CN110143955A - Oxadiazole derivatives containing heterocyclic side chain, synthetic method and application thereof - Google Patents

Abstract

The present invention discloses an oxadiazole derivative containing a heterocyclic side chain, a synthesis method and application thereof. The structure of the oxadiazole derivative is shown in general formula I, wherein the definitions of the substituents are as described in the description and the claims. described in the book. The compound of the present invention has strong IDO inhibitory activity, good drug absorption potential, and good development prospect.

Description

Oxadiazole derivatives containing heterocyclic side chain, synthetic method and application thereof

technical field

The present invention relates to oxadiazole derivatives containing heterocyclic side chains, synthesis methods and applications thereof.

Background technique

Indoleamine 2,3-dioxygenase (IDO, Indoleamine 2,3-dioxygenase) is an enzyme containing heme in cells, which was first discovered in 1967. It consists of 403 amino acids with a molecular weight of about 45KD, forming a large and small two-folded α-helical domain.

Tryptophan is one of the essential amino acids for humans, and IDO is closely related to it. Part of the tryptophan taken in by the human body is used to synthesize protein, serotonin and melatonin, and the other part is metabolized by the kynurenine pathway. IDO and TDO are the first and rate-limiting catalytic enzymes in the kynurenine pathway, which can promote the oxidative cleavage of the 2,3-double bond of the indole ring in tryptophan to generate N-formylkynurenine , and then further metabolized to produce kynurenine and other metabolites. IDO is widely distributed in mammalian tissues other than the liver, can be induced by IFN-α, and is expressed in myeloid series cell lines (dendritic cells, monocytes, macrophages, eosinophils), epithelial cells, Fibroblasts, vascular smooth muscle and endothelial cells, and certain tumor cell lines. While TDO is mainly expressed in the liver. Studies have shown that IDO is closely related to the pathogenesis of cancer, Alzheimer's disease, autoimmune diseases, AIDS, depression, and cataracts.

In the tumor microenvironment, IDO activates the stress kinase GCN2 by depleting local tryptophan. GCN2 activation in T cells can inhibit self-proliferation and can bias naive CD4 ⁺ T cells to differentiate into Treg cells. In addition, the metabolism of tryptophan by IDO produces kynurenine and downstream metabolites that bind and activate the aryl hydrocarbon receptor (AhR). AhR can promote Treg cell differentiation and can also bias dendritic cells and macrophages towards an immunosuppressive phenotype. GCN2 can also directly affect the phenotype of dendritic cells and macrophages. All of these pathways can have profound effects on antigen-presenting cells and the antigen-presenting environment. In addition, it has been reported in the literature that most tumors consistently express IDO. Therefore, IDO is a reliable tumor immunotherapy target.

Drugs related to IDO targets have good market prospects. At present, many companies and scientific research institutions are carrying out research on new IDO inhibitors in full swing, and some compounds have entered the clinical trial stage, such as Incyte's Epacadostat, Pfizer's PF-06840003, Bristol-Myers Squibb's BMS-986205, etc.

Among them, Incyte's Epacadostat has entered Phase III clinical trials and is the most advanced compound in this field. The compound has good enzymatic and cellular activities and excellent performance in animal level, but it has certain disadvantages such as low oral bioavailability due to glucuronidation and too large polar surface area (PSA). Therefore, it is hoped to develop a selective IDO inhibitor with high efficiency, low toxicity and good metabolism to provide new treatment options for tumor patients.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a class of oxadiazole derivatives containing heterocyclic side chains, and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof.

In a first aspect of the present invention, there is provided a compound of general formula I, its enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or solvates:

In the formula,

A is -SO ₂ -, -C(=O)- or -S(=O)-;

X is O, S, _CH2 or NH;

Z is CH, N, S, C or O;

R ¹ is absent, hydrogen, halogen, hydroxyl, amino, carboxyl, cyano, C1-C6 alkylsulfonyl, C1-C6 alkanoyl, substituted or unsubstituted C1-C6 alkyl, -C(=O)- O-C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycle Alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl;

R ² and R ³ are independently selected from H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, or R ² and R ³ and the attached carbon form a substituted or unsubstituted C3-C7 aliphatic ring, or a substituted or unsubstituted C3-C7 aliphatic ring Substituted 3-6 membered heterocycle;

n is 1, 2, 3 or 4;

Or R ¹ and Z together with R ² or R ³ and the attached carbon form a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted C3-C7 aliphatic ring, a substituted or unsubstituted 5-6 membered heterocyclic ring , or a substituted or unsubstituted 5-10-membered heteroaromatic ring;

R ⁴ , R ⁵ , R ⁶ , R ⁷ are independently selected from hydrogen, C1-C6 alkyl, hydroxyl, halogen, cyano, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; or, R ⁴ and R ⁵ and the attached carbon, or R ⁶ and R ⁷ and the attached carbon independently together form a substituted or unsubstituted C3-C7 aliphatic ring, or a substituted or unsubstituted 3-6 membered heterocycle;

R ⁸ is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

m is 0, 1, 2, 3, 4, 5,

Wherein, each substitution independently refers to being substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 halocycloalkane group, 3-7 membered heterocycloalkyl, NR ⁹ R ¹⁰ ; R ⁹ and R ¹⁰ are independently selected from H, C1-C3 alkyl.

In another preferred example, R ¹ is absent, hydrogen, halogen, hydroxyl, amino, carboxyl, cyano, C1-C4 alkylsulfonyl, C1-C4 alkanoyl, substituted or unsubstituted C1-C4 alkyl, -C(=O)-O-C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted Substituted C3-C6 heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-6 membered heteroaryl;

The substitution refers to substitution with one or more substituents selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 halocycloalkyl , 3-7 membered heterocycloalkyl, NR ⁹ R ¹⁰ ; R ⁹ and R ¹⁰ are independently selected from H, C1-C3 alkyl.

In another preferred example, R ¹ and Z, and R ² or R ³ and the attached carbon together form a C6-C10 aromatic ring, a C3-C7 aliphatic ring, a 5-6-membered heterocyclic ring, or a 5-10-membered heteroaromatic ring .

In another preferred example, X is NH.

In another preferred example, R ¹ is absent, hydrogen, halogen, hydroxyl, amino, carboxyl, cyano, substituted or unsubstituted C1-C6 alkyl, -C(=O)-O-C1-C6 alkyl , substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl;

Alternatively R1 and Z and ^R2 or ^R3 together with the carbon to which they are attached form ^a C6 aromatic ring.

