A disulfonamide derivative, its preparation method and application

Abstract

The present invention provides a disulfonamide compound, a preparation method thereof, and a use as a RORγt agonist. Such compounds have RORγt agonist activity and are expected to be used in the preparation of drugs for preventing or treating diseases related to RORγt and / or Th17 cell differentiation (including tumors or cancers, viral infections, immunodeficiency disorders, etc.).

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a disulfonamide compound and a preparation method thereof, as well as the use as a RORγt agonist. Such compounds have RORγt agonist activity and are expected to be used in the preparation of drugs for preventing or treating diseases related to RORγt and / or Th17 cell differentiation. Background Art

[0002] Retinoic acid receptor-related orphan receptor (ROR) is a member of the ligand-dependent transcription factor nuclear receptor (NR) superfamily. The ROR family mainly includes three types: RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3). The three different RORs are expressed and distributed in different tissues and regulate different physiological processes. RORα is widely distributed in adipose tissue, liver, skin, kidney, skeletal muscle, lung, thymus, and brain; RORβ has a small distribution range and is mainly expressed in the central nervous system; RORγ has two subtypes: RORγ1 and RORγ2 (also known as RORγt), where RORγ1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart, and liver, etc., while RORγt is only expressed in certain immune cells.

[0003] RORγt is a key regulatory factor for the differentiation of T helper 17 (Th17) cells and the production of interleukin-17 (IL-17). Th17 cells and the IL-17 secreted by them play important roles in the occurrence and development of autoimmune diseases and inflammation. RORγt inhibitors or inverse agonists can be used to treat autoimmune diseases (including rheumatoid arthritis, multiple sclerosis, psoriasis, and inflammatory bowel disease, etc.), inflammation, and certain cancers with high expression of RORγt.

[0004] Cancer immunotherapy has attracted much attention in recent years and is the focus in the field of cancer treatment. Cancer immunotherapy mobilizes the body's immune system to enhance the anti-tumor immunity in the tumor microenvironment, thereby controlling and killing tumor cells. Its target is the human immune system rather than directly targeting the tumor. At present, cancer immunotherapy has demonstrated strong anti-tumor activity in the treatment of some tumor types such as melanoma and non-small cell lung cancer, etc., and there are already cancer immunotherapy monoclonal antibody drugs approved by the US FDA for marketing.

[0005] Current research has found that Th17 cells are widely present in tumor tissues. In 2009, Professor Chen Dong published an article in *Immunity*, mainly analyzing that Th17 cells can promote the activation of cytotoxic T cells (Tc) and play a role in tumor immunity. The research found that mice deficient in IL-17A are more prone to develop lung melanoma (a type of cancer). If T cell therapy is applied to mice, treatment with T cells secreting IL-17A can effectively prevent tumor development. More importantly, with the assistance of IL-17A, Th17 cells show a stronger therapeutic effect than Th1 cells. Even more unexpectedly, treatment with Th17 cells can also effectively activate tumor-specific CD8 + T cells, among which, CD8 + T cells are essential cells for anti-tumor. Research shows that Th17 cells can recruit dendritic cells into tumor tissues and can cause CD8α + dendritic cells to aggregate in tumor tissues. In addition, Th17 cells activate the chemokine CCL20 in tumor tissues. Generally speaking, Th17 cells can effectively promote the activity of tumor-specific CD8 + T cells. These findings broaden the horizons for tumor immunotherapy.

[0006] Th17 cells specifically express RORγt. Activation of RORγt can promote the differentiation of Th17 cells and produce the pro-inflammatory cytokine IL-17. Therefore, in theory, the differentiation of Th17 cells can be increased by activating RORγt, thereby promoting the activity of tumor-specific CD8 + T cells and playing a role in tumor immunity. In February 2015, Lycera announced that its oral RORγt agonist can improve the efficacy of T cells, increase the production of IL-17, promote the expression of Tc cells, and thus stimulate the immune response against tumor cells, bringing a lasting effect of killing tumor cells. On June 9, 2015, Celgene Corporation in the United States reached an agreement with Lycera for its T cell anti-cancer drug with an upfront payment of $82.5 million plus a recent payment of $22.5 million. In December 2016, the drug cintirorgon (LYC-55716) officially entered clinical Phase I / II trials. In August 2018, its Phase I clinical trial of combined treatment with the PD-1 monoclonal antibody pembrolizumab for metastatic non-small cell lung cancer was launched. This fully demonstrates the great potential of RORγt agonists for tumor immunotherapy.

[0007] Therefore, RORγt can be used as a target for potential tumor immunotherapy. RORγt agonists can effectively activate the RORγt receptor, stimulate the differentiation of Th17 cells, and increase the production of IL-17. They can be used as immune activators for the drug treatment of diseases related to RORγt and / or Th17 cell differentiation (including tumors or cancers, viral infections, and immunodeficiency disorders, etc.). Summary of the Invention

[0008] Problems to be Solved by the Invention:

[0009] The object of the present invention is to provide a disulfonamide derivative as a novel RORγt agonist, which has RORγt agonist activity and can be used for preparing drugs for preventing or treating diseases related to RORγt and / or Th17 cell differentiation (including tumors or cancers, viral infections, and immunodeficiency disorders, etc.).

[0010] Means for Solving the Problems:

[0011] To solve the above technical problems, in the first aspect, the present invention provides a disulfonamide derivative of the following general chemical formula I, or a pharmaceutically acceptable salt or solvate thereof:

[0012]

[0013] Wherein,

[0014] Groups A and B are independently selected from substituted or unsubstituted aryl, heteroaryl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl or C3-C8 oxocycloalkyl, and the substituents are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen;

[0015] R 1 、R 2 、R 3 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or halogen;

[0016] R 4 、R 5 、R 6 are independently selected from hydrogen or C1-C4 alkyl;

[0017] R 7 is selected from substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 oxocycloalkyl, aryl, heteroaryl, cyano or carboxyl, and the substituents are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen;

[0018] Q is selected from a carbonyl group, an alkylene group, or a covalent bond.

[0019] Preferably, the groups A and B are independently selected from a substituted or unsubstituted phenyl group, 2-pyridyl group, 3-pyridyl group, or 4-pyridyl group, and the substituents are selected from C1-C4 alkyl groups, C1-C4 alkoxy groups, C1-C4 haloalkyl groups, C1-C4 haloalkoxy groups, cyano groups, or halogen atoms. More preferably, the substituents are methyl groups, trifluoromethyl groups, or halogen atoms.

[0020] Preferably, R 1 and R 4 are connected to form an alkylene group, and together with the carbon atom to which they are attached, form a five- to seven-membered alicyclic ring; or, R 2 and R 4 are connected to form an alkylene group, and together with the carbon atom to which they are attached, form a five- to seven-membered alicyclic ring; or R 5 and R 6 are connected to form an alkylene group, and together with the adjacent nitrogen atom, bridge to form a five- to seven-membered nitrogen-containing heterocyclic ring.

[0021] Preferably, R 1 and R 4 are connected to form an alkylene group, and together with the carbon atom to which they are attached, form the structure of indene, i.e., Or, R 2 and R 4 are connected to form an alkylene group, and together with the carbon atom to which they are attached, form the structure of indene, i.e., Or, R 5 and R 6 are connected to form an alkylene group, and together with the adjacent nitrogen atom, form a bridged ring structure of 3,8-diazabicyclo[3,2,1]octane, i.e.,

[0022] Preferably, R 7 is selected from a substituted or unsubstituted methyl group, isopropyl group, cyclopentyl group, cyclohexyl group, phenyl group, 4-methylsulfonylphenyl group, pyridyl group, pyrrolyl group, furyl group, thienyl group, pyrrolidinyl group, tetrahydrofuryl group, tetrahydropyranyl group, dioxotetrahydrothiophenyl group, or carboxyl group, and the substituents are selected from C1-C4 alkyl groups, C1-C4 alkoxy groups, C1-C4 haloalkyl groups, C1-C4 haloalkoxy groups, cyano groups, or halogen atoms. More preferably, the substituents are methyl groups, trifluoromethyl groups, or halogen atoms.

[0023] Preferably, the compound is selected from the following compounds:

[0024]

[0025]

[0026]

[0027]

[0028]

[0029] In the second aspect, the present invention provides a method for preparing the bis-sulfonamide derivative or a pharmaceutically acceptable salt or solvate thereof as described above, which includes two synthetic schemes:

[0030] The first synthetic scheme:

[0031] <L

[0032] Reaction conditions: (a) NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (b) hydrochloric acid / dioxane, DCM, room temperature, 2 h; (c) acyl chloride (R 7 -COCl, Q = carbonyl in the product), DIEA, DCM, 0 °C to room temperature, 2 h; (d) carboxylic acid (R 7 -COOH, Q = carbonyl in the product), HATU or T3P, DIEA or TEA, DCM, room temperature, overnight; (e) haloalkane (R 7 -alkylidene chloride, Q = alkylidene in the product), DIEA, EtOH, reflux, 6 h; (f) aldehyde (R 7 CHO, Q = alkylidene in the product), NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (g) Zn, HCOONH4, MeOH / H2O, reflux, 3 h; (h) pyridine, THF, room temperature, 6 h; (i) TEA, DCM, room temperature, overnight;

[0033] Reaction process: Using 3-nitrobenzaldehyde or ketone as the raw material, a reductive amination reaction with Boc-piperazine is carried out under the action of acetic acid and sodium triacetoxyborohydride, and the Boc group is removed with hydrochloric acid / dioxane solution to obtain the benzylpiperazine intermediate. Then, amide condensation is carried out with different acyl chlorides or carboxylic acids, or nucleophilic substitution is carried out with different haloalkanes, or reductive amination reaction is carried out with different aldehydes to obtain intermediate (A). Intermediate (A) is reduced by zinc powder and ammonium formate to obtain the key aniline intermediate (B); then, under the action of sulfonyl chloride, the target compound (I) is prepared through two-step sulfonylation or one-step bis-sulfonylation reaction;

[0034] The second synthetic scheme:

[0035]

[0036] Reaction conditions: (a) NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (b) Zn, HCOONH4, MeOH / H2O, reflux, 3 h; (c) pyridine, THF, room temperature, 6 h; (d) TEA, DCM, room temperature, overnight; (e) hydrochloric acid / dioxane, DCM, room temperature, 2 h; (f) acyl chloride (R 7 -COCl, Q = carbonyl in the product), DIEA, DCM, 0 °C to room temperature, 2 h; (g) carboxylic acid (R 7 -COOH, Q = carbonyl in the product), HATU or T3P, DIEA or TEA, DCM, room temperature, overnight; (h) alkyl halide (R 7 -alkylidene chloride, Q = alkylidene in the product), DIEA, EtOH, reflux, 6 h; (i) aldehyde (R 7 CHO, Q = alkylidene in the product), NaBH(OAc)3, AcOH, DCM, room temperature, overnight;

[0037] Reaction process: Using 3-nitrobenzaldehyde or ketone as the raw material, under the action of acetic acid and sodium triacetoxyborohydride, it undergoes reductive amination reaction with Boc-piperazine, and then is reduced by zinc powder and ammonium formate to obtain aniline intermediate. Then, it undergoes two-step sulfonylation reaction under the action of sulfonyl chloride, and the Boc group is removed with hydrochloric acid / dioxane solution to obtain the key bis-sulfonamide intermediate (C). The key intermediate (C) undergoes amide condensation with different acyl chlorides or carboxylic acids, or nucleophilic substitution with different alkyl halides, or reductive amination reaction with different aldehydes to prepare the target compound (I).

[0038] In a third aspect, the present invention provides a pharmaceutical composition, comprising the bis-sulfonamide derivative or its pharmaceutically acceptable salt or solvate as described above, and a pharmaceutically acceptable carrier.

