Phenothiazine sulfonamide compound or salt thereof, and preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses phenothiazine sulfonamide compounds shown in a general formula (I) or salts thereof, and a preparation method and application thereof. The compounds and pharmaceutically acceptable salts, isomers, prodrug co-crystallization compounds, hydrates and solvates thereof can be used as agonists of retinoic acid receptor related orphan receptor-gamma t (ROR gamma t). # imgabs0 # (I).

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry and relates to a phenothiazine sulfonamide derivative, or a pharmaceutically acceptable salt, isomer, prodrug co-crystal complex, hydrate, or solvate thereof, which can be used as an agonist of retinoic acid receptor-related orphan receptor-γt (RORγt). The present invention also relates to the application of these compounds in tumor immunotherapy. Background Art

[0002] Retinoic acid receptor-related orphan receptor (ROR) is a member of the ligand-dependent transcription factor nuclear receptor superfamily, including three subtypes: RORα, RORβ and RORγ. Among them, RORγ includes two subtypes: RORγ1 and RORγ2 (RORγt), which show different tissue specificity. RORγ1 is widely distributed in multiple organs such as liver, adipose tissue, muscle and kidney, while RORγt is mainly expressed in lymphoid organs such as thymus. This RORγ specifically expressed in the thymus is called RORγt.

[0003] The structure of RORγt is similar to that of ordinary nuclear receptors, and is composed of four parts: the variable N-terminal region (AF1, N-terminaldomian, i.e., activation function region 1), the DNA binding region (DBD), the hinge region (Hinge), and the C-terminal ligand binding domain (LBD). Among them, the ligand-dependent activation function region 2 (AF2) is located in the LBD region, which can regulate the transcription of downstream target genes by recruiting / repelling co-stimulatory factors or co-inhibitory factors, and is an important active region for the design and synthesis of small molecule drugs.

[0004] The co-crystal structure of RORγt-LBD has been resolved. It is a three-layer folded structure composed of 12 α helices (H1-H12) and 2-3 β folds, including two binding sites, the orthosteric site and the allosteric site. Small molecule drugs can bind to the orthosteric site or the allosteric site to regulate the function of RORγt. The regulation of its function is mainly related to the "agonist lock", which is formed by His479-Tyr502-Phe506 residues. When the small molecule enters the active pocket of the orthosteric site of LBD and maintains a suitable distance from AF2, it can stabilize the hydrogen bond between Tyr502-His479, thereby stabilizing AF2, recruiting costimulatory factors such as SRC1, and exerting transcriptional activity. At this time, it is called a RORγt small molecule agonist; conversely, small molecules that destroy the AF2 structure and cause the Tyr502-His479 hydrogen bond to break and repel costimulatory factors will inhibit the transcriptional activity of RORγt, and are called RORγt small molecule inhibitors. Small molecule drugs can act as agonists or inhibitors by strengthening or disrupting the key hydrogen-bonding interactions within Tyr502 and His479 in the RORγt-LBD to stabilize or disrupt the activation state of AF2, thereby regulating the function of RORγt.

[0005] Studies have shown that RORγt is a key transcription factor for Th17 cell differentiation. It can promote the differentiation of Th17 cells with anti-tumor efficacy, regulate the survival of T cells, drive the activation of T cells, and promote the secretion of effector factors such as IL-17 to improve the effector function of immune cells. Therefore, RORγt agonists can play a role in cancer immunity by promoting the differentiation of Th17 cells and the production of IL-17A, and are new targets for cancer immunotherapy. In addition, studies have also shown that RORγt agonists can also inhibit the expression of PD-1 on the surface of T cells and reduce the proportion of regulatory T cells to improve the immune microenvironment, thereby exerting an immunosuppressive mechanism.

[0006] Currently, the only RORγt agonist that has entered the clinical research stage is LYC-55716 (also known as cintirorgon) developed by Lycera. Studies have found that this compound can reduce tumor growth in preclinical tumor models and is a highly orally bioavailable RORγt agonist for tumor immunotherapy. The drug has certain safety and tolerability, so it has been identified as a clinical development candidate for evaluation in patients with solid tumors, and has completed phase 1 / 2a of clinical research. In addition, few RORγt agonists have been reported. Summary of the invention

[0007] The purpose of the present invention is to provide a phenothiazine sulfonamide compound represented by general formula (I) in view of the current status of the prior art.

[0008] Another object of the present invention is to provide a pharmaceutically acceptable salt, solvate, precursor compound or polymorph of the phenothiazine sulfonamide compound.

[0009] Another object of the present invention is to provide a method for preparing the phenothiazine sulfonamide compounds.

[0010] The fourth object of the present invention is to provide a pharmaceutical composition.

[0011] The fifth object of the present invention is to provide the use of the phenothiazine sulfonamide compound, its pharmaceutically acceptable salt, solvate, prodrug or polymorph in medicine.

[0012] To achieve the above object, the technical solution adopted by the present invention is: The molecular structure formula of the phenothiazine sulfonamide derivatives is: Among them, R 1 independently selected from hydrogen, 7-C 1-5 Alkoxy, phenoxy, benzyloxy, oxetane-3-oxy, C 1-4 Alkyl, phenyl, 3-pyridyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, benzyl; 8-C1 alkyl, C3 cycloalkyl, phenyl, p-fluorophenyl; R 2 Selected from hydrogen, C 1-7 Alkyl, acetyl, 4-trifluorobenzenesulfonyl, 3-trifluorobenzenesulfonyl. RHS is selected from p-ethylsulfonylphenyl, p-methylsulfonylphenyl, p-methylsulfonylpyridinyl, p-ethylsulfonylpyridinyl, p-(N-methyl)sulfamoylphenyl or p-cyanophenyl.