In the present invention, the compound is a racemic compound or an optically pure compound, and the configuration of each chiral carbon is independently S or R.

In the present invention, pharmaceutically acceptable salts include, but are not limited to: inorganic acid salts, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc.; organic acid salts, such as formate, ethyl acetate, etc. acid salt, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, etc.; alkyl sulfonate, such as methanesulfonate, ethylsulfonate acid salts, etc.; aryl sulfonates, such as benzenesulfonates, p-toluenesulfonates, etc.

In another preferred embodiment, the compound is:

The second aspect of the present invention provides the preparation method of the compound of the general formula described in the first aspect, comprising the following steps:

Compound A1 is hydrolyzed and ring-opened to obtain the compound of general formula I,

Wherein, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z, A, n, X, and m are as described in the first aspect.

In another preferred embodiment, compound A1 is subjected to ring-opening under the condition of alkali hydrolysis (such as sodium hydroxide aqueous solution or methanol solution) to obtain the compound of general formula I as the final product.

The third aspect of the present invention provides the preparation method of the compound of general formula I described in the first aspect, comprising the following steps:

Compound A2 and A3 react under the catalysis of alkali (such as sodium hydroxide) to obtain the final product compound of general formula I,

Wherein, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z, A, n, X, and m are as described in the first aspect.

In another preferred embodiment, compounds A2 and A3 are catalyzed by a base (such as sodium hydroxide) to obtain the compound of general formula I as the final product.

The fourth aspect of the present invention provides a pharmaceutical composition, comprising:

The compound of the first aspect, a pharmaceutically acceptable salt or solvate thereof; and

A pharmaceutically acceptable carrier.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that each component of the composition can be admixed with the compounds of general formula I of the present invention, pharmaceutically acceptable salts or solvates thereof, and with each other, without appreciably decreasing The efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The fifth aspect of the present invention provides the use of the compound of general formula I described in the first aspect, a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition described in the fourth aspect,

(1) for the preparation of indoleamine 2,3-dioxygenase inhibitors;

(2) Used as a selective inhibitor of indoleamine 2,3-dioxygenase;

(3) Medicines for preventing or treating tumors, Alzheimer's disease, autoimmune diseases, AIDS, depression or cataracts.

In another preferred embodiment, the tumor is selected from the group consisting of breast cancer, cervical cancer, lung cancer, stomach cancer, kidney cancer, prostate cancer, pancreatic cancer, colon cancer, rectal cancer, oral cancer, skin cancer, brain cancer, ovarian cancer, Bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, melanoma, solid tumor, glioma, hepatocellular carcinoma, lymphoma, myeloma, non-small cell lung cancer, head and neck tumor, mastoid nephroma, peritoneal tumor .

The present invention also provides a method for inhibiting tumor cell growth in vitro, by adding the compound described in the first aspect, a pharmaceutically acceptable salt or solvate thereof to the tumor cell culture medium.

The compounds of the present invention can be used as indoleamine 2,3-dioxygenase (IDO) selective inhibitors, and have further application potential for IDO-related diseases.

The present invention also provides a method for treating tumors, which comprises administering the compound, pharmaceutically acceptable salt or solvate thereof of the first aspect to a subject in need thereof.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification may be replaced by any alternative feature serving the same, equivalent or similar purpose. Due to space limitations, they will not be repeated here.

Detailed ways

After extensive and in-depth research, the inventors of the present application have developed for the first time a class of novel structures with selective inhibition of indoleamine 2,3-dioxygenase by optimizing the diversity of the chain-like sulfonamide groups in the solvent region of the compound. Active compounds of general formula I and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof can be used for the preparation of prevention or treatment of tumors, Alzheimer's disease, autoimmune diseases, AIDS, various Types of depression as well as cataract medications. On this basis, the present invention has been completed.

the term

In the present invention, C1-C6 means having 1 to 6 carbon atoms, and so on.

In the present invention, the term "alkyl" refers to straight or branched chain alkyl groups including, but not limited to, methyl, ethyl, propyl, isopropyl. The term "alkylene" refers to a hydrocarbon group formed by missing two hydrogen atoms in an alkane molecule, and includes, without limitation, methylene, ethylene, and propylene. The term "alkenyl" refers to a straight or branched chain hydrocarbon moiety containing at least one double bond, eg -CH=CH- _CH3 . The term "alkynyl" refers to a straight or branched chain hydrocarbon moiety containing at least one triple bond, eg -C≡C- _CH3 .

In the present invention, the term "alkoxy" refers to -O alkyl, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy.

In the present invention, the term "haloalkyl" refers to a straight or branched chain alkyl group substituted with one or more halogens, including without limitation _CHF2 , _CH3CHBr , _CF3 , _CH3CH2CHCl , _{CH 3} CHFCH ₂ .

In the present invention, the term "halogen" refers to F, Cl, Br, I.

The term "aryl" refers to a hydrocarbon group containing one or more aromatic rings, examples of aryl moieties include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthracenyl, and phenanthrenyl.

The term "heteroaryl" means a group comprising one or more aromatic rings having at least one heteroatom (eg, N, O, or S). Examples of heteroaryl groups include, but are not limited to, furanyl, fluorenyl, pyrrolyl, thiophene oxazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl and indolyl. The term "heteroaromatic ring" means containing one or more aromatic rings having at least one heteroatom (eg, N, O or S).

The term "cycloalkyl" denotes a saturated cyclic hydrocarbyl moiety such as cyclohexyl, cyclopentyl.

The term "alicyclic" refers to a cycloalkane ring.

The term "heterocycle" refers to a cycloalkane ring containing at least one ring heteroatom (eg, N, O or S).

The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one ring heteroatom (eg, N, O or S).

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental method of unreceipted specific conditions in the following examples, usually according to normal conditions (people such as Sambrook, molecular cloning: conditions described in laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989)) or according to the manufacturer the proposed conditions. Percentages and parts are weight percentages and parts unless otherwise specified.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.

