS(ESI)[M+H] + :451.8.Retention time:2.314.HPLC purity=100.00%.

[0537] 1 H NMR(400MHz,Chloroform-d)δ9.67(s,1H),8.26(s,1H),8.16(dd,J=8.4,1.5Hz,1 H),8.09(d,J=2.7Hz,1H),7.60(dd,J=8.0,1.6Hz,1H),7.54(dd,J=8.9,2.7Hz,1H) ,7.45(dd,J=8.1,1.5Hz,1H),7.42-7.35(m,3H),7.27(dtd,J=21.5,7.5,1.5Hz,2H ),7.09(dd,J=8.2,1.5Hz,1H),7.03(td,J=7.7,1.6Hz,1H),6.74(d,J=8.9Hz,1H).

[0538] Compound 74:

[0539]

[0540] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and phenol (0.03 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-phenoxy-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.48 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.12 g, 0.72 mmol) were converted into compound 74 and purified by silica gel column chromatography. A pale yellow solid (45 mg, 0.10 mmol, 5-step yield 9.04%) was obtained.

[0541] LC-MS(ESI)[M+H] + :425.9.Retention time:2.256.HPLC purity=98.40%.

[0542] 1 H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.78-8.65(m,1H),8.32(s,1H),8.27-8.13(m,1H),8.11-7.85(m,4H ),7.83-7.60(m,6H),7.59-7.45(m,1H),3.95(d,J=4.1Hz,2H),2.92-2.74(m,3H),1.75(dt,J=10.6,5.0Hz,3H).

[0543] Compound 75:

[0544]

[0545] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and 2-trifluoromethylphenylboronic acid (0.07 mg, 0.36 mmol) were used as starting materials to synthesize the 4-amino-N-(2,4-dimethoxybenzyl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-sulfonamide intermediate without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.43 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.10 g, 0.64 mmol) were converted to compound 75 and purified by silica gel column chromatography. A yellow solid (21 mg, 0.04 mmol, 5-step yield 3.6%) was obtained.

[0546] LC-MS(ESI)[M+H] + :494.0.Retention time:2.357.HPLC purity=100.00%.

[0547] 1 H NMR(400MHz,Chloroform-d)δ9.65(s,1H),8.66(d,J=2.8Hz,1H),8.35-8.22(m,2H),8.22-8.10(m,2H),7.85(t,J=7 .6Hz,1H),7.78-7.59(m,5H),7.46(dd,J=8.7,4.5Hz,2H),3.86(d,J=2.2Hz,3H),3.13(q,J=7.5Hz,2H),2.75(s,3H).

[0548] Compound 76:

[0549]

[0550] Following the general synthetic procedure GP1, GP2.1, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and phenol (0.03 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-phenoxy-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.48 mmol) and 2-chlorophenyl isocyanate (0.11 g, 0.72 mmol) were converted into compound 76 and purified by silica gel column chromatography. A pale yellow solid (26 mg, 0.06 mmol, 5-step yield 5.32%) was obtained.

[0551] LC-MS(ESI)[M+H] + :417.8.Retention time:2.270.HPLC purity=96.48%.

[0552] 1 H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.26(s,1H),8.15(d,J=8.5Hz,1H),8.07(d,J=2.7Hz,1H),7.56 (dd,J=8.9,2.7Hz,1H),7.48-7.23(m,6H),7.14(t,J=7.4Hz,1H),7.08-6.98(m,3H),6.93(d,J=8.7Hz,1H).

[0553] Compound 77:

[0554]

[0555] Following the general synthetic procedure GP1, GP2.3, and GP3, 2-chloro-5-nitrobenzenesulfonyl chloride (0.30 g, 1.17 mmol), 2,4-dimethoxybenzylamine (0.20 g, 1.17 mmol), and bromomethylcyclobutane (0.05 mg, 0.36 mmol) were used as starting materials to synthesize the intermediate 5-amino-2-(cyclobutylmethoxy)-N-(2,4-dimethoxybenzyl)benzenesulfonamide without further purification. Then, following the general synthetic steps GP4.1 and GP5, the above intermediate (0.20 g, 0.49 mmol) and 2-ethyl-6-methylphenyl isocyanate (0.12 g, 0.74 mmol) were converted into compound 77 and purified by silica gel column chromatography. A yellow solid (15 mg, 0.04 mmol, 3.6% yield in 5 steps) was obtained.

[0556] LC-MS(ESI)[M+H] + :418.0.Retention time:2.275.HPLC purity=100.00%.

