CN113912597B

CN113912597B - ROR gamma inhibitor, preparation method and medical application thereof

Info

Publication number: CN113912597B
Application number: CN202110760907.8A
Authority: CN
Inventors: 阳安乐; 何权鸿; 张德伟; 李泽睿; 余攀; 杨旭东; 张章; 李志勇; 钱欣颖; 张晓东
Original assignee: Scinnohub Pharmaceutical Co Ltd
Current assignee: Scinnohub Pharmaceutical Co Ltd
Priority date: 2020-07-07
Filing date: 2021-07-06
Publication date: 2023-06-13
Anticipated expiration: 2041-07-06
Also published as: CN113912597A

Abstract

The present specification provides compounds having the formula (I): or a pharmaceutically acceptable salt, deuterated compound, tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, a process for preparing such compound, and the use of such compound as rory inhibitor.

Description

ROR gamma inhibitor, preparation method and medical application thereof

Technical Field

The invention belongs to the field of medicines, and relates to a ROR gamma inhibitor, a preparation method and application thereof in medicines. In particular, the present invention relates to compounds of general formula (I), to processes for their preparation, to pharmaceutical compositions containing them, to their use as rory inhibitors and to their use in medicaments for the prophylaxis and/or treatment of autoimmune and inflammatory diseases.

Background

Retinoic acid receptor-related orphan receptors (retinoic acid receptor-related orphan receptors, RORs) are a class of ligand-dependent transcription factors that play an important role in a range of physiological pathological processes such as reproductive development, circadian rhythm regulation, metabolic disorders, inflammation, immune system regulation, etc. The ROR family has three subtypes: rorα, rorβ, and rorγ. They are widely distributed in body tissues, and most subtypes can directly enter the nucleus to regulate transcription of target genes, so that different tissue specificities are shown and different physiological processes are involved. Especially rorα and rorγ play a vital role in mediating Th17 cell differentiation.

Where rory can in turn be divided into rorγ1 and rorγt (rorγ2), which exhibit different tissue specificities. Rorγ1 is found in many tissues, such as: thymus, muscle, kidney and liver, while roryt is expressed only in immune cells (Eur J immunol.1999Dec,29 (12): 4072-80). Rorγt is thought to be able to regulate differentiation of T cell helper T cells 17 (Th 17) (J immunol.2014mar 15,192 (6): 2564-75). Th17 is a cell of the class of helper T cells that produce interleukin 17 (IL-17) and other cytokines. Th17 cells are associated with the pathology of numerous autoimmune and inflammatory diseases including, but not limited to, psoriasis, multiple sclerosis, rheumatoid arthritis, crohn's disease, asthma, chronic obstructive pulmonary disease, behcet's disease, and irritable bowel syndrome, among others (j. Med. Chem.2018,61, 10976-10995).

Currently, rory has been highly valued in the pharmaceutical community as an inhibitor, which is a hot spot of research, and published patent applications include WO2019044940, WO2018229155, WO2018185236, WO2018165501, WO2018160550, WO2018149991, etc.

Disclosure of Invention

The compounds of the invention have high rory inhibitory activity and or good pharmacokinetic profile.

The present application provides a compound represented by the general formula (I):

or a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof,

wherein:

the A ring is selected from substituted or unsubstituted 6-membered aryl, 5-to 6-membered heteroaryl; wherein the substituents are selected from halogen, C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl, hydroxy substituted C ₁ ～C ₆ One or more of the alkyl groups, the heteroatom being N, O, S;

R ¹ selected from C ₁ ～C ₆ Alkyl, C ₃ ～C ₆ Cycloalkyl, wherein said alkyl, cycloalkyl are each independently optionally substituted with a member selected from the group consisting of halogen, -CF ₃ 、C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ One or more substituents in the alkoxy group;

R ² 、R ³ independently selected from hydrogen, C ₁ ～C ₆ Alkyl, - (CH) ₂ ) _a O(CH ₂ ) _b R ⁵ 、-(CH ₂ ) _a O(CH ₂ ) _b C(O)R ⁵ 、-(CH ₂ ) _a O(CH ₂ ) _b C(O)NH ₂ 、-(CH ₂ ) _a O(CH ₂ ) _b C(O)OR ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ⁵ Selected from hydrogen, C ₁ ～C ₆ Alkyl, halogenated C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ One or more of the alkoxy groups; a may be selected from 1,2,3; b may be selected from 0 or 1;

X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ can be independently selected from CH, N, C-R ⁶ Wherein X is ¹ 、X ² 、X ³ 、X ⁴ At most one of them is N; r is R ⁶ Selected from halogen, C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ Alkoxy, halo C ₁ ～C ₆ Alkyl, hydroxy substituted C ₁ ～C ₆ An alkyl group;

R ⁴ selected from hydrogen, C ₁ ～C ₆ Alkyl, C ₁ ～C ₆ An alkoxy group;

m is selected from 0,1,2, 3, 4, 5, 6, 7, 8, preferably 0,1,2;

Alternatively, when m is 2, and two R' s ⁴ On the same carbon, it mayA ternary cycloalkyl group with the carbon atom;

W ¹ selected from CH ₂ 、O；

W ² Selected from C or N;

n is selected from 0, 1, 2, 3, preferably 1;

q is selected from 0, 1, 2, 3.

Further a compound of formula (I) or a tautomer, cis-trans-isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, which is a compound of formula (II):

therein A, R ¹ 、R ² 、R ⁴ 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ 、W ¹ 、W ² Q, m are as defined above.

Further described by the general formula (I) or the general formula (II) or a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, wherein X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ At most one of which is N.

Further a compound of any one of formula (I) or formula (II) herein or a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, wherein R ¹ Selected from C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl; as the preferable R ¹ Selected from ethyl group,

Further the application is generalA compound of any one of formula (I) or formula (II) or a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, wherein R ² Can be selected from hydrogen, -CH ₂ O(CH ₂ ) _b R ⁵ 、-CH ₂ O(CH ₂ ) _b C(O)R ⁵ 、-CH ₂ O(CH ₂ ) _b C(O)NH ₂ 、-CH ₂ O(CH ₂ ) _b C(O)OR ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ⁵ Selected from hydrogen or C ₁ ～C ₃ An alkyl group; b may be selected from 0 or 1; as the preferable R ² Selected from hydrogen,

Further described by general formula (I) or general formula (II) of the present application, or a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, wherein R ⁴ Selected from hydrogen, C ₁ ～C ₃ Alkyl, C ₁ ～C ₃ An alkoxy group; preferably hydrogen, methyl; m is selected from 0,1,2; alternatively, when m is 2, and two R' s ⁴ On the same carbon, it may be a ternary cycloalkyl group with that carbon atom; preferably, the ternary cycloalkyl is cyclopropane.

Further described by the general formula (I) or the general formula (II) or a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, wherein X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ Can be independently selected from CH, N, C-R ⁶ ，X ¹ 、X ² 、X ³ 、X ⁴ At most one of them is N; r is R ⁶ Selected from halogen,C ₁ ～C ₃ An alkyl group; as the preferable R ⁶ Selected from halogen or methyl.

Further, the compound shown in the general formula (I) or the general formula (II) or a tautomer, a cis-trans isomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt and a deuterated compound thereof are shown in the general formula (III):

wherein R is ¹ 、R ² 、R ⁴ 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ 、W ¹ 、W ² Q, m are as defined in the foregoing; y is Y ¹ 、Y ² 、Y ³ 、Y ⁴ Independently selected from CR ⁷ 、N；R ⁷ Selected from hydrogen, halogen, C ₁ ～C ₃ Alkyl, C ₁ ～C ₃ Alkoxy, halo C ₁ ～C ₃ An alkyl group.

Further filed is a compound of formula (I) or formula (II) or a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, which is a compound of formula (iv):

wherein R is ¹ 、R ² 、R ⁴ 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ 、W ¹ 、W ² Q, m are as defined in the foregoing; v (V) ¹ 、V ² 、V ³ Independently selected from CR ⁷ 、NR ⁷ 、O、S；R ⁷ Selected from hydrogen, halogen, C ₁ ～C ₃ Alkyl, C ₁ ～C ₃ Alkoxy, halo C ₁ ～C ₃ An alkyl group.

Further, a compound represented by the general formula (I) or a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, has the following structure:

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One or more embodiments of the present application also provide pharmaceutical compositions comprising a compound of the present application, a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof; a pharmaceutically acceptable diluent or carrier.

One or more embodiments of the present application also provide the use of a compound of the present application, a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of prevention and/or treatment of autoimmune-related diseases, inflammatory diseases; preferably the related disease is selected from psoriasis, multiple sclerosis, rheumatoid arthritis, crohn's disease, asthma, chronic obstructive pulmonary disease, behcet's disease and irritable bowel syndrome.

One or more embodiments of the present application provide the use of a compound of the present application, a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound, or pharmaceutical composition comprising a compound of the present application, in the preparation of a rory inhibitor.

One or more embodiments of the present application provide methods of treating a disease or disorder comprising administering a compound of the present application, a tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, deuterated compound, or pharmaceutical composition comprising a compound of the present application, to a subject in need thereof.

One or more embodiments of the present application provide a compound of the present application, a tautomer, a cis-trans isomer, a meso, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, a deuterated compound thereof, for use as a medicament.

One or more embodiments of the present application provide compounds of the present application, their tautomers, cis-trans isomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, deuterated compounds thereof, for use in the treatment and/or inhibition of a disease or disorder.

In one or more embodiments, the disease is an autoimmune-related disease, an inflammatory disease.

In one or more embodiments, the above-described prevention and/or treatment of autoimmune-related diseases, inflammatory diseases are selected from psoriasis, multiple sclerosis, rheumatoid arthritis, crohn's disease, asthma, chronic obstructive pulmonary disease, behcet's disease, and irritable bowel syndrome.

The invention provides a synthesis method of a compound of a formula (I), which comprises the following steps:

therein A, R ¹ 、R ² 、R ³ 、R ⁴ 、X ¹ 、X ² 、X ³ 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ 、X ⁸ 、W ¹ 、W ² Q, m, n are as defined in the foregoing;

the method comprises the following specific steps:

condensing the hydrochloride of the compound b and the compound c under the conditions of organic alkali, condensing agent and organic solvent to obtain a compound (I); wherein the condensing agent is selected from the group consisting of O- (7-azobenzotriazole-1-oxy) -N, N ' -tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N ' -tetramethylurea hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, a catchment, 1H-benzotriazol-1-yloxytripyrrolidine hexafluorophosphate, N, N ' -diisopropylcarbodiimide, preferably O- (7-azobenzotriazole-1-oxy) -N, N ' -tetramethylurea hexafluorophosphate; wherein the organic base is selected from N, N-diisopropylethylamine, triethylamine, N-methylmorpholine, preferably triethylamine; wherein the organic solvent is selected from tetrahydrofuran, N, N-dimethylformamide, dichloromethane, acetonitrile, preferably tetrahydrofuran.

The invention also provides a synthesis method of the compound b, which comprises the following steps:

therein A, R ⁴ 、X ¹ 、X ² 、X ³ 、X ⁴ 、W ¹ 、W ² Q, m are as defined in claim 1, R ⁸ Can be selected from ester group, amide, cyano group, as R is preferred ⁸ Is an ester group, more preferably R ⁸ Is ethyl ester;

hydrolyzing the compound a in an organic solvent under alkaline conditions to obtain a compound b; preferably wherein the base is selected from inorganic bases; more preferably, the base is sodium hydroxide, lithium hydroxide or potassium hydroxide.

The present invention also provides an intermediate compound of formula (ia):

therein A, R ⁴ 、X ¹ 、X ² 、X ³ 、X ⁴ 、W ¹ 、W ² 、q、m、R ⁷ As defined in the foregoing; r is R ⁸ Can be selected from ester group, amide and cyano.

The present invention also provides an intermediate compound of formula (ib):

therein A, R ⁴ 、X ¹ 、X ² 、X ³ 、X ⁴ 、W ¹ 、W ² Q, m are as defined in the foregoing.

The aforementioned intermediate compound (ia), its tautomers, cis-trans isomers, meso forms, racemates, enantiomers, diastereomers or mixtures thereof, has in particular the following structure:

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unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, oleophobic, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl and carboxylate groups, cyano.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein the alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, hydrophobic, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl and carboxylate groups, cyano.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, cyano.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred are, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably a pyridyl group.

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, hydrophobic, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl and carboxylate groups, cyano.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "hydroxy" refers to an-OH group.

The term "ester group" refers to the group-C (O) OC ₁ -C ₆ An alkyl group.

The term "amide" refers to-C (O) NH ₂ 。

The term "cyano" refers to-CN.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

Meaning that the bond may be selected from double bonds or single bonds.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.

The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F、 ¹²³ I、 ¹²⁵ I and ³⁶ cl, and the like.

Certain isotopically-labeled compounds of the present disclosure (e.g., with ³ H is H ¹⁴ C-labeled) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e ³ H) And carbon-14 (i.e ¹⁴ C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as ¹⁵ O、 ¹³ N、 ¹¹ C and C ¹⁸ F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below, by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.

In addition, the use of heavier isotopes (such as deuterium (i.e. ² H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.

The compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, cis-trans isomers, enantiomers and diastereomers. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

In the present disclosure, unless specifically defined, the abbreviations used have the meanings indicated below:

min refers to minutes;

h means hours;

d refers to the day;

DEG C refers to degrees Celsius;

v is the volume ratio;

DCM refers to dichloromethane;

EA or EtOAc refers to ethyl acetate;

PE refers to petroleum ether;

MeOH refers to methanol;

EtOH refers to ethanol;

THF refers to tetrahydrofuran;

pyridine refers to Pyridine;

Pd(dppf)Cl ₂ refers to [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride;

DMF refers to N, N-dimethylformamide;

t-BuOK refers to potassium tert-butoxide;

n-BuLi refers to n-butyllithium;

NaOH refers to sodium hydroxide;

NaH refers to sodium hydride;

Et ₂ o refers to diethyl ether;

EtONa refers to sodium ethoxide;

AcOH refers to acetic acid;

Ac ₂ o refers to acetic anhydride;

AcOK refers to potassium acetate;

NaIO ₄ sodium periodate;

BnSH refers to benzyl mercaptan;

Pd ₂ (dba) ₃ refers to tris (dibenzylideneacetone) dipalladium;

Pd(PPh ₃ ) ₄ refers to tetraphenylpalladium phosphate;

Brettphos-Pd (G1) refers to chloro (2-dicyclohexylphosphino-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethylphenyl) ] palladium (II);

brettphos refers to 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl;

xantphos refers to 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene;

Tolene refers to Toluene;

NCS refers to N-chlorosuccinimide;

CH ₃ CN refers to acetonitrile;

Br ₂ bromine is meant;

CHCl ₃ refers to chloroform;

PCl ₃ refers to phosphorus trichloride;

CH ₃ MgCl is methyl magnesium chloride;

CH ₃ MgBr is methyl magnesium bromide;

NaBH ₄ sodium borohydride;

BH ₃ refers to borane;

H ₂ O ₂ refers to hydrogen peroxide;

H ₂ refers to hydrogen;

NH ₃ refers to ammonia gas;

Pd/C refers to palladium on carbon;

(HCHO) _n refers to paraformaldehyde;

TBSCl refers to tert-butyldimethylchlorosilane;

TMSI refers to trimethyliodosilane;

DMAP refers to 4-dimethylaminopyridine;

HCl/dioxane refers to a dioxane solution of hydrochloric acid;

oxone refers to potassium hydrogen persulfate;

BBr ₃ refers to boron tribromide;

SOCl ₂ refers to thionyl chloride;

hcl means concentrated hydrochloric acid;

H ₂ SO ₄ means commercial concentrated sulfuric acid;

HNO ₃ means commercially available concentrated nitric acid;

(COCl) ₂ refers to oxalyl chloride;

DMSO refers to dimethyl sulfoxide;

ClSO ₃ h refers to chlorosulfonic acid;

TEA refers to triethylamine;

TBAF refers to tetrabutylammonium fluoride;

pyridine refers to Pyridine;

CH ₃ i is methyl iodide;

CH ₃ I ₂ refers to diiodomethane;

K ₃ PO ₄ refers to potassium phosphate;

PPh ₃ refers to triphenylphosphine;

HATU refers to O- (7-azobenzotriazol-1-yloxy) -N, N "-tetramethylurea hexafluorophosphate;

DIEA refers to N, N-diisopropylethylamine;

DIAD refers to diisopropyl azodicarboxylate;

PCC refers to pyridinium chlorochromate;

Cu(OAc) ₂ Copper acetate;

Cs ₂ CO ₃ cesium carbonate;

K ₂ CO ₃ refers to potassium carbonate;

CuI refers to cuprous iodide;

TFA refers to trifluoroacetic acid;

DCE refers to 1, 2-dichloroethane;

MWI refers to microwave initiation;

LCMS refers to liquid chromatography combined with mass spectrometry;

TLC refers to thin layer chromatography;

Prep-TLC refers to preparative thin layer chromatography;

Prep-HPLC refers to preparative high performance liquid chromatography;

m refers to molar units mol/L, e.g., 2M refers to 2mol/L;

mM refers to molar concentration units millimoles per liter, e.g., 2mM refers to 2mmol/L;

n refers to the equivalent concentration, e.g., 1N HCl refers to hydrochloric acid at a concentration of 1 mol/L; 2N NaOH refers to sodium hydroxide with the concentration of 2mol/L;

tf means trifluoromethanesulfonyl;

et refers to ethyl;

me means methyl;

ac refers to acetyl.