1H-NMR was measured with Varian MercuryAMX300 and Varian MR-400 instruments; reagents were purchased from J&KChemica Bailingwei Chemical Reagent Co., Ltd., Shaoyuan Technology (Shanghai) Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., Shanghai Shuya Pharmaceutical Technology Co., Ltd., other reagents Purchased from Sinopharm Group Chemical Reagent Co., Ltd. All solvents were re-distilled before use, and the anhydrous solvents used were obtained by drying treatment according to standard methods; all reactions were carried out under nitrogen protection and tracked by TLC unless otherwise stated, and were subjected to saturated chlorination during post-treatment. Sodium aqueous solution washing and anhydrous sodium sulfate drying process; silica gel (200-300 mesh) column chromatography is used for product purification unless otherwise specified; wherein silica gel (200-300 mesh) is produced by Qingdao Ocean Chemical Factory, GF-254 thin layer The silicone plate is produced by Yantai Jiangyou Silicone Development Co., Ltd.

The preparation of embodiment 1 compound S1

The synthesis of compound 1-1 refers to CN 104042611.

Synthesis of compounds 1-2:

Compound 1-1 (3 g, 6.5 mmol), triethylamine (1.96 g, 19.4 mmol), 4-dimethylaminopyridine (160 mg, 1.3 mmol) were dissolved in 40 ml of dichloromethane, and dicarbonic acid was added in an ice bath Di-tert-butyl ester (2.8 g, 13 mmol) was stirred for 20 min and the ice bath was removed. After stirring at room temperature for 2 hours, TLC detected the reaction and added water for extraction. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 2.8 g of a white solid with a yield of 76%.

¹ H NMR(300MHz, DMSO)δ7.98(d,J=5.8Hz,1H),7.54-7.62(m,2H),4.38(t,J=5.2Hz,2H),3.95(t,J=4.4 Hz, 2H), 3.15(s, 3H), 1.41(s, 9H).

Synthesis of compounds 1-3:

Compound 1-2 (170 mg, 0.3 mmol), 1,2,5-thiadiazoline-1,1-dioxide (55 mg, 0.452 mmol), cesium carbonate (295 mg, 0.904 mmol) were dissolved in 3 ml N, N-dimethylformamide (DMF), stirred at room temperature for 1.5 h, TLC detected the reaction, and added water for extraction. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 41 mg of a colorless oil with a yield of 23%.

¹ H NMR (300 MHz, DMSO) δ 7.99 (d, J=4.8 Hz, 1H), 7.68-7.52 (m, 2H), 7.17 (t, J=6.1 Hz, 1H), 3.79 (t, J=7.3 Hz, 2H), 3.32–3.20 (m, 4H), 3.15 (t, J=6.1Hz, 2H), 1.44 (s, 9H).

Synthesis of compounds 1-4:

Compound 1-3 (40 mg, 0.068 mmol) was dissolved in 2 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, it was concentrated under reduced pressure to obtain 33 mg of a colorless oil with a yield of 98 %. Without further processing, it was directly used in the next reaction.

Synthesis of compound S1:

Compound 1-4 (33 mg, 0.067 mmol) was dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (0.335 mmol) was added, and stirred at room temperature for 20 min. After the reaction was detected by TLC, water was added for extraction. The organic layer was washed with water and saturated brine successively. , dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 22 mg of white solid with a yield of 71%.

¹ H NMR (300MHz, DMSO) δ 11.46(s, 1H), 8.90(s, 1H), 7.19(t, J=6.8Hz, 1H), 7.15-7.08(m, 2H), 6.80-6.73(m ,1H),6.31(t,J＝5.6Hz,1H),3.49-3.39(m,2H),3.40-3.23(m,4H),3.11(t,J＝6.4Hz,2H).

The preparation of embodiment 2 compound S2

Synthesis of compound 2-1:

Compound 1-2 (140 mg, 0.248 mmol), 2-methyl-1,2,5-thiadiazoline-1,1-dioxide (51 mg, 0.372 mmol), cesium carbonate (243 mg, 0.744 mmol) Dissolve in 3ml N,N-dimethylformamide (DMF), stir at room temperature for 4h, add water to extract after TLC detection, wash the organic layer with water and saturated brine successively, and dry over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 62 mg of an oily product with a yield of 41%.

¹ H NMR(300MHz,DMSO)δ7.96(d,J=7.8Hz,1H),7.65-7.53(m,2H),3.78(t,J=6.8Hz,2H),3.29-3.13(m,6H) ), 2.54(s, 3H), 1.41(s, 9H).

Synthesis of compound 2-2:

Compound 2-1 (60 mg, 0.1 mmol) was dissolved in 2 ml of dichloromethane, stirred at room temperature for 2 h, and after the reaction was detected by TLC, concentrated under reduced pressure to obtain 48 mg of a colorless oil with a yield of 95%. Without further processing, it was directly used in the next reaction.

Synthesis of compound S2:

Compound 2-2 (48 mg, 0.095 mmol) was dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (0.476 mmol) was added, and stirred at room temperature for 30 min. After the reaction was detected by TLC, water was added for extraction. The organic layer was washed with water and saturated brine successively. , dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 30 mg of white solid with a yield of 66%.

¹ H NMR (400MHz, CD ₃ CN) δ 9.14 (s, 1H), 7.49 (s, 1H), 7.22 (dd, J=6.0, 2.7Hz, 1H), 7.09 (t, J=8.7Hz, 1H) ),6.93(ddd,J=8.8,4.1,2.8Hz,1H),6.04(t,J=5.8Hz,1H),3.50(q,J=6.1Hz,2H),3.37(t,J=6.3Hz ,2H),3.29–3.24(m,4H),2.24(s,3H).

The preparation of embodiment 3 compound S3

The synthesis of compound 3-1 refers to CN 104042611.

Synthesis of compound 3-2:

Compound 3-1 (2 g, 5.85 mmol) was placed in a round-bottomed flask, 23 ml of trifluoroacetic acid and 15 ml of 30% hydrogen peroxide solution were added, and the reaction was carried out at 45° C. for 2 days. After TLC detected the reaction, 50 ml of saturated aqueous sodium thiosulfate solution and 25 ml of ethyl acetate were added, and the mixture was stirred for 20 min. Water was added for extraction, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 1.12 g of product with a yield of 46%.

¹ H NMR (300 MHz, DMSO) δ 8.05 (dd, J=6.1, 2.4 Hz, 1H), 7.73–7.63 (m, 1H), 7.57 (t, J=8.7 Hz, 1H).