[0013] Preferably, the substituent R 1 are independently selected from hydrogen or 7-C 1-5 Alkoxy. The substituent R 2 are independently selected from hydrogen, C 1-7 alkyl, 3-trifluorobenzenesulfonyl or 4-trifluorobenzenesulfonyl. The substituent RHS is selected from p-(N-methyl)sulfamoylphenyl, p-methylsulfonylpyridinyl, p-ethylsulfonylpyridinyl, p-ethylsulfonylphenyl or p-methylsulfonylphenyl.

[0014] Compounds 1, 34, 35, 37 and 38 are more preferred.

[0015] Unless otherwise specified, the present invention (C 1-5)Alkoxy is (C1-C5) straight chain, branched or cyclic alkoxy, refers to an alkoxy group containing 1 to 5 carbon atoms, including but not limited to methoxy, ethoxy, isopropoxy, cyclobutyloxy, and cyclopentyloxy.

[0016] Unless otherwise specified, the present invention (C 1-4 ) alkyl is (C 1-4 ) Straight chain, branched or cyclic alkyl refers to branched, unbranched and cyclic saturated hydrocarbon chains containing 1-4 carbon atoms, including but not limited to methyl, ethyl, isobutyl and cyclobutyl.

[0017] As one of the best embodiments, the phenothiazine sulfonamide derivatives of the present invention are the following specific compounds: N-(4-(Ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-methoxy-10H-phenothiazine-2-carboxamide 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-isopropoxy-10H-phenothiazine-2-carboxamide 7-Cyclobutyloxy-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-(oxetan-3-yloxy)-10H-phenothiazine-2-carboxamide 7-(Cyclopentyloxy)-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-phenoxy-10H-phenothiazine-2-carboxamide 7-(Benzyloxy)-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-methyl-10H-phenothiazine-2-carboxamide 7-Ethyl-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-isobutyl-10H-phenothiazine-2-carboxamide 7-Cyclopropyl-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-phenyl-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-(3-pyridyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-(2-fluorophenyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-(3-fluorophenyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-7-(4-fluorophenyl)-10H-phenothiazine-2-carboxamide 7-Benzyl-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-8-methyl-10H-phenothiazine-2-carboxamide 8-Cyclopropyl-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-8-phenyl-10H-phenothiazine-2-carboxamide N-(4-(Ethylsulfonyl)benzyl)-8-(4-fluorophenyl)-10H-phenothiazine-2-carboxamide 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-methyl-phenothiazine-2-carboxamide 7-Ethoxy-10-ethyl-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-propyl-phenothiazine-2-carboxamide 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-isopropyl-phenothiazine-2-carboxamide 10-(Cyclopropylmethyl)-7-ethoxy-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-isobutyl-phenothiazine-2-carboxamide 10-(Cyclobutylmethyl)-7-ethoxy-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide 10-(Cyclohexylmethyl)-7-ethoxy-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide 10-Acetyl-7-ethoxy-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-((4-(trifluoromethyl)phenyl)sulfonyl)-phenothiazine-2-carboxamide 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-((3-(trifluoromethyl)phenyl)sulfonyl)-phenothiazine-2-carboxamide 7-Ethoxy-10-methyl-N-(4-(methylsulfonyl)phenyl)-10H-phenothiazine-2-carboxamide 7-Ethoxy-10-methyl-N-(5-(methylsulfonyl)pyridine)-10H-phenothiazine-2-carboxamide 7-Ethoxy-N-(5-(methylsulfonyl)pyridin-2-methyl)-10-methyl-10H-phenothiazine-2-carboxamide 7-Ethoxy-N-[(5-(ethylsulfonyl)pyridin-2-methyl]-10-methyl-10H-phenothiazine-2-carboxamide 7-Ethoxy-10-methyl-N-(4-(N-methylthioformyl)phenyl)-10H-phenothiazine-2-carboxamide N-(4-cyanophenyl)-7-ethoxy-10-methyl-10H-phenothiazine-2-carboxamide

[0018] To achieve the above second purpose, the technical solution adopted by the present invention is:

[0019] The phenothiazine sulfonamide derivatives can be pharmaceutically acceptable salts, solvates, prodrugs or polymorphs thereof, characterized in that the pharmaceutically acceptable salts are inorganic salts, organic salts or amino acid salts; The inorganic salt is: sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromide or nitrate; The organic salts are: maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, oxalate; The amino acid salt is arginine, ornithine, lysine, leucine, isoleucine, glycine, cystine, cysteine, tyrosine, alanine, phenylalanine, histidine, serine, threonine, methionine, tryptophan, glutamate, aspartate, valine, methionine, proline or hydroxyproline.

[0020] In order to achieve the third object, the present invention adopts the following technical solution: The phenothiazine sulfonamide R 1 , R 2 The preparation method wherein the substituent is selected from hydrogen can be synthesized by the following process, comprising the following steps:

[0021] Preparation of intermediate b The raw material a is dissolved in a mixed solution of acetic acid and hydrochloric acid for hydrolysis reaction, and then refluxed and stirred to obtain the intermediate b.

[0022] Preparation of Compound Ⅰ Dissolve intermediate b in dichloromethane, add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and p-ethylbenzenesulfonamide, and stir at room temperature to obtain compound I.