Detailed Description

The present invention is further explained below with reference to specific examples, which are not intended to limit the present invention in any way.

Preparation of intermediates

Preparation example 1: preparation of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethan-1-ol

Step 1: preparation of 2- (t-butyldimethylsilyl) oxy) ethanol

To a solution of ethane-1, 2-diol (5 g) in anhydrous dichloromethane (50 mL) was added triethylamine (9.8 g), and a solution of t-butyldimethylchlorosilane (12 g) in dichloromethane (30 mL) was slowly added dropwise at 0℃and reacted overnight at room temperature. The system was quenched with saturated ammonium chloride solution, the aqueous phase was extracted with methyl tert-butyl ether, the organic phases were combined, concentrated under reduced pressure, the crude product obtained was redissolved in methyl tert-butyl ether, washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound 14g was obtained and used in the next step without further purification.

Step 2:2- ((tert-butyldimethylsilyl) oxy) acetaldehyde

Oxalyl chloride (7.87 g) was added dropwise to a dichloromethane (120 mL) solution cooled to-30 ℃, -dimethyl sulfoxide (9.8 g) was slowly added dropwise at 78 ℃, and the mixture was stirred at that temperature for 30 minutes. A solution of 2- ((tert-butyldimethylsilyl) oxy) ethanol (10 g) in methylene chloride (50 mL) was continuously added dropwise at-78deg.C, and the reaction was stirred at this temperature for 1 hour. Triethylamine (28.7 g) was continuously added dropwise at-78 ℃ and the reaction stirred at that temperature for 30 minutes, returned to room temperature and stirred for 30 minutes. The system was quenched with water, adjusted to ph=5 with 2M hydrochloric acid, extracted three times with dichloromethane, the organic phases were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the title compound 9.36g, which was used directly in the next step without further purification.

Step 3: preparation of (R, E) -N- (2- ((tert-butyldimethylsilyl) oxy) ethylene) -2-methylpropane-2-sulfinamide

2- ((tert-Butyldimethylsilyl) oxy) acetaldehyde (9.36 g), (R) -2-methylpropane-2-sulfinamide (7.82 g) and cesium carbonate (26 g) were weighed into dichloromethane (150 mL) at room temperature and stirred for 20 minutes, and TLC showed complete consumption of starting material. The system was concentrated directly and the crude product was purified by column chromatography to give the title compound 2.2g.

MS(ESI)m/z(M+H) ⁺ ＝278.2.

Step 4: preparation of (R) -N- ((R) -2- ((tert-butyldimethylsilyl) oxy) -1- (4- (ethylsulfanylphenyl) ethyl) -2-methylpropane-2-sulfinamide

N-butyllithium (3.8 mL, 2.5M) was added dropwise to a solution of (4-bromophenyl) (ethyl) sulfane (2.05 g) in anhydrous tetrahydrofuran (20 mL) at-78deg.C, the reaction was continued with stirring at this temperature for 30 minutes, a solution of (R, E) -N- (2- ((tert-butyldimethylsilyl) oxy) ethylene) -2-methylpropane-2-sulfinamide (2.2 g) in anhydrous tetrahydrofuran (25 mL) was continuously added dropwise slowly, the reaction was continued with stirring at this temperature for 1 hour, the temperature was allowed to return to room temperature naturally, and the reaction was continued for 1 hour, TLC showed complete consumption of the starting material. The system was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, the organic phases were washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.3g.

MS(ESI)m/z(M+H) ⁺ ＝416.2.

Step 5: preparation of (R) -2-amino-2- (4- (ethylsulfanyl) phenyl) ethanol

(R) -N- ((R) -2- ((tert-Butyldimethylsilyl) oxy) -1- (4- (ethylsulfanylphenyl) ethyl) -2-methylpropane-2-sulfinamide (1.3 g) was weighed out and dissolved in dioxane hydrochloride (13 mL, 6M), reacted overnight at room temperature, LCMS showed complete consumption of starting material.

MS(ESI)m/z(M+H) ⁺ ＝198.1.

Step 6: preparation of (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol

To a solution of (R) -2-amino-2- (4- (ethylsulfanyl) phenyl) ethanol (630 mg) in methanol (8 mL) was added dropwise an aqueous solution (10 mL) of potassium hydrogen persulfate (4 g) at 0℃and the system was allowed to return to room temperature for 30 minutes to react, and LCMS showed complete consumption of the starting material. The system was adjusted to ph=6 with saturated sodium bicarbonate solution, concentrated under reduced pressure to remove methanol, purified by Prep-HPLC and freeze dried to give 320mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝230.1.

Preparation example 2: preparation of ethyl 4- ((5-bromo-2-hydroxy-4-methylphenyl) sulfonamide) -3-fluorobenzoate

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Step 1: preparation of 5-bromo-2-methoxy-4-methylbenzenesulfonyl chloride

1-bromo-4-methoxy-2-methylbenzene (7.0 g) was weighed and dissolved in dry dichloromethane (100 mL) at room temperature, chlorosulfonic acid (16.23 g) was added to the system, and the reaction was completed by TLC at room temperature for 4 hours. The solvent was removed by concentrating under reduced pressure, adding water quench system, extracting with ethyl acetate, combining the organic phases, backwashing the organic phases three times with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 7.3g.

Step 2: preparation of ethyl 4- ((5-bromo-2-methoxy-4-methylphenyl) sulfonamide) -3-fluorobenzoate

Ethyl 4-amino-3-fluorobenzoate (4.46 g) and 5-bromo-2-methoxy-4-methylbenzenesulfonyl chloride (7.3 g) were weighed out and dissolved in pyridine (80 mL), and the system was reacted at 50℃for 1 hour, and TLC showed that the raw material consumption was complete. The system was quenched with water, pH adjusted to acidic with 2.0M hydrochloric acid, extracted with ethyl acetate, the organic phases combined, backwashed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give the title compound 2.7g.

MS(ESI)m/z(M+H) ⁺ ＝446.0.

Step 3: preparation of ethyl 4- ((5-bromo-2-hydroxy-4-methylphenyl) sulfonamide) -3-fluorobenzoate

4- ((5-bromo-2-methoxy-4-methylphenyl) sulfamido) -3-fluorobenzoic acid ethyl ester (1.0 g) is weighed and dissolved in dichloromethane (15 mL), boron tribromide (6.61 g) is slowly added dropwise at the temperature of 0 ℃, after the addition, the system is restored to room temperature for reaction for 1 hour, and TLC shows that the raw materials are completely reacted. Water quenching, 2.0M hydrochloric acid adjusting the pH to 3-4, ethyl acetate extraction, combining the organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating to afford the title compound 470.0mg.

MS(ESI)m/z(M+H) ⁺ ＝432.0.

Preparation example 3: preparation of ethyl 4- ((5-bromo-2-hydroxy-4-methylphenyl) sulfonamide) -3-methylbenzoate

The preparation was similar to that used in preparation example 2.

Preparation example 4: preparation of N- (tert-butyl) -2, 5-dimethylbenzenesulfonamide

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Step 1: preparation of 2, 5-dimethylbenzenesulfonyl chloride

Paraxylene (3.0 g) was weighed into a reaction flask, chlorosulfonic acid (9.9 g) was slowly added dropwise at 0 ℃, the reaction was resumed at room temperature after the addition for 4 hours, and TLC showed completion of the reaction. The system was slowly added dropwise to ice water, extracted three times with ethyl acetate, the organic phases were combined, the organic phases were backwashed once with saturated sodium carbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 3.7g, which was used directly in the next step without purification.

Step 2: preparation of N- (tert-butyl) -2, 5-dimethylbenzenesulfonamide

Tert-butylamine (805.0 mg) and triethylamine (3.7 g) were weighed out and dissolved in methylene chloride (20 mL), a solution of 2, 5-dimethylbenzenesulfonyl chloride (2.5 g) in methylene chloride (5 mL) was added dropwise to the system at 0℃and reacted overnight at room temperature. TLC showed complete reaction, quenched with water, extracted three times with dichloromethane, combined with the organic phases, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 2.7g.

MS(ESI)m/z(M+H) ⁺ ＝242.1.

Step 3: preparation of N- (tert-butyl) -2- (2-hydroxyethyl) -5-methylbenzenesulfonamide

N- (tert-butyl) -2, 5-dimethylbenzenesulfonamide (2.5 g) was weighed and dissolved in tetrahydrofuran (20 mL), N-butyllithium (9.13 mL) was slowly added dropwise to the system at 0℃and the reaction was continued for 40min after the addition, paraformaldehyde (1.12 g) was added to the system, and the reaction was continued at room temperature after the addition was resumed for 2 hours. TLC showed complete reaction, quench the system in saturated ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, backwash the organic phase once with saturated sodium chloride solution, dry over anhydrous sodium sulfate and concentrate under reduced pressure. The crude product was purified by column chromatography to give the title compound 2.44g.

MS(ESI)m/z(M+H) ⁺ ＝272.1.

Preparation example 5: preparation of N- (tert-butyl) -2- (2-hydroxyethyl) -4-methylbenzenesulfonamide

The preparation was similar to that used in preparation example 4.

Preparation example 6: preparation of N- (tert-butyl) -4-chloro-2- (2-hydroxyethyl) benzenesulfonamide

The preparation was similar to that used in preparation example 4.

Preparation example 7: preparation of ethyl 4- ((4-chloro-2-methoxyphenyl) sulfamido) -3-fluorobenzoate

Step 1: preparation of benzyl (4-chloro-2-methoxyphenyl) sulfoxide

1-bromo-4-chloro-2-methoxybenzene (1.0 g), benzylmercaptan (560.0 mg), tris (dibenzylideneandene acetone) dipalladium (206.0 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (260.0 mg), N-diisopropylethylamine (1.16.0 g) were weighed out at room temperature and dissolved in toluene (15 mL), nitrogen was replaced three times, the system was reacted overnight at 110℃and TLC showed complete reaction of the starting materials. Quenching with water, extracting with ethyl acetate, mixing the organic phases, backwashing the organic phases with saturated sodium chloride solution once, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.1g.

Step 2: preparation of 4-chloro-2-methoxybenzenesulfonyl chloride

Benzyl (4-chloro-2-methoxyphenyl) sulfoxide (1.1 g) was weighed and dissolved in acetonitrile, N-chlorosuccinimide (1.66 g) and hydrochloric acid (2M, 0.21 mL) were added at 0deg.C, and the reaction was maintained at this temperature for 2 hours, and TLC showed complete consumption of the starting material. Water quenching, pH adjustment with 2.0M hydrochloric acid, extraction with ethyl acetate, combining the organic phases, backwashing the organic phases three times with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 830.0mg of the title compound.

Step 3: preparation of ethyl 4- ((4-chloro-2-methoxyphenyl) sulfamido) -3-fluorobenzoate

4-chloro-2-methoxybenzenesulfonyl chloride (830.0 mg) and ethyl 4-amino-3-fluorobenzoate (630.0 mg) were weighed and dissolved in pyridine (10 mL), and reacted at room temperature for 1 hour, and TLC showed that the raw material consumption was complete. Water quenching, pH adjustment with 2.0M hydrochloric acid, extraction with ethyl acetate, backwashing the organic phase three times with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 410.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝388.0.

Preparation example 8: preparation of ethyl 4- ((2- (2- (benzyloxy) ethyl) -5-fluorophenyl) sulphonamido) -3-fluorobenzoate

The preparation was similar to that used in preparation example 7.

Preparation example 9: preparation of ethyl 4- ((4-chloro-5-fluoro-2-methoxyphenyl) sulfamido) -3-fluorobenzoate

Step 1: preparation of 2-bromo-5-chloro-4-fluorophenol

3-chloro-4-fluorophenol (2.0 g) was weighed out and dissolved in chloroform (30 mL), bromine (2.18 g) was slowly added dropwise at 0deg.C, and the reaction was maintained at this temperature for 1 hour after the addition, LCMS showed complete reaction of the starting materials. Water quenching, dichloromethane extraction, backwashing the organic phase once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product obtained was dissolved in petroleum ether and then cooled to precipitate, and filtered to give the title compound (1.8 g).

MS(ESI)m/z(M-H) ^- ＝223.0.

Step 2: preparation of 1-bromo-4-chloro-5-fluoro-2-methoxybenzene

2-bromo-5-chloro-4-fluorophenol (600.0 mg) was dissolved in N, N-dimethylformamide (20 mL), followed by addition of potassium carbonate (1.11 g) and methyl iodide (571.0 mg), and reaction was carried out at room temperature for 1 hour, with TLC indicating complete consumption of the starting material. The system was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 600.0mg of the title compound.

The preparation method of the subsequent step is similar to that adopted in the preparation example 7.

Preparation example 10: preparation of ethyl 3-fluoro-4- (6-methoxy-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) benzoate

Step 1: preparation of 1- (6-methoxypyridin-2-yl) propan-2-ol

2-methoxy-6-methylpyridine (5.0 g) was weighed and dissolved in dry tetrahydrofuran (50 mL), n-butyllithium (17.9 mL) was slowly added dropwise at 78℃and the reaction was continued for 30 minutes at 0 ℃. Cooling to-78 ℃, adding anhydrous acetaldehyde (2.68 g), recovering to 0 ℃ after the addition, and continuing to react for 1 hour, wherein TLC indicates that the raw materials are consumed. Water quenching, extraction with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution three times, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 2.0g.

MS(ESI)m/z(M+H) ⁺ ＝168.1.

Step 2: preparation of 1- (3-bromo-6-methoxypyridin-2-yl) propan-2-ol

1- (6-methoxypyridin-2-yl) propan-2-ol (2.0 g) was weighed and dissolved in ethanol (30 mL), bromine (2.3 g) was slowly added dropwise at 0℃and reacted at this temperature for 30 minutes, and TLC showed that the raw material consumption was complete. The system was quenched by addition of aqueous sodium thiosulfate (20 mL), extracted with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 2.0g.

MS(ESI)m/z(M+H) ⁺ ＝246.1.

Step 3: preparation of 1- (3- (benzylthio) -6-methoxypyridin-2-yl) propan-2-ol

1- (3-bromo-6-methoxypyridin-2-yl) propan-2-ol (2.0 g), benzyl mercaptan (1.1 g), tris (dibenzylideneande-propanone) dipalladium (206.0 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (260.0 mg), N-diisopropylethylamine (1.16 g) were weighed and suspended in toluene (30 mL), the system was reacted at 130℃for 4 hours with nitrogen substitution three times, and TLC showed complete reaction of the starting materials. Quenching with water, extracting with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.95g.

MS(ESI)m/z(M+H) ⁺ ＝290.1.

Step 4: preparation of 1- (3- (benzylthio) -6-methoxypyridin-2-yl) propan-2-yl acetate

1- (3- (benzylthio) -6-methoxypyridin-2-yl) propan-2-ol (1.95 g) was dissolved in methylene chloride (20 mL), and triethylamine (1.26 g), acetic anhydride (635 mg) and 4-dimethylaminopyridine (51 mg) were sequentially added to react at 60℃for 10 minutes, and TLC showed complete consumption of the starting material. Water quenching, extraction with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution three times, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 2.0g.

MS(ESI)m/z(M+H) ⁺ ＝332.1.

Step 5: preparation of 1- (3- (chlorosulfonyl) -6-methoxypyridin-2-yl) propan-2-yl acetate

1- (3- (benzylthio) -6-methoxypyridin-2-yl) propan-2-yl acetate (2.0 g) was dissolved in acetonitrile (20 mL), N-chlorosuccinimide (1.66 g) and 2.0M hydrochloric acid (0.21 mL) were added at 0℃and the reaction was maintained at this temperature for 2 hours, and TLC showed that the starting material was consumed. Water quenching, pH adjustment with 2.0M hydrochloric acid, extraction with ethyl acetate, three backwashing of the organic phase with saturated sodium chloride, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.84g.

MS(ESI)m/z(M+H) ⁺ ＝308.1.

Step 6: preparation of ethyl 4- ((2- (2-acetoxypropyl) -6-methoxypyridine) -3-sulfonylamino) -3-fluorobenzoate

1- (3- (chlorosulfonyl) -6-methoxypyridin-2-yl) propan-2-yl acetate (1.84 g) and ethyl 4-amino-3-fluorobenzoate (1.1 g) were dissolved in pyridine (20 mL) and reacted at room temperature for 1 hour, and TLC showed that the raw materials were consumed. Most of pyridine was removed by concentrating under reduced pressure, quenching with water, adjusting pH to neutrality with 1.0M hydrochloric acid, extracting with ethyl acetate, backwashing the organic phase three times with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.0g.

MS(ESI)m/z(M+H) ⁺ ＝455.0.

Step 7: preparation of ethyl 3-fluoro-4- ((2- (2-hydroxypropyl) -6-methoxypyridine) -3-sulfonylamino) benzoate

Ethyl 4- ((2- (2-acetoxypropyl) -6-methoxypyridine) -3-sulfonylamino) -3-fluorobenzoate (1.0 g) was dissolved in ethanol (20 mL), sodium ethoxide (273.0 mg) was added and the system reacted at 60 ℃ for 12 minutes, TLC indicated complete consumption of the starting material. Concentrating under reduced pressure to remove most ethanol, adding 1.0M hydrochloric acid quenching system, adjusting pH to neutrality with sodium bicarbonate, extracting with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution for three times, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 900.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝413.1.