[0039] In a fourth aspect, the present invention provides the use of the bis-sulfonamide derivative or its pharmaceutically acceptable salt or solvate as described above in the preparation of a drug for preventing or treating diseases related to RORγt and / or Th17 cell differentiation, and the diseases include tumors or cancers, viral infections, and immunodeficiency disorders.

[0040] In a fifth aspect, the present invention provides an RORγt agonist, comprising the bis-sulfonamide derivative or its pharmaceutically acceptable salt or solvate as described above. Detailed implementation manners

[0041] The present invention will be further described below in conjunction with the implementation manners. It should be understood that the following implementation manners are only used to illustrate the present invention and do not limit the present invention.

[0042] The present invention provides a novel RORγt agonist, which is a disulfonamide derivative of the following general chemical structure formula I, or a pharmaceutically acceptable salt or solvate thereof:

[0043]

[0044] Wherein,

[0045] Groups A and B are independently selected from substituted or unsubstituted aryl, heteroaryl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl or C3-C8 oxocycloalkyl, and the substituents are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen;

[0046] R 1 、R 2 、R 3 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or halogen;

[0047] R 4 、R 5 、R 6 are independently selected from hydrogen or C1-C4 alkyl;

[0048] R 7 is selected from substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 oxocycloalkyl, aryl, heteroaryl, cyano or carboxyl, and the substituents are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen;

[0049] Q is selected from carbonyl, alkylene or a covalent bond.

[0050] In a preferred embodiment of the present invention, groups A and B are independently selected from substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, and the substituents are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen. More preferably, the substituents are methyl, trifluoromethyl or halogen.

[0051] In a preferred embodiment of the present invention, R 1 and R 4 are connected to form alkylene and together with the carbon atom to which they are attached form a five- to seven-membered alicyclic ring; or, R 2 and R 4 are connected to form alkylene and together with the carbon atom to which they are attached form a five- to seven-membered alicyclic ring; or R 5 and R 6Link to form an alkylene group and, together with an adjacent nitrogen atom, bridge to form a five- to seven-membered nitrogen-containing heterocycle.

[0052] In a preferred embodiment of the present invention, R 1 and R 4 Link to form an alkylene group and, together with the carbon atom to which they are attached, form the structure of indene, i.e., Alternatively, R 2 and R 4 Link to form an alkylene group and, together with the carbon atom to which they are attached, form the structure of indene, i.e., Alternatively, R 5 and R 6 Link to form an alkylene group and, together with an adjacent nitrogen atom, form a bridged ring structure of 3,8-diazabicyclo[3.2.1]octane, i.e.,

[0053] In a preferred embodiment of the present invention, R 7 is selected from substituted or unsubstituted methyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-methylsulfonylphenyl, pyridyl, pyrrolyl, furyl, thienyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, dioxotetrahydrothiophenyl or carboxyl, and the substituents are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen. More preferably, the substituents are methyl, trifluoromethyl or halogen.

[0054] In a preferred embodiment of the present invention, the compound is selected from the following compounds:

[0055]

[0056]

[0057]

[0058]

[0059]

[0060] The compound of general formula I provided by the present invention can be synthesized by the following synthetic scheme:

[0061] The first synthetic scheme:

[0062]

[0063] Reaction conditions: (a) NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (b) hydrochloric acid / dioxane, DCM, room temperature, 2 h; (c) acyl chloride (R 7-COCl, where Q = carbonyl in the product), DIEA, DCM, 0 °C to room temperature, 2 h; (d) carboxylic acid (R 7 -COOH, where Q = carbonyl in the product), HATU or T3P, DIEA or TEA, DCM, room temperature, overnight; (e) alkyl halide (R 7 -alkylidene chloride, where Q = alkylidene in the product), DIEA, EtOH, reflux, 6 h; (f) aldehyde (R 7 CHO, where Q = alkylidene in the product), NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (g) Zn, HCOONH4, MeOH / H2O, reflux, 3 h; (h) pyridine, THF, room temperature, 6 h; (i) TEA, DCM, room temperature, overnight;

[0064] Reaction process: Using 3-nitrobenzaldehyde or ketone as the raw material, under the action of acetic acid and sodium triacetoxyborohydride, carry out reductive amination reaction with Boc-piperazine, and use hydrochloric acid / dioxane solution to remove Boc to obtain the benzylpiperazine intermediate. Then carry out amide condensation with different acyl chlorides or carboxylic acids, or carry out nucleophilic substitution with different alkyl halides, or carry out reductive amination reaction with different aldehydes to obtain intermediate (A). Intermediate (A) is reduced by zinc powder and ammonium formate to obtain the key aniline intermediate (B); then under the action of sulfonyl chloride, the target compound (I) is prepared through two-step sulfonylation or one-step double sulfonylation reaction;

[0065] The second synthesis scheme:

[0066]

[0067] Reaction conditions: (a) NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (b) Zn, HCOONH4, MeOH / H2O, reflux, 3 h; (c) pyridine, THF, room temperature, 6 h; (d) TEA, DCM, room temperature, overnight; (e) hydrochloric acid / dioxane, DCM, room temperature, 2 h; (f) acyl chloride (R 7 -COCl, where Q = carbonyl in the product), DIEA, DCM, 0 °C to room temperature, 2 h; (g) carboxylic acid (R 7 -COOH, where Q = carbonyl in the product), HATU or T3P, DIEA or TEA, DCM, room temperature, overnight; (h) alkyl halide (R 7 -alkylidene chloride, where Q = alkylidene in the product), DIEA, EtOH, reflux, 6 h; (i) aldehyde (R 7 CHO, where Q = alkylidene in the product), NaBH(OAc)3, AcOH, DCM, room temperature, overnight;

[0068] Reaction process: Using 3-nitrobenzaldehyde or ketone as the raw material, under the action of acetic acid and sodium triacetoxyborohydride, it undergoes reductive amination reaction with Boc-piperazine, and then is reduced by zinc powder and ammonium formate to obtain aniline intermediate. Then, under the action of sulfonyl chloride, it undergoes two-step sulfonylation reaction, and the Boc group is removed with hydrochloric acid / dioxane solution to obtain the key bis-sulfonamide intermediate (C). The key intermediate (C) undergoes amide condensation with different acyl chlorides or carboxylic acids, or nucleophilic substitution with different haloalkanes, or reductive amination reaction with different aldehydes to prepare the target compound (I).

[0069] Unless otherwise specified, the meanings of the groups and terms in the above synthetic scheme are the same as those in the compound of general formula I.

[0070] The above synthetic scheme only lists the preparation methods of some compounds in the present invention. Referring to the commonly used technical means and the prior art in the field, those skilled in the art can synthesize the compounds of the present invention by similar methods based on the above synthetic scheme.

[0071] The "compounds" described in the present invention include all stereoisomers, geometric isomers, tautomers and isotopes.

[0072] The "compounds" described in the present invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms in the present invention can be isolated in optically active pure form or racemic form; the optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.

[0073] The "compounds" described in the present invention also include tautomeric forms; the tautomeric forms result from the exchange of a single bond with an adjacent double bond and are accompanied by the migration of a proton.

[0074] The present invention also includes all isotopic atoms, whether in the intermediate or the final compound; the isotopic atoms include those having the same atomic number but different mass numbers. For example, the isotopes of hydrogen include deuterium and tritium. Also, if needed, for example, for special treatment or diagnostic treatment, isotopes or radioactive isotopes known in the prior art can be introduced into the compounds of the present invention, such as 3 H, 15 O, 13 C or 13 N isotopes.

[0075] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable salts that, while maintaining the pharmacological activity of their parent compounds, improve physicochemical properties or metabolic properties, etc. Such salts include acid addition salts and base addition salts prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, inorganic bases), or mixtures of both. In the present invention, suitable inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or similar acids; suitable organic acids are, for example, acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, salicylic acid, stearic acid, muconic acid, or the like.

[0076] The compounds according to the present invention may also exist in the form of their solvates. For example, hydrates (hemihydrate, monohydrate, dihydrate, trihydrate, etc.).

[0077] In the present invention, unless otherwise specified, the terms used have the following meanings.

[0078] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0079] The term "oxo group" refers to =O.

[0080] The term "carbonyl group" refers to C=O.

[0081] The term "carboxyl group" refers to -(C=O)OH.

[0082] The term "cyano group" refers to -CN.

[0083] The term "sulfonyl group" refers to -S(=O)2(alkyl) or -S(=O)2(cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0084] The term "sulfinyl group" refers to -S(=O)(alkyl) or -S(=O)(cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0085] The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, which is a straight-chain or branched-chain alkyl containing 1 to 20 carbon atoms (C1-C 20(alkyl), preferably a C1-C8 alkyl group, more preferably a C1-C6 alkyl group, even more preferably a C1-C4 haloalkyl group, for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl), hexyl (n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl), etc.; the alkyl group may be unsubstituted or substituted by one or more substituents, and the substituents include but are not limited to alkyl groups and halogens, for example, forming a haloalkyl group, preferably a C1-C8 haloalkyl group, more preferably a C1-C6 haloalkyl group, even more preferably a C1-C4 haloalkyl group.

[0086] The term "alkoxy" refers to -O-alkyl, where the alkyl group is as defined above.

[0087] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (fused ring, spiro ring or bridged ring) cyclic hydrocarbon substituent, and the cycloalkyl group contains 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, etc. The cycloalkyl group may be unsubstituted or substituted by one or more substituents, and the substituents include but are not limited to alkyl groups, halogens, sulfonyl groups, sulfinyl groups, for example, forming a halocycloalkyl group, preferably a C3-C8 halocycloalkyl group, more preferably a C3-C6 halocycloalkyl group.

[0088] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (fused ring, spiro ring or bridged ring) cyclic hydrocarbon substituent containing one or more heteroatoms of N, O or S, and the heterocycloalkyl group contains 3 to 8 ring atoms, where 1-3 of them are heteroatoms; preferably contains 3 to 6 ring atoms, where 1-2 of them are heteroatoms. Typically, it is a 3-6 membered heterocyclic group containing one or more heteroatoms of N, O or S, for example, aziridin-1-yl, oxetan-3-yl, azetidin-3-yl, azetidin-1-yl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxotetrahydrothiopyranyl, morpholinyl and its derivatives. The heterocycloalkyl group may be unsubstituted or substituted by one or more substituents, and the substituents include but are not limited to alkyl groups, halogens, sulfonyl groups, sulfinyl groups, oxo groups, for example, forming a haloheterocycloalkyl group, preferably a haloheterocycloalkyl group containing 3-8 ring atoms.

[0089] The term "alkylene" refers to a divalent group obtained by removing one hydrogen atom from an alkyl group, where the alkyl group is as defined above. The alkylene group contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. For example, methylene, ethylene, propylene, butylene, etc.

[0090] The term "aryl" refers to a monocyclic or fused ring of all carbon atoms having a fully conjugated π - electron system, usually having 6 - 14 carbon atoms, preferably 6 - 12 carbon atoms, and most preferably 6 carbon atoms. The aryl group can be unsubstituted or substituted by one or more substituents, including but not limited to alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylate, sulfonyl, sulfinyl, phosphoryl. Examples of unsubstituted aryl groups include but are not limited to phenyl, naphthyl, and anthryl.

[0091] The term "heteroaryl" refers to a monocyclic or fused ring containing 5 - 12 ring atoms, where 1 - 4 ring atoms are selected from N, O, S, the remaining ring atoms are C, and having a fully conjugated π - electron system, including but not limited to pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrazolyl. The heteroaryl group can be unsubstituted or substituted, and the substituents include but are not limited to alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylate, sulfonyl, sulfinyl, phosphoryl.

[0092] Administration and pharmaceutical compositions

[0093] The "pharmaceutical composition" according to the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier commonly accepted in the art for delivering bioactive compounds to an organism (such as a human). The purpose of the pharmaceutical composition is to facilitate the administration and delivery to the organism.

