Phenothiazine sulfonamides or salts thereof, and methods of making and uses thereof

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and discloses a phenothiazine sulfonamide compound shown in a general formula (I) or a salt thereof, a preparation method and application thereof. The compound, a pharmaceutically acceptable salt, an isomer, a prodrug, a co-crystal complex, a hydrate or a solvate thereof can be used as an agonist of a retinoic acid receptor-related orphan receptor-gamma t (RORgamma t).

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry technology and relates to a phenothiazine sulfonamide derivative, or a pharmaceutically acceptable salt, isomer, prodrug co-crystallized 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 use of these compounds in tumor immunotherapy. Background Art

[0002] The retinoic acid receptor-related orphan receptor (ROR) belongs to the ligand-dependent nuclear receptor superfamily of transcription factors and includes three subtypes: RORα, RORβ, and RORγ. RORγ includes two subtypes: RORγ1 and RORγ2 (RORγt), which exhibit different tissue specificities. RORγ1 is widely distributed in multiple organs, including the liver, adipose tissue, muscle, and kidney, while RORγt is primarily expressed in lymphoid organs, such as the thymus. This thymus-specific RORγ is called RORγt.

[0003] The structure of RORγt is similar to that of common nuclear receptors, consisting of four parts: the variable N-terminal region (AF1, or activation function domain 1), the DNA-binding domain (DBD), the hinge region, and the C-terminal ligand-binding domain (LBD). The ligand-dependent activation function domain 2 (AF2) is located in the LBD and regulates the transcription of downstream target genes by recruiting or repelling co-stimulatory or co-repressive factors. It is a key active region in the design and synthesis of small molecule drugs.

[0004] The co-crystal structure of RORyt-LBD has been resolved, which is a three-layer folded structure composed of 12 alpha helices (H1-H12) and 2-3 beta folds, containing two binding sites of ortho-site and allo-site, and small molecule drugs can be combined with ortho-site or allo-site to regulate the function of RORyt. The regulation of its function is mainly related to "agonist lock", which is formed by His479-Tyr502-Phe506 residues. When the small molecule enters the LBD ortho-site active pocket and maintains the appropriate distance with AF2, the hydrogen bond between Tyr502-His479 can be stabilized, thereby stabilizing AF2, recruiting co-stimulators such as SRC1, and exerting transcriptional activity. At this time, it is called RORyt small molecule agonist. On the contrary, small molecules that disrupt AF2 structure to break the hydrogen bond between Tyr502-His479 and exclude co-stimulators will inhibit the transcriptional activity of RORyt, which is called RORyt small molecule inhibitor. Small molecule drugs can stabilize or destroy the activated state of AF2 by strengthening or destroying the key hydrogen bond interaction between Tyr502 and His479 in RORyt-LBD, thereby regulating the function of RORyt to act as an agonist or inhibitor.

[0005] Studies have shown that RORyt is a key transcription factor for Th17 cell differentiation, can promote the differentiation of Th17 cells with anti-tumor effect, regulate the survival of T cells, drive the activation of T cells, and promote the secretion of IL-17 and other effector factors to improve the effector function of immune cells. Therefore, RORyt agonists can promote Th17 cell differentiation and IL-17A production to exert cancer immunization effect, and are a new target for cancer immunotherapy. In addition, studies have also shown that RORyt agonists can also inhibit the expression of PD-1 on the surface of T cells, reduce the proportion of regulatory T cells to improve the immune microenvironment, thereby exerting immune suppression mechanism.

[0006] Currently, the agonist of RORyt only has LYC-55716 (also known as cintirorgon) developed by Lycera company entering the clinical research stage. Studies have found that the compound can reduce tumor growth in preclinical tumor models, and is an oral RORyt agonist with high bioavailability for tumor immunotherapy. The drug has certain safety and tolerability, and is therefore determined as a clinical development candidate drug for evaluation of patients with solid tumors. At present, it has completed the 1 / 2a phase of clinical study. In addition, few RORyt agonists have been reported. SUMMARY

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

[0008] Another object of the present invention is to provide pharmaceutically acceptable salts, solvates, precursor compounds or polymorphs of the phenothiazine sulfonamide compounds.

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

[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:

[0013] The molecular structure formula of the phenothiazine sulfonamide derivatives is:

[0014]

[0015] 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;

[0016] R 2 Selected from hydrogen, C 1-7 Alkyl, acetyl, 4-trifluorophenylsulfonyl, 3-trifluorophenylsulfonyl.

[0017] RHS is selected from p-ethylsulfonylphenyl, p-methylsulfonylphenyl, p-methylsulfonylpyridinyl, p-ethylsulfonylpyridinyl, p-(N-methyl)sulfamoylphenyl or p-cyanophenyl.