Synthesis of compound S3:

Compound 3-2 (50 mg, 0.134 mmol) and 1-(2-aminoethyl)-2-imidazolidinone (21 mg, 0.161 mmol) were dissolved in 2 ml of tetrahydrofuran, and 2.5 M aqueous sodium hydroxide solution (0.67 mmol) was added , and stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added for extraction. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 24 mg of white solid with a yield of 42%.

¹ H NMR (400MHz, CD ₃ CN) δ 10.07 (s, 1H), 7.50 (s, 1H), 7.23 (dd, J=6.0, 2.6Hz, 1H), 7.11 (t, J=8.7Hz, 1H) ), 6.94(ddd, J=8.8, 4.0, 2.9Hz, 1H), 6.08(s, 1H), 5.01(s, 1H), 3.53–3.30(m, 8H).

The preparation of embodiment 4 compound S4

Synthesis of compound 4-1

Dissolve 2-oxazolidinone (200mg, 2.3mmol) and sodium hydride (97mg, 2.414mmol) in 5ml DMF, stir for 30min, add dropwise a solution of N-Boc-bromoethylamine (515mg) in 2ml DMF, stir for 1 After one hour, TLC detected the reaction and added water for extraction. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 30 mg of oil with a yield of 6%.

¹ H NMR (300MHz, CDCl ₃ ) δ 4.87(s, 1H), 4.50-4.17(m, 2H), 3.65(t, J=8.0Hz, 2H), 3.53-3.16(m, 4H), 1.42( s, 9H).

Synthesis of compound 4-2

Compound 4-1 (30 mg, 0.13 mmol) was dissolved in 2 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 16 mg of colorless oil with a yield of 95%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S4

Compound 3-2 (37 mg, 0.1 mmol) and compound 4-2 (16 mg, 0.123 mmol) were dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (0.5 mmol) was added, and stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 21 mg of white solid with a yield of 49%.

¹ H NMR (400MHz, CD ₃ CN) δ 9.46 (s, 1H), 7.52 (s, 1H), 7.24 (dd, J=6.0, 2.7Hz, 1H), 7.11 (t, J=8.7Hz, 1H) ), 7.04–6.86 (m, 1H), 6.04 (s, 1H), 4.47–4.10 (m, 2H), 3.72–3.58 (m, 2H), 3.58–3.35 (m, 4H).

The preparation of embodiment 5 compound S5

Synthesis of compound 5-1

Dissolve isothiazolidine 1,1-dioxide (150mg, 1.24mmol) and sodium hydride (52mg, 1.30mmol) in 3ml DMF, after stirring for 30min, add dropwise dissolved N-Boc-bromoethylamine (276mg, 1.24mmol) ) in 2 ml DMF solution, stirred overnight, TLC detected the reaction and added water for extraction, the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 150 mg of white solid with a yield of 46%.

¹ H NMR (300MHz, CDCl ₃ )δ4.91(s,1H), 3.39-3.27(m,4H), 3.20-3.11(m,4H), 2.43-2.29(m,2H), 1.44(s,9H) ).

Synthesis of compound 5-2

Compound 5-1 (48 mg, 0.182 mmol) was dissolved in 2 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, concentrated under reduced pressure to obtain 29 mg of white solid with a yield of 97%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S5

Compound 5-2 (29 mg, 0.18 mmol) and compound 3-2 (60 mg, 0.16 mmol) were dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (0.9 mmol) was added, and stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 40 mg of white solid with a yield of 48%.

¹ H NMR (400MHz, CD ₃ CN) δ 9.18 (s, 1H), 7.48 (s, 1H), 7.21 (dd, J=6.0, 2.7Hz, 1H), 7.08 (t, J=8.7Hz, 1H) ),6.92(ddd,J=8.8,4.0,2.8Hz,1H),6.01(t,J=5.7Hz,1H),3.46(q,J=6.0Hz,2H),3.29(t,J=6.7Hz ,2H),3.22(t,J＝6.0Hz,2H),3.14–3.06(m,2H),2.33–2.21(m,2H).

The preparation of embodiment 6 compound S6

Synthesis of compound 6-1

Dissolve 2-methyl-[1,2,6]thiadiane 1,1-dioxide (100 mg, 0.667 mmol) and sodium hydride (28 mg, 0.7 mmol) in 3 ml of DMF, stir for 30 min, and add the solution dropwise. A solution of N-Boc-bromoethylamine (165 mg, 0.733 mmol) in 2 ml of DMF was stirred overnight. After the reaction was detected by TLC, water was added for extraction. The organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 140 mg of white solid with a yield of 72%.

¹ H NMR (300MHz, CDCl ₃ )δ4.86(s,1H), 3.51-3.41(m,2H), 3.39-3.13(m,6H), 2.76(s,3H), 1.86-1.72(m,2H) ),1.40(d,J=18.5Hz,9H).

Synthesis of compound 6-2

Compound 6-1 (60 mg, 0.204 mmol) was dissolved in 2 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 40 mg of colorless oil with a yield of 101%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S6

Compound 6-2 (40 mg, 0.2 mmol) and compound 3-2 (70 mg, 0.188 mmol) were dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (1.0 mmol) was added, and the mixture was stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 35 mg of white solid with a yield of 36%.

¹ H NMR (400MHz, CD ₃ CN) δ 9.13 (s, 1H), 7.51 (s, 1H), 7.24 (dd, J=6.1, 2.7Hz, 1H), 7.12 (t, J=8.7Hz, 1H) ),6.95(ddd,J=8.8,4.0,2.8Hz,1H),6.04(t,J=5.9Hz,1H),3.55-3.40(m,4H),3.40-3.25(m,4H),2.72( s,3H),1.85–1.77(m,2H).

The preparation of embodiment 7 compound S7

The synthesis of compound 7-1 refers to CN 107406439.

Synthesis of compound 7-2

Compound 7-1 (200 mg, 0.9 mmol) and sodium hydride (54 mg, 1.35 mmol) were dissolved in 3 ml of DMF and stirred for 30 minutes, 2-bromoethyl methyl ether (138 mg, 0.99 mmol) in 2 ml of DMF was added, and the solution was stirred at room temperature overnight. The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 110 mg of a colorless oil with a yield of 44%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.78 (t, J=6.4 Hz, 2H), 3.63 (t, J=5.0 Hz, 2H), 3.48 (t, J=6.5 Hz, 2H), 3.36 (s ,3H),3.25(t,J＝5.0Hz,2H),1.53(s,9H).