[0094] The term "pharmaceutically acceptable carrier" refers to a substance co-administered with the active ingredient and facilitating the administration of the active ingredient, including but not limited to any glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the State Food and Drug Administration for use in humans or animals (such as livestock). For example, including but not limited to calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0095] The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0096] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill manufacturing methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0097] The administration routes of the compounds or their pharmaceutically acceptable salts or their pharmaceutical compositions of the present invention include, but are not limited to, oral, rectal, transmucosal, enteral administration, or local, transdermal, inhaled, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred administration route is oral administration.

[0098] For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, pastes, suspensions, etc. for oral administration to patients. For example, for a pharmaceutical composition for oral administration, tablets can be obtained in the following manner: combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and if necessary adding a small amount of excipients to process the mixture or granules to form tablets or tablet cores. The tablet cores can be combined with an optionally suitable enteric coating material and processed into a coated preparation form that is more conducive to absorption by an organism (such as a human).

[0099] "Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, that is, causing the symptoms of the clinical disease not to develop; (2) inhibiting the disease, that is, preventing the development of clinical symptoms; (3) alleviating the disease, that is, causing the clinical symptoms to subside.

[0100] The present invention provides a class of bissulfonamide derivatives with the structural characteristics of general formula I. These compounds can effectively activate the RORγt receptor, stimulate the differentiation of Th17 cells, increase the production of IL-17, and can be used as immune activators for the drug treatment of diseases related to RORγt and / or Th17 cell differentiation (including tumors or cancers, viral infections, and immunodeficiency disorders, etc.).

[0101] The present invention will be further described in detail below in conjunction with specific embodiments. It should also be understood that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention all fall within the protection scope of the present invention. The specific process parameters and the like in the following examples are also only examples within a suitable range, that is, those skilled in the art can make selections within a suitable range through the description in this article, rather than being limited to the specific values in the following examples.

[0102] In the method for preparing the target compound provided by the present invention, silica gel (200 - 300 mesh) produced by Rushan Sun Desiccant Co., Ltd. is used for column chromatography; thin-layer chromatography uses GF254; nuclear magnetic resonance chromatography (NMR) is measured using a Varian-400 nuclear magnetic resonance spectrometer; liquid chromatography-mass spectrometry (LC / MS) uses an Agilent Technologi ESI 6120 liquid chromatography-mass spectrometry instrument.

[0103] In addition, all operations involving raw materials that are prone to oxidation or hydrolysis are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be directly used without further purification.

[0104] Example 1: Preparation of Compound 1

[0105] Preparation of 3-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide

[0106]

[0107] Step 1: Preparation of tert-butyl 4-(3-nitrobenzyl)piperazine-1-carboxylate

[0108]

[0109] At room temperature, m-nitrobenzaldehyde (3.02 g, 20.0 mmol), Boc-piperazine (4.09 g, 22.0 mmol), acetic acid (4.60 g, 80.0 mmol) and dichloromethane (50 mL) were added to a 100 mL single-necked flask. The mixture was stirred at room temperature for 1 hour, sodium triacetoxyborohydride (6.36 g, 30.0 mmol) was added, and the reaction was continued overnight. After TLC detection showed that the raw materials had completely reacted, water (50 mL) was added to quench the reaction. The layers were separated, and the organic phase was washed with deionized water and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure from the filtrate. The remaining mixture was purified by silica gel column chromatography to obtain 4.80 g of tert-butyl 4-(3-nitrobenzyl)piperazine-1-carboxylate with a yield of 74.8%. MS(ESI) m / z: 322.3 [M+H]+ .

[0110] Step 2: Preparation of 1-(3-nitrobenzyl)piperazine

[0111]

[0112] Add dichloromethane (20 mL) to a 100 mL reaction flask containing tert-butyl 4-(3-nitrobenzyl)piperazine-1-carboxylate (4.80 g, 14.95 mmol). After stirring to dissolve, add dioxane hydrochloride solution (4 M, 10 mL), and continue stirring the reaction at room temperature for 2 hours. After detecting that the raw materials have completely reacted by TLC, stop stirring, pour off the supernatant, and rotary evaporate the residual white solid under reduced pressure, and directly put it into the next step of the reaction. MS(ESI) m / z: 222.3 [M+H] + .

[0113] Step 3: Preparation of cyclohexyl(4-(3-nitrobenzyl)piperazin-1-yl)methanone

[0114]

[0115] Dissolve the crude product 1-(3-nitrobenzyl)piperazine (3.30 g, 14.95 mmol) obtained from the previous step in dichloromethane (50 mL) and N,N-diisopropylethylamine (5.79 g, 44.85 mmol). Slowly add cyclohexanecarbonyl chloride (3.29 g, 22.43 mmol) to the reaction mixture. After the addition is complete, continue the reaction at room temperature for 2 hours. After detecting that the raw materials have completely reacted by TLC, add methanol (5 mL) to quench the reaction, rotary evaporate the reaction mixture under reduced pressure, and purify the residue by silica gel column chromatography to obtain 2.10 g of the target compound with a yield of 42.4%. MS(ESI) m / z: 332.2 [M+H] + .

[0116] Step 4: Preparation of (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone

[0117]

[0118] In a 50 mL reaction flask, add cyclohexyl(4-(3-nitrobenzyl)piperazin-1-yl)methanone (2.00 g, 6 mmol), zinc powder (1.17 g, 18 mmol) and ammonium formate (1.19 g, 30 mmol), 15 mL each of methanol and water, and heat under reflux in an oil bath for 3 hours. After TLC detection shows that the raw materials have completely reacted, filter, and rotary evaporate the filtrate under reduced pressure. The residue is dissolved in dichloromethane (50 mL), washed with saturated sodium bicarbonate solution, filtered to remove insoluble substances, separated, the organic phase is washed with deionized water and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, the solvent is removed from the filtrate under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the target compound (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone 1.50 g, with a yield of 82.9%. MS(ESI) m / z: 302.2[M+H] + .

[0119] Step 5: Preparation of 3-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0120]

[0121] At room temperature, slowly add m-chlorobenzenesulfonyl chloride (68 mg, 0.32 mmol) dropwise to a dichloromethane solution containing (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone (81 mg, 0.27 mmol) and triethylamine (138 μL, 1 mmol), and continue the reaction at room temperature for 6 hours. After TLC detection shows that the reaction is complete, add methanol (1 mL) to quench the reaction, remove the solvent from the reaction mixture under reduced pressure, and the remaining mixture is purified by silica gel column chromatography to obtain the target compound 70 mg, with a yield of 54.5%, a white solid. 1 HNMR(400MHz,CDCl3)δ7.78 - 7.77(m,1H),7.69 - 7.67(m,1H),7.55 - 7.51(m,1H),7.42 - 7.38(m,1H),7.27 - 7.24(m,1H),7.13 - 7.09(m,3H),3.65 - 3.53(m,6H),2.47 - 2.39(m,5H),1.83 - 1.81(m,2H),1.74 - 1.71(m,3H),1.59 - 1.50(m,2H),1.30 - 1.26(m,3H).MS (ESI)m / z:476.2[M+H] + .

[0122] Step 6: Preparation of 3-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide

[0123]

[0124] At room temperature, benzenesulfonyl chloride (74 mg, 0.42 mmol) was slowly added dropwise to a mixture containing 3-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide (100 mg, 0.21 mmol), triethylamine (139 μL, 1 mmol) and dichloromethane (3 mL). The reaction was carried out overnight. After the reaction of the starting materials was complete as detected by TLC, methanol (1 mL) was added to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. The remaining mixture was purified by silica gel column chromatography and reverse-phase medium-pressure preparative system to obtain 55 mg of the target compound, with a yield of 42.5%. 1 1H NMR (400 MHz, CDCl3) δ 7.96 - 7.89 (m, 2H), 7.90 - 7.89 (m, 2H), 7.75 - 7.67 (m, 2H), 7.61 - 7.52 (m, 4H), 7.42 - 7.38 (m, 1H), 7.03 (m, 2H), 3.63 - 3.56 (m, 5H), 2.48 - 2.42 (m, 4H), 1.83 - 1.50 (m, 10H), 1.33 - 1.28 (m, 2H). MS (ESI) m / z: 616.2 [M+H] + .

[0125] Example 2: Preparation of Compound 2

[0126] Preparation of N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)-N-(phenylsulfonyl)benzenesulfonamide

[0127]

[0128] The intermediate (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone was synthesized according to Steps 1 - 4 of Example 1. According to Step 5 of Example 1, using benzenesulfonyl chloride (105 mg, 0.5 mmol), (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone (60 mg, 0.2 mmol), and triethylamine (138 μL, 1 mmol) as starting materials, 93 mg of the target compound was obtained, with a yield of 71.5%. 1 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.69 (t, J = 8.0 Hz, 2H), 7.55 (t, J = 8.0 Hz, 4H), 7.43 - 7.33 (m, 2H), 6.99 (s, 2H), 3.57 - 3.49 (m, 5H), 2.46 - 2.32 (m, 4H), 1.80 - 1.47 (m, 9H), 1.31 - 1.25 (m, 3H). MS (ESI) m / z: 581.8 [M+H]+ .

[0129] Example 3: Preparation of Compound 3

[0130] Preparation of 3-chloro-N-(3-chlorophenyl)sulfonyl)-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0131]

[0132] Referring to the synthetic route of Example 1. According to Step 6 of Example 1, using 3-chlorobenzenesulfonyl chloride (87 mg, 0.42 mmol), 3-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide (100 mg, 0.21 mmol), and triethylamine (139 μL, 1 mmol) as raw materials, 65 mg of the target compound was obtained, yield: 47.5%. 1 H NMR (400 MHz, CDCl3) δ 7.87 - 7.85 (m, 4H), 7.68 - 7.66 (m, 2H), 7.55 - 7.51 (m, 3H), 7.41 - 7.38 (m, 1H), 7.01 - 7.00 (m, 2H), 3.60 - 3.52 (m, 5H), 2.46 - 2.39 (m, 4H), 1.80 - 1.46 (m, 10H), 1.31 - 1.27 (m, 2H). MS(ESI) m / z: 650.1 [M + H] + .

[0133] Example 4: Preparation of Compound 4

[0134] Preparation of 2-chloro-N-((3-chlorophenyl)sulfonyl)-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0135]

[0136] Referring to the synthetic route of Example 1. According to Step 6 of Example 1, using o-chlorobenzenesulfonyl chloride (68 mg, 0.32 mmol), 3-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide (100 mg, 0.21 mmol), and triethylamine (87.6 μL, 0.63 mmol) as raw materials, 45 mg of the target compound was obtained, yield: 33.0%. 11H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 8.0, 1.2 Hz, 1H), 7.70 - 7.57 (m, 5H), 7.53 - 7.37 (m, 4H), 7.21 (m, 2H), 7.01 - 7.00 (m, 2H), 3.52 (m, 5H), 2.46 - 2.34 (m, 4H), 1.81 - 1.47 (m, 10H), 1.31 - 1.28 (m, 2H). MS (ESI) m / z: 650.1 [M+H] + .

[0137] Example 5: Preparation of Compound 5

[0138] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0139]

[0140] The intermediate (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone was obtained according to Steps 1 - 4 of Example 1. Then, according to Step 5 of Example 1, using 2-chlorobenzenesulfonyl chloride (105.5 mg, 0.5 mmol), (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone (60 mg, 0.2 mmol), and triethylamine (138 μL, 1 mmol) as raw materials, 64 mg of the target compound was obtained with a yield of 49.2%. 1 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.0, 1.2 Hz, 2H), 7.71 - 7.68 (m, 2H), 7.63 - 7.56 (m, 2H), 7.52 - 7.37 (m, 5H), 7.24 - 7.18 (m, 3H), 3.57 (m, 5H), 2.46 - 2.40 (m, 4H), 1.80 - 1.47 (m, 10H), 1.30 - 1.25 (m, 2H). MS (ESI) m / z: 649.7 [M+H] + .