[0557] 1 H NMR(400MHz,Chloroform-d)δ8.82(s,1H),7.92(d,J=2.8Hz,1H),7.64(s,1H),7.56(dd,J=8.9,2.8Hz,1H),7.11(dt,J=8.9,7.0Hz,4H),6.75(s,2H) ,5.76(s,3H),4.07(d,J=6.7Hz,2H),2.87-2.75(m,1H),2.58(q,J=7.6Hz, 2H), 2.21 (s, 3H), 2.05 (qd, J=7.4, 3.6Hz, 2H), 1.88 (dq, J=7.5, 4.3Hz, 4H).

[0558] Compound Bioactivity Validation Examples

[0559] I. In vitro bioactivity evaluation:

[0560] 1. hP2X4 calcium flux detection:

[0561] This experiment used the FLIPR Calcium 5 Assay kit to screen small molecules. HeLa cells transfected with human P2X4 protein for about 24 hours were pre-coated into 96-well plates for adherent culture. After reaching a suitable density, the culture medium was discarded, and a membrane-permeable calcium ion concentration indicator (FLIPR Calcium 5 Assay kit) prepared with extracellular buffer (HBSS) was added and incubated with the cells at 37°C and 5% CO2 for 50 minutes. Then, different concentrations of compound solutions and positive inhibitors were added to the 96-well plates, and a blank control was set up for further incubation for 15 minutes. The compounds were prepared as 10 μM stock solutions with DMSO and then diluted to the required concentrations with extracellular buffer containing DMSO and F68 co-solvent (the final concentration of DMSO did not exceed 2.5%, and the final concentration of F68 did not exceed 0.5%). The blank control was an extracellular buffer containing the corresponding concentration of DMSO co-solvent. The plate was kept in the dark throughout the incubation process. After incubation, the 96-well plate was placed in a Flexstation3 multi-functional plate reader. The P2X4 agonist BzATP sample plate was pre-loaded into the microplate reader's pipette, with a concentration of 200 μM (final liquid level in wells: 50 μM). The test program was set, cell fluorescence was excited at 485 nM, and fluorescence emission was detected at 525 nM. The test time per well was 90 s, with a data acquisition interval of 1.52 s. After recording for 25 s, the positive agonist BzATP (final concentration 50 μM) was added via the instrument's dispensing arm, and the remaining data points were collected. After all wells were tested, the fluorescence intensity change curves output by the machine were used to calculate the fluorescence increase before and after the addition of the agonist in all wells. This was then normalized to the fluorescence increase in the corresponding blank control wells to obtain the inhibition rate of fluorescence intensity under different concentrations of the compound. The result was then plotted in GraphPad using curve fitting (Y = 100 / (1+10...). ^ (LogIC50-X*Hillslope))) yields the inhibition curve of the concentration logarithm versus the inhibition rate. All graphs were generated using GraphPadprism version 8.0.

[0562] 2. ZFP2X4 Patch Clamp Testing

[0563] Whole-cell patch-clamp technique can be used to record the currents of zebrafish P2X4 (zfP2X4) channels in cell lines. HeLa cells transfected with channel proteins for approximately 24 hours were harvested, the culture medium was discarded, and extracellular fluid was added. Extracellular fluid at 22°C was continuously perfused into the recording bath. A peristaltic pump perfusion system was used to control the flow rate of the perfusion solution, maintaining a flow rate of 2 mL / min. Suitable target cells were located under a microscope; typically, single, plump cells with clear edges and no depressions were selected. Pre-fabricated glass microelectrodes with an infusion impedance of 2-2.5 MΩ were filled with electrode fluid. The glass electrode was moved by micromanipulation, while the gas pressure inside the glass electrode was controlled using a syringe to establish a high-resistance (GΩ) seal between the glass electrode opening and the cell membrane. Negative pressure was continued to be applied to the glass electrode to rupture the cell membrane, allowing communication between the intracellular fluid and the glass electrode. The intracellular fluid and the glass electrode fluid could exchange. An amplifier connected to the glass electrode (HEKAEPC10 amplifier, with accompanying patchmaster recording software) could control the intracellular voltage. Different voltage settings allowed for the recording of whole-cell channel currents. The extracellular fluid formulation used for recording the zfP2X4 channel current was as follows: 140 μM NaCl, 5 μM KCl, 1 μM MgCl2, 2 μM CaCl2, 10 μM HEPES, and 10 μM D-glucose, dissolved in deionized water. The pH was adjusted to 7.4 using NaOH, and the measured osmotic pressure was approximately 319 mOsm. The electrode intraelectrode formulation was as follows: 130 μM KCl, 10 μM NaCl, 1 μM MgCl2, 0.5 μM CaCl2, 5 μM EGTA, and 10 μM HEPES, dissolved in deionized water. The pH was adjusted to 7.4 using KOH, and the osmotic pressure was approximately 313 mOsm.