Step 8: preparation of ethyl 3-fluoro-4- (6-methoxy-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) benzoate

Ethyl 3-fluoro-4- ((2- (2-hydroxypropyl) -6-methoxypyridine) -3-sulfonylamino) benzoate (900.0 mg) and triphenylphosphine (2.3 g) were weighed out in tetrahydrofuran (10 mL), diisopropyl azodicarboxylate (1.78 g) was added at room temperature, and the reaction was continued for 15 minutes after the addition, and TLC showed complete reaction of the starting materials. Quenching with water, extracting with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 405.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝395.0.

Preparation example 11: preparation of ethyl 4- (3, 7-dimethyl-1, 1-dioxide-4, 5-dihydrobenzo [ f ] [1,2] thiazolin-2 (3H) -yl) -3-fluorobenzoate

Step 1: preparation of 3- (2-bromo-5-methylphenyl) propionic acid

Triethylamine (10.66 g) was weighed into a reaction flask, formic acid (9.7 g) was slowly added dropwise at 0℃and 2-bromo-5-methylbenzaldehyde (3.5 g) and cyclopropylester malonate (5.07 g) were sequentially added, and after the addition, the system was reacted at 120℃for 18 hours, and TLC showed that the reaction of the raw materials was completed. The system was slowly added dropwise to a saturated ammonium chloride solution to quench it, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 5.2g.

MS(ESI)m/z(M-H) ^- ＝241.0.

Step 2: preparation of 3- (2-bromo-5-methylphenyl) -N-methoxy-N-methylpropanamide

3- (2-bromo-5-methylphenyl) propionic acid (5.2 g), O- (7-azobenzotriazole-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (9.8 g) was weighed out in tetrahydrofuran (80 mL), N-diisopropylethylamine (8.32 g), dimethylhydroxylamine hydrochloride (2.5 g) were added in order, and after addition, the reaction was completed at room temperature for 3 hours, and LCMS showed complete reaction of the starting materials. Water quenching, ethyl acetate extraction, backwashing the organic phase once with saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, purifying the crude product by column chromatography to obtain the title compound 2.65g.

MS(ESI)m/z(M+H) ⁺ ＝286.0.

Step 3: preparation of 4- (2-bromo-5-methylphenyl) butan-2-one

3- (2-bromo-5-methylphenyl) -N-methoxy-N-methylpropanamide (2.65 g) was weighed in tetrahydrofuran (30 mL), methyl magnesium chloride (11.1 mL) was slowly added dropwise at 40℃and the reaction was allowed to proceed to room temperature for 2 hours after the addition, and TLC indicated complete reaction of the starting materials. Water quenching, ethyl acetate extraction, backwashing the organic phase once with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 2.3g of crude product.

Step 4: preparation of 4- (2-bromo-5-methylphenyl) butan-2-ol

4- (2-bromo-5-methylphenyl) butan-2-one (2.3 g) was weighed into methanol (30 mL), sodium borohydride (704.0 mg) was added in portions at room temperature, and the reaction was continued for 30 min after the addition, with TLC indicating complete reaction of starting materials. Water quenching, ethyl acetate extraction, backwashing the organic phase once with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 2.4g of crude product.

The preparation method of the subsequent step is similar to that adopted in the preparation example 10.

Preparation example 12: preparation of 1, 1-dioxido-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-6-yl triflate

Step 1: preparation of ethyl 2- (3-methoxyphenyl) acetate

2- (3-methoxyphenyl) acetic acid (17.0 g) was weighed out and dissolved in ethanol (200 mL), concentrated sulfuric acid (1.09 mL) was slowly added at room temperature, and the system was reacted overnight at 80 ℃. TLC showed the starting material was reacted, concentrated under reduced pressure to remove most of the solvent, quenched with water, ph=8 adjusted with sodium bicarbonate, extracted three times with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 19.8g of crude product.

Step 2: preparation of ethyl 2- (2- (chlorosulfonyl) -5-methoxyphenyl) acetate

Ethyl 2- (3-methoxyphenyl) acetate (10.0 g) was weighed and dissolved in dichloromethane (100 mL), chlorosulfonic acid (18.0 g) was slowly added dropwise at 0 ℃, the temperature was maintained for reaction for 1 hour, thionyl chloride (12.3 g) was continuously slowly added dropwise at 0 ℃, the system was returned to room temperature after the addition and reaction was carried out overnight, and TLC showed that the consumption of the raw materials was completed. Water quenching, extraction with ethyl acetate, backwashing the organic phase once with saturated sodium chloride, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 12.6g of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝293.1.

Step 3: preparation of ethyl 2- (5-methoxy-2-sulfamylphenyl) acetate

Ethyl 2- (2- (chlorosulfonyl) -5-methoxyphenyl) acetate (12.6 g) was weighed and dissolved in tetrahydrofuran (150 mL), methanolic ammonia solution (30.8 mL) and triethylamine (13.07 g) were slowly added dropwise in this order at 0 ℃, and after the addition, the reaction was carried out at room temperature for 2 hours, and TLC showed complete reaction of the starting materials. Quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 11.3g.

MS(ESI)m/z(M+H) ⁺ ＝274.1.

Step 4: preparation of 6-methoxy-2H-benzo [ e ] [1,2] thiazine-3 (4H) -1, 1-dioxide

Ethyl 2- (5-methoxy-2-sulfamylphenyl) acetate (11.3 g) was weighed out and dissolved in tetrahydrofuran (150 mL), sodium hydride (4.97 g) was added in portions at 0℃and reacted at room temperature for 2 hours after the addition, and TLC showed complete consumption of starting material. The system was quenched by slowly dropping into 1.0M hydrochloric acid (300 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 8.93g of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝228.1.

Step 5: preparation of 6-methoxy-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

6-methoxy-2H-benzo [ e ] [1,2] thiazine-3 (4H) -1, 1-dioxide (8.9 g) was dissolved in tetrahydrofuran (150 mL), a solution of borane in tetrahydrofuran (78.7 mL) was slowly added at room temperature, and the system was reacted at 70℃for 2 hours, and TLC showed complete consumption of the starting material. The mixture was quenched by dropwise addition of methanol at 0℃and extracted three times with water and ethyl acetate, and the organic phase was backwashed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 6.2g.

MS(ESI)m/z(M+H) ⁺ ＝214.1.

Step 6: preparation of 6-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

6-methoxy-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (3.0 g) was weighed out in dichloromethane (30 mL), boron tribromide (21.1 mL) was added and reacted at room temperature for 2 hours, TLC indicated complete reaction of starting material. Water quenching, 2.0M hydrochloric acid regulating pH to 3-4, ethyl acetate extraction, backwashing the organic phase once with saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating, purifying the crude product by column chromatography to obtain the title compound 2.4g.

MS(ESI)m/z(M+H) ⁺ ＝200.1.

Step 7: preparation of 1, 1-dioxido-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-6-yl triflate

6-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (700.0 mg) was weighed into dichloromethane (10 mL), N-phenyl bis (trifluoromethanesulfonyl) imine (1.9 g) and triethylamine (1.06 g) were added in this order at room temperature, the reaction was continued for 30 minutes after the addition, and TLC showed that the reaction of the starting materials was completed. Saturated ammonium chloride solution was added to quench, extraction was performed three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to give the title compound 1.1g.

MS(ESI)m/z(M+H) ⁺ ＝332.0.

Preparation example 13: preparation of N- (tert-butyl) -4-chloro-2- (2-hydroxyethyl) -5-methylbenzenesulfonamide

The preparation was similar to that used in preparation example 4.

Preparation example 14: preparation of ethyl 4- (6-chloro-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoate

Step 1: preparation of 2- (2-bromo-5-chlorophenyl) -N-methoxy-N-methylacetamide

2- (2-bromo-5-chlorophenyl) acetic acid (5.0 g), O- (7-azobenzotriazole-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (2.3 g) was dissolved in tetrahydrofuran (15 mL), N-diisopropylethylamine (7.9 g), N, O-dimethylhydroxylamine (2.3 g) was added and reacted at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. Quenching with water, extracting with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 4.0g of the title compound.

MS(ESI)m/z(M+H)+＝292.0.

Step 2: preparation of 1- (2-bromo-5-chlorophenyl) propan-2-one

2- (2-bromo-5-chlorophenyl) -N-methoxy-N-methylacetamide (4.0 g) was weighed and dissolved in tetrahydrofuran (8 mL), argon was replaced three times, methyl magnesium bromide (6.9 mL,3.0mol/L in THF) was slowly added dropwise at 0deg.C, and the reaction was continued with stirring for 30 minutes after the addition was resumed at room temperature, and TLC showed complete reaction. The system was slowly quenched by dropwise addition of water, extracted with ethyl acetate, the organic phases combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 900.0mg of the title compound.

Step 3: preparation of 1- (2-bromo-5-chlorophenyl) propan-2-ol.

1- (2-bromo-5-chlorophenyl) propan-2-one (1.0 g) was weighed out in methanol (8 mL), sodium borohydride (310.0 mg) was added slowly in portions at 0deg.C, bi Tiji was added and reacted at room temperature for 1 hour, and TLC showed complete consumption of starting material. The system was quenched with water, extracted with ethyl acetate, the organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 840.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝249.0.

Step 4: preparation of 1- (2- (benzylthio) -5-chlorophenyl) propan-2-ol

1- (2-bromo-5-chlorophenyl) propan-2-ol (840.0 mg), benzyl mercaptan (630.0 mg), N-diisopropylethylamine (877.0 mg), tris (dibenzylideneandene acetone) dipalladium (155.0 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (115.0 mg) were weighed and suspended in toluene (6 mL), argon was replaced three times, and the system was reacted at 120℃for 2 hours, and TLC showed complete reaction of the starting materials. Quenching with water, extracting with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 850.0mg of the title compound.

MS(ESI)m/z(M+H)+＝293.1.

Step 5: preparation of 1- (2- (benzylthio) -5-chlorophenyl) propan-2-yl acetate

1- (2- (benzylthio) -5-chlorophenyl) propan-2-ol (850.0 mg) was weighed and dissolved in methylene chloride (4 mL), triethylamine (1.7 g) and acetic anhydride (1.5 g) were slowly added dropwise at room temperature in this order, and after the addition, the reaction was completed for 0.5 hour, and TLC showed complete reaction of the starting materials. Water quenching, dichloromethane extraction, combining organic phases, back washing with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 940.0mg of the title compound.

MS(ESI)m/z(M+H)+＝335.1.

Step 6: preparation of 1- (5-chloro-2- (chlorosulfonyl) phenyl) propan-2-yl acetate

1- (2- (benzylthio) -5-chlorophenyl) propan-2-yl acetate (940.0 mg) was dissolved in acetonitrile (6.0 mL), N-chlorosuccinimide (1.1 g) and 2.0M hydrochloric acid (0.7 mL) were added at 0℃and the reaction was continued at room temperature for 0.5 hours, and TLC showed complete consumption of the starting material. The pH of the saturated sodium bicarbonate solution was adjusted to 7-8, extracted with ethyl acetate, the organic phases were combined, the saturated sodium chloride solution was backwashed once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 820.0mg.

MS(ESI)m/z(M+H)+＝311.0.

Step 7: preparation of ethyl 4- ((4-chloro-2- (2-hydroxypropyl) phenyl) sulfonamide) -3-fluorobenzoate

Ethyl 4-amino-3-fluorobenzoate (120.0 mg) was weighed out and dissolved in tetrahydrofuran (2 mL), argon was substituted three times, sodium hydride (46 mg) was added at 0℃and the reaction was continued for 20 minutes after the addition. 1- (5-chloro-2- (chlorosulfonyl) phenyl) propan-2-yl acetate (100 mg) was added to the system while maintaining the temperature, and after the addition, the reaction was returned to room temperature for 2 hours, and TLC showed complete reaction of the starting materials. Quenching with water, extracting with ethyl acetate, mixing the organic phases, backwashing with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 30.0mg.

MS(ESI)m/z(M+H)+＝416.1.

Step 8: preparation of ethyl 4- (6-chloro-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoate

Ethyl 4- ((4-chloro-2- (2-hydroxypropyl) phenyl) sulfonamide) -3-fluorobenzoate (30.0 mg) and triphenylphosphine (58.0 mg) were dissolved in tetrahydrofuran (4 mL), diisopropyl azodicarboxylate (58 mg) was added at 0 ℃, and after the addition, the reaction was continued at room temperature for 0.5 hours, and TLC showed complete consumption of starting material. Quenching with water, extracting with ethyl acetate, mixing the organic phases, backwashing with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 25.0mg.

MS(ESI)m/z(M+H)+＝398.0.

Preparation example 15: preparation of ethyl 4- ((4-chloro-6-methylpyridine) -3-sulfonylamino) -3-fluorobenzoate

Step 1: preparation of 5-bromo-2-methylpyridine 1-oxide

5-bromo-2-methylpyridine (5.0 g) was weighed and dissolved in acetic acid (25 mL), 30% hydrogen peroxide (25 mL) was added at room temperature, and after the addition, the reaction was carried out at 90℃for 24 hours, and TLC showed complete reaction of the starting materials. Water quenching, chloroform extraction, anhydrous sodium sulfate drying, vacuum concentration, crude product 5.7g.

MS(ESI)m/z(M+H) ⁺ ＝188.1.

Step 2: preparation of 5-bromo-2-methyl-4-nitropyridine 1-oxide

Concentrated sulfuric acid (25 mL) was slowly added dropwise to concentrated nitric acid (25 mL) at 0deg.C, 5-bromo-2-methylpyridine 1-oxide (5.7 g) was added, the system was reacted at 90deg.C for 72 hours, and TLC showed complete reaction of starting materials. Slowly dropwise adding the system into ice water for quenching, filtering to obtain a filter cake, washing the filter cake with ethyl acetate, and drying to obtain 2.7g of crude product.

MS(ESI)m/z(M+H) ⁺ ＝233.1.

Step 3: preparation of 5-bromo-4-chloro-2-methylpyridine 1-oxide

5-bromo-2-methyl-4-nitropyridine 1-oxide (2.7 g) was weighed out and dissolved in concentrated hydrochloric acid (25 mL) and the system was reacted at 105℃for 4 hours, TLC indicated complete reaction of starting material. Water quenching, chloroform extraction, anhydrous sodium sulfate drying, vacuum concentration, crude product 2.4g.

MS(ESI)m/z(M+H) ⁺ ＝222.1.

Step 4: preparation of 5-bromo-4-chloro-2-methylpyridine

5-bromo-4-chloro-2-methylpyridine 1-oxide (2.4 g) was weighed and dissolved in 1, 2-dichloroethane (25 mL), phosphorus trichloride (2.96 g) was added at room temperature and reacted for 3 hours after the addition, and TLC showed complete reaction of the starting materials. Water quenching, pH adjustment with saturated sodium bicarbonate solution to alkaline, chloroform extraction, drying with anhydrous sodium sulfate, and vacuum concentrating to obtain crude product 1.25g.

MS(ESI)m/z(M+H) ⁺ ＝206.1.

Step 5: preparation of 5- (benzylthio) -4-chloro-2-methylpyridine

5-bromo-4-chloro-2-methylpyridine (1.25 g), benzylmercaptan (913.0 mg), tris (dibenzylideneandene acetone) dipalladium (206.0 mg), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (260.0 mg), N-diisopropylethylamine (1.16 g) were weighed out and suspended in toluene (30 mL), and after three times of addition, nitrogen substitution was performed, and the system was reacted at 90℃for 2 hours, TLC showed complete reaction of the starting materials. Quenching with water, extracting with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.0g.

MS(ESI)m/z(M+H) ⁺ ＝250.1.

Step 6: preparation of 4-chloro-6-methylpyridine-3-sulfonyl chloride

5- (benzylthio) -4-chloro-2-methylpyridine (1.0 g) was weighed out in acetonitrile (20 mL), N-chlorosuccinimide (1.66 g) and 2.0M hydrochloric acid (0.21 mL) were added at 0℃and the reaction was maintained at this temperature for 10 minutes, and TLC showed complete consumption of the starting material. Water quenching, easy pH adjustment with saturated sodium carbonate to alkaline, extraction with ethyl acetate, backwashing the organic phase with saturated sodium chloride solution three times, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 0.9g.

MS(ESI)m/z(M+H) ⁺ ＝226.1.

Step 7: preparation of ethyl 4- ((4-chloro-6-methylpyridine) -3-sulfonylamino) -3-fluorobenzoate

4-chloro-6-methylpyridine-3-sulfonyl chloride (0.9 g) and ethyl 4-amino-3-fluorobenzoate (732.0 mg) were weighed and dissolved in pyridine (20 mL) and reacted at room temperature for 3 hours, and TLC showed that the raw material consumption was complete. The system was concentrated to remove most of the pyridine, quenched with water, adjusted to neutral pH with 2.0M hydrochloric acid, extracted with ethyl acetate, and the organic phase was backwashed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 780.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝373.0.

Preparation example 16: preparation of ethyl 4- ((4-chloro-2, 5-difluorophenyl) sulfamido) -3-fluorobenzoate

The preparation was similar to that used in preparation example 7.

Preparation example 17: preparation of 1- ((tert-butyldimethylsilyl) oxy) propan-2-ol

Step 1: preparation of 1- ((tert-butyldimethylsilyl) oxy) propan-2-ol

Propane 1, 2-diol (1 g) was weighed out and dissolved in methylene chloride (20 mL), imidazole (894 mg) was added, a solution of t-butyldimethylchlorosilane (1.98 g) in methylene chloride (10 mL) was slowly added dropwise at 0℃and the reaction was maintained at this temperature overnight, and TLC showed complete consumption of starting material. The system was filtered and the filtrate was concentrated under reduced pressure to give 2.1g of crude product.