[0141] Example 6: Preparation of Compound 6

[0142] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-acetylpiperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0143]

[0144] Step 1: Preparation of tert-butyl 4-(3-aminobenzyl)piperazine-1-carboxylate

[0145]

[0146] In a 100 mL reaction flask, 4-(3-nitrobenzyl)piperazine-1-carboxylic acid tert-butyl ester (4.63 g, 14.4 mmol), zinc powder (2.80 g, 43.2 mmol), and ammonium formate (4.54 g, 72 mmol) were added, along with 30 mL each of methanol and water. The mixture was heated under reflux in an oil bath for 3 hours. After TLC detection showed that the raw materials had completely reacted, the mixture was filtered, and the filtrate was concentrated under reduced pressure by rotary evaporation. The residue was dissolved in dichloromethane (100 mL), washed with saturated sodium bicarbonate solution, filtered to remove insoluble substances, separated by liquid-liquid extraction, and the organic phase was washed with deionized water and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.32 g of the target compound 4-(3-aminobenzyl)piperazine-1-carboxylic acid tert-butyl ester, with a yield of 79.2%. MS(ESI) m / z: 292.1 [M+H] + .

[0147] Step 2: Preparation of tert-butyl 4-(3-((2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfamoyl)phenyl)piperazine-1-carboxylate

[0148]

[0149] At room temperature, o-chlorobenzenesulfonyl chloride (3.40 g, 16.07 mmol) was slowly added dropwise to a mixture containing 4-(3-aminobenzyl)piperazine-1-carboxylic acid tert-butyl ester (1.87 g, 6.43 mmol), triethylamine (4.5 mL, 32.15 mmol), and dichloromethane (60 mL). The reaction was carried out overnight. After TLC detection showed that the raw materials had completely reacted, methanol (20 mL) was added to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the remaining mixture was purified by silica gel column chromatography and medium-pressure preparative reverse-phase chromatography to obtain 3.34 g of the target compound, with a yield of 81.3%. MS(ESI) m / z: 639.7 [M+H] + .

[0150] Step 3: Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfamoyl)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide

[0151]

[0152] Add dichloromethane (20 mL) to a 100 mL reaction flask containing tert-butyl 4-(3-((2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfamoyl)phenyl)piperazine-1-carboxylate (3.34 g, 5.2 mmol). After stirring to dissolve, add dioxane hydrochloride solution (4 M, 10 mL). Continue stirring the reaction at room temperature for 2 hours. After detecting by TLC that the raw materials have completely reacted, stop stirring, pour off the supernatant, spin-dry the residual white solid under reduced pressure, and directly put it into the next reaction. MS (ESI) m / z: 539.7 [M+H] + .

[0153] Step 4: Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-acetylpiperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0154]

[0155] Dissolve the crude product 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfamoyl)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol) obtained from the previous step in dichloromethane (3 mL) and N,N-diisopropylethylamine (100 μL, 0.6 mmol). Slowly add acetyl chloride (24 mg, 0.3 mmol) dropwise to the reaction mixture. After the addition is complete, continue the reaction at room temperature for 2 hours. After detecting by TLC that the raw materials have completely reacted, add methanol (0.5 mL) to quench the reaction. Spin-dry the reaction mixture under reduced pressure, and purify the residue by silica gel column chromatography to obtain the target compound. 1 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 7.6 Hz, 2H), 7.83–7.65 (m, 4H), 7.63 - 7.48 (m, 2H), 7.39–7.31 (m, 2H), 7.24–7.06 (m, 2H), 3.35–3.27 (m, 4H), 3.18–3.09 (m, 2H), 2.30–2.07 (m, 4H), 2.02–1.91 (m, 3H). MS(ESI) m / z: 581.7 [M+H] + .

[0156] Example 7: Preparation of Compound 7

[0157] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-isobutyrylpiperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0158]

[0159] Refer to the synthetic route of Example 6. According to Step 4 of Example 6, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and isobutyryl chloride (32 mg, 0.3 mmol) as raw materials, the target compound (64 mg) was obtained with a yield of 52.4%. 1 H NMR(400MHz,CDCl3)δ8.18(dm,J=8.0Hz,2H),7.59-7.55(m,2H),7.50- 7.41(m,5H),7.34-7.31(m,3H),3.58(m,5H),2.80-2.73(m,1H),2.43-2.32(m,3H),1.34-1.28(m,2H),1.12(d,J=8.0Hz,6H).MS(ESI)m / z:609.7[M+H] + .

[0160] Example 8: Preparation of Compound 8

[0161] Preparation of N-(3-((4-benzoylpiperazin-1-yl)methyl)phenyl)-2-chloro-N-((2-chlorophenyl)sulfonyl)benzenesulfonamide

[0162]

[0163] Refer to the synthetic route of Example 6. According to Step 4 of Example 6, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and benzoyl chloride (42 mg, 0.3 mmol) as raw materials, the target compound (74.7 mg) was obtained with a yield of 57.9%. 1 H NMR(400MHz,CDCl3)δ8.18(dd,J=8.0,1.2,2H),7.57-7.54(m,2H), 7.49-7.39(m,10H),7.34-7.30(m,3H),3.77-3.45(m,6H),2.43-2.36(m,4H).MS(ESI)m / z:643.6[M+H] + .

[0164] Example 9: Preparation of Compound 9

[0165] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(pyridine-2-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0166]

[0167] Synthesize intermediate 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfamoyl)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide according to Steps 1-3 of Example 6. Dissolve intermediate 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfamoyl)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol) in dichloromethane (2 mL) and N,N-diisopropylethylamine (100 μL, 0.6 mmol), add 2-pyridinecarboxylic acid (25.9 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) to the reaction mixture, and react overnight at room temperature. After detecting that the raw materials have completely reacted by TLC, spin-dry the reaction mixture under reduced pressure, and purify the residue by silica gel column chromatography and reverse-phase medium-pressure preparative system to obtain 76.7 mg of the target compound with a yield of 59.4%. 1 1H NMR (400 MHz, CDCl3) δ 8.59 - 8.57 (dm, J = 8.0, 1H), 8.18 (dd, J = 8.0, 1.6 Hz, 2H), 7.81 (td, J = 8.0, 1.6 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.59 - 7.55 (m, 2H), 7.52 - 7.48 (m, 3H), 7.45 - 7.41 (m, 2H), 7.37 - 7.33 (m, 4H), 3.90 - 3.66 (m, 6H), 2.60 (m, 4H). MS (ESI) m / z: 644.6 [M + H] + .

[0168] Example 10: Preparation of Compound 10

[0169] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(pyridine-3-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0170]

[0171] Refer to the synthesis route of Example 9. According to Example 9, use 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfamoyl)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), nicotinic acid (25.9 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as raw materials to obtain 66.1 mg of the target compound with a yield of 51.2%. 11H NMR (400 MHz, CDCl3) δ 8.67 - 8.66 (m, 2H), 8.18 (dd, J = 8.0, 1.2 Hz, 2H), 7.76 - 7.74 (m, 1H), 7.59 - 7.55 (m, 2H), 7.49 - 7.42 (m, 5H), 7.38 - 7.35 (m, 4H), 3.82 - 3.59 (m, 6H), 2.49 (m, 4H). MS (ESI) m / z: 644.6 [M + H] + .

[0172] Example XI: Preparation of Compound 11

[0173] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(pyridine-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0174]

[0175] Referring to the synthetic route of Example IX. According to Example IX, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazin-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), isonicotinic acid (25.9 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as raw materials, the target compound 92.4 mg was obtained with a yield of 71.6%. 1 1H NMR (400 MHz, CDCl3) δ 8.70 - 8.69 (dm, J = 4.0, 2H), 8.18 (dd, J = 8.0, 0.8 Hz, 2H), 7.59 - 7.55 (m, 2H), 7.49 - 7.39 (m, 6H), 7.35 - 7.27 (m, 4H), 3.82 - 3.44 (m, 6H), 2.51 (m, 4H). MS (ESI) m / z: 644.6 [M + H] + .

[0176] Example XII: Preparation of Compound 12

[0177] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(4-(methylsulfonyl)benzoyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0178]

[0179] Refer to the synthetic route of Example 9. According to Example 9, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), 4-methylsulfonylbenzoic acid (42 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as starting materials, the target compound (30 mg) was obtained with a yield of 20.8%. 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.0, 1.2, 2H), 8.00 (d, J = 8.0, 2H), 7.60 - 7.55 (m, 4H), 7.49 - 7.40 (m, 8H), 3.79 - 3.36 (m, 5H), 3.06 (s, 3H), 2.48 - 2.39 (m, 3H), 1.27 - 1.24 (m, 2H). MS (ESI) m / z: 721.5 [M + H] + .

[0180] Example 13: Preparation of Compound 13

[0181] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(1,1-dioxidotetrahydro-2H-thiopyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0182]

[0183] Refer to the synthetic route of Example 9. According to Example 9, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (38 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as starting materials, the target compound (99 mg) was obtained with a yield of 70.8%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.01 (dd, J = 8.4, 1.6 Hz, 2H), 7.81 - 7.73 (m, 4H), 7.61 - 7.57 (m, 2H), 7.39 - 7.38 (m, 2H), 7.22 - 7.20 (m, 1H), 7.16 (s, 1H), 3.65 - 3.58 (m, 1H), 3.47 - 3.43 (m, 4H), 3.24 - 3.00 (m, 6H), 2.26 - 2.18 (m, 4H), 1.99 - 1.95 (m, 4H). MS (ESI) m / z: 699.5 [M + H]+ .

[0184] Example XIV: Preparation of Compound 14

[0185] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-2-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0186]

[0187] Referring to the synthetic route of Example IX. According to Example IX, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazin-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), tetrahydropyran-2-carboxylic acid (27.3 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as starting materials, the target compound was obtained as 49.3 mg with a yield of 37.8%. 1 H NMR(400MHz,DMSO-d6)δ8.03 (dm,J=8.0Hz,2H),7.83-7.74(m,4H),7.63-7.51(m,5H),7.38-7.36(m,1H),4.42(m,2H),4.17 (m,2H),3.89-3.86(m,1H),3.58-3.52(m,3H),3.32(m,1H),3.19(m,2H),2.95-2.84(m,2H),1.81(m,1H),1.60-1.50(m,5H).MS(ESI)m / z:651.6[M+H] + .

[0188] Example XV: Preparation of Compound 15

[0189] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-3-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0190]

[0191] Refer to the synthetic route of Example 9. According to Example 9, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethyl)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), tetrahydropyran-3-carboxylic acid (27.3 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as starting materials, the target compound was obtained as 121 mg with a yield of 92.7%. 1 H NMR(400MHz,CDCl3)δ8.18(dd, J=8.0,1,2Hz,2H),7.59-7.55(m,2H),7.50-7.42(m,5H),7.37-7.29(m,3H),3.94-3.91(m,2H), 3.63-3.50(m,6H),3.44-3.37(m,1H),2.81-2.74(m,1H),2.55-2.44(m,3H),1.89-1.64(m,5H),1.54-1.43(m,1H).MS(ESI)m / z:651.6[M+H] + .

[0192] Example 16: Preparation of Compound 16

[0193] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0194]

[0195] Refer to the synthetic route of Example 9. According to Example 9, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethyl)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), tetrahydropyran-4-carboxylic acid (27.3 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as starting materials, the target compound was obtained as 68.2 mg with a yield of 52.3%. 11H NMR (400 MHz, CDCl3) δ 8.18 (dm, J = 8.0 Hz, 2H), 7.59 - 7.55 (m, 2H), 7.50 - 7.42 (m, 5H), 7.36 - 7.28 (m, 3H), 4.02 - 3.99 (m, 2H), 3.58 (m, 4H), 3.48 - 3.40 (m, 2H), 2.74 - 2.66 (m, 1H), 2.50 - 2.39 (m, 3H), 1.95 - 1.85 (m, 2H), 1.66 - 1.57 (m, 5H). MS (ESI) m / z: 651.7 [M + H] + .