Synthesis of Compound 7-3

Compound 7-2 (110 mg, 0.392 mmol) was dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 67 mg of colorless oil with a yield of 95%. Without further processing, it was directly used in the next reaction.

¹ H NMR (300MHz, CDCl ₃ ) δ 4.54(s, 1H), 3.61(t, J=5.2Hz, 2H), 3.51(s, 3H), 3.40-3.34(m, 4H), 3.28-3.17( m, 2H).

Synthesis of Compounds 7-4

Compound 7-3 (60 mg, 0.333 mmol) and sodium hydride (15 mg, 0.37 mmol) were dissolved in 3 ml of DMF and stirred for 30 minutes, N-Boc-bromoethylamine (82 mg, 0.37 mmol) in 2 ml of DMF was added, and the mixture was stirred at room temperature overnight . The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 70 mg of colorless oil with a yield of 65%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.92 (s, 1H), 3.61 (t, J=5.1 Hz, 2H), 3.48-3.40 (m, 2H), 3.40-3.32 (m, 7H), 3.24 ( t, J=5.2Hz, 2H), 3.17 (t, J=6.0Hz, 2H), 1.44 (s, 9H).

Synthesis of Compounds 7-5

Compound 7-4 (70 mg, 0.216 mmol) was dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 49 mg of colorless oil with a yield of 102%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S7

Compound 7-5 (39 mg, 0.175 mmol) and compound 3-2 (65 mg, 0.175 mmol) were dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (0.875 mmol) was added, and stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 37 mg of white solid with a yield of 40%.

¹ H NMR (400MHz, CD ₃ CN) δ 9.14 (s, 1H), 7.51 (s, 1H), 7.25 (dd, J=6.0, 2.7Hz, 1H), 7.12 (t, J=8.7Hz, 1H) ),6.96(dddd,J=8.8,4.2,2.7,0.5Hz,1H),6.07(t,J=5.9Hz,1H),3.64–3.47(m,4H),3.39(d,J=9.5Hz, 4H), 3.34(s, 3H), 3.28(t, J=6.0Hz, 2H), 3.16(dd, J=7.2, 3.5Hz, 2H).

The preparation of embodiment 8 compound S8

Synthesis of Compound 8-1

Compound 7-1 (200 mg, 0.9 mmol) and sodium hydride (54 mg, 1.35 mmol) were dissolved in 3 ml of DMF and stirred for 30 minutes, 2-bromoethyl acetate (165 mg, 0.99 mmol) in 2 ml of DMF was added, and the solution was stirred at room temperature overnight. The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 172 mg of a colorless oil with a yield of 61%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 4.30 (m, 2H), 3.81 (t, J=6.5 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 3.32 (m, 2H), 2.09 (s,3H),1.54(s,9H).

Synthesis of Compound 8-2

Compound 8-1 (170 mg, 0.55 mmol) was dissolved in 3 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 115 mg of colorless oil with a yield of 100%. Without further processing, it was directly used in the next reaction.

¹ H NMR (300MHz, CDCl ₃ ) δ 4.52(s, 1H), 4.27(t, J=5.4Hz, 2H), 3.50(s, 4H), 3.29(m, 2H), 2.08(m, 3H) .

Synthesis of Compound 8-3

Compound 8-2 (84 mg, 0.403 mmol) and sodium hydride (18 mg, 0.444 mmol) were dissolved in 3 ml of DMF and stirred for 30 minutes, N-Boc-bromoethylamine (100 mg, 0.444 mmol) in 2 ml of DMF was added, and the solution was stirred at room temperature overnight . The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 75 mg of colorless oil with a yield of 53%.

¹ H NMR (300MHz, CDCl ₃ ) δ 4.91(s, 1H), 4.41-4.19(m, 2H), 3.45-3.26(m, 8H), 3.15(t, J=6.0Hz, 2H), 2.08( s,3H),1.43(s,9H).

Synthesis of Compounds 8-4

Compound 8-3 (66 mg, 0.188 mmol) was dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 46 mg of colorless oil with a yield of 99%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S8

Compound 8-4 (46 mg, 0.183 mmol) and compound 3-2 (62 mg, 0.1664 mmol) were dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (0.915 mmol) was added, and stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 22 mg of white solid with a yield of 23%.

¹ H NMR (400MHz, CD ₃ CN) δ 9.25 (s, 1H), 7.52 (s, 1H), 7.25 (dd, J=6.0, 2.7Hz, 1H), 7.12 (t, J=8.7Hz, 1H) ),6.95(ddd,J=8.8,4.1,2.8Hz,1H),6.09(t,J=5.9Hz,1H),3.70(q,J=5.6Hz,2H),3.54(q,J=6.0Hz ,2H),3.40(d,J＝9.8Hz,4H),3.34–3.25(m,2H),3.11(t,J＝5.5Hz,2H),3.05(t,J＝5.8Hz,1H).

The preparation of embodiment 9 compound S9

Synthesis of compound 9-1

Compound 7-1 (200 mg, 0.9 mmol), N,N-dimethylaminoethyl bromide hydrobromide (231 mg, 0.99 mmol), and cesium carbonate (880 mg, 2.7 mmol) were dissolved in 5 ml of DMF, and stirred at room temperature overnight. The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 145 mg of a colorless oil with a yield of 55%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.78 (t, J=6.5 Hz, 2H), 3.43 (t, J=6.5 Hz, 2H), 3.15 (t, J=6.5 Hz, 2H), 2.58 (t , J=6.5Hz, 2H), 2.28(s, 6H), 1.55–1.49(m, 9H).

Synthesis of compound 9-2

Compound 9-1 (145 mg, 0.55 mmol) was dissolved in 3 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 108 mg of colorless oil with a yield of 102%. Without further processing, it was directly used in the next reaction.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.65-3.35 (m, 4H), 3.11 (t, J=6.3 Hz, 2H), 2.56 (t, J=6.3 Hz, 2H), 2.39-2.16 (m, 6H).

Synthesis of compound 9-3

Compound 9-2 (58 mg, 0.3 mmol) and sodium hydride (18 mg, 0.45 mmol) were dissolved in 3 ml of DMF and stirred for 30 minutes, and a solution of N-Boc-bromoethylamine (101 mg, 0.45 mmol) in 2 ml of DMF was added and stirred at room temperature overnight. The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 27 mg of a colorless oil with a yield of 27%.