Preparation example 18: preparation of N- (tert-butyl) -2- (2-hydroxypropyl) -4-methylbenzenesulfonamide

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The preparation was similar to that used in preparation example 4.

Preparation example 19: preparation of N- (tert-butyl) -2- (3-hydroxypropyl) -4-methylbenzenesulfonamide

The preparation was similar to that used in preparation example 4.

Preparation example 20: preparation of ethyl 4- (7-chloro-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoate

Step 1: preparation of 2- (2-bromo-4-chlorophenyl) -N-methoxy-N-methylacetamide

2- (2-bromo-4-chlorophenyl) acetic acid (3.0 g) was weighed and dissolved in tetrahydrofuran (30 mL), N-diisopropylethylamine (2.1 g), O- (7-azobenzene triazole-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (6.34 g), N, O-dimethylhydroxylamine (1.20 g) were added sequentially, and after the addition, room temperature reaction was carried out for 1 hour, TLC showed complete reaction. Quenched with water, extracted three times with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 2.47g.

MS(ESI)m/z(M+H)+＝292.0.

Step 2: preparation of 1- (2-bromo-4-chlorophenyl) propan-2-one

2- (2-bromo-4-chlorophenyl) -N-methoxy-N-methylacetamide (2.5 g) was dissolved in tetrahydrofuran (20 mL), methyl magnesium bromide (5.1mL,3.0M in THF) was slowly added dropwise at 0deg.C, and the reaction was maintained at this temperature for 30 minutes after the addition, and TLC showed completion of the reaction. Quenched with water, extracted three times with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 600mg of the title compound.

Step 3: preparation of 1- (2-bromo-4-chlorophenyl) propan-2-ol

1- (2-bromo-4-chlorophenyl) propan-2-one (600.0 mg) was weighed out and dissolved in methanol (5 ml), sodium borohydride (119.0 mg) was slowly added in portions at 0℃and the reaction was allowed to resume at room temperature for 1.5 hours after the addition, and TLC showed completion of the reaction. The system was quenched by addition to an aqueous solution of ammonium chloride, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 610mg of crude product.

MS(ESI)m/z(M+H)+＝249.0.

Step 4: preparation of 1- (2- (benzylthio) -4-chlorophenyl) propan-2-ol

1- (2-bromo-4-chlorophenyl) propan-2-ol (600.0 mg), benzyl mercaptan (300.0 mg) and N, N-diisopropylethylamine (600.0 mg) were weighed out in toluene, tris (dibenzylideneacetone) dipalladium (110.0 mg) and 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (140.0 mg) were added, argon was replaced three times, and the system was reacted at 130℃for 4 hours, and TLC showed complete reaction. Quenched with water, extracted three times with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 500mg.

MS(ESI)m/z(M+H)+＝293.0.

Step 5: preparation of 1- (2- (benzylthio) -4-chlorophenyl) propan-2-yl acetate

1- (2- (benzylthio) -4-chlorophenyl) propan-2-ol (500.0 mg) was weighed and dissolved in methylene chloride (5 mL), triethylamine (700.0 mg) was added, acetic anhydride (500.0 mg) was slowly added dropwise at 0℃and the reaction was allowed to proceed to room temperature for 12 hours after the addition, and TLC showed completion of the reaction. Quenched with water, extracted three times with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 602mg of the title compound.

MS(ESI)m/z(M+H)+＝335.1.

Step 6: preparation of 1- (4-chloro-2- (chlorosulfonyl) phenyl) propan-2-yl acetate

1- (2- (benzylthio) -4-chlorophenyl) propan-2-yl acetate (600.0 mg) was dissolved in acetonitrile (5 mL), 2.0M hydrochloric acid (0.4 mL) and N-chlorosuccinimide (700.0 mg) were added at 0℃and the reaction was allowed to proceed to room temperature for 1.5 hours after the addition, and TLC showed complete reaction. Quenched with water, extracted three times with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 200mg of the title compound.

MS(ESI)m/z(M+H)+＝311.0.

Step 7: preparation of ethyl 4- ((2- (2-acetoxypropyl) -5-chlorophenyl) sulfonamide) -3-fluorobenzoate

1- (4-chloro-2- (chlorosulfonyl) phenyl) propan-2-yl acetate (200.0 mg) was weighed out in pyridine, ethyl 4-amino-3-fluorobenzoate (120.0 mg) was added, the system was stirred at 40℃for 1h, and TLC showed completion of the reaction. Water quenching, 2.0M hydrochloric acid adjustment of ph=4, ethyl acetate extraction three times, combined organic phases, anhydrous sodium sulfate drying, decompression concentration, the title compound 35mg.

MS(ESI)m/z(M+H)+＝458.0.

Step 8: preparation of ethyl 4- ((5-chloro-2- (2-hydroxypropyl) phenyl) sulfonamide) -3-fluorobenzoate

Ethyl 4- ((2- (2-acetoxypropyl) -5-chlorophenyl) sulfonamide) -3-fluorobenzoate (35.0 mg) was weighed out in ethanol (2 mL), potassium carbonate (45.0 mg) was added and the system reacted at 80 ℃ for 3 hours, TLC indicated complete reaction. Quenched with water, extracted three times with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 25mg.

MS(ESI)m/z(M+H) ⁺ ＝416.0.

Step 9: preparation of ethyl 4- (7-chloro-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoate

Ethyl 4- ((5-chloro-2- (2-hydroxypropyl) phenyl) sulfonamide) -3-fluorobenzoate (25.0 mg) and triphenylphosphine (50.0 mg) were weighed out in tetrahydrofuran (2 mL), diisopropyl azodicarboxylate (40.0 mg) was slowly added dropwise at 0 ℃, after addition, the reaction was resumed at room temperature for 1 hour, and TLC showed complete reaction. Quenched with water, extracted three times with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 20mg.

MS(ESI)m/z(M+H)+＝398.0.

Preparation example 21: preparation of 2- ((tert-butyldimethylsilyl) oxy) propan-1-ol

Step 1: preparation of (((1- (benzyloxy) propan-2-yl) oxy) (tert-butyl) dimethylsilane

1- (benzyloxy) propan-2-ol (300 mg) was weighed out and dissolved in dichloromethane (20 mL), imidazole (134 mg) was added, a solution of tert-butyldimethylchlorosilane (295 mg) in dichloromethane (5 mL) was slowly added dropwise at 0℃and the reaction was maintained at this temperature for 5 hours, and TLC showed complete consumption of starting material. Suction filtration and concentration of the filtrate under reduced pressure gave 500mg of the title compound.

Step 2: preparation of 2- ((tert-butyldimethylsilyl) oxy) propan-1-ol

((1- (benzyloxy) prop-2-yl) oxy) (tert-butyl) dimethylsilane (300 mg) was weighed into methanol (5 mL), palladium on carbon (60.0 mg) was added, hydrogen was replaced three times, and the reaction was completed by TLC at room temperature for 3 hours. Suction filtration and concentration of the filtrate under reduced pressure gave 90mg of the title compound.

Preparation example 22: preparation of ethyl 4- ((4-bromo-2-fluorophenyl) sulphonamido) -3-fluorobenzoate

The preparation was similar to that used in preparation example 7.

Preparation example 23: preparation of ethyl 4-amino-3-fluorobenzoate

Step 1: preparation of ethyl 4-amino-3-fluorobenzoate

4-amino-3-fluorobenzoic acid (2.0 g) was weighed out and dissolved in ethanol (20 mL), concentrated sulfuric acid (0.2 mL) was slowly added dropwise at 0deg.C, and the system was reacted overnight at 80deg.C after the addition, TLC showed complete consumption of starting material. Concentrating under reduced pressure to remove most of ethanol, slowly adding the reaction solution into water at 0 ℃ to quench, regulating the pH to 8-9 by using saturated sodium bicarbonate solution, extracting by using ethyl acetate for three times, combining organic phases, backwashing the organic phases by using saturated sodium chloride aqueous solution once, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the title compound 2.2g.

MS(ESI)m/z(M+H) ⁺ ＝184.1.

Preparation example 24: preparation of ethyl 4-bromo-3-fluorobenzoate

The preparation was similar to that used in preparation example 23.

Preparation example 25: preparation of ethyl 4-amino-3-methylbenzoate

The preparation was similar to that used in preparation example 23.

Preparation example 26: preparation of (4- (ethoxycarbonyl) -2-fluorophenyl) boronic acid

Step 1: preparation of ethyl 3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoate

Ethyl 4-bromo-3-fluorobenzoate (200 mg), bis-pinacolato borate (267.4 mg), potassium acetate (158.7 mg), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (29.6 mg) were weighed and suspended in 1, 4-dioxane (5 mL), and Bi Tiji was reacted at 85℃for 8 hours, followed by TLC detection of no starting material remaining. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 160mg of the title compound.

Step 2: preparation of (4- (ethoxycarbonyl) -2-fluorophenyl) boronic acid

Ethyl 3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoate (160 mg) was dissolved in acetonitrile (6 mL), an aqueous solution (2 mL) of sodium periodate (349.4 mg) was added dropwise, and the mixture was reacted at room temperature for 6 hours, whereby no starting material remained by TLC detection. Water was added, extraction was performed three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 96mg of the title compound.

Preparation example 27: preparation of (R) -2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethan-1-ol

The preparation was similar to that used in preparation example 1.

Preparation example 28: preparation of methyl 5- ((4-chloro-2, 5-difluorophenyl) sulfamido) -6-methylpyridine carboxylate

Step 1: preparation of 6-methyl-5-nitropyridine amide

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6-bromo-2-methyl-3-nitropyridine (10.0 g), cuprous cyanide (8.25 g) and tetrakis (triphenylphosphine) palladium (5.3 g) were weighed and dissolved in N, N-dimethylacetamide (20 mL), nitrogen was replaced three times, and the system was subjected to microwave reaction at 150℃for 2 hours, and TLC showed the completion of the reaction of the raw materials. The solvent was removed by concentrating under reduced pressure, quenched with water, extracted with ethyl acetate, the organic phases combined, backwashed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 2.6g.

MS(ESI)m/z(M+H) ⁺ ＝182.0.

Step 2: preparation of methyl 6-methyl-5-nitropicolinate

6-methyl-5-nitropyridine amide (2.6 g) was weighed out and dissolved in methanol (40 mL), concentrated sulfuric acid (3 mL) was added and the system was reacted at 60℃for 4 hours, and TLC showed complete consumption of starting material. The system was quenched with water, extracted with ethyl acetate, the organic phases combined, backwashed three times with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 1.3g.

MS(ESI)m/z(M+H) ⁺ ＝197.0.

Step 3: preparation of methyl 5-amino-6-methylpyridine carboxylate

Methyl 6-methyl-5-nitropicolinate (1.3 g) was weighed out in methanol (50 mL), 10% palladium on carbon (260.0 mg) was added, hydrogen was replaced, and the reaction was performed at room temperature for 1 hour, TLC indicated complete reaction of starting materials. The system was filtered to give a filtrate, which was concentrated under reduced pressure to give 780.0mg of crude product.

MS(ESI)m/z(M+H) ⁺ ＝167.0.

Step 4: preparation of methyl 5- ((4-chloro-2, 5-difluorophenyl) sulfamido) -6-methylpyridine carboxylate

Methyl 5-amino-6-methylpyridine carboxylate (220.0 mg) and 4-chloro-2, 5-difluorobenzenesulfonyl chloride (327.0 mg) were weighed and suspended in pyridine (2 mL) and reacted at room temperature for 1 hour, TLC showed complete reaction of the starting materials. The system was quenched with water, extracted with ethyl acetate, the organic phases combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 245mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝377.0.

Example 1: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (7-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzamide

Step 1: preparation of 2- (tert-butyl) -7-methyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

N- (tert-butyl) -2- (2-hydroxyethyl) -5-methylbenzenesulfonamide (1.0 g) and triphenylphosphine (1.45 g) were dissolved in tetrahydrofuran (20 mL), diisopropyl azodicarboxylate (1.12 g) was slowly added dropwise at 0℃and the reaction was continued for 10min while maintaining the temperature. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product purified by column chromatography to give the title compound 0.8g.

MS(ESI)m/z(M+H) ⁺ ＝254.1.

Step 2: preparation of 7-methyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

2- (tert-butyl) -7-methyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (0.8 g) was weighed out and dissolved in trifluoroacetic acid (8 mL) and reacted at 75℃for 1 hour. TLC showed complete reaction, concentrated under reduced pressure, the residue was quenched by slowly dropping into water, extracted three times with ethyl acetate, the organic phases were combined, the organic phases were backwashed once each with saturated sodium carbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 0.4g.

MS(ESI)m/z(M+H) ⁺ ＝198.1.

Step 3: preparation of ethyl 3-fluoro-4- (7-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoate

7-methyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (100.0 mg) was dissolved in N, N-dimethylformamide (2 mL), ethyl 4-bromo-3-fluorobenzoate (400.0 mg), cesium carbonate (401.0 mg) and 2- (2-methyl-1-oxopropane) cyclohexanone (28.0 mg) were sequentially added at room temperature, the addition was completed, nitrogen was replaced three times, finally cuprous iodide (16 mg) was added, nitrogen was replaced three times again, and the system was reacted at 90℃for 2 hours. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 10mg.

MS(ESI)m/z(M+H) ⁺ ＝364.1.

Step 4: preparation of 3-fluoro-4- (7-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoic acid

Ethyl 3-fluoro-4- (7-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoate (10.0 mg) was weighed out in methanol (1 mL), an aqueous solution (0.2 mL) of sodium hydroxide (5.0 mg) was added at room temperature, and the reaction was continued at room temperature for 1 hour. TLC showed complete reaction, the system was concentrated, the residue was pH adjusted to 5 with 2.0M hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound 15.0mg was obtained and the crude product was used in the next step without purification.

MS(ESI)m/z(M-H) ^- ＝334.1.

Step 5: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (7-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzamide

3-fluoro-4- (7-methyl-1, 1-dihydro-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoic acid (15.0 mg) was dissolved in tetrahydrofuran (5 mL), N-diisopropylethylamine (29.0 mg) and O- (7-azobenzotriazol-1-yloxy) -N, N' -tetramethylurea hexafluorophosphate (26.0 mg) were added, and the mixture was reacted at room temperature for 30 minutes. (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethan-1-ol (12.0 mg) was added to the system, and the reaction was continued at room temperature for 1 hour after the addition. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to give the title compound 1.52mg.

MS(ESI)m/z(M+H) ⁺ ＝547.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.8Hz,1H),7.91–7.79(m,3H),7.71(dd,J＝8.4,1.9Hz,1H),7.67–7.58(m,3H),7.48–7.42(m,1H),7.36(dd,J＝15.9,8.0Hz,2H),5.14–5.06(m,2H),4.12(t,J＝6.3Hz,2H),3.70–3.64(m,2H),3.25(q,J＝7.3Hz,2H),3.12(t,J＝6.4Hz,2H),2.37(s,3H),1.09(t,J＝7.3Hz,3H).

Example 2: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (8-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) benzamide

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Step 1: preparation of 2-methoxy-5-methylbenzenesulfonyl chloride

Para-toluene methyl ether (5.0 g) was weighed into a reaction flask, chlorosulfonic acid (14.32 g) was slowly added dropwise to the system at 0 ℃, and after the addition, the reaction was continued at room temperature for 4 hours. TLC showed complete reaction, the system was slowly added dropwise to ice water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium carbonate solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound 7.2g was obtained and the crude product was used in the next step without purification.

Step 2: preparation of ethyl 3-fluoro-4- ((2-methoxy-5-methylphenyl) sulfonamide) benzoate

Ethyl 4-amino-3-fluorobenzoate (1.66 g) was weighed out and dissolved in pyridine (20 mL), 2-methoxy-5-methylbenzenesulfonyl chloride (4.0 g) was added to the system at room temperature, and the reaction was continued for 2 hours after the addition. TLC showed complete reaction, concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with 1.0M hydrochloric acid, the organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 2.5g.

MS(ESI)m/z(M+H) ⁺ ＝368.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.28(s,1H),7.69–7.61(m,2H),7.56(d,J＝2.2Hz,1H),7.46(t,J＝8.2Hz,1H),7.40(dd,J＝8.7,2.3Hz,1H),7.08(d,J＝8.5Hz,1H),4.26(q,J＝7.1Hz,2H),3.75(s,3H),2.25(s,3H),1.27(t,J＝7.1Hz,3H).

Step 3: preparation of ethyl 3-fluoro-4- ((2-hydroxy-5-methylphenyl) sulfonamide) benzoate

Ethyl 3-fluoro-4- ((2-methoxy-5-methylphenyl) sulfamido) benzoate (500.0 mg) was weighed out and dissolved in methylene chloride (10 mL), and boron tribromide (2.72mL,1.0M in Et) was slowly added dropwise to the system at 0 ℃ ₂ O), the reaction was continued for 1 hour while maintaining this temperature after the addition. TLC showed complete reaction, the system was slowly added dropwise to ice water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound 510.0mg was obtained and the crude product was used in the next step without purification.

MS(ESI)m/z(M+H) ⁺ ＝354.1.