[0196] Example XVII: Preparation of Compound 17

[0197] Preparation of 2 - chloro - N - ((2 - chlorophenyl)sulfonyl)-N-(3 - ((4 - (tetrahydrofuran - 2 - carbonyl)piperazin - 1 - yl)methyl)phenyl)benzenesulfonamide

[0198]

[0199] Referring to the synthetic route of Example IX. According to Example IX, using 2 - chloro - N - ((2 - chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3 - (piperazin - 1 - ylmethyl)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N - diisopropylethylamine (100 μL, 0.6 mmol), 2 - tetrahydrofuroic acid (24.4 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as raw materials, the target compound 45.6 mg was obtained with a yield of 35.7%. 1 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.0, 1.2 Hz, 2H), 7.62 - 7.58 (m, 2H), 7.52 - 7.44 (m, 5H), 7.34 (m, 3H), 4.63 - 4.60 (m, 1H), 3.99 - 3.94 (m, 1H), 3.90 - 3.84 (m, 1H), 3.68 - 3.55 (m, 6H), 2.44 - 2.22 (m, 5H), 2.21 - 1.98 (m, 2H), 1.94 - 1.88 (m, 1H). MS (ESI) m / z: 637.6 [M + H] + .

[0200] Example XVIII: Preparation of Compound 18

[0201] Preparation of 2 - chloro - N - ((2 - chlorophenyl)sulfonyl)-N-(3 - ((4 - (tetrahydrofuran - 3 - carbonyl)piperazin - 1 - yl)methyl)phenyl)benzenesulfonamide

[0202]

[0203] Refer to the synthesis route of Example 9. According to Example 9, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), 3-tetrahydrofuroic acid (24.4 mg, 0.21 mmol) and HATU (114 mg, 0.3 mmol) as raw materials, the target compound 60.8 mg was obtained with a yield of 47.6%. 1 H NMR(400MHz,CDCl3)δ8.18(dd, J=8.0,1.2Hz,2H),7.59-7.55(m,2H),7.49-7.42(m,5H),7.36-7.29(m,3H),4.01-3.97(m,1H), 3.91-3.82(m,3H),3.61-3.55(m,6H),3.25-3.17(m,1H),2.44-2.36(m,4H),2.26-2.18(m,1H),2.11-2.02(m,1H).MS(ESI)m / z:637.6[M+H] + .

[0204] Example 19: Preparation of Compound 19

[0205] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(cyclohexanemethyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0206]

[0207] Synthesize the intermediate 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide according to Steps 1-3 of Example 6. Dissolve the intermediate 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol) in anhydrous ethanol (2 mL) and N,N-diisopropylethylamine (100 μL, 0.6 mmol), add bromomethylcyclohexane (39 mg, 0.22 mmol) to the reaction mixture, heat to reflux in an oil bath, and react overnight. After TLC detection shows that the raw materials have completely reacted, rotary evaporate the reaction mixture under reduced pressure, and purify the residue by silica gel column chromatography and reverse-phase medium-pressure preparation system to obtain the target compound 79 mg with a yield of 62%. 11H NMR (400 MHz, CDCl3) δ 8.17 (dm, J = 8.0 Hz, 2H), 7.57 - 7.53 (m, 2H), 7.49 - 7.47 (m, 2H), 7.44 - 7.36 (m, 3H), 7.29 - 7.28 (m, 3H), 3.44 (s, 2H), 2.44 - 2.20 (m, 9H), 1.80 - 1.65 (m, 7H), 1.25 - 1.17 (m, 3H), 0.94 - 0.85 (m, 2H). MS (ESI) m / z: 636.7 [M+H] + .

[0208] Example 20: Preparation of Compound 20

[0209] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-((tetrahydro-2H-pyran-2-yl)methyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0210]

[0211] Referring to the synthetic route of Example 19. According to Example 19, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazin-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and 2-bromomethyltetrahydropyran (39.4 mg, 0.22 mmol) as starting materials, the target compound (43.4 mg) was obtained with a yield of 34.0%. 1 1H NMR (400 MHz, CDCl3) δ 8.19 (dm, J = 8.0 Hz, 2H), 7.60 - 7.56 (m, 2H), 7.52 - 7.50 (m, 2H), 7.46 - 7.39 (m, 3H), 7.30 (m, 3H), 4.02 - 4.00 (m, 1H), 3.60 - 3.41 (m, 4H), 2.61 - 2.48 (m, 10H), 1.87 - 1.85 (m, 1H), 1.61 - 1.51 (m, 4H), 1.33 - 1.30 (m, 1H). MS (ESI) m / z: 637.5 [M+H] + .

[0212] Example 21: Preparation of Compound 21

[0213] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-((tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0214]

[0215] Refer to the synthetic route of Example XIX. According to Example XIX, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethyl)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and 3-bromomethyltetrahydropyran (39.4 mg, 0.22 mmol) as starting materials, the target compound (20.7 mg) was obtained with a yield of 16.2%. 1 H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.0, 1.2 Hz, 2H), 7.57 - 7.53 (m, 2H), 7.49 - 7.47 (m, 2H), 7.43 - 7.37 (m, 3H), 7.32 - 7.22 (m, 3H), 3.96 - 3.83 (m, 2H), 3.44 - 3.36 (m, 3H), 3.15 - 3.10 (m, 1H), 2.40 - 2.19 (m, 10H), 1.85 - 1.83 (m, 2H), 1.61 - 1.59 (m, 2H), 1.21 (m, 1H). MS (ESI) m / z: 637.6 [M+H] + .

[0216] Example XXII: Preparation of Compound 22

[0217] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0218]

[0219] Refer to the synthetic route of Example XIX. According to Example XIX, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethyl)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and 4-bromomethyltetrahydropyran (39.4 mg, 0.22 mmol) as starting materials, the target compound (50.7 mg) was obtained with a yield of 39.7%. 11H NMR (400 MHz, CDCl3) δ 8.18 (dm, J = 8.0 Hz, 2H), 7.58 - 7.53 (m, 2H), 7.49 - 7.47 (m, 2H), 7.44 - 7.37 (m, 3H), 7.32 - 7.22 (m, 3H), 3.98 - 3.94 (m, 2H), 3.48 - 3.47 (m, 2H), 3.41 - 3.35 (m, 2H), 2.46 - 2.26 (m, 8H), 1.78 - 1.67 (m, 5H), 1.34 - 1.27 (m, 2H). MS (ESI) m / z: 637.6 [M+H] + .

[0220] Example 23: Preparation of Compound 23

[0221] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0222]

[0223] Referring to the synthetic route of Example 19. According to Example 19, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and 2-(bromomethyl)tetrahydrofuran (36.3 mg, 0.22 mmol) as raw materials, the target compound 46.9 mg was obtained with a yield of 37.5%. 1 1H NMR (400 MHz, CDCl3) δ 8.17 - 8.15 (dm, J = 8.0 Hz, 2H), 7.57 - 7.53 (m, 2H), 7.49 - 7.47 (m, 2H), 7.43 - 7.36 (m, 3H), 7.28 - 7.26 (m, 3H), 4.12 - 4.06 (m, 1H), 3.91 - 3.85 (m, 1H), 3.78 - 3.72 (m, 1H), 3.43 (s, 2H), 2.61 - 2.44 (m, 8H), 2.05 - 1.97 (m, 2H), 1.90 - 1.81 (m, 3H), 1.53 - 1.43 (m, 1H). MS (ESI) m / z: 623.7 [M+H] + .

[0224] Example 24: Preparation of Compound 24

[0225] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-((tetrahydrofuran-3-yl)methyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0226]

[0227] Referring to the synthetic route of Example XIX. According to Example XIX, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazin-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and 3-(bromomethyl)tetrahydrofuran (36.3 mg, 0.22 mmol) as raw materials, the target compound 93 mg was obtained with a yield of 74.4%. 1 H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.0, 1.2 Hz, 2H), 7.57 - 7.53 (m, 2H), 7.49 - 7.47 (m, 2H), 7.43 - 7.36 (m, 3H), 7.29 - 7.23 (m, 3H), 3.89 - 3.81 (m, 2H), 3.76 - 3.70 (m, 1H), 3.51 - 3.48 (m, 1H), 3.44 (s, 2H), 2.48 - 2.32 (m, 10H), 2.06 - 1.98 (m, 1H), 1.65 - 1.56 (m, 1H), 1.30 (m, 1H). MS (ESI) m / z: 623.6 [M + H] + .

[0228] Example 25: Preparation of Compound 25

[0229] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(pyridin-2-ylmethyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0230]

[0231] Synthesize 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide according to steps 1-3 of Example 6. At room temperature, add 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide (162 mg, 0.3 mmol), 3-pyridinecarboxaldehyde (70 mg, 0.6 mmol), acetic acid (72 mg, 1.2 mmol) and dichloromethane (5 mL) into a 10 mL single-necked flask. Stir the mixture at room temperature for 1 hour, add sodium triacetoxyborohydride (96 mg, 0.45 mmol), and continue the reaction overnight. After detecting that the raw materials have completely reacted by TLC, add water (5 mL) to quench the reaction. Separate the layers, wash the organic phase with deionized water and saturated NaCl solution, dry over anhydrous Na2SO4, filter, and remove the solvent under reduced pressure from the filtrate. The remaining mixture is purified by silica gel column chromatography to obtain 40 mg of the target compound with a yield of 21.1%. 1 1H NMR (400 MHz, CDCl3) δ 8.59 - 8.58 (d, J = 4.4 Hz, 1H), 8.16 (dd, J = 8.0, 1.2 Hz, 2H), 7.70 - 7.66 (m, 1H), 7.56 - 7.52 (m, 2H), 7.48 - 7.39 (m, 6H), 7.29 - 7.27 (m, 3H), 7.22 - 7.19 (m, 1H), 3.76 (m, 2H), 2.64 - 2.50 (m, 8H). MS (ESI) m / z: 630.7 [M + H] + .

[0232] Example 26: Preparation of Compound 26

[0233] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0234]

[0235] Refer to the synthetic route of Example 25. According to Example 25, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazin-1-ylmethyl)phenyl)benzenesulfonamide (162 mg, 0.3 mmol), 3-pyridinecarboxaldehyde (70 mg, 0.6 mmol), acetic acid (72 mg, 1.2 mmol), and sodium triacetoxyborohydride (96 mg, 0.45 mmol) as raw materials, 52 mg of the target compound is obtained with a yield of 27.4%. 11H NMR (400 MHz, CDCl3) δ 8.55 - 8.53 (m, 2H), 8.18 (dd, J = 8.0, 1.6 Hz, 2H), 7.74 (m, 1H), 7.56 - 7.52 (m, 2H), 7.48 - 7.40 (m, 5H), 7.31 - 7.26 (m, 4H), 3.59 - 3.53 (m, 4H), 2.56 - 2.51 (m, 8H). MS (ESI) m / z: 630.7 [M + H] + .

[0236] Example 27: Preparation of Compound 27

[0237] Preparation of 2 - chloro - N - ((2 - chlorophenyl)sulfonyl)-N-(3 - ((4-(pyridin - 4 - ylmethyl)piperazin - 1 - yl)methyl)phenyl)benzenesulfonamide

[0238]

[0239] Referring to the synthetic route of Example 25. According to Example 25, using 2 - chloro - N - ((2 - chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine - 1 - ylmethylene)phenyl)benzenesulfonamide (162 mg, 0.3 mmol), 4 - pyridinecarboxaldehyde (70 mg, 0.6 mmol), acetic acid (72 mg, 1.2 mmol), and sodium triacetoxyborohydride (96 mg, 0.45 mmol) as starting materials, the target compound (93 mg, yield 49.1%) was obtained. 1 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 6.0 Hz, 2H), 8.17 (dd, J = 8.0, 1.2 Hz, 2H), 7.56 - 7.52 (m, 2H), 7.48 - 7.40 (m, 5H), 7.33 - 7.28 (m, 5H), 3.54 (s, 4H), 2.52 (m, 8H). MS (ESI) m / z: 630.7 [M + H] + .