[0023] To achieve the third purpose, the second technical solution adopted by the present invention is: The phenothiazine sulfonamide R 1 The substituent is selected from the 7-C 1-5 The preparation method of alkoxy, phenoxy, benzyloxy, and oxetane-3-yloxy compounds can be synthesized by the following process, including the following steps:

[0024] Preparation of intermediate d The raw material c and differently substituted halogenated hydrocarbons are dissolved in N,N-dimethylformamide to carry out a substitution reaction, and the reaction is refluxed and stirred to obtain the intermediate d.

[0025] Preparation of intermediate e The intermediate d and tert-butyl mercaptan are dissolved in N,N-dimethylformamide, potassium carbonate is added, and the mixture is stirred at room temperature to obtain the intermediate e.

[0026] Preparation of intermediate f The intermediate e is dissolved in N,N-dimethylformamide, trifluoroacetic acid is added, and the mixture is stirred at room temperature to obtain the intermediate f after the tert-butyl group is removed.

[0027] Preparation of intermediate g The intermediate f is dissolved in a mixed solution of ethanol and water, iron powder and ammonium chloride are added, and the mixture is refluxed with stirring to obtain the intermediate g.

[0028] Preparation of intermediate h Dissolve intermediate g in dichloromethane, add acetic anhydride, and stir at room temperature to obtain intermediate h.

[0029] Preparation of intermediate i The intermediate h and methyl 3-bromo-4-iodobenzoate are dissolved in N,N-dimethylformamide, and cesium carbonate is added and refluxed with stirring to obtain the intermediate i.

[0030] Preparation of intermediate j The intermediate i and di-tert-butyl dicarbonate were dissolved in acetonitrile, 4-dimethylaminopyridine was added, and the mixture was stirred at room temperature to obtain the intermediate j.

[0031] Preparation of intermediate k The intermediate j is dissolved in a mixed solution of methanol and water, potassium hydroxide is added, and the mixture is refluxed with stirring to obtain the intermediate k.

[0032] Preparation of intermediate 1 Intermediate k and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and (4-(ethylsulfonyl)phenyl)formamide were dissolved in dichloromethane, stirred at room temperature and condensed to obtain intermediate l.

[0033] Preparation of Compound II Dissolve intermediate 1 in dichloromethane, add trifluoroacetic acid, and stir at room temperature to obtain compound II.

[0034] To achieve the third purpose, the third technical solution adopted by the present invention is: The phenothiazine sulfonamide R 2 The substituents are selected from hydrogen, R 1 The substituent is selected from the 7-C 1-4 The preparation method of alkyl, phenyl, 3-pyridyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl and benzyl compounds can be synthesized by the following process, including the following steps:

[0035] Preparation of intermediate n The raw material m and tert-butyl mercaptan are dissolved in N,N-dimethylformamide, potassium carbonate is added, and the mixture is stirred at room temperature to obtain the intermediate n.

[0036] Preparation of intermediate o The intermediate n is dissolved in N,N-dimethylformamide, trifluoroacetic acid is added, and the mixture is stirred at room temperature to obtain the intermediate o after the tert-butyl group is removed.

[0037] Preparation of intermediate p The intermediate o is dissolved in a mixed solution of ethanol and water, iron powder and ammonium chloride are added, and the mixture is refluxed with stirring to obtain the intermediate p.

[0038] Preparation of intermediate q The intermediate p is dissolved in dichloromethane, acetic anhydride is added, and the mixture is stirred at room temperature to obtain the intermediate q.

[0039] Preparation of intermediate r The intermediate q and methyl 3-bromo-4-iodobenzoate are dissolved in N,N-dimethylformamide, and cesium carbonate is added and refluxed with stirring to obtain the intermediate r.

[0040] Preparation of intermediates The intermediate r and di-tert-butyl dicarbonate are dissolved in acetonitrile, 4-dimethylaminopyridine is added, and the mixture is stirred at room temperature to obtain the intermediate s.

[0041] Preparation of intermediate t Intermediate s is subjected to coupling reaction with boronic acid compounds with different substitutions to obtain intermediate t.

[0042] Preparation of intermediate u The intermediate t is dissolved in a mixed solution of methanol and water, potassium hydroxide is added, and the mixture is refluxed with stirring to obtain the intermediate u.

[0043] Preparation of intermediate v The intermediate u and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and (4-(ethylsulfonyl)phenyl)formamide are dissolved in dichloromethane, stirred at room temperature, and condensed to obtain the intermediate v.

[0044] Preparation of compound III Dissolve intermediate v in dichloromethane, add trifluoroacetic acid, and stir at room temperature to obtain compound III.

[0045] To achieve the third objective, the fourth technical solution adopted by the present invention is: The phenothiazine sulfonamide R 2 The substituents are selected from hydrogen, R 1 The substituent is selected from 8-C1 alkyl, C3 cycloalkyl, phenyl, and p-fluorophenyl. The preparation method of the compound can be synthesized by the following process, comprising the following steps:

[0046] Preparation of intermediate x Dissolve the raw material w in dichloromethane, add acetic anhydride, and stir at room temperature to obtain the intermediate x.

[0047] Preparation of intermediate y The intermediate x and methyl 3-bromo-4-iodobenzoate are dissolved in N,N-dimethylformamide, and cesium carbonate is added and refluxed with stirring to obtain the intermediate y.

[0048] Preparation of intermediate z The intermediate y and di-tert-butyl dicarbonate are dissolved in acetonitrile, 4-dimethylaminopyridine is added, and the mixture is stirred at room temperature to obtain the intermediate z.

[0049] Preparation of intermediate aa Intermediate z is subjected to coupling reaction with boronic acid compounds with different substitutions to obtain intermediate aa.