[0018] Preferably, the substituent R 1 independently selected from hydrogen or 7-C 1-5 Alkoxy.

[0019] The substituent R 2 are independently selected from hydrogen, C 1-7 alkyl, 3-trifluorophenylsulfonyl or 4-trifluorophenylsulfonyl.

[0020] The substituent RHS is selected from p-(N-methyl)sulfamoylphenyl, p-methylsulfonylpyridinyl, p-ethylsulfonylpyridinyl, p-ethylsulfonylphenyl or p-methylsulfonylphenyl.

[0021] Compounds 1, 34, 35, 37, and 38 are more preferred.

[0022] Unless otherwise stated, the present invention (C 1-5 )Alkoxy is a (C1-C5) straight chain, branched or cyclic alkoxy group, which refers to an alkoxy group containing 1 to 5 carbon atoms, including but not limited to methoxy, ethoxy, isopropoxy, cyclobutyloxy, and cyclopentyloxy.

[0023] Unless otherwise stated, the present invention (C 1-4 ) alkyl is (C 1-4 ) Straight chain, branched or cyclic alkyl refers to a branched, unbranched and cyclic saturated hydrocarbon chain containing 1 to 4 carbon atoms, including but not limited to methyl, ethyl, isobutyl and cyclobutyl.

[0024] As one of the best embodiments, the phenothiazine sulfonamide derivatives of the present invention are the following specific compounds:

[0025] N-(4-(Ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide

[0026] N-(4-(Ethylsulfonyl)benzyl)-7-methoxy-10H-phenothiazine-2-carboxamide

[0027] 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide

[0028] N-(4-(Ethylsulfonyl)benzyl)-7-isopropoxy-10H-phenothiazine-2-carboxamide

[0029] 7-Cyclobutyloxy-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide

[0030] N-(4-(Ethylsulfonyl)benzyl)-7-(oxetan-3-yloxy)-10H-phenothiazine-2-carboxamide

[0031] 7-(Cyclopentyloxy)-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide

[0032] N-(4-(Ethylsulfonyl)benzyl)-7-phenoxy-10H-phenothiazine-2-carboxamide

[0033] 7-(Benzyloxy)-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide

[0034] N-(4-(Ethylsulfonyl)benzyl)-7-methyl-10H-phenothiazine-2-carboxamide

[0035] 7-Ethyl-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide

[0036] N-(4-(Ethylsulfonyl)benzyl)-7-isobutyl-10H-phenothiazine-2-carboxamide

[0037] 7-Cyclopropyl-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide

[0038] N-(4-(Ethylsulfonyl)benzyl)-7-phenyl-10H-phenothiazine-2-carboxamide

[0039] N-(4-(Ethylsulfonyl)benzyl)-7-(3-pyridyl)-10H-phenothiazine-2-carboxamide

[0040] N-(4-(Ethylsulfonyl)benzyl)-7-(2-fluorophenyl)-10H-phenothiazine-2-carboxamide

[0041] N-(4-(Ethylsulfonyl)benzyl)-7-(3-fluorophenyl)-10H-phenothiazine-2-carboxamide

[0042] N-(4-(Ethylsulfonyl)benzyl)-7-(4-fluorophenyl)-10H-phenothiazine-2-carboxamide

[0043] 7-Benzyl-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide

[0044] N-(4-(Ethylsulfonyl)benzyl)-8-methyl-10H-phenothiazine-2-carboxamide

[0045] 8-Cyclopropyl-N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide

[0046] N-(4-(Ethylsulfonyl)benzyl)-8-phenyl-10H-phenothiazine-2-carboxamide

[0047] N-(4-(Ethylsulfonyl)benzyl)-8-(4-fluorophenyl)-10H-phenothiazine-2-carboxamide

[0048] 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-methyl-phenothiazine-2-carboxamide

[0049] 7-Ethoxy-10-ethyl-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide

[0050] 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-propyl-phenothiazine-2-carboxamide

[0051] 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-isopropyl-phenothiazine-2-carboxamide

[0052] 10-(Cyclopropylmethyl)-7-ethoxy-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide

[0053] 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-isobutyl-phenothiazine-2-carboxamide

[0054] 10-(Cyclobutylmethyl)-7-ethoxy-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide

[0055] 10-(Cyclohexylmethyl)-7-ethoxy-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide

[0056] 10-Acetyl-7-ethoxy-N-(4-(ethylsulfonyl)benzyl)-phenothiazine-2-carboxamide

[0057] 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-((4-(trifluoromethyl)phenyl)sulfonyl)-phenothiazine-2-carboxamide