Step 4: preparation of ethyl 3-fluoro-4- (8-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl benzoate

Ethyl 3-fluoro-4- ((2-hydroxy-5-methylphenyl) sulfamide) benzoate (100.0 mg) was dissolved in N, N-dimethylformamide (2 mL), cesium carbonate (456.0 mg) and 1, 2-dibromoethane (254.8 mg) were added at room temperature, and the system was reacted at 90℃for 4 hours after the addition. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, washed twice with pure water, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 40.0mg.

MS(ESI)m/z(M+H) ⁺ ＝380.1.

Step 5: preparation of 3-fluoro-4- (8-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) benzoic acid

Ethyl 3-fluoro-4- (8-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazolin-2-ylbenzoate (40.0 mg) was weighed out in methanol (3 mL), an aqueous solution (0.6 mL) of sodium hydroxide (21.0 mg) was added at room temperature, and the reaction was continued for 1 hour after the addition, TLC showed complete reaction, the system was concentrated under reduced pressure, the residue was adjusted to pH 5 with 2.0M hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, the organic phases were backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 30.0mg of the title compound, and the obtained crude product was directly used in the next step without purification.

MS(ESI)m/z(M-H) ^- ＝350.1.

Step 6: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (8-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) benzamide

3-fluoro-4- (8-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazolin-2-yl) benzoic acid (3.0 mg) was dissolved in tetrahydrofuran (3 mL), N-diisopropylethylamine (37.0 mg) and O- (7-azobenzotriazol-1-yloxy) -N, N' -tetramethylurea hexafluorophosphate (41.0 mg) were added at room temperature, and the reaction was continued for 30 minutes at room temperature. (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethan-1-ol (18.0 mg) was added to the system, and the reaction was continued for 1 hour after the addition. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined organic phases, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to give the title compound 5.0mg.

MS(ESI)m/z(M+H) ⁺ ＝563.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.92(d,J＝7.8Hz,1H),7.87–7.80(m,3H),7.69–7.61(m,3H),7.48–7.45(m,2H),7.25(d,J＝8.0Hz,1H),7.19(t,J＝8.0Hz,1H),5.13–5.04(m,2H),4.30(dd,J＝5.8,3.2Hz,2H),4.05(t,J＝4.3Hz,2H),3.74–3.63(m,2H),3.25(t,J＝7.3Hz,2H),2.34(s,3H),1.09(t,J＝7.3Hz,3H).

Example 3: preparation of (R) -4- (7-chloro-1, 1-dioxide-2H, 4H-spiro [ benzo [ b ] [1,4,5] oxathiazin-3, 1' -cyclopropan ] -2-yl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Step 1: preparation of (1-aminocyclopropyl) methoxide

Tert-butyl (1- (hydroxymethyl) cyclopropyl) carbamate (400.0 mg) was weighed into a reaction flask, dioxane hydrochloride solution (5 mL, 4.0M) was added, and the reaction was carried out at room temperature for 1 hour after the addition. After TLC showed complete reaction, the system was concentrated under reduced pressure. 400.0mg of the title compound was obtained and the crude product was used in the next step without purification.

Step 2: preparation of 4-chloro-2-fluoro-N- (1- (hydroxymethyl) cyclopropyl) benzenesulfonamide

4-chloro-2-fluorobenzenesulfonyl chloride (400.0 mg) was weighed and dissolved in methylene chloride (8 mL), triethylamine (720.0 mg) and (1-aminocyclopropyl) methanol hydrochloride (280.0 mg) were added in this order at room temperature, and the reaction was continued at room temperature for 1 hour after the addition. TLC showed complete reaction, quenched with water, extracted three times with dichloromethane, combined with the organic phases, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 0.4g.

MS(ESI)m/z(M+H) ⁺ ＝280.0.

Step 3: preparation of 7-chloro-2H, 4H-spiro [ benzo [ b ] [1,4,5] oxathiazine-3, 1' -cyclopropane ]1, 1-dioxide

4-chloro-2-fluoro-N- (1- (hydroxymethyl) cyclopropyl) benzenesulfonamide (280.0 mg) was dissolved in dimethyl sulfoxide (2 mL), potassium t-butoxide (168.9 mg) was added thereto, and the mixture was reacted at 80℃for 20 minutes by microwaves. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, backwashed with pure water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 220.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝260.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.42(s,1H),7.76(dd,J＝8.0,0.7Hz,1H),7.42–7.36(m,2H),4.00(s,2H),0.96–0.88(m,4H).

Step 4: preparation of ethyl 4- (7-chloro-1, 1-dioxide-2H, 4H-spiro [ benzo [ b ] [1,4,5] oxathiazin-3, 1' -cyclopropane ] -2-yl) -3-fluorobenzoate

7-chloro-2H, 4H-spiro [ benzo [ b ] [1,4,5] oxathiazin-3, 1' -cyclopropane ]1, 1-dioxide (20 mg) and cesium carbonate (53 mg) were weighed and suspended in N, N-dimethylformamide (1 mL), 2- (2-methyl-1-oxopropane) cyclohexanone (2.0 mg) and ethyl 4-bromo-3-fluorobenzoate (190.0 mg) were sequentially added at room temperature, nitrogen was replaced three times after the addition, cuprous iodide (1 mg) was added to the system, nitrogen was replaced three times again after the addition, and the system was reacted at 110℃for 2 hours. TLC showed complete reaction, the system was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 10mg.

MS(ESI)m/z(M+H) ⁺ ＝426.0.

Step 5: preparation of 4- (7-chloro-1, 1-dioxide-2H, 4H-spiro [ benzo [ b ] [1,4,5] oxathiazin-3, 1' -cyclopropane ] -2-yl) -3-fluorobenzoic acid

Ethyl 4- (7-chloro-1, 1-dioxide-2 h,4 h-spiro [ benzo [ b ] [1,4,5] oxathiazin-3, 1' -cyclopropane ] -2-yl) -3-fluorobenzoate (10.0 mg) was weighed out and dissolved in methanol (1 mL), an aqueous solution (0.2 mL) of sodium hydroxide (9.0 mg) was added, and the reaction was carried out at room temperature for 1 hour after the addition. TLC showed complete reaction, concentrated under reduced pressure, the residue was pH adjusted to 5 with 2.0M hydrochloric acid, extracted three times with ethyl acetate, the organic phases combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. 10.0mg of the title compound was obtained and the crude product was used in the next step without purification.

MS(ESI)m/z(M-H) ^- ＝396.0.

Step 6: preparation of (R) -4- (7-chloro-1, 1-dioxide-2H, 4H-spiro [ benzo [ b ] [1,4,5] oxathiazin-3, 1' -cyclopropan ] -2-yl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

4- (7-chloro-1, 1-dioxide-2H, 4H-spiro [ benzo [ b ] [1,4,5] oxathiazin-3, 1 '-cyclopropane ] -2-yl) -3-fluorobenzoic acid (10.0 mg) was dissolved in tetrahydrofuran (1 mL), N-diisopropylethylamine (6.0 mg) and O- (7-azobenzotriazole-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (12.0 mg) were added, and the reaction was carried out at room temperature for 30 minutes. (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethan-1-ol (6.3 mg) was added to the system, and the reaction was continued at room temperature for 1 hour. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to give the title compound 0.83mg.

MS(ESI)m/z(M+H) ⁺ ＝609.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.8Hz,1H),7.89–7.77(m,3H),7.72–7.51(m,5H),7.41(dd,J＝8.4,2.1Hz,1H),7.32(t,J＝8.0Hz,1H),5.12–5.04(m,2H),4.29(s,2H),3.73–3.64(m,2H),3.26(d,J＝7.3Hz,2H),1.23(s,4H),1.08(d,J＝7.3Hz,3H).

Example 4: preparation of 4- (3, 7-dimethyl-1, 1-dioxa-2-yl-3, 4-dihydro-2H-pyridinyl [2,3-b ] [1,4,5] oxaazepin-2-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Step 1: preparation of 3- (benzylthio) -2-chloro-6-methylpyridine

3-bromo-2-chloro-6-methylpyridine (1.0 g) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (214.0 mg) were weighed and suspended in toluene (10 mL), N-diisopropylethylamine (952.0 mg) and benzylmercaptan (0.5 g) were added, nitrogen was replaced three times, tris (dibenzylideneacetone) dipalladium (169.0 mg) was added, nitrogen was replaced three times again after the addition, and the system was reacted at 100℃for 2 hours. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 550mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝250.0.

Step 2: preparation of 2-chloro-6-methylpyridine-3-sulfonyl chloride

3- (benzylthio) -2-chloro-6-methylpyridine (400.0 mg) was weighed and dissolved in acetonitrile (8 mL), hydrochloric acid (0.4 mL, 2.0M) and N-chlorosuccinimide (644 mg) were sequentially added to the system at 0℃and the reaction was continued for 10 minutes at this temperature. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. 400mg of the title compound was obtained and the crude product was used in the next step without purification.

MS(ESI)m/z(M+H) ⁺ ＝226.0.

Step 3: preparation of ethyl 4- ((2-chloro-6-methylpyridine) -3-sulfonylamino) -3-fluorobenzoate

Ethyl 4-amino-3-fluorobenzoate (292.0 mg) was dissolved in pyridine (8 mL), and 2-chloro-6-methylpyridine-3-sulfonyl chloride (400.0 mg) was added thereto, followed by reaction at room temperature for 4 hours. TLC showed complete reaction, concentrated under reduced pressure, the residue was dissolved with ethyl acetate, washed with 1.0M hydrochloric acid, the organic phase was backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 330mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝373.0.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.16(s,1H),8.24(d,J＝8.0Hz,1H),7.77–7.63(m,2H),7.49–7.38(m,2H),4.27(q,J＝7.1Hz,2H),2.52(s,3H),1.28(t,J＝7.1Hz,3H).

Step 4: preparation of ethyl 4- ((N- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -2-chloro-6-methylpyridine) -3-sulfonylaminoethyl-3-fluorobenzoate

Ethyl 4- ((2-chloro-6-methylpyridine) -3-sulfonylamino) -3-fluorobenzoate (200.0 mg) and triphenylphosphine (704.0 mg) were dissolved in tetrahydrofuran (10 mL), 1- ((tert-butyldimethylsilyl) oxy) propan-2-ol was added, diisopropyl azodicarboxylate (543.0 mg) was slowly added dropwise at 0℃and the reaction was resumed at room temperature after the addition for 6 hours. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 0.4g.

MS(ESI)m/z(M+H) ⁺ ＝545.1.

Step 5: preparation of ethyl 4- (3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate

Ethyl 4- ((N- (1- ((tert-butyldimethylsilyl) oxy) prop-2-yl) -2-chloro-6-methylpyridine) -3-sulfonylaminoethyl-3-fluorobenzoate (150.0 mg) was weighed out in tetrahydrofuran (2 mL), tetrabutylammonium fluoride (1 m,0.41 mL) was added and reacted at Bi Weibo ℃ for 25 minutes, TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, the organic phases combined, the organic phase saturated sodium chloride solution backwashed once, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product obtained was purified by Prep-HPLC to afford 30.00mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝395.1.

Step 6: preparation of 4- (3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridinyl [2,3-b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoic acid

Ethyl 4- (3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate (30.0 mg) was weighed out and dissolved in methanol (3 mL), an aqueous solution (0.6 mL) of sodium hydroxide (30.0 mg) was added, and the reaction was carried out at room temperature for 1 hour after the addition. TLC showed complete reaction, concentrated under reduced pressure, the residue was pH adjusted to 5 with 2.0M hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound 30.0mg, and the crude product was used in the next step without purification.

MS(ESI)m/z(M-H) ^- ＝365.1.

Step 7: preparation of 4- (3, 7-dimethyl-1, 1-dioxa-2-yl-3, 4-dihydro-2H-pyridinyl [2,3-b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Crude 4- (3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridinyl [2,3-b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoic acid (30.0 mg) was weighed out and dissolved in tetrahydrofuran (2 mL), N-diisopropylethylamine (21.0 mg) and O- (7-azobenzotriazole-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (47.0 mg) were added, and the reaction was carried out at room temperature for 5 minutes. (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethan-1-ol (19 mg) was added to the system, and the reaction was continued at room temperature for 40 minutes. TLC showed complete reaction, quenched with water, extracted three times with ethyl acetate, combined with the organic phase, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Prep-HPLC and freeze-dried to give the title compound 30.2mg.

MS(ESI)m/z(M+H) ⁺ ＝578.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.8Hz,1H),7.96(d,J＝7.8Hz,1H),7.85–7.80(m,J＝8.9,2.1Hz,3H),7.69–7.61(m,3H),7.30(t,J＝8.0Hz,1H),7.19(d,J＝7.9Hz,1H),5.13–5.05(m,2H),4.61-4.59(m,2H),4.45-4.43(m,1H),3.78–3.61(m,2H),3.25(q,J＝8.1,2H),2.48(s,3H),1.20(d,J＝24.6Hz,3H),1.08(d,J＝7.4Hz,3H).

Example 5: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (6-methyl-1, 1-dioxabenzo [ e ] [1,4,3] oxathiazin-2 (3H) -yl) benzamide

Step 1: preparation of ethyl 4- (7-bromo-6-methyl-1, 1-dioxobenzo [ e ] [1,4,3] oxathiazin-2 (3H) -yl) -3-fluorobenzoate

Ethyl 4- ((5-bromo-2-hydroxy-4-methylphenyl) sulfonamide) -3-fluorobenzoate (100.0 mg) and potassium carbonate (95.0 mg) were weighed out and dissolved in N, N-dimethylformamide (2 mL), diiodomethane (123.0 mg) was added, and the system was reacted at 100 ℃ for 1 hour, TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate three times, combining the organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure to give 100.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝444.0.

Step 2: preparation of ethyl 3-fluoro-4- (6-methyl-1, 1-dibenzo [ e ] [1,4,3] oxathiazin-2 (3H) -yl) benzoate

Ethyl 4- (7-bromo-6-methyl-1, 1-dioxobenzo [ e ] [1,4,3] oxathiolan-2 (3H) -yl) -3-fluorobenzoate (100.0 mg) was weighed into methanol (20 mL), 10% palladium on carbon (40.0 mg) was added, hydrogen was replaced three times, and the system was reacted at 60 ℃ for 1 hour, LCMS showed complete reaction of the starting material. Filtering to obtain filtrate, and concentrating under reduced pressure. The title compound 81.0mg was obtained and used in the next step without further purification.

MS(ESI)m/z(M+H) ⁺ ＝366.1.

Step 3: preparation of 3-fluoro-4- (6-methyl-1, 1-dibenzo [ e ] [1,4,3] oxathiazin-2 (3H) -yl) benzoic acid

Ethyl 3-fluoro-4- (6-methyl-1, 1-dibenzo [ e ] [1,4,3] oxathiolan-2 (3H) -yl) benzoate (81.0 mg) was weighed out and dissolved in methanol (5 mL), an aqueous solution (1 mL) of sodium hydroxide (36.0 mg) was added, and the reaction was carried out at room temperature for 1 hour, wherein TLC showed that the reaction of the starting material was complete. Adding water, adjusting pH to 3-4 with 2.0M hydrochloric acid, extracting with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The title compound 71.0mg was obtained and used in the next step without further purification.

MS(ESI)m/z(M-H) ^- ＝336.1.

Step 4: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (6-methyl-1, 1-dioxabenzo [ e ] [1,4,3] oxathiazin-2 (3H) -yl) benzamide

3-fluoro-4- (6-methyl-1, 1-dibenzoxaprop-2 (3H) -yl) benzoic acid (30.0 mg), O- (7-azobenzotriazol-1-yloxy) -N, N' -tetramethylurea hexafluorophosphate (51.0 mg) were weighed into tetrahydrofuran (3 mL), N-diisopropylethylamine (34.0 mg), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (20.0 mg) was added in this order, and the reaction was carried out at room temperature for 1 hour after addition, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-TLC and Prep-HPLC and freeze-dried to give 35.1mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝549.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(d,J＝7.8Hz,1H),7.92(dd,J＝10.8,2.0Hz,1H),7.84(d,J＝8.4Hz,2H),7.77–7.71(m,1H),7.65(d,J＝8.2Hz,3H),7.51–7.43(m,1H),7.13–7.04(m,2H),6.02(s,2H),5.16–5.06(m,2H),3.79–3.67(m,2H),3.26(q,J＝7.3Hz,2H),2.37(s,3H),1.09(t,J＝7.3Hz,3H).

Example 6: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (6-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzamide

Step 1: preparation of 6-methyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

1, 1-Di-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-6-yl trifluoromethane sulfonate (500.0 mg), potassium methyltrifluoroborate (369.0 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (110.0 mg) and potassium phosphate (960.0 mg) were weighed and suspended in dioxane/water (5 mL/1 mL), the system was reacted at 90℃for 3 hours, and TLC showed that the reaction of the starting materials was completed. Quenched with water, extracted three times with ethyl acetate, the combined organic phases dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product purified by column chromatography and Prep-HPLC to afford the title compound 210.0mg.

MS(ESI)m/z(M+H) ⁺ ＝198.0.

Step 2: preparation of ethyl 3-fluoro-4- (6-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoate

6-methyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (50.0 mg), cuprous iodide (24.0 mg), cesium carbonate (248.0 mg), ethyl 4-bromo-3-fluorobenzoate (125 mg) and 2- (2-methyl-1-oxopropane) cyclohexanone (21 mg) were weighed and suspended in N, N-dimethylformamide (3 mL), nitrogen was replaced three times, and the system was reacted at 90℃for 3 hours, and TLC showed complete consumption of the starting material. Quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product obtained was purified by column chromatography to give 80.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝364.1.