[0050] Preparation of intermediate ab The intermediate aa is dissolved in a mixed solution of methanol and water, potassium hydroxide is added, and the mixture is refluxed with stirring to obtain the intermediate ab.

[0051] Preparation of intermediate ac The intermediate ab and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and (4-(ethylsulfonyl)phenyl)formamide are dissolved in dichloromethane, stirred at room temperature, and condensed to obtain the intermediate ac.

[0052] Preparation of Compound IV The intermediate ac is dissolved in dichloromethane, trifluoroacetic acid is added, and the mixture is stirred at room temperature to obtain compound IV.

[0053] To achieve the third purpose, the fifth technical solution adopted by the present invention is: The phenothiazine sulfonamide R 2 The substituents are selected from hydrogen, C 1-7 The preparation method of alkyl, acetyl, 4-trifluorobenzenesulfonyl and 3-trifluorobenzenesulfonyl compounds can be synthesized by the following process, comprising the following steps:

[0054] Preparation of intermediate ae The raw material ad and iodoethane are dissolved in N,N-dimethylformamide for substitution reaction, and refluxed with stirring to obtain the intermediate ae.

[0055] Preparation of intermediate af The intermediate ae and tert-butyl mercaptan are dissolved in N,N-dimethylformamide, potassium carbonate is added, and the mixture is stirred at room temperature to obtain the intermediate af.

[0056] Preparation of intermediate ag The intermediate af is dissolved in N,N-dimethylformamide, trifluoroacetic acid is added, and the mixture is stirred at room temperature to obtain the intermediate ag after the tert-butyl group is removed.

[0057] Preparation of intermediate ah The intermediate ag is dissolved in a mixed solution of ethanol and water, iron powder and ammonium chloride are added, and the mixture is refluxed with stirring to obtain the intermediate ah.

[0058] Preparation of intermediate ai The intermediate ah is dissolved in dichloromethane, acetic anhydride is added, and the mixture is stirred at room temperature to obtain the intermediate ai.

[0059] Preparation of intermediate aj The intermediate ai and methyl 3-bromo-4-iodobenzoate are dissolved in N,N-dimethylformamide, and cesium carbonate is added and refluxed with stirring to obtain the intermediate aj.

[0060] Preparation of intermediate ak Dissolve the intermediate aj, sodium hydride and alkyl halide in N,N-dimethylformamide and stir at room temperature to obtain the intermediate ak.

[0061] Preparation of intermediate al The intermediate ak is dissolved in a mixed solution of methanol and water, potassium hydroxide is added, and the mixture is refluxed with stirring to obtain the intermediate a1.

[0062] Preparation of Compound V The intermediate a1 and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and (4-(ethylsulfonyl)phenyl)formamide are dissolved in dichloromethane, stirred at room temperature and condensed to obtain compound V.

[0063] To achieve the third purpose above, the sixth technical solution adopted by the present invention is:

[0064] Preparation of intermediate am Dissolve the intermediate aj, sodium hydride and methyl iodide in N,N-dimethylformamide and stir at room temperature to obtain the intermediate am.

[0065] Preparation of intermediate an The intermediate am is dissolved in a mixed solution of methanol and water, potassium hydroxide is added, and the mixture is refluxed with stirring to obtain the intermediate an.

[0066] Preparation of Compound VI The intermediate an, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine and different RHS amino-substituted compounds on the right are dissolved in dichloromethane, stirred at room temperature, and condensed to obtain compound VI.

[0067] The RHS substituent of the phenothiazine sulfonamide is selected from p-ethylbenzenesulfonyl, p-methylbenzenesulfonyl, p-methylpyridinesulfonyl, p-ethylpyridinesulfonyl, p-methylaminobenzenesulfonyl, and p-cyanophenyl. The preparation method of the intermediates with different substituents can be synthesized by the following steps:

[0068] Preparation of intermediate ap The raw material ao is dissolved in water with sodium bicarbonate and sodium sulfite, and the mixture is heated and stirred for reaction. Then, a halogenated alkane is added to N,N-dimethylformamide and heated and stirred for reaction to obtain the intermediate ap.

[0069] Preparation of intermediate aq The intermediate ap is dissolved in methanol, palladium carbon is added, and the reaction is stirred at room temperature under a hydrogen atmosphere to obtain the intermediate aq.

[0070] Preparation of intermediates The raw material ar and alkylsulfonyl chloride are dissolved in dimethyl sulfoxide, heated and stirred to obtain the intermediate as.

[0071] Preparation of intermediates The intermediate ar is dissolved in methanol, palladium carbon is added, and the reaction is stirred at room temperature under a hydrogen atmosphere to obtain the intermediate at.

[0072] Preparation of intermediate av The raw material au, methylamine, dimethylaminopyridine and N,N-diisopropylethylamine are dissolved in dichloromethane and stirred at room temperature to react to obtain the intermediate av.

[0073] Preparation of intermediate aw The intermediate au is dissolved in methanol, palladium carbon is added, and the reaction is stirred at room temperature under a hydrogen atmosphere to obtain the intermediate aw.

[0074] To achieve the fourth objective, the present invention adopts the following technical solution: A pharmaceutical composition comprising a) the above-mentioned phenothiazine sulfonamide derivatives and / or the pharmaceutically acceptable salts, solvates, precursor compounds or polymorphs of the above-mentioned phenothiazine sulfonamide derivatives, and b) a pharmaceutically acceptable carrier thereof.