[0058] 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-((3-(trifluoromethyl)phenyl)sulfonyl)-phenothiazine-2-carboxamide

[0059] 7-Ethoxy-10-methyl-N-(4-(methylsulfonyl)phenyl)-10H-phenothiazine-2-carboxamide

[0060] 7-Ethoxy-10-methyl-N-(5-(methylsulfonyl)pyridinium)-10H-phenothiazine-2-carboxamide

[0061] 7-Ethoxy-N-(5-(methylsulfonyl)pyridin-2-methyl)-10-methyl-10H-phenothiazine-2-carboxamide

[0062] 7-Ethoxy-N-[(5-(ethylsulfonyl)pyridin-2-methyl]-10-methyl-10H-phenothiazine-2-carboxamide

[0063] 7-Ethoxy-10-methyl-N-(4-(N-methylthioformyl)phenyl)-10H-phenothiazine-2-carboxamide

[0064] N-(4-Cyanophenyl)-7-ethoxy-10-methyl-10H-phenothiazine-2-carboxamide

[0065] To achieve the above second purpose, the technical solution adopted by the present invention is:

[0066] 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;

[0067] The inorganic salt is: sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromide or nitrate;

[0068] Among them, the organic salts are: maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, and oxalate;

[0069] 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.

[0070] In order to achieve the third purpose above, the present invention adopts the following technical solution:

[0071]

[0072] 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:

[0073] Preparation of intermediate b

[0074] The raw material a is dissolved in a mixed solution of acetic acid and hydrochloric acid to undergo a hydrolysis reaction, and the mixture is refluxed and stirred to obtain the intermediate b.

[0075] Preparation of compound Ⅰ

[0076] 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.

[0077] In order to achieve the third purpose above, the second technical solution adopted by the present invention is:

[0078]

[0079] 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, comprising the following steps:

[0080] Preparation of intermediate d

[0081] The raw material c and differently substituted halogenated hydrocarbons are dissolved in N,N-dimethylformamide to carry out a substitution reaction, and the mixture is refluxed and stirred to obtain the intermediate d.

[0082] Preparation of intermediate e

[0083] 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 intermediate e.

[0084] Preparation of intermediate f

[0085] 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.

[0086] Preparation of intermediate g

[0087] 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.

[0088] Preparation of intermediate h

[0089] Dissolve intermediate g in dichloromethane, add acetic anhydride, and stir at room temperature to obtain intermediate h.

[0090] Preparation of intermediate i

[0091] Intermediate h and methyl 3-bromo-4-iodobenzoate are dissolved in N,N-dimethylformamide, and cesium carbonate is added and the mixture is refluxed with stirring to obtain intermediate i.

[0092] Preparation of intermediate j

[0093] 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 intermediate j.

[0094] Preparation of intermediate k

[0095] 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 intermediate k.

[0096] Preparation of intermediate 1

[0097] Intermediate k, 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 1.

[0098] Preparation of compound II

[0099] Dissolve intermediate 1 in dichloromethane, add trifluoroacetic acid, and stir at room temperature to obtain compound II.

[0100] To achieve the third purpose above, the third technical solution adopted by the present invention is:

[0101]

[0102] 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:

[0103] Preparation of intermediate n

[0104] 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.

[0105] Preparation of intermediate o

[0106] Dissolve intermediate n in N,N-dimethylformamide, add trifluoroacetic acid, and stir at room temperature to obtain intermediate o after removing the tert-butyl group.

[0107] Preparation of intermediate p

[0108] 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.

[0109] Preparation of intermediate q

[0110] Dissolve intermediate p in dichloromethane, add acetic anhydride, and stir at room temperature to obtain intermediate q.

[0111] Preparation of intermediate r

[0112] Intermediate q and methyl 3-bromo-4-iodobenzoate are dissolved in N,N-dimethylformamide, and cesium carbonate is added and the mixture is refluxed with stirring to obtain intermediate r.

[0113] Preparation of intermediates

[0114] Dissolve intermediate r and di-tert-butyl dicarbonate in acetonitrile, add 4-dimethylaminopyridine, and stir at room temperature to obtain intermediate s.

[0115] Preparation of intermediate t

[0116] Intermediate s is subjected to a coupling reaction with a differently substituted boronic acid compound to obtain intermediate t.

[0117] Preparation of intermediate u

[0118] Dissolve intermediate t in a mixed solution of methanol and water, add potassium hydroxide, and reflux with stirring to obtain intermediate u.

[0119] Preparation of intermediate v

[0120] Intermediate u, 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 intermediate v.