¹ H NMR (300MHz, CDCl ₃ ) δ 4.96 (s, 1H), 3.48-3.28 (m, 6H), 3.16 (t, J=5.9Hz, 4H), 2.58 (t, J=6.7Hz, 2H) ,2.28(s,6H),1.43(s,9H).

Synthesis of Compounds 9-4

Compound 9-3 (27 mg, 0.08 mmol) was dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 19 mg of colorless oil with a yield of 99%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S9

Compound 9-4 (19 mg, 0.08 mmol) and compound 3-2 (33 mg, 0.089 mmol) were dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (0.40 mmol) was added, and stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 15 mg of white solid with a yield of 35%.

¹ H NMR (400 MHz, CD ₃ CN) δ 7.51 (s, 1H), 7.22 (dd, J=6.0, 2.6 Hz, 1H), 7.11 (t, J=8.7 Hz, 1H), 6.94 (dd, J =7.7,4.9Hz,1H),6.16(s,1H),3.53(dd,J=11.4,5.8Hz,2H),3.49–3.37(m,4H),3.37–3.28(m,2H),3.21( t, J=6.8Hz, 2H), 2.75(t, J=6.9Hz, 2H), 2.34(s, 6H).

Example 10 Preparation of compound S10

Synthesis of Compound 10-1

Compound 7-1 (250 mg, 1.13 mmol), 4-(2-bromoethyl)morpholine hydrobromide (372 mg, 1.35 mmol), and cesium carbonate (1.1 g, 3.38 mmol) were dissolved in 5 ml of DMF at room temperature. Stir overnight. The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 340 mg of a colorless oil with a yield of 90%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.79 (t, J=6.4 Hz, 2H), 3.75-3.65 (m, 4H), 3.46 (t, J=6.4 Hz, 2H), 3.20 (t, J= 6.5Hz, 2H), 2.65(t, J=6.5Hz, 2H), 2.50(s, 4H), 1.59–1.48(m, 9H).

Synthesis of Compound 10-2

Compound 10-1 (340 mg, 1.02 mmol) was dissolved in 5 ml of dichloromethane, 1.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 240 mg of a colorless oil with a yield of 99%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound 10-3

Compound 10-2 (250 mg, 1.07 mmol), N-Boc-bromoethylamine (288 mg, 1.284 mmol) in 3 ml DMF, cesium carbonate (1.05 g, 3.21 mmol) were stirred at room temperature overnight. The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 320 mg of a colorless oil with a yield of 79%.

¹ H NMR (300MHz, CDCl ₃ )δ4.98(s,1H), 3.80-3.62(m,4H), 3.47-3.26(m,6H), 3.22-3.05(m,4H), 2.67-2.54(m ,2H),2.52–2.39(m,4H),1.41(s,9H).

Synthesis of Compound 10-4

Compound 10-3 (100 mg, 0.264 mmol) was dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 74 mg of colorless oil with a yield of 99%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S10

Compound 10-4 (74 mg, 0.264 mmol) and compound 3-2 (98 mg, 0.264 mmol) were dissolved in 2 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (1.32 mmol) was added, and the mixture was stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 41 mg of white solid with a yield of 27%.

¹ H NMR (400 MHz, CD ₃ CN) δ 7.53 (s, 1H), 7.21 (dd, J=6.0, 2.7 Hz, 1H), 7.09 (t, J=8.7 Hz, 1H), 6.92 (ddd, J =8.8,4.1,2.8Hz,1H),6.05(t,J=5.8Hz,1H),3.70–3.57(m,4H),3.50(dd,J=11.8,5.9Hz,2H),3.46–3.34( m, 4H), 3.28 (t, J=5.9Hz, 2H), 3.21–3.11 (m, 2H), 2.64 (t, J=6.9Hz, 2H), 2.49 (s, 4H).

Example 11 Preparation of compound S11

Synthesis of Compound 11-1

[1,2,6]thiadiane 1,1-dioxide (100 mg, 0.734 mmol) and sodium hydride (33 mg, 0.808 mmol) were dissolved in 3 ml of DMF solution, and after stirring at room temperature for 30 min, N-Boc-bromine was added. A solution of ethylamine (411 mg, 1.835 mmol) in DMF was then stirred overnight. The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 145 mg of a colorless oil with a yield of 47%.

Synthesis of Compound 11-2

Compound 11-1 (145 mg, 0.343 mmol) was dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, the mixture was concentrated under reduced pressure to obtain 76 mg of colorless oil with a yield of 99%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S11

Compound 11-2 (76 mg, 0.342 mmol) and compound 3-2 (127 mg, 0.342 mmol) were dissolved in 3 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (1.71 mmol) was added, and stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 32 mg of white solid with a yield of 18%.

¹ H NMR (400MHz, CD ₃ CN) δ 7.55 (s, 1H), 7.20 (dd, J=6.0, 2.7Hz, 1H), 7.11 (t, J=8.7Hz, 1H), 6.92 (ddd, J =8.9,4.2,2.7Hz,1H),6.06(s,1H),3.66–3.53(m,2H),3.44(dd,J=10.4,5.3Hz,4H),3.35–3.20(m,4H), 3.01(d,J=5.9Hz,2H),1.90-1.75(m,2H).

Example 12 Preparation of compound S12

Synthesis of Compound 12-1

2,3-Dihydro-1,1-dioxo-1,2-benzisothiazole (150 mg, 0.887 mmol), N-Boc-bromoethylamine (238 mg, 1.064 mmol) and cesium carbonate (867 mg, 2.66 mmol) in 5 ml of DMF and stirred overnight. The next day, after TLC detection was completed, water was added for extraction, and the organic layer was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 124 mg of white solid with a yield of 45%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.78 (d, J=7.8 Hz, 1H), 7.65-7.46 (m, 2H), 7.38 (d, J=7.6 Hz, 1H), 4.43 (s, 2H) ,3.56–3.31(m,4H),1.32(d,J=38.2Hz,9H).

Synthesis of Compound 12-2

Compound 12-1 (100 mg, 0.32 mmol) was dissolved in 3 ml of dichloromethane, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was detected by TLC, concentrated under reduced pressure to obtain 68 mg of white solid with a yield of 100%. Without further processing, it was directly used in the next reaction.