[0075] The pharmaceutical composition may be a pharmaceutical preparation in solid or liquid form, and the dosage form of the pharmaceutical composition includes but is not limited to tablets, capsules, powders, granules, suspensions or injections.

[0076] To achieve the fifth purpose, the present invention adopts the following technical solution: The use of the phenothiazine sulfonamide derivatives, their pharmaceutically acceptable salts, solvates, prodrugs, polymorphs or pharmaceutical compositions in the preparation of drugs is generally suitable for exciting RORγt. Therefore, in some embodiments, the present invention provides a compound or composition that can be used for tumor immunotherapy and stimulating retinoic acid-related orphan receptor-γt (RORγt). More specifically, the compounds and compositions described herein act as agonists of RORγt. DETAILED DESCRIPTION

[0077] The present invention is further explained below in conjunction with specific examples, but the examples do not limit the present invention in any form. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0078] The structure of the compound is determined by nuclear magnetic resonance (NMR) or high resolution (HRMS). NMR is measured using Bruker's Ascend nuclear magnetic resonance instrument, chemical shift values ​​are expressed as δ, the unit is ppm, coupling constants are expressed as J, the unit is Hz, the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0079] MS was measured using a Micromass Q-TOF mass spectrometer.

[0080] High performance liquid chromatography (HPLC) analysis was performed using an Agilent 1260 high performance liquid chromatograph.

[0081] Thin layer chromatography silica gel plate using Shandong Yantai Xinnuo Chemical Co., Ltd. GF 254 Silicone sheet.

[0082] Silica gel column chromatography generally uses GF from Shandong Yantai Xinnuo Chemical Co., Ltd. 254 Silica gel 200-300 mesh silica gel is used as the carrier.

[0083] The present invention is further described in the following examples, but the examples are not intended to limit the scope of protection of the present invention.

[0084] Example 1 Preparation of N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide (Compound 1) Referring to the synthetic route I, step 1: preparation of 2-cyano phenothiazine (intermediate b) 2-Cyanophenothiazine (200 mg, 0.89 mmol) was added to a mixed solution of acetic acid and concentrated hydrochloric acid (v:v=3:1), protected under nitrogen for 15 minutes, and then heated to 117°C for 18 hours. Then it was diluted with ice water, the pH was adjusted to alkaline, extracted with ethyl acetate, the aqueous phase was collected, the pH was adjusted to acidic, extracted with ethyl acetate (15 mL×3), the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain; yield: 100 mg, 45%; yellow solid. Step 2: Preparation of N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide (Compound 1) The intermediate b (50 mg, 0.21 mmol) was added to a 50 mL round-bottom flask, and HATU (91 mg, 0.24 mmol) and DIPEA (31 mg, 0.24 mmol) were added in sequence using dichloromethane as solvent. An amine compound (48 mg, 0.24 mmol) was added under stirring at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by monitoring by TLC, the reaction solution was extracted with dichloromethane (15 mL × 3), washed with saturated aqueous ammonium chloride solution (35 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain compound 1 with a yield of 27 mg, 30%; as a white solid.