Step 3: preparation of 3-fluoro-4- (6-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoic acid

Ethyl 3-fluoro-4- (6-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoate (80.0 mg) was weighed out and dissolved in methanol (3 mL), an aqueous solution (0.5 mL) of sodium hydroxide (35.0 mg) was added, and the reaction was carried out at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. The system was added with water, pH was adjusted to 3-4 with 2.0M hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 72.0mg of the title compound.

MS(ESI)m/z(M-H) ^- ＝334.1.

Step 4: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (6-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzamide

3-fluoro-4- (6-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoic acid (35.0 mg), O- (7-azobenzotriazol-1-yloxy) -N, N' -tetramethylurea hexafluorophosphate (60.0 mg) were weighed into tetrahydrofuran (4 mL), N-diisopropylethylamine (40.0 mg), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (37.0 mg) was added in this order, and reacted at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, ethyl acetate extraction three times, combining organic phases, organic phase backwash once with saturated sodium chloride solution, anhydrous sodium sulfate drying, decompression concentration, the crude purification by Prep-TLC and Prep-HPLC, the title compound 22.1mg.

MS(ESI)m/z(M+H) ⁺ ＝547.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,J＝7.8Hz,1H),7.92–7.79(m,3H),7.75–7.61(m,4H),7.40–7.26(m,3H),5.18–5.04(m,2H),4.13(t,J＝6.3Hz,2H),3.79–3.63(m,2H),3.27(q,J＝7.3Hz,2H),3.13(t,J＝6.3Hz,2H),2.38(s,3H),1.09(t,J＝7.3Hz,3H).

Example 7: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-methyl-4- (7-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) benzamide

The preparation was similar to that used in example 5 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.80(d,J＝7.9Hz,1H),7.86(s,1H),7.84–7.79(m,2H),7.63(d,J＝8.2Hz,2H),7.59–7.50(m,2H),7.21(dd,J＝1.7,0.8Hz,1H),7.15(ddd,J＝7.8,1.7,0.8Hz,1H),6.80(d,J＝8.3Hz,1H),5.10(q,J＝7.0Hz,1H),5.03(t,J＝5.9Hz,1H),4.48(d,J＝13.3Hz,1H),4.34(t,J＝12.7Hz,1H),4.16(t,J＝11.6Hz,1H),3.75–3.62(m,2H),3.54(d,J＝15.3Hz,1H),3.26(q,J＝7.3Hz,2H),2.40(s,3H),2.38(s,3H),1.09(t,J＝7.3Hz,3H).

Example 8: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (7-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) benzamide

The preparation was similar to that used in example 5 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.93(d,J＝7.8Hz,1H),7.86–7.80(m,3H),7.67–7.61(m,3H),7.57(d,J＝8.0Hz,1H),7.21–7.13(m,3H),5.12–5.04(m,2H),4.32(dd,J＝5.6,3.2Hz,2H),4.09–4.02(m,2H),3.74–3.63(m,2H),3.26(q,J＝7.3Hz,2H),2.39(s,3H),1.09(t,J＝7.3Hz,3H).

Example 9: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (6-methyl-1, 1-dioxide-2H-benzo [ e ] [1,2] thiazin-2-yl) benzamide

Step 1: preparation of 2- (tert-butyl) -6-methyl-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

N- (tert-butyl) -2- (2-hydroxyethyl) -4-methylbenzenesulfonamide (0.93 g) was dissolved in methylene chloride (15 mL), pyridinium chlorochromate (1.48 g) was added and reacted at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 610.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝252.0.

Step 2: preparation of 6-methyl-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

2- (tert-butyl) -6-methyl-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (610.0 mg) was weighed out in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added and the system was reacted at 40℃for 1 hour, and TLC showed complete reaction of the starting material. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 310.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝196.0.

Step 3: preparation of ethyl 3-fluoro-4- (6-methyl-1, 1-dioxide-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoate

6-methyl-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (310.0 mg), (4- (ethoxycarbonyl) -2-fluorophenyl) boric acid (1.69 g), copper acetate (289.0 mg) were weighed out and suspended in methylene chloride (20 mL), pyridine (628.0 mg) was added, oxygen was replaced three times, and the reaction was carried out at room temperature overnight, and LCMS showed complete reaction of the starting materials. Water quenching, extraction with dichloromethane three times, combining the organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 20.0mg.

MS(ESI)m/z(M+H) ⁺ ＝362.1.

Step 4: preparation of 3-fluoro-4- (6-methyl-1, 1-dioxide-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoic acid

Ethyl 3-fluoro-4- (6-methyl-1, 1-dioxide-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoate (20.0 mg) was weighed out and dissolved in methanol (5 mL), an aqueous solution (1 mL) of sodium hydroxide (11.0 mg) was added, and the reaction was carried out at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. The system was taken up in water, pH was adjusted to 3-4 with 2.0M hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound 20.0mg, which was used directly in the next step without further purification.

MS(ESI)m/z(M-H) ^- ＝332.1.

Step 5: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (6-methyl-1, 1-dioxide-2H-benzo [ e ] [1,2] thiazin-2-yl) benzamide

3-fluoro-4- (6-methyl-1, 1-dioxide-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoic acid (20.0 mg), O- (7-azobenzotriazol-1-yloxy) -N, N' -tetramethylurea hexafluorophosphate (31.0 mg) was dissolved in tetrahydrofuran (3 mL), and N, N-diisopropylethylamine (34.0 mg), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (11.0 mg) was added in this order, and reacted at room temperature for 1 hour, whereby TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-TLC and Prep-HPLC and lyophilized to give 21.5mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝545.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.05(d,J＝7.8Hz,1H),7.96(dd,J＝10.9,1.9Hz,1H),7.89–7.81(m,3H),7.79(d,J＝8.1Hz,1H),7.71–7.64(m,2H),7.55–7.49(m,2H),7.47–7.42(m,1H),7.04(dd,J＝7.8,0.8Hz,1H),6.61(d,J＝7.8Hz,1H),5.18–5.08(m,2H),3.79–3.67(m,2H),3.27(q,J＝7.4Hz,2H),2.45(s,3H),1.10(t,J＝7.3Hz,3H).

Example 10: preparation of (R) -4- (6-chloro-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -N- (1- (4- (ethanesulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 1 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(d,J＝7.8Hz,1H),7.88–7.80(m,4H),7.72(dd,J＝8.3,1.9Hz,1H),7.65(d,J＝8.2Hz,3H),7.57(dd,J＝8.5,2.1Hz,1H),7.39(t,J＝8.1Hz,1H),5.16–5.04(m,2H),4.15(t,J＝6.3Hz,2H),3.78–3.68(m,2H),3.26(q,J＝7.3Hz,2H),3.19(t,J＝6.4Hz,2H),1.09(t,J＝7.3Hz,3H).

Example 11: preparation of (R) -4- (7-chloro-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Step 1: preparation of ethyl 4- ((4-chloro-2-hydroxyphenyl) sulphonamido) -3-fluorobenzoate

Ethyl 4- ((4-chloro-2-methoxyphenyl) sulfamido) -3-fluorobenzoate (410 mg) was weighed out in dichloromethane (10 mL), boron tribromide (4.67 g) was added at room temperature and the reaction was completed by TLC for 1 hour. Adding water for quenching, adjusting the pH to 3-4 by using 2.0M hydrochloric acid, extracting with ethyl acetate for three times, combining organic phases, backwashing the organic phases once by using saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 40.0mg.

MS(ESI)m/z(M+H) ⁺ ＝374.0.

Step 2: preparation of ethyl 4- (7-chloro-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate

Ethyl 4- ((4-chloro-2-hydroxyphenyl) sulphonamido) -3-fluorobenzoate (40.0 mg) and potassium carbonate (95.0 mg) were weighed into N, N-dimethylformamide (2 mL), dibromoethane (123.0 mg) was added and the system was reacted at 80 ℃ for 1 hour, TLC indicated complete reaction of starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 40.0mg.

MS(ESI)m/z(M+H) ⁺ ＝400.0.

Step 3: preparation of 4- (7-chloro-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoic acid

Ethyl 4- (7-chloro-1, 1-dihydro-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate (40.0 mg) was weighed and dissolved in methanol (5 mL), an aqueous solution (1 mL) of sodium hydroxide (36.0 mg) was added, and the reaction was carried out at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, 2.0M hydrochloric acid adjusting pH to 3-4, extraction three times with ethyl acetate, combining ethyl acetate, backwashing the organic phase once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, concentrating under reduced pressure to give 35.0mg of the title compound, which is used directly in the next step without further purification.

MS(ESI)m/z(M-H) ^- ＝370.1.

Step 4: preparation of (R) -4- (7-chloro-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

4- (7-chloro-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazolin-2-yl) -3-fluorobenzoic acid (30.0 mg), O- (7-azobenzotriazol-1-yloxy) -N, N' -tetramethylurea hexafluorophosphate (51.0 mg) were weighed into tetrahydrofuran (3 mL), N-diisopropylethylamine (34.0 mg), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (20.0 mg) was added in this order, and reacted at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-TLC and Prep-HPLC and freeze-dried to give 35.1mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝583.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.94(d,J＝7.8Hz,1H),7.87–7.80(m,3H),7.71–7.60(m,4H),7.52(d,J＝2.1Hz,1H),7.43(dd,J＝8.5,2.1Hz,1H),7.28(t,J＝8.0Hz,1H),5.14–5.04(m,2H),4.40(dd,J＝5.6,3.3Hz,2H),4.09–4.07(m,2H),3.74–3.65(m,2H),3.25(t,J＝7.3Hz,2H),1.09(t,J＝7.3Hz,3H).

Example 12: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (8-methyl-1, 1-dioxide-4, 5-dihydrobenzo [ b ] [1,4,5] oxathiolazol-2-2 (3H) -yl) benzamide

The preparation was similar to that used in example 5 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.91(d,J＝7.8Hz,1H),7.85–7.78(m,3H),7.64(dd,J＝8.5,2.0Hz,3H),7.56(d,J＝8.0Hz,1H),7.35(t,J＝1.0Hz,1H),7.18–7.11(m,1H),6.96(t,J＝8.0Hz,1H),5.14–5.03(m,2H),4.32(t,J＝6.4Hz,2H),4.09–3.99(m,2H),3.74–3.65(m,2H),3.25(q,J＝8.0Hz,2H),2.41(s,3H),1.77–1.74(m,2H),1.09(t,J＝7.3Hz,3H).

Example 13: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (7-fluoro-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzamide

Step 1: preparation of ethyl 3-fluoro-4- ((5-fluoro-2- (2-hydroxyethyl) phenyl) sulfonamide) benzoate

Ethyl 4- ((2- (2- (benzyloxy) ethyl) -5-fluorophenyl) sulfonamide) -3-fluorobenzoate (100.0 mg) was weighed into methanol (20 mL), 10% palladium on carbon (20.0 mg) was added, hydrogen was replaced three times, and reaction was performed at room temperature for 1 hour, LCMS showed complete reaction of starting materials. Filtering to obtain filtrate, washing filter cake with methanol, collecting filtrate, and concentrating under reduced pressure. The title compound 77.0mg was obtained and used in the next step without further purification.

MS(ESI)m/z(M+H) ⁺ ＝386.0.

Step 2: preparation of ethyl 3-fluoro-4- (7-fluoro-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoate

Ethyl 3-fluoro-4- ((5-fluoro-2- (2-hydroxyethyl) phenyl) sulfonamide) benzoate (77.0 mg) and triphenylphosphine (210.0 mg) were weighed and dissolved in tetrahydrofuran (10 mL), diisopropyl azodicarboxylate (162.0 mg) was slowly added dropwise at 0 ℃, after the addition was completed, the reaction was resumed at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 61.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝368.0.

Step 3: preparation of 3-fluoro-4- (7-fluoro-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoic acid

Ethyl 3-fluoro-4- (7-fluoro-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoate (61.0 mg) was weighed out and dissolved in methanol (5 mL), an aqueous solution (1 mL) of sodium hydroxide (36.0 mg) was added, and the reaction was carried out at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, 2.0M hydrochloric acid regulating pH to 3-4, extraction with ethyl acetate three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 54.0mg of the title compound.

MS(ESI)m/z(M-H) ^- ＝338.0.

Step 4: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (7-fluoro-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzamide

3-fluoro-4- (7-fluoro-1, 1-dihydro-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) benzoic acid (54.0 mg), O- (7-azobenzotriazol-1-yloxy) -N, N' -tetramethylurea hexafluorophosphate (84.0 mg) were weighed into tetrahydrofuran (3 mL), N-diisopropylethylamine (34.0 mg) and (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (51.0 mg) were sequentially added, and reacted at room temperature for 1 hour, whereby TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-TLC and Prep-HPLC and frozen to give 25.1mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝551.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.8Hz,1H),7.88–7.81(m,3H),7.74–7.71(m,1H),7.69–7.63(m,3H),7.60–7.53(m,2H),7.38(t,J＝8.0Hz,1H),5.14–5.05(m,2H),4.15(t,J＝6.4Hz,2H),3.76–3.65(m,2H),3.26(q,J＝7.3Hz,2H),3.16(t,J＝6.4Hz,2H),1.09(t,J＝7.3Hz,3H).

Example 14: preparation of (R) -4- (7-chloro-8-fluoro-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxadiazol-2-yl) -N- (1- (4- (ethylsulphonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 11 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.9Hz,1H),7.88–7.81(m,3H),7.74(d,J＝6.2Hz,1H),7.70–7.62(m,4H),7.33(t,J＝8.1Hz,1H),5.13–5.04(m,2H),4.37(t,J＝4.4Hz,2H),4.09(t,J＝4.4Hz,2H),3.75–3.64(m,2H),3.26(q,J＝7.4Hz,2H),1.09(t,J＝7.3Hz,3H).

Example 15: preparation of 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) -N- ((R-1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Step 1: preparation of ethyl 3-fluoro-4- (6-hydroxy-3-methyl-1, 1-dioxido-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) benzoate

Ethyl 3-fluoro-4- (6-methoxy-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) benzoate (405.0 mg) was weighed out and dissolved in acetonitrile (10 mL), trimethyliodosilane (411.0 mg) was added at room temperature, and the reaction was continued for 6 hours after the addition, and TLC showed complete reaction of the starting materials. The system was quenched with sodium thiosulfate solution, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 360mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝381.0.

Step 2: preparation of ethyl 3-fluoro-4- (3-methyl-1, 1-dioxido-6- ((((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl ] benzoate

6-hydroxy-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (360.0 mg) was dissolved in dichloromethane (10 mL), N-phenyl bis (trifluoromethanesulfonyl) imide (507.0 mg) and triethylamine (106.0 mg) were added in this order at room temperature, and the reaction was continued for 30 minutes at this temperature, and TLC showed that the reaction of the starting materials was completed. The system was quenched by addition of saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 485.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝513.0.

Step 3: preparation of ethyl 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) -3-fluorobenzoate

Ethyl 3-fluoro-4- (3-methyl-1, 1-dioxo-6- ((((trifluoromethyl) sulphonyl) oxy) -3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl ] benzoate (100.0 mg), potassium methyltrifluoroborate (49.0 mg), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (11.0 mg), potassium phosphate (96.0 mg) were weighed and suspended in dioxane/water (5 mL/1 mL), nitrogen was displaced three times, the system was reacted at 90 ℃ for 1 hour, TLC showed that the starting material was reacted, quenched with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to give 77.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝379.1.

Step 4: preparation of 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) -3-fluorobenzoic acid

Ethyl 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) -3-fluorobenzoate (77.0 mg) was weighed out and dissolved in methanol (5 mL), an aqueous solution (1 mL) of sodium hydroxide (36.0 mg) was added at room temperature, and the reaction was completed for 1 hour by TLC, indicating complete reaction of the starting materials. Water quenching, 2.0M hydrochloric acid pH adjustment to neutral, ethyl acetate extraction three times, combining the organic phases, backwash the organic phase once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, vacuum concentrating to get the title compound 60.0mg, which is used directly in the next step without further purification.

MS(ESI)m/z(M+H) ⁺ ＝351.1.

Step 5: preparation of 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) -N- ((R-1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) -3-fluorobenzoic acid (13.0 mg), O- (7-azobenzotriazol-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (25.0 mg) were dissolved in tetrahydrofuran (3 mL), N-diisopropylethylamine (17.0 mg), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (15.0 mg) was added in this order, and the reaction was carried out at room temperature for 30 minutes, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-TLC and Prep-HPLC and lyophilized to give the title compound 13.2mg.

MS(ESI)m/z(M+H) ⁺ ＝562.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(d,J＝7.8Hz,1H),8.06(d,J＝8.1Hz,1H),7.87–7.79(m,3H),7.73–7.64(m,3H),7.41(d,J＝8.1Hz,1H),7.31(t,J＝8.0Hz,1H),5.13–5.07(m,2H),4.57–4.45(m,1H),3.75–3.68(m,2H),3.28–3.23(m,3H),3.17–3.08(m,1H),2.57(s,3H),1.23(d,J＝6.5Hz,3H),1.09(t,J＝7.3Hz,3H).