Synthesis of Compound S12

Compound 12-2 (68 mg, 0.32 mmol) and compound 3-2 (132 mg, 0.354 mmol) were dissolved in 3 ml of tetrahydrofuran, 2.5 M aqueous sodium hydroxide solution (1.6 mmol) was added, and stirred at room temperature for 40 min. After the reaction was detected by TLC, water was added. After extraction, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 42 mg of white solid with a yield of 26%.

¹ H NMR (400MHz, CD ₃ CN) δ 8.99 (s, 1H), 7.81 (d, J=7.8Hz, 1H), 7.72 (td, J=7.6, 1.2Hz, 1H), 7.67-7.54 (m ,2H),7.49(s,1H),7.23(dd,J＝6.1,2.8Hz,1H),7.08(t,J＝8.7Hz,1H),6.94(ddd,J＝8.8,4.2,3.0Hz, 1H), 6.12(s, 1H), 4.55(s, 2H), 3.66(q, J=5.9Hz, 2H), 3.55(dd, J=6.4, 5.0Hz, 2H).

Example 13 Preparation of compound S13

Substitute compound 7-1 for isothiazolidine 1,1-dioxide, and synthesize with reference to Example 5.

¹ H NMR (400MHz, CD ₃ CN) δ 9.08 (s, 1H), 7.52 (s, 1H), 7.24 (dd, J=6.0, 2.7Hz, 1H), 7.11 (t, J=8.7Hz, 1H) ),6.95(ddd,J＝8.5,3.8,2.7Hz,1H),6.08(d,J＝5.9Hz,1H),3.79(t,J＝6.4Hz,2H),3.56(dd,J＝12.1, 6.0Hz, 2H), 3.45(t, J=6.4Hz, 2H), 3.31(t, J=6.0Hz, 2H), 1.52(s, 9H).

Example 14 Preparation of compound S14

Substitute 3-(bromomethyl)-1,1-difluorocyclobutane for 2-bromoethyl methyl ether, and synthesize with reference to Example 7.

¹ H NMR (400MHz, CD ₃ CN) δ 9.04 (s, 1H), 7.51 (s, 1H), 7.25 (dd, J=6.1, 2.7Hz, 1H), 7.12 (t, J=8.8Hz, 1H) ),7.03–6.88(m,1H),6.05(s,1H),3.54(dd,J=12.2,6.1Hz,2H),3.40(t,J=6.5Hz,2H),3.33(dd,J= 6.7, 5.6Hz, 2H), 3.28 (t, J=6.1Hz, 2H), 3.11 (d, J=7.4Hz, 2H), 2.80-2.64 (m, 2H), 2.54-2.25 (m, 3H).

Example 15 Preparation of compound S15

The isothiazolidine 1,1-dioxide was replaced with 1,2,3-oxathiazolidine-2,2,dioxide, and the synthesis was carried out with reference to Example 5.

¹ H NMR (300MHz, DMSO) δ 11.48(s, 1H), 8.85(s, 1H), 7.34(t, J=6.8Hz, 1H), 7.15-7.03(m, 2H), 6.52(t, J = 5.6Hz, 1H), 3.92–3.76 (m, 2H), 3.59–3.42 (m, 4H), 3.28 (t, J=6.4Hz, 2H).

Example 16 Preparation of compound S16

Substitute 1-cyclopropyl-2-methoxyethylamine for 2-methoxyethylamine, and synthesize with reference to Example 1.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20 (s, 1H), 7.21 (dd, J=5.9, 2.5 Hz, 1H), 7.02 (t, J=8.4 Hz, 1H), 6.96-6.84 (m, 2H), 6.20(d, J＝7.0Hz, 1H), 4.62(t, J＝5.5Hz, 1H), 3.59(dd, J＝8.3, 4.0Hz, 1H), 3.52–3.32(m, 5H), 3.19–3.06 (m, 1H), 1.03 (dd, J=17.3, 6.9Hz, 1H), 0.58 (t, J=8.3Hz, 3H), 0.30–0.22 (m, 1H).

Example 17

Evaluation of inhibitory activity at the molecular level of IDO

IDO enzyme inhibitory activity measurement method:

The compounds were initially screened in a 96-well plate system, and the initial screening concentration of the compounds was 1 μmol/L, 3-fold gradient dilution, and double wells for each concentration.

Reaction system: 100mM phosphate buffer, 20μmol/L methylene blue, 200μg/ml catalase, 40mmol/L ascorbic acid and 0.01% Triton X-100, rhIDO1 enzyme (0.3μL in 96-well plate), 250μmol/LL-tryptophan , the above concentrations of the compounds to be tested. After 30 minutes of reaction at 37°C, TCA with a final concentration of 30% was added, the reaction solution was heated at 65°C for 15 minutes, DMAB acetic acid solution was added, and a microplate reader was used for detection at a wavelength of 492 nm. The inhibition rate of the compound to rhIDO1 enzyme was calculated according to the following formula.

Analysis of results: inhibition rate=(OD value of control group─OD value of administration group)/(OD value of control group-blankOD value)*100%

Table 1 shows the test results of IDO enzyme activity and polar surface area of each compound.

Table 1 IDO enzyme activity test results and polar surface area (PSA) size:

Example 18

Evaluation of the inhibitory activity of IDO at the cellular level

Compounds were initially screened in a 96-well plate system, and the initial screening concentration was 300 nmol/L gradient 3-fold dilution, two duplicate wells, and the positive compound was Epacadostat (300 nmol/L, 3-fold dilution, 6 concentration gradients).

Reaction system: 293T cells were transfected with recombinant human IDO1 plasmid for 24 hours and then inoculated into a 96-well plate. At the same time, the compound to be tested and 200 μmol/L L-tryptophan were added. After 12 hours of reaction in a 37°C incubator, 30% TCA was added. Heat at 65°C for 20 minutes, take the supernatant and add DMAB acetic acid solution, use a microplate reader to detect the OD value at a wavelength of 492 nm, and calculate the inhibitory rate of the compound on rhIDO1 enzyme according to the following formula.

Result analysis:

Inhibition rate=(OD value of control group-OD value of administration group)/(OD value of control group-blankOD value)*100%

Table 2 shows the test results of IDO cell activity of each compound.