[0564] Using 800 μM ATP (dissolved in extracellular fluid) as the agonist of the zfP2X4 channel, daughter cells were stimulated with a voltage ramp ranging from -140 mV to +140 mV for 500 ms, with stimulation occurring every 5 s, while maintaining a cell voltage of 0 mV. Channel currents were continuously recorded at a sampling frequency of 50 kHz, and a 2.9 kHz low-pass filter was used to remove high-frequency interference noise. When examining the effect of compounds targeting zfP2X4 on channel currents, different compound concentration gradients were set, dissolved in extracellular fluid. For drugs insoluble in water, DMSO and F68 were used as dissolution aids. The final concentration of DMSO should not exceed 0.3% of the compound, and the final concentration of F68 should not exceed 0.5%, to avoid damage to the recorded cells. Different concentrations of the compound were continuously administered via a drug delivery device while recording currents, and the effect of different concentrations on cell currents was observed. The current amplitude at a stimulation voltage of 140 mV was calculated, and a scatter plot of the amplitude versus time was generated. To calculate the half-maximal inhibitory concentration (IC50) of the drug against zfP2X4.50 Typically, 5-6 concentration gradients are set, and the inhibition rate of the current at different concentrations is calculated. The concentration-inhibition curves are fitted using the Hill equation in GraphPad software to calculate the half-inhibition concentration. Before formally testing compounds, the system is tested using a positive inhibitor of ZFP2X4 to ensure that the patch-clamp recording system is functioning correctly.

[0565] The in vitro bioactivity measured by the above methods is presented in Tables 1 and 2:

[0566] Table 1. In vitro inhibitory activity of the compounds in the examples against the P2X4 receptor.

[0567]

[0568]

[0569] Note: +: The compound showed an inhibition rate of 5-20% in the patch-clamp assay of zebrafish P2X4 cells; ++: The compound showed an inhibition rate of 20-50% in the patch-clamp assay of zebrafish P2X4 cells; +++: The compound showed an inhibition rate of 50-100% in the patch-clamp assay of zebrafish P2X4 cells.

[0570] Table 2. In vitro inhibitory activity of the compounds in the examples against the P2X4 receptor.

[0571]

[0572]

[0573] Note: +: IC of compound 50 Values ​​range from 100-200 μM; ++: Compound IC 50 Value 50-100µM; +++: Compound IC 50 The value is <50uM.

[0574] II. Evaluation of in vivo biological activity:

[0575] 2.1 Materials

[0576] 2.1.1 Animals:

[0577] SD rats (Sprague Dawley rat, male, 8 weeks old) were provided by the Animal Experiment Center of Xuzhou Medical University.

[0578] 2.1.2 Instruments

[0579] BW-FIP801 Automatic Formalin Pain Detector, Shanghai Ruanlong Technology Development Co., Ltd.

[0580] 2.1.3 Reagents

[0581] 20% formalin was purchased from Sigma-Aldrich (R04587).

[0582] DMSO was purchased from Sigma-Aldrich (D2650).

[0583] PEG300 was purchased from Sigma-Aldrich (202371).

[0584] BAY-1797 was synthesized by itself.

[0585] 2.1.4 Solution Preparation

[0586] 5% formalin solution: Dissolve 20% formalin in double-distilled water.

[0587] Blank solvent (for animal injection): 5% DMSO, 30% PEG-300, 65% physiological saline.

[0588] 2.2 Formalin test (evaluation of efficacy of anti-mechanical pain and inflammatory pain).

[0589] 2.2.1 Animal grouping

[0590] Rats were divided into 5 groups of 4 rats each, as follows: VEH group (blank control), intraperitoneally injected with blank solvent; Yang drug group, intraperitoneally injected with 20 mg / kg BAY-1797 (dissolved in blank solvent); Compound 4 group, intraperitoneally injected with 20 mg / kg Compound 4 (dissolved in blank solvent); Compound 11 group, intraperitoneally injected with 20 mg / kg Compound 11 (dissolved in blank solvent); Compound 43 group, intraperitoneally injected with 20 mg / kg Compound 43 (dissolved in blank solvent).