[0121] Preparation of compound III

[0122] Dissolve intermediate v in dichloromethane, add trifluoroacetic acid, and stir at room temperature to obtain compound III.

[0123] To achieve the third purpose above, the fourth technical solution adopted by the present invention is:

[0124]

[0125] 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:

[0126] Preparation of intermediate x

[0127] Dissolve the raw material w in dichloromethane, add acetic anhydride, and stir at room temperature to obtain the intermediate x.

[0128] Preparation of intermediate y

[0129] Dissolve the intermediate x and methyl 3-bromo-4-iodobenzoate in N,N-dimethylformamide, add cesium carbonate and reflux with stirring to obtain the intermediate y.

[0130] Preparation of intermediate z

[0131] Dissolve intermediate y and di-tert-butyl dicarbonate in acetonitrile, add 4-dimethylaminopyridine, and stir at room temperature to obtain intermediate z.

[0132] Preparation of intermediate aa

[0133] Intermediate z is subjected to a coupling reaction with a differently substituted boronic acid compound to obtain intermediate aa.

[0134] Preparation of intermediate ab

[0135] 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.

[0136] Preparation of intermediate ac

[0137] Intermediate ab, 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 ac.

[0138] Preparation of compound IV

[0139] Dissolve intermediate ac in dichloromethane, add trifluoroacetic acid, and stir at room temperature to obtain compound IV.

[0140] To achieve the third purpose above, the fifth technical solution adopted by the present invention is:

[0141]

[0142] 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:

[0143] Preparation of intermediate ae

[0144] The raw materials ad and iodoethane are dissolved in N,N-dimethylformamide to carry out substitution reaction, and reflux with stirring to obtain the intermediate ae.

[0145] Preparation of intermediate af

[0146] Dissolve intermediate ae and tert-butyl mercaptan in N,N-dimethylformamide, add potassium carbonate, and stir at room temperature to obtain intermediate af.

[0147] Preparation of intermediate ag

[0148] 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.

[0149] Preparation of intermediate ah

[0150] 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.

[0151] Preparation of intermediate ai

[0152] Dissolve the intermediate ah in dichloromethane, add acetic anhydride, and stir at room temperature to obtain the intermediate ai.

[0153] Preparation of intermediate aj

[0154] Dissolve the intermediate ai and methyl 3-bromo-4-iodobenzoate in N,N-dimethylformamide, add cesium carbonate and reflux with stirring to obtain the intermediate aj.

[0155] Preparation of intermediate ak

[0156] Dissolve intermediate aj, sodium hydride and alkyl halide in N,N-dimethylformamide and stir at room temperature to obtain intermediate ak.

[0157] Preparation of intermediate al

[0158] 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.

[0159] Preparation of Compound V

[0160] Intermediate a1, 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 compound V.

[0161] To achieve the third purpose above, the sixth technical solution adopted by the present invention is:

[0162]

[0163] Preparation of intermediate am

[0164] Dissolve intermediate aj, sodium hydride and iodomethane in N,N-dimethylformamide and stir at room temperature to obtain intermediate am.

[0165] Preparation of intermediate an

[0166] 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.

[0167] Preparation of Compound VI

[0168] 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.

[0169] 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 intermediate with different substituents can be synthesized by the following steps:

[0170]

[0171] Preparation of intermediate ap

[0172] Dissolve the raw material ao, sodium bicarbonate and sodium sulfite in water, heat and stir to react, then add halogenated alkane in N,N-dimethylformamide and heat and stir to react to obtain the intermediate ap.

[0173] Preparation of intermediate aq

[0174] The intermediate ap is dissolved in methanol, palladium carbon is added, and the mixture is stirred at room temperature under a hydrogen atmosphere to obtain the intermediate aq.

[0175] Preparation of intermediates as

[0176] Dissolve the raw material ar and alkylsulfonyl chloride in dimethyl sulfoxide, heat and stir to obtain the intermediate as.

[0177] Preparation of intermediate at

[0178] The intermediate ar is dissolved in methanol, palladium carbon is added, and the mixture is stirred at room temperature under a hydrogen atmosphere to obtain the intermediate at.

[0179] Preparation of intermediate av

[0180] The raw material au is dissolved in dichloromethane with methylamine, dimethylaminopyridine and N,N-diisopropylethylamine, and the mixture is stirred at room temperature to react to obtain the intermediate av.

[0181] Preparation of intermediate aw

[0182] The intermediate au is dissolved in methanol, palladium carbon is added, and the mixture is stirred at room temperature under a hydrogen atmosphere to obtain the intermediate aw.