Example 16: preparation of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (6-methoxy-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-pyrido [2,3-e ] [1,2] thiazin-2-yl) benzamide

Step 1: preparation of 3-fluoro-4- (6-methoxy-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-pyridinyl [2,3-e ] [1,2] thiazin-2-yl) benzoic acid

Ethyl 3-fluoro-4- (6-methoxy-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [2,3-e ] [1,2] thiazin-2-yl) benzoate (40.0 mg) was weighed out and dissolved in methanol (5 mL), an aqueous solution (1 mL) of sodium hydroxide (36.0 mg) was added and reacted at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. The pH was adjusted to neutrality with 2.0M hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 35.0mg of the title compound, which was used in the next step without further purification.

MS(ESI)m/z(M+H) ⁺ ＝367.1.

Step 2: preparation of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (6-methoxy-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-pyrido [2,3-e ] [1,2] thiazin-2-yl) benzamide

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3-fluoro-4- (6-methoxy-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-pyridinyl [2,3-e ] [1,2] thiazin-2-yl) benzoic acid (35.0 mg), O- (7-azobenzotriazol-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (25.0 mg) were dissolved in tetrahydrofuran (3 mL), and N, N-diisopropylethylamine (17.0 mg), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (22.0 mg) was added in this order, and reacted at room temperature for 1 hour, whereby TLC showed the completion of the starting material reaction. Water quenching, ethyl acetate extraction three times, combining organic phases, organic phase backwash once with saturated sodium chloride solution, anhydrous sodium sulfate drying, vacuum concentration, purification of the crude product by Prep-TLC and Prep-HPLC, freeze drying to get the title compound 15.5mg.

MS(ESI)m/z(M+H) ⁺ ＝578.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.98(d,J＝7.8Hz,1H),8.06(d,J＝8.7Hz,1H),7.89–7.80(m,3H),7.75–7.69(m,1H),7.69–7.62(m,2H),7.32(t,J＝8.0Hz,1H),6.93(d,J＝8.7Hz,1H),5.15–5.05(m,2H),4.61–4.52(m,1H),3.95(s,3H),3.76–3.64(m,2H),3.26(q,J＝8.0Hz,2H),3.17–3.03(m,2H),1.20(d,J＝6.6Hz,3H),1.09(t,J＝7.3Hz,3H).

Example 17: preparation of 4- (3, 7-dimethyl-1, 1-dioxide-4, 5-dihydrobenzo [ f ] [1,2] thiazolin-2 (3H) -yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 16 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.93(d,J＝7.8Hz,1H),7.91–7.72(m,3H),7.64(d,J＝8.3Hz,2H),7.49(brs,1H),7.43–7.33(m,2H),7.21–7.13(m,1H),6.43(brs,1H),5.14–5.02(m,2H),4.66(brs,1H),3.76–3.54(m,3H),3.26(q,J＝7.3Hz,2H),3.09–3.01(m,1H),2.38(s,3H),1.98–1.92(m,1H),1.70(brs,1H),1.12–1.04(m,3H),0.90(d,J＝6.7Hz,3H).

Example 18: preparation of 4- (3, 7-dimethyl-1, 1-dioxo-3, 4-dihydro-2H-pyridine [4,3-b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (4- (ethylsulphonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Step 1: preparation of ethyl 4- ((N- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -4-chloro-6-methylpyridine) -3-sulfonylaminoethyl-3-fluorobenzoate

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Ethyl 4- ((4-chloro-6-methylpyridine) -3-sulfonylamino) -3-fluorobenzoate (200.0 mg), triphenylphosphine (420.0 mg), 1- ((tert-butyldimethylsilyl) oxy) propan-2-ol (376.0 mg) were weighed out in tetrahydrofuran (10 mL), diisopropyl azodicarboxylate (322.0 mg) was added at room temperature and the system reacted at 60℃for 20 minutes, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 220.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝545.0.

Step 2: preparation of ethyl 4- (3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-pyridine [4,3-b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate

Ethyl 4- ((N- (1- ((tert-butyldimethylsilyl) oxy) prop-2-yl) -4-chloro-6-methylpyridine) -3-sulfonylaminoethyl-3-fluorobenzoate (220.0 mg) was weighed out and dissolved in tetrahydrofuran (15 mL), tetrabutylammonium fluoride (0.55 mL) was added and the system reacted at 90 ℃ for 20 min by microwave, TLC showed complete reaction of the starting materials, quenched by water, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product obtained was purified by column chromatography to afford the title compound 51.0mg.

MS(ESI)m/z(M+H) ⁺ ＝395.0.

Step 3: preparation of 4- (3, 7-dimethyl-1, 1-dioxo-3, 4-dihydro-2H-pyridine [4,3-b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoic acid

Ethyl 4- (3, 7-dimethyl-1, 1-dioxo-3, 4-dihydro-2H-pyridine [4,3-b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate (51.0 mg) was weighed and dissolved in methanol (5 mL), an aqueous solution (1 mL) of sodium hydroxide (36.0 mg) was added and reacted at room temperature for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, adjusting pH to neutrality with 2.0M hydrochloric acid, extracting with ethyl acetate three times, mixing organic phases, backwashing the organic phases with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to give 30.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝367.1.

Step 4: preparation of 4- (3, 7-dimethyl-1, 1-dioxo-3, 4-dihydro-2H-pyridine [4,3-b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (4- (ethylsulphonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

4- (N, 4-Dimethylcyclohexanesulfonamido) -3-fluorobenzoic acid (15.0 mg), O- (7-azobenzotriazol-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (23.0 mg) were dissolved in tetrahydrofuran (5 mL), N-diisopropylethylamine (26.0 mg) and (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (9.0 mg) were added in this order, and the reaction was carried out at room temperature for 1 hour after the addition, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-TLC and Prep-HPLC and freeze-dried to give the title compound 6.7mg.

MS(ESI)m/z(M+H) ⁺ ＝578.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,J＝7.8Hz,1H),8.54(s,1H),7.88–7.77(m,3H),7.73–7.67(m,1H),7.67–7.60(m,2H),7.42–7.22(m,1H),7.17(s,1H),5.15–5.04(m,2H),4.82(brs,1H),4.72–4.63(m,1H),4.34(brs,1H),3.69(brs,2H),3.25(q,J＝8.0Hz,2H),2.49(s,3H),1.22(d,J＝6.5Hz,3H),1.09(t,J＝7.3Hz,3H).

Example 19: preparation of 4- ((S) -3, 7-dimethyl-1, 1-dioxo-3, 4-dihydro-2H-pyridine [4,3-b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (4- (ethylsulphonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 18 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,J＝7.8Hz,1H),8.54(s,1H),7.88–7.77(m,3H),7.73–7.67(m,1H),7.67–7.60(m,2H),7.42–7.22(m,1H),7.17(s,1H),5.15–5.04(m,2H),4.82(brs,1H),4.72–4.63(m,1H),4.34(brs,1H),3.69(brs,2H),3.25(q,J＝7.3Hz,2H),2.49(s,3H),1.22(d,J＝6.5Hz,3H),1.09(t,J＝7.3Hz,3H).

Example 20: preparation of (R) -4- (6-ethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -N- (1- (4- (ethanesulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Step 1: preparation of 6-vinyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

1, 1-Di-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-6-yl triflate (70.0 mg), ethylene potassium trifluoroborate salt (30 mg), potassium carbonate (82 mg) and tetraphenylpalladium phosphate (12 mg) were weighed and suspended in dioxane/water (2 mL/0.4 mL), argon was replaced three times, and the system was reacted at 100℃for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 40.0mg.

MS(ESI)m/z(M+H) ⁺ ＝210.1.

Step 2: preparation of 6-ethyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide

6-vinyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (40.0 mg) was weighed into methanol (3 mL), palladium on carbon (12.0 mg) was slowly added in portions, hydrogen was replaced three times, and the reaction was carried out at room temperature for 1 hour, and TLC showed complete consumption of raw materials. Filtering to obtain filtrate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 26.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝212.1.

Step 3: preparation of ethyl 4- (6-ethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoate

6-ethyl-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazine 1, 1-dioxide (75.0 mg), ethyl 4-bromo-3-fluorobenzoate (450.0 mg), cesium carbonate (350.0 mg) were dissolved in N, N-dimethylformamide (2.0 mL), replaced with argon three times, cuprous iodide (8.0 mg) and 2- (2-methyl-1-oxopropane) cyclohexanone (6 mg) were sequentially added, replaced with argon three times again, the system was reacted at 100℃for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 20.0mg.

MS(ESI)m/z(M+H) ⁺ ＝378.1.

Step 4: preparation of 4- (6-ethyl-1, 1-dioxido-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoic acid

Ethyl 4- (6-ethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoate (26.0 mg) was weighed out and dissolved in methanol/water (2.0 mL/0.4 mL), sodium hydroxide (55.0 mg) was added and reacted at room temperature for 2 hours, and TLC showed complete consumption of the starting material. The pH was adjusted to 5-6 with 2.0M hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 20.0mg.

MS(ESI)m/z(M+H) ⁺ ＝350.1.

Step 5: preparation of (R) -4- (6-ethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -N- (1- (4- (ethanesulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

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4- (6-Ethyl-1, 1-dihydro-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoic acid (20.0 mg), O- (7-azobenzotriazol-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (68.0 mg) were weighed into tetrahydrofuran (2 mL), N-diisopropylethylamine (60.0 mg) and (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethan-1-ol (26.0 mg) were sequentially added, and the reaction was completed at room temperature after the addition for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to give the title compound 1.4mg.

MS(ESI)m/z(M+H) ⁺ ＝561.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(d,J＝7.8Hz,1H),7.85(dd,J＝11.2,8.9Hz,3H),7.75–7.60(m,4H),7.41–7.29(m,3H),5.14–5.06(m,2H),4.13(t,J＝6.3Hz,2H),3.70(dq,J＝11.1,6.0,5.3Hz,2H),3.26(q,J＝7.4Hz,2H),3.15(t,J＝6.3Hz,2H),2.69(q,J＝1.4Hz,2H),1.21(t,J＝7.6Hz,3H),1.09(t,J＝7.3Hz,3H).

Example 21: preparation of (R) -4- (6-chloro-7-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -N- (1- (4- (ethylsulphonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 1 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.8Hz,1H),7.90–7.79(m,4H),7.72(dd,J＝8.4,2.2Hz,1H),7.68–7.60(m,3H),7.37(t,J＝8.1Hz,1H),5.13–5.08(m,2H),4.13(t,J＝6.3Hz,2H),3.77–3.65(m,2H),3.25(q,J＝8.0Hz,2H),3.13(t,J＝6.4Hz,2H),2.39(s,3H),1.09(t,J＝7.4Hz,3H).

Example 22: preparation of 4- (6-chloro-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 16 above.

The title compound was resolved in two configurations by chiral column preparation with retention times of 30.704min and 37.908min, respectively. ( Instrument: waters 2695; chromatographic conditions: chromatographic column: AD-H; mobile phase: n-hexane/ethanol=50/50 (V: V); flow rate: 1mL/min; column temperature: 25 ℃; sample injection amount: 60. Mu.L; )

Configuration one (retention time 30.704 min): ¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.8Hz,1H),7.87–7.79(m,3H),7.76–7.62(m,5H),7.57(dd,J＝8.3,2.1Hz,1H),7.25(t,J＝8.0Hz,1H),5.14–5.06(m,2H),4.34–4.23(m,1H),3.76–3.70(m,2H),3.26(q,J＝7.3Hz,3H),3.07(dd,J＝16.5,11.5Hz,1H),1.25(d,J＝6.4Hz,3H),1.09(t,J＝7.3Hz,3H).

configuration two (retention time 37.908 min): ¹ H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.8Hz,1H),7.87–7.79(m,3H),7.76–7.62(m,5H),7.57(dd,J＝8.3,2.1Hz,1H),7.25(t,J＝8.0Hz,1H),5.14–5.06(m,2H),4.34–4.23(m,1H),3.76–3.70(m,2H),3.26(q,J＝7.3Hz,3H),3.07(dd,J＝16.5,11.5Hz,1H),1.25(d,J＝6.4Hz,3H),1.09(t,J＝7.3Hz,3H).

example 23: preparation of 4- ((R) -7-chloro-8-fluoro-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 18 above.

¹ H NMR(400MHz,Methanol-d ₄ )δ7.91–7.83(m,2H),7.74(dd,J＝10.4,2.0Hz,1H),7.64(dd,J＝8.6,2.2Hz,3H),7.52–7.41(m,2H),7.31–7.17(m,1H),5.22(t,J＝6.4Hz,1H),4.61–4.36(m,3H),3.86(d,2H),3.18(q,J＝7.4Hz,2H),1.19(t,J＝7.4Hz,6H).

Example 24: preparation of 4- ((R) -3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- ((R)) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Step 1: preparation of ethyl (R) -4- (((4-bromo-N- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -2-fluorophenyl) sulphonamido) -3-fluorobenzoate

Ethyl 4- ((4-bromo-2-fluorophenyl) sulphonamido) -3-fluorobenzoate (100.0 mg) and triphenylphosphine (300.0 mg) were dissolved in tetrahydrofuran (4 mL), and (S) -1- ((tert-butyldimethylsilyl) oxy) propan-2-ol (380.0 mg) and diisopropyl azodicarboxylate (240.0 mg) were added in sequence at 0deg.C, and after addition, the reaction was resumed to room temperature for 4 hours, and TLC showed complete consumption of starting material. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 100.0mg of the title compound.

MS(ESI)m/z(M+H)+＝592.1.

Step 2: preparation of ethyl (R) -4- (7-bromo-3-methyl-1, 1-dioxido-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate

Ethyl (R) -4- (((4-bromo-N- (1- ((tert-butyldimethylsilyl) oxy) prop-2-yl) -2-fluorophenyl) sulphonyl) -3-fluorobenzoate (100.0 mg) was weighed into tetrahydrofuran (4 mL), tetrabutylammonium fluoride (0.25mL,1.0M in THF) was added and reacted at 80 ℃ for 10 minutes, TLC showed complete reaction, the reaction system was quenched by pouring into water, extraction with ethyl acetate three times, the organic phases were combined, the organic phases were backwashed once with saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure, the crude product obtained was purified by column chromatography to give 50.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝458.0.

Step 3: preparation of (R) -4- (3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoic acid ethyl ester

Ethyl (R) -4- (7-bromo-3-methyl-1, 1-dihydro-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate (15.0 mg), methylboronic acid (4.0 mg), potassium phosphate (20.0 mg) were weighed and suspended in N, N-dimethylformamide (1 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (2.0 mg) was added thereto, argon was substituted three times, and the system was reacted at 100 ℃ for 1 hour, and TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give the title compound 10mg.

MS(ESI)m/z(M+H)+＝394.1.

Step 4: preparation of (R) -4- (3, 7-dimethyl-1, 1-dioxido-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoic acid

Ethyl (R) -4- (3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoate (10.0 mg) was weighed out and dissolved in methanol/water (2.0 mL/0.4 mL), sodium hydroxide (20.0 mg) was added and reacted at room temperature for 1 hour, and TLC showed complete consumption of the starting material. The pH is regulated to 5-6 by 2.0M hydrochloric acid, extraction is carried out three times by ethyl acetate, the organic phases are combined, the organic phases are backwashed once by saturated sodium chloride solution, dried by anhydrous sodium sulfate and concentrated under reduced pressure. 10.0mg of the title compound was obtained and used in the next step without further purification.

MS(ESI)m/z(M+H) ⁺ ＝366.0.

Step 5: preparation of 4- ((R) -3, 7-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- ((R)) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

(R) -4- (3, 7-dimethyl-1, 1-dioxido-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -3-fluorobenzoic acid (10.0 mg), O- (7-azobenzotriazol-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (12.0 mg) were dissolved in tetrahydrofuran (2 mL), and N, N-diisopropylethylamine (10.0 mg), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethan-1-ol (10.0 mg) was added in this order, and after the addition, the reaction was carried out at room temperature for 1 hour, and TLC showed the completion of the starting material reaction. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to give the title compound 1.46mg.

MS(ESI)m/z(M+H) ⁺ ＝577.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(d,J＝7.8Hz,1H),7.82(dd,J＝8.4,1.8Hz,3H),7.64(d,J＝8.2Hz,3H),7.44(d,J＝8.0Hz,1H),7.24–6.95(m,3H),5.12–5.06(m,2H),4.49–4.46(m,3H),3.77–3.60(m,2H),3.25(q,J＝7.4Hz,2H),2.37(s,3H),1.18–0.89(m,6H).

Example 25: preparation of (S) -4- (3, 7-dimethyl-1, 1-dioxido-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in the previous example 24.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(d,J＝8.0Hz,1H),7.93–7.75(m,3H),7.64(d,J＝8.2Hz,3H),7.45(d,J＝8.0Hz,1H),7.28–6.94(m,3H),5.15–5.03(m,2H),4.49–4.32(m,3H),3.82–3.61(m,2H),3.26(q,J＝7.3Hz,2H),2.38(s,3H),1.11–1.07(m,6H).

Example 26: preparation of 4- (7-chloro-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (4- (ethylsulphonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in the previous example 24.

The title compound was resolved in two configurations by chiral column preparation with retention times of 35.476min and 39.146min, respectively. ( Instrument: waters 2695; chromatographic conditions: chromatographic column: AD-H; mobile phase: n-hexane/isopropanol=70/30 (V: V); flow rate: 0.8mL/min; column temperature: 25 ℃; sample injection amount: 50. Mu.L; )

Configuration one (retention time 35.476 min): 1H NMR(400MHz,DMSO-d ₆ )δ8.96(d,J＝7.9Hz,1H),7.90–7.75(m,3H),7.73–7.53(m,4H),7.49(s,1H),7.34(d,J＝8.0Hz,1H),7.21(brs,1H),5.15–5.00(m,2H),4.61–4.19(m,3H),3.77–3.62(m,2H),3.25(q,J＝7.4Hz,2H),1.09(t,J＝7.3Hz,6H).