[0591] 2.2.2 Animal Modeling of Pain

[0592] Thirty minutes after intraperitoneal injection of the drug into rats, a metal detection foot ring was placed on the right hind foot of each group of rats, and 750 μL of 5% formalin solution was injected subcutaneously on the inner side of the foot ring using a Hamilton microsyringe to obtain a pain model.

[0593] 2.2.3 Pain (mechanical pain and inflammatory pain) test

[0594] After establishing the animal model of pain, rats were immediately placed in a BW-FIP801 formalin-based automatic pain detector. The number of toe twitches (flich) per minute was automatically recorded using a detection ring on the right hind foot. The detection lasted for 60 minutes. The cumulative number of flich occurrences in the treated rats from 0-10 minutes after formalin modeling was recorded as Phase I, serving as an indicator of mechanical pain. A lower number of flich occurrences in Phase I indicates a weaker mechanical pain response, suggesting a stronger anti-mechanical pain effect of the compound, and vice versa. The cumulative number of flich occurrences in the treated rats from 20-60 minutes after formalin modeling was recorded as Phase II, serving as an indicator of inflammatory pain. A lower number of flich occurrences in Phase II indicates a weaker inflammatory pain response, suggesting a stronger anti-inflammatory pain effect of the compound, and vice versa. The cumulative Flich mean values ​​of rats in the VEH group, positive group, and compound group in Phase I and Phase II were substituted into Graphpad Prism 8.2 for statistical difference analysis to evaluate the efficacy against mechanical and inflammatory pain. Results are as follows: Figure 1 As shown.

[0595] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0596] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. It should be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. An aromatic sulfonamide compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt thereof, said aromatic sulfonamide compound having the structural features shown in formula (I): in, R 1 H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-10 ring atoms, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5 to 20-membered heteroaryl groups or combinations thereof, wherein the heteroaryl and heterocycloalkyl groups each contain at least one heteroatom selected from nitrogen, oxygen or sulfur; R 2 Independently, it can be H, halogen, hydroxyl, nitro, cyano, carboxyl, aldehyde, amide, ester, -C(O)-C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups containing 3-10 ring atoms, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5- to 20-membered heteroaryl groups or combinations thereof, wherein the heteroaryl and heterocyclic groups each contain at least one heteroatom selected from nitrogen, oxygen or sulfur, and optionally, the heterocyclic or aryl group may share two carbon atoms with the substituted benzene ring to form a fused ring; n can be 0, 1, 2, 3, 4, or 5.

2. The aromatic sulfonamide compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that, R 1 for Among them, R 1-1 H, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5 to 20 heteroaryl groups or combinations thereof.

3. The aromatic sulfonamide compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitrogen oxide, solvate, or solvate of a pharmaceutically acceptable salt according to claim 2, characterized in that, R 1-1 C 6-10 aryl, with one or more R b Replacement C 6-10 aryl, 5-10 heteroaryl, with one or more R b Substituted 5-10 heteroaryl groups or combinations thereof; said R b Independent of H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen-substituted C 1-6 Alkyl, C 1-6 Alkoxy, nitro, carbonyl, cyano, or hydroxyl.

4. The aromatic sulfonamide compound according to claim 3, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that, The R 1-1 It is one of the following groups: Where p is 0, 1, 2, 3, 4 or 5.

5. The aromatic sulfonamide compound according to claim 3, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that, The R b Independently, it is H, halogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, or cyclobutyl.

6. The aromatic sulfonamide compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that, R 1 for Among them, R 1-2 For substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted 5 to 20 heteroaryl groups or combinations thereof.

7. The aromatic sulfonamide compound according to claim 6, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that, R 1-2 C is either replaced by one or more Rc or not replaced. 1-6 Alkyl groups, C groups substituted with one or more Rc groups, or C groups that are not substituted 3-8 Cycloalkyl, 3- to 10-membered heterocyclic alkyl groups substituted with or unsubstituted with one or more Rc groups, C-membered heterocyclic alkyl groups substituted with or unsubstituted with one or more Rc groups 6-20 Aryl, 5- to 20-membered heteroaryl groups substituted or unsubstituted with Rc, or combinations thereof; wherein Rc is independently H, halogen, or C. 1-3 Alkyl, C 3-10 Cycloalkyl, halogen-substituted C 1-3 Alkyl, C 1-3 alkoxy, carbonyl, at least one C 1-3 Alkyl-substituted amino, cyano, hydroxyl, C 6-10 Aryl, -OC 6-10 Aryl or -C(O)-5 to 10 heteroaryl groups.