[0183] To achieve the fourth purpose, the present invention adopts the following technical solutions:

[0184] A pharmaceutical composition comprising a) the above-mentioned phenothiazine sulfonamide derivatives and / or pharmaceutically acceptable salts, solvates, precursor compounds or polymorphs of the above-mentioned phenothiazine sulfonamide derivatives, and b) a pharmaceutically acceptable carrier thereof.

[0185] 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.

[0186] To achieve the fifth purpose, the present invention adopts the following technical solutions:

[0187] The use of the phenothiazine sulfonamide derivatives, pharmaceutically acceptable salts, solvates, prodrugs, polymorphs, or pharmaceutical compositions thereof in the manufacture of a medicament, generally useful for agonizing RORyt. Thus, in some embodiments, the present application provides a compound or composition that agonizes retinoic acid-related orphan receptor-gamma t (RORyt), and is useful for tumor immunotherapy. More specifically, the compounds and compositions described herein act as agonists of RORyt. DETAILED DESCRIPTION

[0188] The present application is further explained with the following specific examples, which do not limit the present application in any form. The experimental methods in the following examples, if not otherwise specified, are generally carried out according to the conventional conditions, or according to the conditions suggested by the manufacturers.

[0189] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or high resolution mass spectrometry (HRMS). The NMR determination is carried out by using Bruker’s Ascend nuclear magnetic resonance instrument, the chemical shift value is expressed by δ, with ppm as the unit, the coupling constant is expressed by J, with Hz as the unit, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0190] The MS determination is carried out by using Micromass Q-TOF mass spectrometer.

[0191] The high performance liquid chromatography (HPLC) analysis is carried out by using Agilent 1260 high performance liquid chromatograph.

[0192] The thin layer chromatography silica gel plate is GF254 silica gel plate from Shandong Yantai Xinnuo Chemical Co., Ltd. 254 Silica gel plate.

[0193] The silica gel column chromatography is generally carried out by using GF254 silica gel from Shandong Yantai Xinnuo Chemical Co., Ltd. 254 Silica gel 200-300 mesh silica gel is used as the carrier.

[0194] The following examples further describe the present application, but the examples are not used to limit the protection scope of the present application.

[0195] Example 1 Preparation of N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide (Compound 1)

[0196]

[0197] Referring to synthesis route I, step 1: preparation of 2-cyanophenothiazine (intermediate b)

[0198]

[0199] 2-Cyanophenothiazine (200 mg, 0.89 mmol) was added to a mixture of acetic acid and concentrated hydrochloric acid (v:v = 3:1). The mixture was incubated under nitrogen for 15 minutes and then heated to 117°C for 18 hours. The mixture was then diluted with ice water, the pH adjusted to alkaline, and extracted with ethyl acetate. The aqueous phase was collected, the pH adjusted to acidic, and extracted with ethyl acetate (15 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid. Yield: 100 mg, 45%.

[0200] Step 2: Preparation of N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide (Compound 1)

[0201] Intermediate b (50 mg, 0.21 mmol) was added to a 50 mL round-bottom flask. 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 completion of the reaction monitored by TLC, the reaction solution was extracted with dichloromethane (15 mL × 3), washed with saturated aqueous ammonium chloride (35 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 1 in a yield of 27 mg, 30% as a white solid.

[0202] Example 2 Preparation of N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide (Compound 2)

[0203]

[0204] Refer to Synthesis Route II, Step 1: Preparation of 2-fluoro-4-methoxy-1-nitrobenzene (Intermediate d)

[0205]

[0206] 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 completion of the reaction, the mixture was extracted with dichloromethane (20 mL × 3) and water. The dichloromethane layer was collected and concentrated under reduced pressure. The product was then back-extracted with ethyl acetate (20 mL × 3) and washed with saturated aqueous sodium chloride solution (30 mL). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was separated and purified by column chromatography to obtain intermediate d in a yield of 1790 mg, 76% as a white solid.

[0207] Step 2: Preparation of tert-butylsulfanyl-(5-methoxy-2-nitrophenyl) (Intermediate e)

[0208]

[0209] Intermediate d (1790 mg, 9.67 mmol) was dissolved in DMF (15 mL), potassium carbonate (2674 mg, 19.35 mmol) was added, followed by tert-butyl mercaptan (1134 mg, 12.57 mmol), and the reaction was allowed to proceed at room temperature overnight. The reaction completion was monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated aqueous sodium chloride solution (35 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate e as yellow colored oil. Yield: 2417 mg, 98 %.

[0210] Step 3: Preparation of 5-methoxy-2-nitrobenzenethiol (Intermediate f)

[0211]

[0212] Intermediate e (2417 mg, 9.48 mmol) was taken in a 50 mL round bottom flask, a mixture of dichloromethane and trifluoroacetic acid (v:v = 3:1) was added, and the reaction was allowed to proceed at room temperature overnight. The reaction completion was monitored by TLC. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain intermediate f as yellow colored solid. Yield: 754 mg, 40 %.