[0085] Example 2 Preparation of N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide (Compound 2) Refer to Synthesis Route II, Step 1: Preparation of 2-fluoro-4-methoxy-1-nitrobenzene (Intermediate d) 3-Fluoro-4-nitro-phenol (2000 mg, 12.73 mmol) was dissolved in DMF (10 mL), and potassium carbonate (2640 mg, 19.10 mmol) and iodomethane (2081 mg, 19.10 mmol) were added in sequence. The mixture was stirred at 120 °C for 1 hour. After the reaction was completed by monitoring by TLC, the mixture was extracted with dichloromethane (20 mL × 3) and water, the dichloromethane layer was collected, concentrated under reduced pressure, and then back-extracted with ethyl acetate (20 mL × 3), washed with saturated aqueous sodium chloride solution (30 mL), the ethyl acetate layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain intermediate d, yield: 1790 mg, 76%; white solid. Step 2: Preparation of tert-butylthio-(5-methoxy-2-nitrophenyl) (Intermediate e) Intermediate d (1790 mg, 9.67 mmol) was dissolved in DMF (15 mL), and potassium carbonate (2674 mg, 19.35 mmol) and tert-butyl mercaptan (1134 mg, 12.57 mmol) were added in sequence. The mixture was reacted at room temperature overnight. After completion of the reaction, the mixture was monitored by TLC. The mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated aqueous sodium chloride solution (35 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate e. Yield: 2417 mg, 98%; yellow oil. Step 3: Preparation of 5-methoxy-2-nitrobenzenethiol (Intermediate f) The intermediate e (2417 mg, 9.48 mmol) was added to a 50 mL round-bottom flask, and a mixed solution of dichloromethane and trifluoroacetic acid (v:v=3:1) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed by monitoring by TLC, a saturated aqueous sodium bicarbonate solution was added to quench, and the mixture was extracted with dichloromethane, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The intermediate f was separated and purified by column chromatography, and the yield was 754 mg, 40%; it was a yellow solid. Step 4: Preparation of 2-amino-5-methoxybenzenethiol (Intermediate g) Intermediate f (754 mg, 3.79 mmol) was added to a mixed solution of ethanol and water (v:v=4:1), and reduced iron powder (1059 mg, 18.94 mmol) and ammonium chloride (406 mg, 7.58 mmol) were added in sequence. The mixture was stirred at 90°C for 1 hour. After the reaction was completed by monitoring by TLC, the reaction solution was cooled to room temperature, the iron powder was filtered through diatomaceous earth, the filtrate was evaporated, extracted with ethyl acetate (20 mL×3), washed with saturated sodium chloride aqueous solution (35 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain intermediate g, yield: 481 mg, 75%; yellow solid. Step 5: Preparation of N-(2-mercapto-4-methoxyphenyl)acetamide (Intermediate h) Dissolve intermediate g (481 mg, 2.85 mmol) in dichloromethane (5 mL), add acetic anhydride (436 mg, 4.27 mmol), stir at room temperature for 20 minutes, monitor the reaction by TLC, quench with saturated aqueous sodium bicarbonate solution (30 mL), evaporate the solvent, rinse and filter with ethyl acetate to obtain intermediate h, yield: 270 mg, 45%; white solid. Step 6: Preparation of methyl 7-methoxy-10H-phenothiazine-2-carboxylate (Intermediate i) The intermediate h (270 mg, 1.28 mmol) was added to a 100 ml round-bottom flask, and cesium carbonate (834 mg, 2.56 mmol) and methyl 3-bromo-4-iodobenzoate (480 mg, 1.41 mmol) were added in sequence. DMF was used as the solvent, and the nitrogen was replaced three times. The reaction was stirred in an oil bath at 130°C under nitrogen protection for 10 hours. After the reaction was completed by monitoring by TLC, it was extracted with dichloromethane and water, and the organic phase was evaporated and dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution for stripping, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The intermediate i was separated and purified by column chromatography. The yield was 166 mg, 43%; it was a yellow solid. Step 7: Preparation of 10-(tert-butyl) 2-methyl 7-methoxy-10H-phenothiazine-2,10-dicarboxylate (Intermediate j) Intermediate i (166 mg, 0.55 mmol) was added to a 50 mL round-bottom flask, and acetonitrile (5 mL) was used as solvent. Di-tert-butyl dicarbonate (144 mg, 0.66 mmol) and 4-dimethylaminopyridine (DMAP) (34 mg, 0.28 mmol) were added in sequence. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by TLC, the acetonitrile was evaporated, extracted with ethyl acetate (15 mL × 3), washed with saturated aqueous solution (35 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate j was separated and purified by column chromatography. Yield: 194 mg, 88%; white solid. Step 8: Preparation of 10-(tert-butoxycarbonyl)-7-methoxy-10H-phenothiazine-2-carboxylic acid (Intermediate k) Intermediate j (194 mg, 0.48 mmol) was added to a 50 mL round-bottom flask, and potassium hydroxide (81 mg, 1.45 mmol) was added with methanol and water (v:v=3:1) as solvent. The mixture was stirred at 80°C for 1 hour. After the reaction was completed by TLC, methanol was evaporated, the pH of the aqueous solution was adjusted to 2-3 with 2M HCl, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate k. Yield: 136 mg, 99%; white solid. Step 9: Preparation of 2-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-methoxy-10H-phenothiazine-10-tert-butoxycarbonyl (Intermediate 1) The intermediate k (136 mg, 0.47 mmol) was added to a 50 mL round-bottom flask, and HATU (217 mg, 0.57 mmol) and DIPEA (74 mg, 0.57 mmol) were added in sequence using dichloromethane as solvent. An amine compound (114 mg, 0.57 mmol) was added under stirring at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by monitoring by TLC, the reaction solution was extracted with dichloromethane (15 mL × 3), washed with saturated aqueous ammonium chloride solution (35 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the intermediate l in a yield of 227 mg, 85%; as a white solid. Step 10: Preparation of N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide (Compound 2) Intermediate k (227 mg, 0.40 mmol) was dissolved in dichloromethane, and trifluoroacetic acid (912 mg, 8.00 mmol) was added. The mixture was reacted at room temperature overnight. After the reaction was completed by monitoring by TLC, the mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain compound 2. Yield: 149 mg, 80%; yellow solid.

[0086] Embodiment 3-9 Example 2 was repeated, except that different raw materials were used to prepare compounds 3-9. Specifically, iodoethane, 2-bromopropane, cyclobutyl bromide, 3-bromobutylene oxide, bromocyclopentane, bromobenzene, benzyl bromide, raw material a in the above embodiment 1 and potassium carbonate were heated to react, and the subsequent operations were consistent with the subsequent operations in embodiment 1 to prepare compounds 3, 4, 5, 6, 7, 8, and 9, respectively.

[0087] Example 10 Preparation of N-(4-(ethylsulfonyl)benzyl)-7-methyl-10H-phenothiazine-2-carboxamide (Compound 10) Referring to the synthetic route III, 10-(tert-butyl) 2-methyl 7-methyl-10H-phenothiazine-2,10-dicarboxylate (intermediate t) was prepared. The intermediate s (100 mg, 0.23 mmol) was added to a 50 mL round-bottom flask, and methylboric acid (18 mg, 0.23 mmol), potassium carbonate (64 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium (9 mg, 0.01 mmol) were added in sequence using toluene as solvent. The mixture was replaced with nitrogen three times, and the reaction was stirred at 110 ° C for 12 hours under a nitrogen environment. After the reaction was completed by monitoring by TLC, toluene was evaporated, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the intermediate t with a yield of 85 mg, 80%, as a white solid. The remaining operation steps of compound 10 are the same as those of Example 1 and Example 2.

[0088] Examples 11-19 Example 10 was repeated, except that different raw materials were used to prepare compounds 11-19. Specifically, ethylboric acid, isobutylboric acid, cyclopropylboric acid, phenylboric acid, 2-pyridineboric acid, o-fluoroboric acid, m-fluoroboric acid, p-fluoroboric acid, benzylboric acid were heated with the intermediate q in the above-mentioned embodiment 2 and potassium carbonate and tetrakis(triphenylphosphine)palladium, and the remaining operations were consistent with the remaining operations in embodiment 2 to prepare compounds 11, 12, 13, 14, 15, 16, 17, 18, 19, respectively.