[0240] Example 28: Preparation of Compound 28

[0241]

[0242] Refer to the synthetic route of Example 25. According to Example 25, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (162 mg, 0.3 mmol), 3-pyrrolecarboxaldehyde (57 mg, 0.6 mmol), acetic acid (72 mg, 1.2 mmol), and sodium triacetoxyborohydride (96 mg, 0.45 mmol) as starting materials to obtain the target compound. 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (brs, 1H), 7.97 (s, 2H), 7.77–7.64 (m, 5H), 7.56 (m, 2H), 7.35 (s, 2H), 7.13 (m, 2H), 6.78 (s, 1H), 6.14 (s, 1H), 4.01 (s, 2H), 3.43 (s, 2H), 2.69 - 2.30 (m, 8H). MS (ESI) m / z: 618.7 [M+H] + .

[0243] Example 29: Preparation of Compound 29

[0244]

[0245] Refer to the synthetic route of Example 25. According to Example 25, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (162 mg, 0.3 mmol), 3-furaldehyde (58 mg, 0.6 mmol), acetic acid (72 mg, 1.2 mmol), and sodium triacetoxyborohydride (96 mg, 0.45 mmol) as starting materials to obtain the target compound. 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (m, 2H), 7.83–7.51 (m, 8H), 7.36 (s, 2H), 7.19 - 7.14 (m, 2H), 6.47 (s, 1H), 3.34 (m, 4H), 2.26 (m, 8H). MS (ESI) m / z: 619.6 [M+H] + .

[0246] Example 30: Preparation of Compound 30

[0247]

[0248] Refer to the synthetic route of Example 25. According to Example 25, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (162 mg, 0.3 mmol), 3-thiophenecarboxaldehyde (67 mg, 0.6 mmol), acetic acid (72 mg, 1.2 mmol), and sodium triacetoxyborohydride (96 mg, 0.45 mmol) as raw materials to obtain the target compound. 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.2 Hz, 2H), 7.78 - 7.70 (m, 5H), 7.66–7.51 (m, 3H), 7.37 (s, 3H), 7.19 - 7.13 (m, 2H), 3.40 (m, 4H), 2.31 (m, 8H). MS (ESI) m / z: 635.6 [M + H] + .

[0249] Example 31: Preparation of Compound 31

[0250] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-phenylpiperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0251]

[0252] Step 1: Preparation of 1-(3-nitrobenzyl)-4-phenylpiperazine

[0253]

[0254] According to Step 1 of Example 1, using m-nitrobenzaldehyde (453 mg, 3.0 mmol), N-phenylpiperazine (535 mg, 3.3 mmol), acetic acid (720 mg, 12.0 mmol), and sodium triacetoxyborohydride (954 mg, 4.5 mmol) as raw materials to obtain 400 mg of 1-(3-nitrobenzyl)-4-phenylpiperazine, with a yield of 44.9%. MS (ESI) m / z: 298.0 [M + H] + .

[0255] Step 2: Preparation of 1-(3-aminobenzyl)-4-phenylpiperazine

[0256]

[0257] According to Step 4 of Example 1, using 1-(3-nitrobenzyl)-4-phenylpiperazine (400 mg, 1.35 mmol), zinc powder (263 mg, 4.4 mmol), and ammonium formate (425 mg, 6.75 mmol) as raw materials, the target compound 1-(3-aminobenzyl)-4-phenylpiperazine was obtained in an amount of 295.6 mg with a yield of 82.0%. MS (ESI) m / z: 268.0 [M+H] + .

[0258] Step 3: Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((4-phenylpiperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0259]

[0260] According to Step 6 of Example 1, using o-chlorobenzenesulfonyl chloride (171.3 mg, 0.812 mmol), 1-(3-aminobenzyl)-4-phenylpiperazine (86.7 mg, 0.325 mmol), and triethylamine (228 μL, 1.625 mmol) as raw materials, the target compound was obtained in an amount of 36.4 mg with a yield of 18.2%. 1 H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 8.0, 1.2 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.52 - 7.44 (m, 5H), 7.39 - 7.30 (m, 5H), 6.96 - 6.89 (m, 3H), 3.65 - 3.27 (m, 6H), 2.65 (m, 4H). MS (ESI) m / z: 615.6 [M+H] + .

[0261] Example 32: Preparation of Compound 32

[0262] Preparation of 2-fluoro-N-(((2-fluorophenyl)sulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0263]

[0264] Step 1: Preparation of (4-(3-nitrobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone

[0265]

[0266] The crude product 1-(3-nitrobenzyl)piperazine (9.27 g, 41.9 mmol) obtained by the reaction in Step 1 to Step 2 of the example was dissolved in dichloromethane. Triethylamine (63.8 mL, 459 mmol), tetrahydro-2H-pyran-4-carboxylic acid (8.724 g, 67.04 mmol), and T3P (33.7 mL, 131.33 mmol) were successively added thereto under an ice bath. After the addition was completed, the reaction was carried out overnight at room temperature. After TLC confirmed that the reaction was complete, it was washed three times with saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 12.0 g of the compound (4-(3-nitrobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone, with a yield of 86.0%.

[0267] Step 2: Preparation of (4-(3-aminobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone

[0268]

[0269] At room temperature, (4-(3-nitrobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone was dissolved in methanol, and platinum dioxide was added. The catalytic reaction was carried out overnight under a hydrogen atmosphere. Column chromatography was performed to obtain 1.61 g of the compound (4-(3-aminobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone, with a yield of 14.7%.

[0270] Step 3: Preparation of 2-fluoro-N-(((2-fluorophenyl)sulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0271]

[0272] (4-(3-aminobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (152.5 mg, 0.503 mmol) was dissolved in dichloromethane. After adding o-fluorobenzenesulfonyl chloride (0.245 mL, 2.01 mmol), triethylamine (0.35 mL) was added dropwise and stirred. The reaction was carried out overnight at room temperature. After TLC detected that the reaction was complete, methanol (1 mL) was added to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residual mixture was separated by column chromatography (DCM / MeOH = 80 / 1) to obtain 59.6 mg of the white solid compound 2-fluoro-N-(((2-fluorophenyl)sulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide, with a yield of 14.53%. 11H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.8, 1.4 Hz, 2H), 8.96 (d, J = 2.2 Hz, 2H), 8.30 (ddd, J = 8.2, 2.3, 1.6 Hz, 2H), 7.80 (dd, J = 8.1, 4.9 Hz, 2H), 7.54–7.45 (m, 2H), 7.12 (dt, J = 6.4, 2.2 Hz, 1H), 6.99 (s, 1H), 3.84 (dd, J = 10.2, 3.0 Hz, 2H), 3.48 (d, J = 20.6 Hz, 6H), 3.38 (td, J = 11.5, 2.3 Hz, 2H), 2.93–2.81 (m, 1H), 2.28 (d, J = 21.4 Hz, 4H), 1.66–1.46 (m, 4H). MS (ESI) m / z: 620.3 [M+H] + .

[0273] Example 33: Preparation of Compound 33

[0274] Preparation of 3-Fluoro-N-(((3-fluorophenyl)sulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0275]

[0276] Referring to the synthetic route of Example 32. According to Step 3 of Example 32, using (4-(3-aminobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (200.6 mg, 0.662 mmol), 3-fluorobenzenesulfonyl chloride (0.180 mL, 1.32 mmol), and triethylamine (0.47 mL) as raw materials, the target compound 353.8 mg was obtained with a yield of 86.2%. 1 1H NMR (400 MHz, DMSO-d6) δ 7.92–7.65 (m, 6H), 7.62 (dd, J = 8.2, 2.1 Hz, 2H), 7.52–7.39 (m, 2H), 7.07 (dt, J = 6.6, 2.1 Hz, 1H), 6.93 (s, 1H), 3.84 (dd, J = 10.3, 3.0 Hz, 2H), 3.56–3.33 (m, 8H), 2.93–2.79 (m, 1H), 2.26 (d, J = 24.7 Hz, 4H), 1.69–1.43 (m, 4H). MS (ESI) m / z: 620.3 [M+H] + .

[0277] Example 34: Preparation of Compound 34

[0278] Preparation of 4-Fluoro-N-(((4-fluorophenyl)sulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0279]

[0280] Referring to the synthetic route of Example 32. According to Step 3 of Example 32, using (4-(3-aminobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (211.9 mg, 0.699 mmol), 4-fluorobenzenesulfonyl chloride (0.272 g, 1.40 mmol), and triethylamine (0.49 mL) as raw materials, the target compound (275.9 mg) was obtained with a yield of 63.7%. 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (ddd, J = 8.1, 5.0, 2.5 Hz, 4H), 7.64–7.34 (m, 6H), 7.13–6.97 (m, 1H), 6.88 (s, 1H), 3.84 (dd, J = 10.4, 3.1 Hz, 2H), 3.55–3.33 (m, 8H), 2.86 (ddd, J = 15.0, 9.5, 3.9 Hz, 1H), 2.24 (dd, J = 8.2, 3.9 Hz, 4H), 1.67–1.42 (m, 4H), 1.28–1.12 (m, 1H). MS (ESI) m / z: 620.4 [M+H] + .

[0281] Example 35: Preparation of Compound 35

[0282] Preparation of 3-Methyl-N-(3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)-N-(m-toluenesulfonyl)benzenesulfonamide

[0283]

[0284] Referring to the synthetic route of Example 32. According to Step 3 of Example 32, using (4-(3-aminobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (214.2 mg, 0.707 mmol), m-toluenesulfonyl chloride (0.440 mL, 2.83 mmol), and triethylamine (0.50 mL) as raw materials, the target compound (136.8 mg) was obtained with a yield of 31.6%. 11H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.8, 1.4 Hz, 2H), 8.96 (d, J = 2.2 Hz, 2H), 8.30 (ddd, J = 8.2, 2.3, 1.6 Hz, 2H), 7.80 (dd, J = 8.1, 4.9 Hz, 2H), 7.54–7.45 (m, 2H), 7.12 (dt, J = 6.4, 2.2 Hz, 1H), 6.99 (s, 1H), 3.84 (dd, J = 10.2, 3.0 Hz, 2H), 3.48 (d, J = 20.6 Hz, 6H), 3.38 (td, J = 11.5, 2.3 Hz, 2H), 2.93–2.81 (m, 1H), 2.28 (d, J = 21.4 Hz, 4H), 1.66–1.46 (m, 4H). MS (ESI) m / z: 612.3 [M+H] + .

[0285] Example 36: Preparation of Compound 36

[0286] Preparation of N-(pyridin-3-ylsulfonyl)-N-(3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)pyridine-3-sulfonamide

[0287]

[0288] Referring to the synthetic route of Example 32. According to Step 3 of Example 32, using (4-(3-aminobenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (217.7 mg, 0.719 mmol), pyridine-3-sulfonyl chloride (0.344 mL, 2.87 mmol), and triethylamine (0.50 mL) as raw materials, the target compound was obtained as 166.2 mg with a yield of 39.5%. 1 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.8, 1.4 Hz, 2H), 8.96 (d, J = 2.2 Hz, 2H), 8.30 (ddd, J = 8.2, 2.3, 1.6 Hz, 2H), 7.80 (dd, J = 8.1, 4.9 Hz, 2H), 7.54–7.45 (m, 2H), 7.12 (dt, J = 6.4, 2.2 Hz, 1H), 6.99 (s, 1H), 3.84 (dd, J = 10.2, 3.0 Hz, 2H), 3.48 (d, J = 20.6 Hz, 6H), 3.38 (td, J = 11.5, 2.3 Hz, 2H), 2.93–2.81 (m, 1H), 2.28 (d, J = 21.4 Hz, 4H), 1.66–1.46 (m, 4H). MS (ESI) m / z: 585.7 [M+H]+ .