Table 2: IDO cell viability test results

Compound number 293T IC₅₀(nM) S1 20～50 S4 <20 S5 20～50 S7 <20 S8 20～50 S10 20～50 Epacadostat <100

It can be seen from the above that the present invention is based on the structure of Epacadostat, a phase III clinical compound of Incyte Company. In view of its metabolism problem, the chain-like sulfonamide group in the solvent region of the compound is diversified and optimized, and a class of compounds with novel structure is obtained. Strong IDO inhibitory activity was maintained, and some even exceeded the positive control compounds. More importantly, the new compounds have lower polar surface area (PSA). In medicinal chemistry, polar surface area is an important indicator for evaluating the transportability of drugs in cells. Penetration is obviously related, and the general ideal value is When the polar surface area of a molecule is greater than , its penetration into cells will be poor. Therefore, the new compound of the present invention has good drug absorption potential and good market development prospect.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. compound of Formula I, its enantiomter, diastereoisomer, racemic modification, pharmaceutically acceptable salt or solvent close Object:

In formula,

A is-SO₂,-C (=O)-or-S (=O)-；

X is O, S, CH₂Or NH；

Z is CH, N, S, C or O；

R¹To be not present, hydrogen, halogen, hydroxyl, amino, carboxyl, cyano, C1-C6 alkyl sulphonyl, C1-C6 alkanoyl, replace or Unsubstituted C1-C6 alkyl ,-C (=O)-O-C1-C6 alkyl, C2-C6 alkenyl substituted or unsubstituted, C2-C6 alkynes substituted or unsubstituted Base, substituted or unsubstituted C3-C7 naphthenic base, substituted or unsubstituted C3-C7 Heterocyclylalkyl, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-10 unit's heteroaryl；

R²、R³It is independently selected from H, halogen, C1-C6 alkyl or C1-C6 halogenated alkyl or R²And R³Formed with the carbon that is connected replace or Unsubstituted C3-C7 cycloaliphatic ring or substituted or unsubstituted 3-6 circle heterocyclic ring；

N is 1,2,3 or 4；

Or R¹With Z and R²Or R³Substituted or unsubstituted C6-C10 aromatic ring, substituted or unsubstituted is collectively formed with the carbon of connection C3-C7 cycloaliphatic ring, substituted or unsubstituted 5-6 circle heterocyclic ring or substituted or unsubstituted 5-10 member hetero-aromatic ring；

R⁴、R⁵、R⁶、R⁷It is independently selected from hydrogen, C1-C6 alkyl, hydroxyl, halogen, cyano, C3-C6 naphthenic base, 4-6 membered heterocycloalkyl；Or Person, R⁴With R⁵With the carbon or R being connected⁶With R⁷Independently be collectively formed with the carbon being connected substituted or unsubstituted C3-C7 cycloaliphatic ring or Substituted or unsubstituted 3-6 circle heterocyclic ring；

R⁸For hydrogen, halogen, C1-C6 alkyl or C1-C6 halogenated alkyl；

M is 0,1,2,3,4,5,

Wherein, it is each replace independently refer to and replaced by one or more substituent groups selected from the group below: halogen, hydroxyl, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 halogenated alkyl, C3-C6 halogenated cycloalkyl, 3-7 membered heterocycloalkyl, NR⁹R¹⁰；R⁹、R¹⁰Be independently selected from H, C1-C3 alkyl.

2. compound of Formula I as described in claim 1, which is characterized in that R¹To be not present, hydrogen, halogen, hydroxyl, amino, carboxylic Base, cyano, C1-C4 alkyl sulphonyl, C1-C4 alkanoyl, C1-C4 alkyl substituted or unsubstituted ,-C (=O)-O-C1-C4 alkane Base, C2-C4 alkynyl substituted or unsubstituted, substituted or unsubstituted C3-C6 naphthenic base, replaces C2-C4 alkenyl substituted or unsubstituted Or unsubstituted C3-C6 Heterocyclylalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-6 unit's heteroaryl；

The substitution refers to be replaced by one or more substituent groups selected from the group below: halogen, hydroxyl, C1-C3 alkoxy, C1-C3 Alkyl, C1-C3 halogenated alkyl, C3-C6 halogenated cycloalkyl, 3-7 membered heterocycloalkyl, NR⁹R¹⁰；R⁹、R¹⁰It is independently selected from H, C1-C3 alkane Base.

3. compound of Formula I as described in claim 1, which is characterized in that R¹With Z and R²Or R³With the common shape of carbon of connection At C6-C10 aromatic ring, C3-C7 cycloaliphatic ring, 5-6 circle heterocyclic ring or 5-10 member hetero-aromatic ring.

4. compound of Formula I as described in claim 1, which is characterized in that X NH.

5. compound of Formula I as described in claim 1, which is characterized in that R¹To be not present, hydrogen, halogen, hydroxyl, amino, carboxylic Base, cyano, C1-C6 alkyl substituted or unsubstituted ,-C (=O)-O-C1-C6 alkyl, substituted or unsubstituted C3-C7 naphthenic base, Substituted or unsubstituted C3-C7 Heterocyclylalkyl；

Or R¹With Z and R²Or R³C6 aromatic ring is collectively formed with the carbon of connection.

6. compound of Formula I as described in claim 1, which is characterized in that the compound are as follows:

7. the preparation method of general formula compound as described in claim 1, which comprises the following steps:

Compound A1 hydrolysis obtains compound of Formula I,

Wherein, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸, the definition of Z, A, n, X, m it is as described in claim 1.

8. the preparation method of compound as described in claim 1, which comprises the following steps:

Compound A2 and A3 reacts under base catalysis obtains final product compound of Formula I, wherein R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、 R⁸, the definition of Z, A, n, X, m it is as described in claim 1.

9. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes:

Compound, its pharmaceutically acceptable salt or solvate as described in claim 1；With

Pharmaceutically acceptable carrier.

10. compound as described in claim 1, its pharmaceutically acceptable salt or solvate or as claimed in claim 9 The purposes of pharmaceutical composition, which is characterized in that (1) be used to prepare indoleamine 2,3-dioxygenase inhibitor；(2) it is used as indoles amine 2,3- dioxygenase selective depressant；(3) prevention or treatment tumour, alzheimer's disease, autoimmune disease are used to prepare The drug of disease, AIDS, depression or cataract.