Configuration two (retention time 39.146 min): 1H NMR (400 MHz, DMSO-d) ⁶ )δ8.96(d,J＝7.9Hz,1H),7.90–7.75(m,3H),7.73–7.53(m,4H),7.49(s,1H),7.34(d,J＝8.0Hz,1H),7.21(brs,1H),5.15–5.00(m,2H),4.61–4.19(m,3H),3.77–3.62(m,2H),3.25(q,J＝7.4Hz,2H),1.09(t,J＝7.3Hz,6H).

Example 27: preparation of 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

Step 1: preparation of 2- (2-hydroxypropyl) -4-methylbenzenesulfonamide

N- (tert-butyl) -2- (2-hydroxypropyl) -4-methylbenzenesulfonamide (500.0 mg) was dissolved in trifluoroacetic acid (5 mL) and reacted at room temperature for 1 hour, and TLC showed completion of the starting material reaction. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by column chromatography to give 300mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝230.1.

Step 2: preparation of ethyl 3-fluoro-4- ((2- (2-hydroxypropyl) -4-methylphenyl) sulfonamide) benzoate

2- (2-hydroxypropyl) -4-methylbenzenesulfonamide (90.0 mg), ethyl 4-bromo-3-fluorobenzoate (780.0 mg), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl (42.0 mg), chloro (2-dicyclohexylphosphino-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2-aminoethylphenyl) ] palladium (II) (62 mg), and potassium t-butoxide (131.0 mg) were weighed and suspended in 1, 4-dioxane (3 mL), and the system was reacted three times with argon substitution at 100℃for 2 hours by TLC, which showed complete consumption of the starting material. Quenched with water, extracted three times with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound 60mg.

MS(ESI)m/z(M+H) ⁺ ＝396.1.

Step 3: preparation of ethyl 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoate

Ethyl 3-fluoro-4- ((2- (2-hydroxypropyl) -4-methylphenyl) sulfonamide) benzoate (20.0 mg) and triphenylphosphine (52.0 mg) were weighed into tetrahydrofuran (1 mL), diisopropyl azodicarboxylate (40.0 mg) was added at 0 ℃, and after addition, room temperature reaction was carried out for 1 hour, TLC showed complete reaction of the starting materials. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-TLC to give 19.0mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝378.1.

Step 4: preparation of 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoic acid

Ethyl 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoate (19.0 mg) was weighed out and dissolved in methanol/water (1 mL/0.5 mL), sodium hydroxide (10.0 mg) was added, and the reaction was stirred for 2 hours, and TLC showed complete consumption of the starting material. Ph=5 was adjusted with 2.0M hydrochloric acid, extraction was performed three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound 16.0mg was obtained and used in the next step without further purification.

MS(ESI)m/z(M+H) ⁺ ＝350.1.

Step 5: preparation of 4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

4- (3, 6-dimethyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -3-fluorobenzoic acid (19.0 mg), O- (7-azobenzotriazol-1-oxy) -N, N' -tetramethylurea hexafluorophosphate (26.0 mg) were weighed into tetrahydrofuran (1 mL), and N, N-diisopropylethylamine (22.0 mg), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethan-1-ol (20.0 mg) was added in this order, and reacted at room temperature for 1 hour, whereby TLC showed the starting material reaction to be complete. Water quenching, extraction with ethyl acetate for three times, combining organic phases, backwashing the organic phases once with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to give 4.8mg of the title compound.

MS(ESI)m/z(M+H) ⁺ ＝561.1.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(d,J＝7.8Hz,1H),7.87–7.78(m,3H),7.72–7.62(m,3H),7.58(d,J＝7.9Hz,1H),7.38–7.27(m,2H),7.18(t,J＝8.0Hz,1H),5.16–5.04(m,2H),4.31–4.22(m,1H),3.78–3.63(m,2H),3.31–3.12(m,3H),3.04(dd,J＝16.4,11.3Hz,1H),2.40(s,3H),1.24(d,J＝6.4Hz,3H),1.09(t,J＝7.3Hz,3H).

Example 28: preparation of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluoro-4- (7-methyl-1, 1-dioxide-4, 5-dihydrobenzo [ f ] [1,2] thiazolin-2 (3H) -yl) benzamide

The preparation was similar to that used in example 1 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.89(d,J＝7.8Hz,1H),7.89–7.74(m,3H),7.66–7.61(m,2H),7.60–7.52(m,2H),7.38(d,J＝1.8Hz,1H),7.23(ddd,J＝7.9,1.8,0.8Hz,1H),6.79(t,J＝8.0Hz,1H),5.17–5.01(m,2H),4.05–3.83(m,2H),3.77–3.59(m,2H),3.33–3.30(m,2H),3.26(q,J＝7.4Hz,2H),2.39(s,3H),1.94–1.79(m,2H),1.09(t,J＝7.4Hz,3H).

Example 29: preparation of 4- ((S) -7-chloro-8-fluoro-3-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 18 above.

¹ H NMR(400MHz,Methanol-d ₄ )δ7.91–7.84(m,2H),7.74(dd,J＝10.4,1.9Hz,1H),7.64(dd,J＝8.7,2.2Hz,3H),7.47(dd,J＝8.8,7.1Hz,2H),7.24(brs,1H),5.23(t,J＝6.4Hz,1H),4.64–4.39(m,3H),3.86(d,2H),3.18(q,J＝7.4Hz,2H),1.19(t,J＝7.4Hz,6H).

Example 30: preparation of 4- (7-chloro-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ e ] [1,2] thiazin-2-yl) -N- ((R) -1- (4- (ethylsulphonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 16 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,J＝7.8Hz,1H),7.90–7.79(m,3H),7.75(d,J＝7.0Hz,2H),7.70(dd,J＝8.2,2.0Hz,1H),7.68–7.61(m,2H),7.60(d,J＝8.9Hz,1H),7.25(t,J＝7.9Hz,1H),5.15–5.05(m,2H),4.31–4.24(m,1H),3.77–3.63(m,2H),3.29–3.22(m,3H),3.03(dd,J＝16.5,11.5Hz,1H),1.26(d,J＝6.4Hz,3H),1.09(t,J＝7.3Hz,3H).

Example 31: preparation of 4- (7-chloro-4-methyl-1, 1-dioxide-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- ((R-1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3-fluorobenzamide

/>

The preparation was similar to that used in example 18 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.94(dd,J＝7.9,2.1Hz,1H),7.87–7.80(m,3H),7.70–7.61(m,4H),7.52(d,J＝2.1Hz,1H),7.45–7.39(m,1H),7.26–7.21(m,1H),5.13–5.05(m,2H),4.44(t,J＝8.2Hz,1H),4.15(dd,J＝15.2,9.9Hz,1H),3.83–3.76(m,1H),3.75–3.63(m,2H),3.25(q,J＝7.3Hz,2H),1.34(d,J＝6.4Hz,3H),1.09(t,J＝7.3Hz,3H).

Example 32: preparation of 4- ((S) -7-chloro-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxathiazin-2-yl) -N- ((R) -1- (5- (ethylsulphonyl) pyridin-2-yl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in the previous example 24.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.04–8.92(m,2H),8.24(dd,J＝8.3,2.4Hz,1H),7.87(dt,J＝10.5,2.1Hz,1H),7.74–7.66(m,2H),7.60(d,J＝8.5Hz,1H),7.55–7.45(m,1H),7.35(dd,J＝8.6,2.0Hz,1H),7.31–7.15(m,1H),5.19(q,J＝6.9Hz,1H),5.04(t,J＝6.0Hz,1H),4.71–4.24(m,3H),3.91–3.76(m,2H),3.44–3.41(m,2H),1.13(t,J＝7.3Hz,6H).

Example 33: preparation of 4- (3, 7-dimethyl-1, 1-dioxide-4, 5-dihydrobenzo [ f ] [1,2] thiazolin-2 (3H) -yl) -N- ((R) -1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -3-fluorobenzamide

The preparation was similar to that used in example 17 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.00–8.91(m,2H),8.22(dd,J＝8.3,2.4Hz,1H),7.84(dd,J＝13.6,5.3Hz,1H),7.68(dd,J＝8.2,1.3Hz,1H),7.57–7.47(m,1H),7.40(dd,J＝8.1,3.4Hz,2H),7.17(d,J＝7.9Hz,1H),6.44(s,1H),5.23–5.09(m,1H),5.10–5.01(m,1H),4.67(s,1H),3.87–3.76(m,2H),3.60(t,J＝13.6Hz,1H),3.39(q,J＝7.3Hz,2H),3.06(dd,J＝14.5,6.6Hz,1H),2.39(s,3H),1.96(dd,J＝14.8,6.6Hz,1H),1.77–1.65(m,1H),1.12(td,J＝7.4,1.3Hz,3H),0.91(s,3H).

Example 34: preparation of 5- ((S) -7-chloro-8-fluoro-3-methyl-1, 1-dioxo-3, 4-dihydro-2H-benzo [ b ] [1,4,5] oxadiazol-2-yl) -N- ((R) -1- (4- (ethylsulphonyl) phenyl) -2-hydroxyethyl) -6-methylpyridine amide

The preparation was similar to that used in example 18 above.

¹ H NMR(400MHz,DMSO-d ₆ )δ9.07(dd,J＝8.1,6.0Hz,1H),7.88–7.62(m,7H),7.53(dd,J＝8.1,4.3Hz,1H),5.24–5.16(m,1H),5.18–5.09(m,1H),4.84–4.73(m,1H),4.65–4.44(m,1H),4.18(dd,J＝13.5,10.4Hz,1H),3.81(t,J＝5.6Hz,2H),3.27(dt,J＝8.2,6.8Hz,2H),2.73(s,1H),2.68(s,2H),1.43(d,J＝6.8Hz,1H),1.10(t,J＝7.3Hz,3H),0.88(d,J＝7.1Hz,2H).

Biological assay

Test example 1: in vitro Activity test 1

1. Purpose of experiment

The compounds of the invention are assayed for their inhibitory activity on rory receptors.

2. Experimental material and instrument

HEK293T cells (ATCC, cat#CRL-3216); pGL4.35[ luc2P/9XGAL4 UAS/Hygro](Promega); pBIND-RORgamma Vector; a cell culture medium; high concentration glucose; fetal bovine serum; penicillin-streptomycin; hydroxyethyl piperazine ethane sulfonic acid;

i serum-reduced medium (Gibico); glo ^TM Luciferase detection system (Promega); transIT-293 transfection reagent (Mirus); ursolic acid (Sigma); 384 well cell culture plates (PerkinElmer); 384-well polypropylene microwell plates (labcell); CO ₂ An incubator; a cell counter; cradle (Thermo).

3. Experimental procedure

3.1 preparation of 10mM ursolic acid solution and 100% DMSO negative control.

3.2 cell incubation was performed according to the ATCC recommended protocol and used for testing during the log phase of cell growth.

3.3 removal of cell culture medium and washing of cells with PBS buffer.

3.4 cells were isolated by adding pancreatin substitute solution to cell culture flasks. Cells were washed once with complete growth medium.

3.5 cells were washed twice with PBS, phenol red removed, and resuscitated in medium to appropriate concentrations. Only cells with a viability of greater than 90% were used for detection.

3.6 will be 2.5 x 10 ⁶ HEK293T cells were transferred to 60mm dishes at 37℃with 5% CO ₂ Incubate for 16 hours in the environment.

3.7 transfection of plasmid into cells at 37℃with 5% CO ₂ Incubate for 5-6 hours in the environment.

3.8 25nL of compound dilutions were transferred to 384 well microplates.

3.9 HEK293T cells were transferred to 384 well cell culture plates with approximately 17000 cells per well. At 37℃with 5% CO ₂ Incubate for 18-20 hours in the environment.

3.10 adding 25. Mu.L of stabilized Glo to each well of the cell culture plate ^TM FluorescenceAnd (3) a luciferase detection reagent, and recording fluorescence readings.

3.11 plotting the inhibition ratio against the logarithmic curve of the compound concentration by GraphPad Prism 6.0 software, calculating the IC of the test compound ₅₀ Values.

The in vitro activity of the compound of the invention on ROR gamma is determined by the above test, and the IC is determined ₅₀ The values are shown in Table 1.

TABLE 1 IC of the in vitro Activity of the inventive Compounds against RORgamma ₅₀ Value of

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Wherein UA has a CAS No. 77-52-1.

Conclusion: from the above table, it can be seen that the compounds of the present invention have a remarkable inhibitory effect on rorγ receptors, and the activity effect of most of the compounds is very remarkable.

Test example 2: pharmacodynamic testing

1. Purpose of experiment

Determination of IL-17 enzyme-linked immunosorbent assay activity of the compound

2. Experimental material and instrument

Human Peripheral Blood Mononuclear Cells (PBMCs); lymphocyte culture medium (Zenbio); texMACS (Miltenyi Biotec); t cell stimulating medium; human IL-17 ELISA kit (R)&D system); CO ₂ Incubator (fisher scientific); centrifuge (fisher scientific); 96-well cell culture plates (Fisher Scientific); microplate reader (Tecan).

3. Experimental procedure

Cryopreserved human Peripheral Blood Mononuclear Cells (PBMCs) were rapidly resuscitated in pre-warmed lymphocyte medium, centrifuged at 1000rpm for 10min, the cell culture supernatant removed, the cells gently suspended in TexMACS medium, and the cells counted. T cell stimulating medium (anti-hCD 28:5 μg/mL; rhTGF-beta 1:5ng/mL; rhIL-6:20ng/mL; rhIL-23:10 ng/m) and then cells were seeded in 96-well cell culture plates at a density of 100. Mu.L peripheral blood mononuclear cells (4X 105)/well. Test compounds were diluted in gradient using TexMACS medium and added to each experimental well, 2 parallel wells per group. Negative control wells containing cells only and no T cell stimulating medium were prepared to obtain background readings. Cell culture plates were placed in 5% CO ₂ And an incubator at 37℃for 2 days. Cell culture supernatants were harvested 2 days after drug treatment and centrifuged to remove suspended material. IL-17 was then quantified in the supernatant using an IL-17 ELISA kit. EC of test compounds was calculated using GraphPadPrism 6.0 ₅₀ Values.

The compound has better inhibition effect on IL-17 secretion.

Test example 3: pharmacokinetic testing

1. Purpose of experiment

Experimental determination of the stability of the Compounds of the invention to liver microsomes

2. Experimental materials

Buffer solution: 100mM potassium phosphate buffer, pH=7.4 and 10mM MgCl ₂ Preparation of compound solution:

2.1 Preparation of 100. Mu.M working solution: mu.L of stock solution (10 mM) of the test group or control group was taken, diluted with 495. Mu.L of methanol, and the resulting compound concentration was 100. Mu.M (99% MeOH).

2.2 Preparation of 10. Mu.M working solution: mu.L of 100. Mu.M working solution was diluted with 450. Mu.L of 100mM potassium phosphate buffer to give a compound concentration of 10. Mu.M (9.9% MeOH).

Composition of NADPH (reduced coenzyme II) regeneration System (final concentration of isocitrate dehydrogenase in culture broth 1.0 unit/mL): beta-nicotinamide adenine dinucleotide phosphate (Chem-impex); isocitrate (Sigma-Aldrich); isocitrate dehydrogenase (Sigma-Aldrich).

Preparation of liver microsome solution (final concentration 0.5mg protein/mL):

hepatic microsomal species	Suppliers (suppliers)
		Human liver microsome	Corning
Mouse liver microsome	Xenotech
		Liver microsome of cynomolgus monkey	Corning

Stop solution: acetonitrile solution containing 100ng/mL of tolbutamide and 100ng/mL of labetalol as internal standard.

The compound of the invention has better metabolic stability.

Claims

1. A compound of the general formula (iii):

wherein:

R ¹ is ethyl;

R ² is-CH ₂ OH；

X ¹ 、X ⁸ Selected from CH, N;

X ³ is CR (CR) ⁶ ，R ⁶ Selected from halogen or methyl;

X ² 、X ⁴ 、X ⁵ 、X ⁶ 、X ⁷ independently selected from CH;

R ⁴ selected from hydrogen or methyl;

m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

W ¹ selected from CH ₂ 、O；

W ² Selected from C;

q is selected from 1, 2, 3;

Y ¹ 、Y ³ selected from CR ⁷ ，R ⁷ Selected from hydrogen, halogen, methyl;

Y ² 、Y ⁴ independently selected from CR ⁷ 、N；R ⁷ Selected from hydrogen, halogen, methyl;

meaning that the bond is selected from single bonds.

2. A compound having any one of the following structures:

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3. use of a compound according to any one of claims 1-2 in the manufacture of a rory inhibitor medicament.

4. Use of a compound according to any one of claims 1-2 in the manufacture of a medicament for the prevention and/or treatment of autoimmune related diseases and inflammatory diseases.

5. The use according to claim 4, wherein the autoimmune-related disease, inflammatory disease is selected from psoriasis, multiple sclerosis, rheumatoid arthritis, crohn's disease, asthma, chronic obstructive pulmonary disease, behcet's disease and irritable bowel syndrome.

6. An intermediate compound having any one of the following structures:

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