[0289] Example 37: Preparation of Compound 37

[0290] Preparation of 2-chloro-N-(5-chloro-2-methyl-3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)-N-((2-chlorophenyl)sulfonyl)benzenesulfonamide

[0291]

[0292] Step 1: Preparation of 1-(5-chloro-2-methyl-3-nitrobenzyl)piperazine

[0293]

[0294] According to Steps 1 to 2 of Example 1, using 5-chloro-2-methyl-3-nitrobenzaldehyde (1 eq) and Boc-piperazine (1.1 eq) as starting materials, the intermediate 1-(5-chloro-2-methyl-3-nitrobenzyl)piperazine was synthesized.

[0295] Step 2: Preparation of (4-(3-amino-5-chloro-2-methylbenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone

[0296]

[0297] According to Steps 1 to 2 of Example 32, using 1-(5-chloro-2-methyl-3-nitrobenzyl)piperazine as the raw material, the intermediate (4-(3-amino-5-chloro-2-methylbenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone was synthesized.

[0298] Step 3: Preparation of 2-chloro-N-(5-chloro-2-methyl-3-((4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)-N-((2-chlorophenyl)sulfonyl)benzenesulfonamide

[0299]

[0300] According to Step 3 of Example 32, using (4-(3-amino-5-chloro-2-methylbenzyl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (1 eq) and o-chlorobenzenesulfonyl chloride (2.5 eq) as raw materials, the target compound was obtained. 11H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.5 Hz, 2H), 7.85–7.59 (m, 6H), 7.47 (s, 1H), 7.16 (s, 1H), 3.80 (s, 2H), 3.31 (m, 6H), 2.83 (m, 2H), 2.27 (m, 5H), 1.98 (s, 3H), 1.58–1.43 (m, 4H). MS (ESI) m / z: 699.5 [M+H] + .

[0301] Example 38: Preparation of Compound 38

[0302] Preparation of (S)-2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((3-methyl-4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0303]

[0304] Referring to the synthetic route of Example 37. Using 3-nitrobenzaldehyde (1 eq) and (S)-1-N-Boc-2-methylpiperazine (1.1 eq) as starting materials, the target compound was obtained through five-step reactions. 1 1H NMR (400 MHz, DMSO-d6) δ 7.98 (m, 3H), 7.74 (m, 4H), 7.58 (m, 2H), 7.34 (m, 2H), 7.15 (m, 1H), 4.49 (s, 1H), 4.16 (s, 1H), 3.81 (m, 3H), 3.26 (m, 2H), 2.79-2.43 (m, 5H), 1.87 (m, 2H), 1.48 (m, 3H), 1.23-1.09 (m, 4H).

[0305] Example 39: Preparation of Compound 39

[0306] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-((8-(tetrahydro-2H-pyran-4-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)benzenesulfonamide

[0307]

[0308] Referring to the synthetic route of Example 37. Using 3-nitrobenzaldehyde (1 eq) and 3,8-diazabicyclo[3.2.1]octane (1.1 eq) as starting materials, the target compound was obtained through five-step reactions. 1H NMR(400MHz, DMSO-d6) δ 8.01(m, 2H), 7.78(m, 4H), 7.61(m, 2H), 7.36(m, 2H), 7.20(m, 2H), 4.37(m, 2H), 3.84(s, 2H), 3.42(m, 2H), 3.23–3.13(m, 1H), 2.75(m, 1H), 2.43(m, 3H), 2.08 - 2.01(m, 2H), 1.81–1.53(m, 8H)..MS(ESI) m / z: 677.6[M + H] + .

[0309] Example 40: Preparation of Compound 40

[0310] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(3-(4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)-2,3-dihydro-1H-inden-5-yl)benzenesulfonamide

[0311]

[0312] Referring to the synthetic route of Example 37. Using 6-nitro-1-indanone (1 eq) and Boc-piperazine (1.1 eq) as starting materials, the target compound was obtained through five-step reactions. 1 H NMR(400MHz, DMSO-d6) δ 8.11(d, J = 7.9Hz, 1H), 7.91 - 7.55(m, 7H), 7.27(d, J = 7.9Hz, 1H), 7.15 - 7.07(m, 2H), 4.31(d, J = 8.4Hz, 1H), 3.94–3.75(m, 2H), 3.59–3.25(m, 8H), 2.94–2.70(m, 3H), 2.24(m, 2H), 2.03(s, 3H), 1.55(m, 3H). MS(ESI) m / z: 677.6[M + H] + .

[0313] Example 41: Preparation of Compound 41

[0314] Preparation of 2-chloro-N-((2-chlorophenyl)sulfonyl)-N-(1-(4-(tetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)-2,3-dihydro-1H-inden-4-yl)benzenesulfonamide

[0315]

[0316] According to the synthetic route of Example 37. Using 4-nitro-1-indanone (1 eq) and Boc-piperazine (1.1 eq) as starting materials, the target compound was obtained through five-step reactions.1 1H NMR (400 MHz, DMSO-d6) δ 8.26–7.99 (m, 2H), 7.89–7.60 (m, 6H), 7.47–7.19 (m, 3H), 4.35 - 4.32 (m, 1H), 3.84 (m, 2H), 3.51–3.37 (m, 8H), 2.88 (m, 1H), 2.30 (m, 4H), 1.82–1.52 (m, 6H). MS (ESI) m / z: 677.6 [M+H] + .

[0317] Example Forty-Two: Preparation of Compound 42

[0318] Preparation of 2-Chloro-N-((4-chlorophenyl)sulfonyl)-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0319]

[0320] Referring to the synthetic route of Example 1. According to Step 5 of Example 1, using 2-chlorobenzenesulfonyl chloride (134 mg, 0.64 mmol), (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone (162 mg, 0.54 mmol), and triethylamine (225 μL, 1.6 mmol) as raw materials, the intermediate 2-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide 130 mg was obtained, with a yield of 50.6%, a white solid. MS (ESI) m / z: 476.2 [M+H] + . Then, according to Step 6 of Example 1, using 4-chlorobenzenesulfonyl chloride (168.8 mg, 0.8 mmol), the intermediate 2-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide (197 mg, 0.4 mmol), and triethylamine (276 μL, 2 mmol) as raw materials, the target compound 130 mg was obtained, with a yield of 50%. 1 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.0, 1.2 Hz, 2H), 7.59 - 7.55 (m, 2H), 7.50 - 7.41 (m, 5H), 7.33 - 7.30 (m, 3H), 3.55 - 3.49 (m, 5H), 2.46 - 2.31 (m, 4H), 1.80 - 1.47 (m, 10H), 1.31 - 1.25 (m, 2H). MS (ESI) m / z: 649.6 [M+H] + .

[0321] Example Forty-Three: Preparation of Compound 43

[0322] Preparation of 3-(4-(3-((2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)benzyl)piperazin-1-yl)propanoic acid

[0323]

[0324] Step 1: Preparation of ethyl 3-(4-(3-((2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)benzyl)piperazin-1-yl)propanoate

[0325]

[0326] Referring to the synthetic route of Example XIX. According to Example XIX, using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and ethyl 3-bromopropionate (40 mg, 0.22 mmol) as raw materials, the target compound ethyl 3-(4-(3-((2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)benzyl)piperazin-1-yl)propanoate 99.4 mg was obtained.

[0327] Step 2: Preparation of 3-(4-(3-((2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)benzyl)piperazin-1-yl)propanoic acid

[0328]

[0329] 99.4 mg of ethyl 3-(4-(3-((2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)benzyl)piperazin-1-yl)propanoate was dissolved in a 5:1 mixture of dioxane and water, NaOH (6.8 mg, 0.17 mmol) was added, and hydrolysis was carried out at room temperature. After TLC detection showed that the raw materials had completely reacted, dioxane was evaporated under reduced pressure, the pH was adjusted with dilute HCl, and the target compound 25 mg was purified using a medium-pressure preparative reverse-phase system, with a yield of 20.4%, a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.00 (dm, J = 8.0 Hz, 2H), 7.82 - 7.73 (m, 4H), 7.61 - 7.58 (m, 2H), 7.47 - 7.44 (m, 1H), 7.37 - 7.25 (m, 3H), 3.55 (m, 8H), 3.07 (m, 3H), 2.82 (m, 3H). MS (ESI) m / z: 611.7 [M + H] + .

[0330] Example Forty-four: Preparation of Compound 44

[0331] Preparation of 3-(4-(3-((2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)benzyl)piperazin-1-yl)acetic acid

[0332]

[0333] Referring to the synthetic route of Example 43. Using 2-chloro-N-((2-chlorophenyl)sulfonyl)phenyl)sulfonamido)-N-(3-(piperazine-1-ylmethylene)phenyl)benzenesulfonamide (108 mg, 0.2 mmol), N,N-diisopropylethylamine (100 μL, 0.6 mmol), and ethyl 3-bromoacetate (40 mg, 0.22 mmol) as starting materials, 65 mg of the target compound was obtained with a yield of 54.3%. 1 HNMR(400MHz,DMSO-d6)δ8.02(dm,J=8.0Hz,2H),7.83-7.74(m,4H),7.62- 7.59(m,2H),7.49-7.34(m,4H),3.40(m,8H),2.98(m,2H),2.77(m,2H).MS(ESI)m / z:597.6[M+H] + .

[0334] Comparative Example 1: Preparation of Compound 45

[0335] Preparation of 3-chloro-N-(3-((4-(cyclohexanecarbonyl)piperazin-1-yl)methyl)phenyl)benzenesulfonamide

[0336]

[0337] The intermediate (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone was obtained according to the steps 1-4 of Example 1. At room temperature, m-chlorobenzenesulfonyl chloride (68 mg, 0.32 mmol) was added to a solution of the intermediate (4-(3-aminobenzyl)piperazin-1-yl)(cyclohexyl)methanone (81 mg, 0.27 mmol) and pyridine (217 μL, 2.7 mmol) in tetrahydrofuran, and the reaction was continued at room temperature for 6 hours. After detecting the completion of the reaction by TLC, the reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with deionized water and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure from the filtrate. The remaining mixture was purified by silica gel column chromatography to obtain 70 mg of the target compound with a yield of 54.5%, as a white solid. 11H NMR (400 MHz, CDCl3) δ 7.78 - 7.77 (m, 1H), 7.69 - 7.67 (m, 1H), 7.55 - 7.51 (m, 1H), 7.42 - 7.38 (m, 1H), 7.27 - 7.24 (m, 1H), 7.13 - 7.09 (m, 3H), 3.65 - 3.53 (m, 6H), 2.47 - 2.39 (m, 5H), 1.83 - 1.81 (m, 2H), 1.74 - 1.71 (m, 3H), 1.59 - 1.50 (m, 2H), 1.30 - 1.26 (m, 3H). MS (ESI) m / z: 476.2 [M+H] + .

[0338] Comparative Example 2: Preparation of Compound 46

[0339] Preparation of 2 - chloro - N - (3 - ((4 - (cyclohexanecarbonyl)piperazin - 1 - yl)methyl)phenyl)benzenesulfonamide

[0340]

[0341] According to Comparative Example 1, using o - chlorobenzenesulfonyl chloride (134 mg, 0.64 mmol), (4 - (3 - aminobenzyl)piperazin - 1 - yl)(cyclohexyl)methanone (162 mg, 0.54 mmol) and pyridine (434 μL, 5.4 mmol) as raw materials, 130 mg of the target compound was obtained, yield: 50.6%, white solid. 1 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 8.0, 0.8 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.34 - 7.31 (m, 1H), 7.20 - 7.14 (m, 2H), 7.07 - 7.05 (m, 2H), 3.60 - 3.49 (m, 6H), 2.46 - 2.39 (m, 2H), 2.29 (m, 2H), 1.82 - 1.68 (m, 7H), 1.56 - 1.47 (m, 2H), 1.31 - 1.28 (m, 2H). MS (ESI) m / z: 476.2 [M+H] + .