[0213] Step 4: Preparation of 2-amino-5-methoxybenzenethiol (Intermediate g)

[0214]

[0215] Intermediate f (754 mg, 3.79 mmol) was taken in a mixture of ethanol and water (v:v = 4:1), iron powder (1059 mg, 18.94 mmol) followed by ammonium chloride (406 mg, 7.58 mmol) were added, and the reaction was allowed to proceed at 90 °C for 1 h. The reaction completion was monitored by TLC. After completion, the reaction mixture was allowed to cool to room temperature, filtered through celite to remove iron powder, and the filtrate was evaporated to dryness. The residue was extracted with ethyl acetate (20 mL x 3), washed with saturated aqueous sodium chloride solution (35 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain intermediate g as yellow colored solid. Yield: 481 mg, 75 %.

[0216] Step 5: Preparation of N-(2-mercapto-4-methoxyphenyl)acetamide (Intermediate h)

[0217]

[0218] Intermediate g (481 mg, 2.85 mmol) was dissolved in dichloromethane (5 mL), and acetic anhydride (436 mg, 4.27 mmol) was added. The mixture was stirred at room temperature for 20 minutes. After completion of the reaction, which was monitored by TLC, the reaction was quenched with saturated aqueous sodium bicarbonate solution (30 mL). The solvent was evaporated to dryness, and the mixture was rinsed and filtered with ethyl acetate to obtain a filter cake of intermediate h, yield: 270 mg, 45%; white solid.

[0219] Step 6: Preparation of methyl 7-methoxy-10H-phenothiazine-2-carboxylate (Intermediate i)

[0220]

[0221] Intermediate h (270 mg, 1.28 mmol) was added to a 100 ml round-bottom flask, followed by cesium carbonate (834 mg, 2.56 mmol) and methyl 3-bromo-4-iodobenzoate (480 mg, 1.41 mmol). DMF was used as the solvent and the atmosphere was replaced with nitrogen three times. The mixture was stirred in an oil bath at 130°C under nitrogen for 10 hours. After completion of the reaction, which was monitored by TLC, the mixture was extracted with dichloromethane and water. The organic phase was evaporated to dryness and then dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution for back extraction, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate i was separated and purified by column chromatography to obtain a yellow solid in a yield of 166 mg, 43%.

[0222] Step 7: Preparation of 10-(tert-butyl) 2-methyl 7-methoxy-10H-phenothiazine-2,10-dicarboxylate (Intermediate j)

[0223]

[0224] 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 completion of the reaction, the acetonitrile was evaporated, the mixture was 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.

[0225] Step 8: Preparation of 10-(tert-Butoxycarbonyl)-7-methoxy-10H-phenothiazine-2-carboxylic acid (Intermediate k)

[0226]

[0227] 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 completion of the reaction, the methanol was evaporated, the pH of the aqueous solution was adjusted to 2-3 with 2M HCl, and the solution 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 in a yield of 136 mg, 99%; it was a white solid.

[0228] Step 9: Preparation of 2-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-methoxy-10H-phenothiazine-10-tert-butoxycarbonyl (Intermediate 1)

[0229]

[0230] 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, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction monitored by TLC, the reaction solution was extracted with dichloromethane (15 mL × 3), washed with saturated aqueous ammonium chloride (35 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 1 in a yield of 227 mg, 85% as a white solid.

[0231] Step 10: Preparation of N-(4-(ethylsulfonyl)benzyl)-10H-phenothiazine-2-carboxamide (Compound 2)

[0232]

[0233] Intermediate k (227 mg, 0.40 mmol) was dissolved in dichloromethane, and trifluoroacetic acid (912 mg, 8.00 mmol) was added. The mixture was allowed to react at room temperature overnight. After completion of the reaction, which was monitored by TLC, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 2 was separated and purified by column chromatography to obtain a yellow solid in a yield of 149 mg, 80%.

[0234] Examples 3-9

[0235] 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, and benzyl bromide were heated to react with raw material a and potassium carbonate in the above embodiment 1, and subsequent operations were consistent with those in embodiment 1 to prepare compounds 3, 4, 5, 6, 7, 8, and 9, respectively.