[0089] Example 20 Preparation of N-(4-(ethylsulfonyl)benzyl)-8-methyl-10H-phenothiazine-2-carboxamide (Compound 20) The preparation method of compound 20 is the same as that of Example 1, Example 2 and Example 10.

[0090] Examples 21-23 Example 20 was repeated, except that different raw materials were used to prepare compounds 21-23. Specifically, cyclopropylboric acid, phenylboric acid, p-fluoroboric acid, intermediate x in the above-mentioned embodiment 3, potassium carbonate, and tetrakis(triphenylphosphine)palladium were heated to react, and the remaining operations were consistent with Example 20 to prepare compounds 21, 22, and 23, respectively.

[0091] Example 24 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-methyl-10H-phenothiazine-2-carboxamide (Preparation of Compound 24) Reference route VI Preparation of 7-ethoxy-10-methyl-10H-phenothiazine-2-carboxylic acid methyl ester (intermediate ak) The intermediate aj (100 mg, 0.33 mmol) was dissolved in DMF (2 mL), and NaH (16 mg, 0.40 mmol) was added at 0°C and stirred for 20 minutes. Then iodomethane (56 mg, 0.40 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed by monitoring by TLC, it was extracted with dichloromethane (15 mL×3), concentrated under reduced pressure, and then back-extracted with ethyl acetate (15 mL×3), washed with saturated aqueous sodium chloride solution (35 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The intermediate ak was separated and purified by column chromatography as a yellow solid. The yield was 89 mg, 90%. The rest of the preparation method of compound 24 is the same as that of Example 1 and Example 2.

[0092] Examples 25-34 Example 24 was repeated, except that different raw materials were used to prepare compounds 25-34. Specifically, iodoethane, 1-iodopropane, 2-bromopropane, isobutyl bromide, bromomethylcyclopropane, bromomethylcyclobutane, bromomethylcyclopentane, acetyl chloride, 4-trifluoromethylbenzenesulfonyl chloride, 3-trifluoromethylbenzenesulfonyl chloride were reacted with the intermediate aj in the above-mentioned embodiment 5 and sodium hydride at room temperature, and the remaining operations were kept consistent with those in Example 24 to prepare compounds 25, 26, 27, 28, 29, 30, 31, 32, 33, and 34, respectively.

[0093] Example 35 Preparation of Compound 35 Refer to Scheme VIII, Step 1 Preparation of 4-(methylsulfonyl)benzonitrile (Intermediate ap) The raw material ao (200 mg, 1 mmol) was dissolved in water with NaOH (80 mg, 2 mmol) and Na2SO3 (252.09 mg, 2 mmol), and heated and stirred at 70°C for 4 hours. Then iodomethane (212.91 mg, 1.5 mmol) was added, dissolved in DMF, and heated and stirred at 70°C for 4 hours. After the reaction was completed by TLC monitoring, it was extracted with dichloromethane (15 mL×3), concentrated under reduced pressure, and then back-extracted with ethyl acetate (15 mL×3), washed with saturated sodium chloride aqueous solution (35 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The intermediate ap was separated and purified by column chromatography as a white solid with a yield of 180 mg, 92%. Step 2 Preparation of (4-(methylsulfonyl)phenyl)methanamine (Intermediate aq) The intermediate ap (170 mg, 0.87 mmol) was dissolved in methanol, palladium carbon was added under hydrogen atmosphere, and the reaction was stirred at room temperature for 12 hours under hydrogen protection. After the reaction was completed by TLC monitoring, it was filtered, washed with methanol (35 mL), and evaporated to dryness to obtain the intermediate aq as a white solid, yield: 150 mg, 93%. The remaining preparation steps of compound 35 are the same as those of Example 1, Example 2 and Example 24.

[0094] Example 36 Preparation of Compound 36 Reference route VIII for the preparation of 5-(methylsulfonyl)pyridinemethylnitrile (intermediate as) The raw material ar (200 mg, 1.1 mmol) was dissolved in DMSO, p-toluenesulfonyl chloride (251.66 mg, 1.32 mmol) was added, and the reaction was stirred at 105°C for 24 hours. After the reaction was completed by TLC monitoring, it was extracted with dichloromethane (15 mL×3), concentrated under reduced pressure, and then back-extracted with ethyl acetate (15 mL×3), washed with saturated sodium chloride aqueous solution (35 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the intermediate as, a white solid, with a yield of 180 mg, 90%. The remaining preparation steps of compound 36 are the same as those of Example 1, Example 2, Example 24 and Example 35.

[0095] Example 37 Preparation of Compound 37 Example 36 was repeated, except that different substituted benzenesulfonyl chlorides were used to prepare compound 37. Specifically, ethylsulfonyl chloride was replaced with methylsulfonyl chloride in the above Example 36, and the remaining operations were the same as in Example 36 to prepare the corresponding compound 37.

[0096] Example 38 Preparation of Compound 38 Reference route VIII for the preparation of 4-cyano-N-methylbenzenesulfonamide (intermediate av) The raw material au (200 mg, 1 mmol) was dissolved in DCM, and methylamine (62.11 mg, 2 mmol), DMAP (61.09 mg, 0.5 mmol) and DIPEA (155.09 mg, 1.2 mmol) were added and stirred at room temperature for 12 hours. After the completion of the reaction monitored by TLC, it was extracted with dichloromethane (15 mL×3), washed with saturated aqueous sodium chloride solution (35 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the intermediate av as a white solid. The yield was 160 mg, 83%. The remaining preparation steps of compound 38 are the same as those of Example 1, Example 2, Example 24 and Example 35.