[0342] Performance Test: In vitro determination of the RORγt Dual FRET activity of the compound

[0343] For the compounds of the present invention, a dual fluorescence resonance energy transfer (Dual FRET) experiment was used to determine the agonist activity of the compounds against the RORγt protein receptor. This agonist activity is expressed by the half - maximal activation concentration (EC 50 ) and the maximum activation percentage (maxact%).

[0344] Experimental method:

[0345] In a 384-well plate (Greiner 78407), 10 μL of buffer (50 mM sodium fluoride, 50 mM 3-(N-morpholino)propanesulfonic acid, pH 7.5, 50 μM 3-[(3-cholesterylaminopropyl)dimethylammonio]propanesulfonate, 0.1 mg / mL bovine serum albumin, and 10 mM dithiothreitol) was added to each well. The europium-labeled steroid receptor coactivator 1 (SRC1) solution was prepared by adding appropriate amounts of biotinylated SRC and europium-labeled streptavidin to the test buffer, with final concentrations of 27 and 3.3 nM, respectively. The allophycocyanin (APC)-labeled LBD solution was prepared by adding appropriate amounts of biotinylated RORc-LBD and APC-labeled streptavidin to the test buffer, with final concentrations of 33 nM for both. After incubation at room temperature for 15 min, 20-fold excess biotin was added to block the remaining free streptavidin. Different concentrations of the test compound were dissolved in DMSO and added to the 384-well plate, 0.1 μL per well. Then, an equal volume of europium-labeled SRC and APC-labeled RORc-LBD was mixed and added to the 384-well plate, 10 μL per well. After incubation at room temperature for 1 h, data were read on a ViewLux, and the half-maximal activation concentration EC 50 and the maximum activation percentage were calculated.

[0346] Table 1 shows the agonistic activities of Compounds 1-44 of the examples of the present invention against RORγt.

[0347] Table 1. Test results of the RORγt Dual FRET activities of Compounds 1-44 of the examples

[0348]

[0349] · The test results are the average of at least two trials, and LYC55716 is the positive control

[0350] The determination results in Table 1 show that the disulfonamide derivative Compounds 1-44 of the present invention have good agonistic activities against RORγt, and like the drug cintirorgon (LYC-55716) in the prior art, also have agonistic activities against RORγt.

[0351] Table 2 shows the activities of the monosulfonamide derivative Compounds 45-46 as comparative examples against RORγt.

[0352] Table 2. Test results of the RORγt Dual FRET activities of Compounds 45-46 of the comparative examples

[0353]

[0354] · The test results are the average of at least two trials, and the maximum inhibition rate is represented by a negative value.

[0355] As can be seen from Table 2, compounds 45 - 46 as comparative examples showed inverse agonistic (i.e., inhibitory) activity against RORγt and cannot be used as RORγt modulators for treating diseases such as tumors or cancers and immunodeficiency disorders.

[0356] As can be seen from Table 1 and Table 2, the disulfonamide structure of the present invention endows the compound with RORγt agonistic activity, while the monosulfonamide derivative compounds 45 and 46 as comparative examples showed strong RORγt inhibitory (inverse agonistic) activity, indicating that the disulfonamide structure is the key for the compound to maintain RORγt agonistic activity.

[0357] Functional test: Determine the RORγt GAL4 cell activity of the compound.

[0358] For some compounds of the present invention, a dual - luciferase reporter gene system was used to determine the agonistic activity of the compound against RORγt at the cellular level. This agonistic activity was represented by two indicators: the half - maximal activation concentration (EC 50 ) and the maximum agonistic response value (E max %).

[0359] The luciferase reporter gene system is a reporter system that uses luciferin as a substrate to detect luciferase activity. The principle is to fuse the coding sequence of the luciferin reporter gene with the gene expression regulatory sequence to form a chimeric gene, so that it is transcribed and expressed under the control of the regulatory sequence, and then the expression status of the target gene is calibrated by the condition of the expressed luciferase decomposing the substrate.

[0360] Experimental method:

[0361] The hRORγt LBD coding sequence was inserted into the pBIND expression vector (Promega, E1581) to express the ROR-Gal4 binding domain chimeric receptor. This expression vector and the reporter vector (pGL4.35 carrying the luciferase reporter gene [luc2P / 9XGal4 UAS / Hygro] stably integrated under the control of the Gal4 promoter) were co-transfected into HEK293T host cells. After the agonist binds to the corresponding ROR-Gal4 chimeric receptor, this chimeric receptor binds to the Gal4 binding site and stimulates the reporter gene. Among the current inverse agonists, the agonist will competitively bind to the nuclear receptor and activate the transcription of the reporter gene. According to the recommendations of ATCC, HEK293T cells were cultured in a medium composed of DMEM containing 5% charcoal-treated FBS at 37 °C in a 5% CO2 atmosphere. Before the assay, the cells were washed with PBS to remove phenol red and suspended in phenol red-free medium (phenol red-free DMEM containing 5% charcoal-treated FBS and penicillin-streptomycin (10,000 U / mL)) at an appropriate concentration. 6×10 6 HEK293T cells were seeded into 100 mm culture dishes and incubated for 16 h. Plasmid DNA (0.5 mg / mL stock solution), containing 5 μg of the RORγ plasmid and 5 μg of the pGL4.35 luciferase plasmid, was added to the reagent mixture of Trans-IT reagent and Opti-MEM (Invitrogen). The mixture was added to the cells in the 100 mm culture dishes and incubated for 5 - 6 hours. The test compounds were serially diluted in DMSO to 5 - 6 doses. LYC-55716 was used as a positive control and 100% DMSO was used as a vehicle control. The compounds (25 nL) were transferred to 384-well plates (white opaque) using an Echo550. Then, the cells were seeded into the 384-well plates containing phenol red-free DMEM with 5% charcoal-treated FBS and 0.25 μM ursolic acid at a concentration of 15,000 cells / well. The cells were incubated at 37 °C, 5% CO2 for 16 - 20 hours. 25 μL of Steady-Glo TM Luciferase Assay Reagent was added to the 384-well plates. The plates were shaken on a plate shaker (avoiding light) for 5 minutes. The luminescence values were recorded on an Envision 2104 plate reader. EC 50 values were calculated by nonlinear regression analysis of the dose-response curve.

[0362] Table 3. Results of RORγt GAL4 functional activity tests for Example Compounds 16 and 22

[0363]

[0364] As can be seen from Table 3, the disulfonamide derivative compounds of the present invention have good RORγt agonist activity at the cellular level.

[0365] The above specific embodiments further elaborate on the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above is only one specific embodiment of the present invention and is not limited to the protection scope of the present invention. Without departing from the gist of the basic features of the present invention, the present invention can be embodied in various forms. Therefore, the embodiments in the present invention are for illustration rather than limitation. Since the scope of the present invention is defined by the claims rather than the specification, and all changes falling within the scope defined by the claims, or within the equivalent scope defined by the claims, should be understood to be included in the claims. Any modifications, equivalent replacements, improvements, etc., made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A disulfonamide derivative of the following general chemical structure formula I or a pharmaceutically acceptable salt thereof: ， Wherein, Groups A and B are independently selected from substituted or unsubstituted aryl and heteroaryl, and the substituents on groups A and B are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen; the aryl has 6-12 carbon atoms; the heteroaryl refers to a monocyclic or fused ring containing 5-12 ring atoms, wherein there are 1-4 ring atoms selected from N, O, S, and the remaining ring atoms are C, and it has a fully conjugated π-electron system; R 1 , R 2 , R 3 independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or halogen; R 4 、R 5 、R 6 are independently selected from hydrogen or C1-C4 alkyl; or R 1 and R 4 are connected to form an alkylene group and, together with the carbon atoms to which they are attached, form a five- to seven-membered alicyclic ring; or, R 2 and R 4 are connected to form an alkylene group and, together with the carbon atoms to which they are attached, form a five- to seven-membered alicyclic ring; or, R 5 and R 6 are connected to form an alkylene group and, together with the adjacent nitrogen atom, are bridged to form a five- to seven-membered nitrogen-containing heterocyclic ring or ; R 7 selected from substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 oxocycloalkyl, aryl, heteroaryl, cyano or carboxyl, and the substituents on said R 7 are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen; the aryl has 6-12 carbon atoms; the heteroaryl refers to a monocyclic or fused ring containing 5-12 ring atoms, wherein 1-4 ring atoms are selected from N, O, S, the remaining ring atoms are C, and it has a fully conjugated π-electron system; Q is selected from a carbonyl group, an alkylene group, or a covalent bond; the alkylene group contains 1 to 6 carbon atoms.

2. The bissulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Groups A and B are independently selected from substituted or unsubstituted phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, and the substituents on groups A and B are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen.

3. The bis-sulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein The substituents on groups A and B are methyl, trifluoromethyl or halogen.

4. The bis-sulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 1 and R 4 are connected to form an alkylene group, and together with the carbon atoms to which they are attached, form the structure of indene, i.e., ; alternatively, R 2 and R 4 are connected to form an alkylene group, and together with the carbon atoms to which they are attached, form the structure of indene, i.e., .

5. The bissulfonamide derivative or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 7 is selected from substituted or unsubstituted methyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrrolyl, furyl, thienyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxotetrahydrothiopyranyl or carboxyl, wherein R 7 The substituents are selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano or halogen.

6. The bissulfonamide derivative or pharmaceutically acceptable salt thereof according to claim 5, characterized in that: The substituent on R 7 is methyl, trifluoromethyl or halogen.

7. A disulfonamide derivative or a pharmaceutically acceptable salt thereof, characterized in that, The disulfonamide derivative is selected from the following compounds: 。 8. A method for preparing a bissulfonamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, characterized in that, Including two synthetic schemes: The first synthetic scheme: ； Reaction conditions: (a) NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (b) hydrochloric acid / dioxane, DCM, room temperature, 2 h; (c) acyl chloride R 7 -COCl, DIEA, DCM, 0 °C to room temperature, 2 h; (d) carboxylic acid R 7 -COOH, HATU or T3P, DIEA or TEA, DCM, room temperature, overnight; (e) alkyl halide R 7 -alkylidene chloride, in the corresponding product Q = alkylidene, the alkylidene contains 1 to 6 carbon atoms, DIEA, EtOH, reflux, 6 h; (f) aldehyde R 7 CHO, NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (g) Zn, HCOONH4, MeOH / H2O, reflux, 3 h; (h) pyridine, THF, room temperature, 6 h; (i) TEA, DCM, room temperature, overnight; The second synthetic scheme: ； Reaction conditions: (a) NaBH(OAc)3, AcOH, DCM, room temperature, overnight; (b) Zn, HCOONH4, MeOH / H2O, reflux, 3h; (c) Pyridine, THF, room temperature, 6 h; (d) TEA, DCM, room temperature, overnight; (e) hydrochloric acid / dioxane, DCM, room temperature, 2 h; (f) acyl chloride R 7 -COCl, DIEA, DCM, 0 °C to room temperature, 2 h; (g) carboxylic acid R 7 -COOH, HATU or T3P, DIEA or TEA, DCM, room temperature, overnight; (h) alkyl halide R 7 -alkylidene chloride, in the corresponding product Q = alkylidene, the alkylidene contains 1 to 6 carbon atoms, DIEA, EtOH, reflux, 6 h; (i) aldehyde R 7 CHO, NaBH(OAc)3, AcOH, DCM, room temperature, overnight.

9. A pharmaceutical composition, characterized in that, Including the disulfonamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, and a pharmaceutically acceptable carrier.

10. Use of the disulfonamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 in the preparation of a drug for preventing or treating diseases related to RORγt, wherein the diseases are selected from tumors, viral infections and immunodeficiency disorders.

11. A RORγt agonist, characterized in that Including the disulfonamide derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-7.

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