8. The aromatic sulfonamide compound according to claim 7, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that, The R 1-2 It is one of the following groups: Where m is 0, 1, 2, 3, 4 or 5.

9. The aromatic sulfonamide compound according to claim 7, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that, The R c Independently, it can be H, halogen, methyl, ethyl, propyl, cyano, -O-Ph, -N(CH3)2, methoxy, ethoxy, propoxy, trifluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclobutyl, phenyl, or 10. The aromatic sulfonamide compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic compound, crystal form, nitrogen oxide, solvate, or solvate of a pharmaceutically acceptable salt thereof, characterized in that, R 2 Independently, it can be H, halogen, hydroxyl, nitro, carbonyl, cyano, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 1-6 alkylthio groups, halogenated C 1-6 Alkylthio, C 3-6 Cycloalkyl groups, heterocyclic groups containing 3-10 ring atoms, or substituted or unsubstituted C4 groups. 6-20 Aryl group, optionally, the heterocyclic group or aryl group may share two carbon atoms with the substituted benzene ring to form a fused ring.

11. The aromatic sulfonamide compound according to claim 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt thereof, characterized in that, R 2 Independently, it can be H, halogen, hydroxyl, nitro, carbonyl, cyano, -C(O)-C 1-6 Alkyl, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 1-6 alkylthio groups, halogenated C 1-6 Alkylthio, C 3-6 Cycloalkyl groups, heterocyclic groups containing 3-10 ring atoms, or those with R d C with or without substitution 6-20 Aryl; the R d For H and C 1-6 Alkoxy group, optionally, the heterocyclic or aryl group may share two carbon atoms with the substituted benzene ring to form a fused ring.

12. The aromatic sulfonamide compound according to claim 11, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopic compound, crystal form, nitride, solvate, or solvate of a pharmaceutically acceptable salt, characterized in that, R 2 Independently, it can be H, halogen, hydroxyl, nitro, carbonyl, cyano, -C(O)-CH3, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, methoxy, ethoxy, propoxy, butoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, fluorobutoxy, methylthio, ethylthio, propylthio, butylthio, fluoromethylthio, fluoroethylthio, fluoropropylthio, fluorobutylthio.

13. A method for preparing the aromatic sulfonamide compound according to any one of claims 1 to 12, characterized in that, Includes the following steps: Compound E was reacted with compound 1 to prepare compound F; The aromatic sulfonamide compound was prepared by subjecting compound F to an amino deprotection reaction. Compound E is Compound 1 is Compound F is 14. The method for preparing aromatic sulfonamide compounds according to claim 13, characterized in that, The preparation method of compound E includes the following steps: Compound D was reduced to prepare compound E; Compound D is 15. The method for preparing aromatic sulfonamide compounds according to claim 14, characterized in that, Compound D can be prepared by method 1, method 2, or method 3: Method 1 includes the following steps: Compound C is reacted with compound VII or compound IX to prepare compound D1; Compound C is Compound VII is R 1-1 -Bpin; Compound IX is R 1-1 -B(OH)2; Compound D1 is Method 2 includes the following steps: Compound C was reacted with compound III to prepare compound D2; Compound C is Compound II is IR 1-2 -OH; Compound D2 is Method 3 includes the following steps: Compound C was hydrolyzed to prepare compound V; Compound V was reacted with compound VI to prepare compound D3; compound C was... Compound V is Compound VI is R 1-2 -X, where X represents halogen; Compound D3 is 16. The method for preparing aromatic sulfonamide compounds according to claim 15, characterized in that, The preparation method of compound C includes the following steps: Compound A is reacted with compound B to prepare compound C; Compound A is Compound B is DMBNH2.

17. A pharmaceutical composition, characterized in that, It includes the aromatic sulfonamide compounds as described in any one of claims 1 to 12, or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic compounds, crystal forms, nitrogen oxides, solvates, solvates of pharmaceutically acceptable salts, and at least one pharmaceutical excipient.

18. The use of any aromatic sulfonamide compound of claims 1 to 12 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope, crystal form, nitride, solvate, solvate of a pharmaceutically acceptable salt, or the pharmaceutical composition of claim 17 in the preparation of a medicament for treating diseases related to or mediated by P2X4 receptor activity.

Images