[0236] Example 10 Preparation of N-(4-(ethylsulfonyl)benzyl)-7-methyl-10H-phenothiazine-2-carboxamide (Compound 10)

[0237]

[0238] Refer to Synthesis Route III to prepare 10-(tert-butyl) 2-methyl 7-methyl-10H-phenothiazine-2,10-dicarboxylate (Intermediate t)

[0239]

[0240] 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 atmosphere was replaced with nitrogen three times, and the reaction was stirred at 110°C under a nitrogen atmosphere for 12 hours. After the completion of the reaction monitored by TLC, the toluene was evaporated, the product was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was separated and purified by column chromatography to obtain intermediate t with a yield of 85 mg, 80%, as a white solid.

[0241] The remaining steps for compound 10 are the same as those in Example 1 and Example 2.

[0242] Examples 11-19

[0243] Example 10 was repeated except that different starting 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, and benzylboric acid were heated to react with the intermediate q in the above-mentioned embodiment 2 and potassium carbonate and tetrakis(triphenylphosphine)palladium, and the remaining operations were consistent with those in embodiment 2 to prepare compounds 11, 12, 13, 14, 15, 16, 17, 18, and 19, respectively.

[0244] Example 20 Preparation of N-(4-(ethylsulfonyl)benzyl)-8-methyl-10H-phenothiazine-2-carboxamide (Compound 20)

[0245]

[0246] The preparation method of compound 20 is the same as that of Example 1, Example 2 and Example 10.

[0247] Examples 21-23

[0248] Example 20 was repeated except that different starting materials were used to prepare compounds 21-23. Specifically, cyclopropylboronic acid, phenylboronic acid, and p-fluoroboric acid were heated to react with the intermediate x in the above-described embodiment 3, potassium carbonate, and tetrakis(triphenylphosphine)palladium. The remaining operations were consistent with those in Example 20 to prepare compounds 21, 22, and 23, respectively.

[0249] Example 24 7-Ethoxy-N-(4-(ethylsulfonyl)benzyl)-10-methyl-10H-phenothiazine-2-carboxamide (Preparation of Compound 24)

[0250]

[0251] Preparation of 7-ethoxy-10-methyl-10H-phenothiazine-2-carboxylic acid methyl ester (Intermediate ak) by reference route VI

[0252]

[0253] 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 completion of the reaction monitored by TLC, the mixture 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. Intermediate ak was separated and purified by column chromatography to obtain a yellow solid in a yield of 89 mg, 90%.

[0254] The rest of the preparation method of compound 24 is the same as that of Example 1 and Example 2.

[0255] Examples 25-34

[0256] Example 24 was repeated except that different starting materials were used to prepare compounds 25-34. Specifically, iodoethane, 1-iodopropane, 2-bromopropane, isobutyl bromide, bromomethylcyclopropane, bromomethylcyclobutane, bromomethylcyclopentane, acetyl chloride, 4-trifluoromethylbenzenesulfonyl chloride, and 3-trifluoromethylbenzenesulfonyl chloride were reacted with the intermediate aj in the above-mentioned embodiment 5 and sodium hydride at room temperature. The remaining operations were consistent with those in Example 24 to prepare compounds 25, 26, 27, 28, 29, 30, 31, 32, 33, and 34, respectively.

[0257] Example 35 Preparation of Compound 35

[0258]

[0259] Refer to Scheme VIII, Step 1 to prepare 4-(methylsulfonyl)benzonitrile (Intermediate ap)

[0260]

[0261] 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 the mixture was heated and stirred at 70°C for 4 hours. Methyl iodide (212.91 mg, 1.5 mmol) was then added and dissolved in DMF, and the mixture was heated and stirred at 70°C for 4 hours. After the reaction was completed as monitored by TLC, the mixture was extracted with dichloromethane (15 mL × 3), concentrated under reduced pressure, and then back-extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated aqueous sodium chloride 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 in a yield of 180 mg, 92%.

[0262] Step 2 Preparation of (4-(methylsulfonyl)phenyl)methanamine (Intermediate aq)

[0263]

[0264] Intermediate ap (170 mg, 0.87 mmol) was dissolved in methanol, palladium on carbon was added under a hydrogen atmosphere, and the reaction was stirred at room temperature under hydrogen protection for 12 hours. After completion of the reaction, which was monitored by TLC, the mixture was filtered, washed with methanol (35 mL), and evaporated to dryness to obtain intermediate aq as a white solid in a yield of 150 mg, 93%.

[0265] The remaining preparation steps of compound 35 are the same as those of Example 1, Example 2 and Example 24.

[0266] Example 36 Preparation of Compound 36

[0267]

[0268] Preparation of 5-(methylsulfonyl)pyridine methylnitrile (Intermediate as) by reference route VIII

[0269]

[0270] The raw material ar (200 mg, 1.1 mmol) was dissolved in DMSO, and 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, and concentrated under reduced pressure. The intermediate as was separated and purified by column chromatography to obtain a white solid in a yield of 180 mg, 90%.