[0097] Example 39 Preparation of Compound 39 According to the preparation route of implementation scheme six, the preparation steps are the same as those of Example 1, Example 2, Example 24 and Example 35.

[0098] The chemical structure of the target product synthesized by the present invention is shown in Table 1. The chemical structure of the target product is characterized by H NMR and high resolution, as shown in Table 2.

[0099] Table 1. Chemical structures of target products Table 2. H NMR spectra and high-resolution data of target compounds

[0100] Example 40 The compounds of the present invention were tested for their agonistic effect on RORγt transcriptional activity using a fluorescent reporter gene assay (Gal4). All cells were cultured according to the method recommended by A TCC and tested during the exponential growth phase of HEK293T cells. HEK293T cells were seeded in 100 mm culture dishes to a density of 6 × 10 6 After that, the cells were incubated at 37°C in a 5% CO2 environment for 16 hours; Trans-IT transfection reagent and Opti-MEM culture medium were mixed at room temperature, plasmid DNA containing the target protein gene was added, and then the mixed reagent was added to the above-mentioned 100 mm culture dish to transfect HEK293T cells, and the cells were incubated at 37°C in a 5% CO2 environment for 5-6 hours; 25nl of compound dilution was transferred to a 384-well plate through Echo655; HEK293T cells were plated on a 384-well plate at a number of 17,000 cells / well; the cells were incubated at 37°C and 5% CO2 for 18-20 hours; 25μl of luciferase reagent per well was added to the 384-well plate; and the fluorescence data was detected and recorded through the Envision2105 detector.

[0101] The following formula was used to calculate the activation rate: %Activity=(Signal cmpd -Signal Ave_VC ) / (Signal Ave_PC -Signal Ave_VC )×100%. Signal ave_pc : Average signal value of all negative controls Signal ave_vc : Average signal value of all positive controls

[0102] The prepared compounds were tested using the above assay procedure and the results are provided in Table 3. The agonist activity values ​​are described in Table 3, where "A" means an agonism greater than 40%; "B" means an agonism less than 40% and greater than 30%; "C" means an agonism less than 30% and greater than 20%; "D" means an agonism less than 20% and greater than 10%; "NA" means not detected. Table 3. Activity data of target compounds As can be seen from Table 3, the compounds of the present invention have agonist activity on RORγt, which lays a foundation for the research and development of new skeleton small molecule RORγt agonists that can be used for tumor immunity and has great development value.

[0103] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art may make several improvements and supplements without departing from the present invention, and these improvements and supplements should also be regarded as within the scope of protection of the present invention.

Claims

1. A phenothiazine sulfonamide derivative, characterized in that: It has a molecular structure shown in general formula (I): Among them, R 1 independently selected from hydrogen, 7-C 1-5 Alkoxy, phenoxy, benzyloxy, oxetane-3-oxy, C 1-4 Alkyl, phenyl, 3-pyridyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, benzyl; 8-C1 alkyl, C3 cycloalkyl, phenyl or p-fluorophenyl; R 2 Selected from hydrogen, C 1-7 Alkyl, acetyl, 4-trifluorobenzenesulfonyl or 3-trifluorobenzenesulfonyl; RHS is selected from p-ethylsulfonylphenyl, p-methylsulfonylphenyl, p-methylsulfonylpyridinyl, p-ethylsulfonylpyridinyl, p-(N-methyl)sulfamoylphenyl or p-cyanophenyl.

2. The phenothiazine sulfonamide derivative according to claim 1, characterized in that: The substituent R 1 are independently selected from hydrogen or 7-C 1-5 Alkoxy; R 2 are independently selected from hydrogen, C 1-7 alkyl, 3-trifluorophenylsulfonyl or 4-trifluorophenylsulfonyl; RHS is selected from p-(N-methyl)sulfamoylphenyl, p-methylsulfonylpyridinyl, p-ethylsulfonylpyridinyl, p-ethylsulfonylphenyl or p-methylsulfonylphenyl.

3. The phenothiazine sulfonamide derivative according to claim 2, characterized in that: Selected from compound 1, 34, 35, 37 or 38, 4. The phenothiazine sulfonamide derivative according to any one of claims 1 to 3, characterized in that: It is a pharmaceutically acceptable inorganic salt, organic salt or amino acid salt; The inorganic salt is: sodium salt, hydrochloride, sulfate, phosphate, diphosphate, hydrobromide or nitrate; The organic salt is: acetate, maleate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate or oxalate; The amino acid salt is: arginine, ornithine, lysine, leucine, isoleucine, glycine, cystine, cysteine, tyrosine, alanine, phenylalanine, histidine, serine, threonine, methionine, tryptophan, glutamate, aspartate, valine, methionine, proline or hydroxyproline.

5. The phenothiazine sulfonamide derivative according to any one of claims 1 to 3, characterized in that: It is a pharmaceutically acceptable solvate, precursor compound or polymorph.

6. The pharmaceutical use of the phenothiazine sulfonamide derivatives according to any one of claims 1 to 5, characterized in that: It is used as an active ingredient to prepare anti-tumor immune drugs.

7. The pharmaceutical use of phenothiazine sulfonamide derivatives according to claim 6, characterized in that: It acts as an agonist of the retinoic acid receptor-related orphan receptor-γt.

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