[0271] The remaining preparation steps of compound 36 are the same as those of Example 1, Example 2, Example 24 and Example 35.

[0272] Example 37 Preparation of Compound 37

[0273]

[0274] Example 36 was repeated except that different substituted benzenesulfonyl chlorides were used to prepare compound 37. Specifically, ethylsulfonyl chloride was substituted for the methylsulfonyl chloride in Example 36, and the remaining operations were the same as in Example 36 to prepare compound 37.

[0275] Example 38 Preparation of Compound 38

[0276]

[0277] Preparation of 4-cyano-N-methylbenzenesulfonamide (Intermediate av) by reference route VIII

[0278]

[0279] 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, the mixture was extracted with dichloromethane (15 mL×3), washed with saturated aqueous sodium chloride solution (35 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The intermediate av was separated and purified by column chromatography to obtain a white solid. The yield was 160 mg, 83%.

[0280] The remaining preparation steps of compound 38 are the same as those of Example 1, Example 2, Example 24 and Example 35.

[0281] Example 39 Preparation of Compound 39

[0282]

[0283] According to the preparation route of Implementation Option 6, the preparation steps are the same as those in Examples 1, 2, 24 and 35.

[0284] The chemical structure of the target product synthesized by the present invention is shown in Table 1. The chemical structure of the target product was characterized by H NMR and high resolution, as shown in Table 2.

[0285] Table 1. Chemical structures of target products

[0286]

[0287]

[0288] Table 2. H NMR spectra and high-resolution data of target compounds

[0289]

[0290]

[0291]

[0292] Example 40 The compounds of the present invention were tested for their agonistic effects on RORγt transcriptional activity using a fluorescent reporter gene assay (Gal4).

[0293] All cells were cultured according to the method recommended by A TCC and tested when HEK293T cells were in the exponential growth phase. HEK293T cells were seeded in 100 mm culture dishes to a density of 6 × 10 6 The cells were then incubated at 37°C in a 5% CO2 environment for 16 hours; Trans-IT transfection reagent and Opti-MEM 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 100mm 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 the compound dilution was transferred to a 384-well plate via Echo655; HEK293T cells were seeded at 17,000 cells / well onto a 384-well plate; the cells were incubated at 37°C in a 5% CO2 atmosphere for 18-20 hours; 25μl of luciferase reagent per well was added to the 384-well plate; and fluorescence data was detected and recorded using an Envision2105 detector.

[0294] The experiment was calculated by the following formula:

[0295] Activity = (Signal cmpd -Signal Ave_VC ) / (Signal Ave_PC -Signal Ave_VC ) x 100%.

[0296] Signal ave_pc : average signal value of all negative controls

[0297] Signal ave_vc : average signal value of all positive controls

[0298] The prepared compounds were tested using the above determination procedure and the obtained results are provided in Table 3. The agonistic activity values are set forth in Table 3, wherein "A" means that the agonistic rate is greater than 40%; "B" means that the agonistic rate is less than 40% and greater than 30%; "C" means that the agonistic rate is less than 30% and greater than 20%; "D" means that the agonistic rate is less than 20% and greater than 10%; and "NA" means not detected.

[0299] Table 3. Activity data of target compounds

[0300]

[0301] As can be seen from Table 3, the compounds of the present application have agonistic activity on RORyt, which lays a foundation for researching and developing novel skeleton small molecule RORyt agonists that can be used for tumor immunity, and has good development value.

[0302] The above only describes the preferred embodiments of the present application, and it should be noted that, for those skilled in the art, without departing from the present application, several improvements and supplements can be made, and these improvements and supplements should also be considered as the protection scope of the present application.

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, C substituted at position 7 in the above molecular formula 1-5 Alkoxy, phenoxy, benzyloxy, oxetane-3-oxy, C 1-4 Alkyl, phenyl, 3-pyridyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, benzyl; C1 alkyl, C3 cycloalkyl, phenyl or p-fluorophenyl substituted at the 8-position in the above molecular structure; R 2 Selected from hydrogen, C 1-7 Alkyl, acetyl, 4-trifluorophenylsulfonyl or 3-trifluorophenylsulfonyl; 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 independently selected from hydrogen or C substituted at position 7 in the above molecular formula 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 or organic 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; 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 pharmaceutical use of the phenothiazine sulfonamide derivative according to any one of claims 1 to 4, characterized in that: It is used as an active ingredient to prepare anti-tumor immune drugs.

6. The pharmaceutical use of the phenothiazine sulfonamide derivatives according to claim 5, characterized in that: It is used as an agonist of the retinoic acid receptor-related orphan receptor-γt.

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