CN111763164B

CN111763164B - Preparation method and application of ortho-carbonyl amino substituted benzene derivatives

Info

Publication number: CN111763164B
Application number: CN201910263113.3A
Authority: CN
Inventors: 陈晓光; 崔华清; 文辉; 来芳芳; 王雨辰; 高永鑫; 尹大力; 王婷; 韩建义; 王淑芳; 季鸣; 李燕; 盛莉; 马辰; 张婷婷
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2019-04-02
Filing date: 2019-04-02
Publication date: 2023-03-10
Anticipated expiration: 2039-04-02
Also published as: WO2020199945A1; CN111763164A

Abstract

The invention discloses a compound shown as a formula (I) and a preparation method and application thereof. In particular, the invention further discloses a compound shown as a formula (I), a stereoisomer, a pharmaceutically acceptable salt and a pharmaceutical composition thereof, which can inhibit the enzymatic activity of human indoleamine 2,3-dioxygenase (IDO) and/or human tryptophan 2,3-dioxygenase (TDO), and can be used for preparing medicines for treating and/or preventing diseases or symptoms related to the over-activity or over-expression of IDO/TDO, such as tumor treatment medicines. Hair brushThe Ming compound has stronger IDO inhibitory activity.

Description

Preparation method and application of ortho-carbonyl amino substituted benzene derivatives

Technical Field

The invention belongs to the technical field of medicine development, and particularly relates to ortho-carbonylamino substituted benzene derivatives with IDO/TDO inhibitory activity, a preparation method thereof, a pharmaceutical composition containing the same, an IDO/TDO micromolecule inhibitor containing the same, and application of the compounds in preparing antitumor medicines.

Background

Tryptophan (Tryptophan) is one of eight essential amino acids for human growth and metabolism, and is a nutrient substance essential for human synthesis of protein, neurotransmitter (such as 5-hydroxytryptamine) and the like. Tryptophan in the body is broken down by two metabolic pathways: a small amount of tryptophan (about 5%) is metabolized by tryptophan hydroxylase to produce 5-hydroxytryptamine. The major Tryptophan (about 95%) is metabolized by Indoleamine 2,3-dioxygenase (IDO 2) or Tryptophan 2,3-dioxygenase (TDO) to form kynurenine. Kynurenine further decomposes 3-hydroxyanthranilic acid, quinolinic acid or kynurenic acid, etc. through different routes. Kynurenine, 3-hydroxy anthranilic acid and the like are involved in the regulation of lymphocyte activity so as to cause the inhibition of the immune system.

Indoleamine 2,3-dioxygenase 1 (indolamine 2,3-dioxygenase 1, ido1, ec 1.13.11.42) is a protease involved in tryptophan metabolism. The human IDO1 gene codes for a gene located on human chromosome 8 and consists of 10 exons and 9 introns, approximately 15kb in length. The human IDO1 protein is composed of 403 amino acid residues and has a molecular weight of approximately 42kDa. IDO1 is a monomeric protein containing iron heme, takes superoxide anion as an auxiliary factor, and catalyzes the epoxidation and cleavage of L-tryptophan indole. Although tryptophan is metabolized to kynurenine, being done by IDO1 in combination with TDO, studies indicate that IDO1 is the rate-limiting enzyme of the tryptophan/kynurenine pathway. Indolamine 2,3-dioxygenase 2 (Indolamine 2,3-dioxygenase 2, IDO2) was also found by the investigator in 2007. The IDO2 gene is located downstream of the IDO1 gene, and IDO2 is highly similar to the gene sequence of IDO 1. IDO2 also catalyzes the degradation of tryptophan, but IDO2 is less active and does not play a dominant role compared to IDO 1. IDO2 is closely related to IDO1, and both may be involved in regulating some physiological functions.

IDO from mammals is distributed in tissue cells outside the liver, including macrophages, dendritic cell DCs, monocytes, astrocytes, microglia, tumor cells, and tumor-associated cells. TDO is expressed in liver and has high selectivity to substrate. In healthy humans, IDO1 expression levels are low.

The research on a pregnant mouse model shows that the syncytium trophoblast cells and the antigen presenting cells at the maternal-fetal interface can synthesize the IDO, the dynamic change of the expression of the IDO is consistent with the formation of an embryo, and if the synthesis of the IDO is specifically blocked, the abortion of the mouse can be caused, which indicates that the high expression of indoleamine 2, 3-dioxygenase in placenta tissues can prevent immunological rejection reaction to the fetus. Experimental results show that high expression of indoleamine 2, 3-dioxygenase in tissue cells can cause the immune system of the tissue microenvironment to be inhibited, or immune inhibited or immune checkpoint. One of the mechanisms leading to the immunosuppression is that high expression of indoleamine 2, 3-dioxygenase causes local L-tryptophan depletion, which is felt by surrounding lymphocytes through GCN2 and the like, causing cell cycle arrest or apoptosis of CD8+ cytotoxic T cells. Another mechanism leading to immunosuppression is that high expression of indoleamine 2, 3-dioxygenase results in elevated kynurenine, which can leave the cell after its formation into the extracellular matrix and then enter nearby lymphocytes to regulate CD8+ T cells and regulatory Treg cells by binding AHR transcription factors, the activity of CD8+ cytotoxic T cells is suppressed, and the regulatory Treg cells are increased in number and activated, resulting in immunosuppression.

IDO activation is closely related to the pathogenesis of various diseases, and indoleamine 2, 3-dioxygenase is abnormally and highly expressed in various tumors, including blood tumors, and solid tumors such as colorectal cancer, liver cancer, lung cancer, pancreatic cancer, throat cancer and the like. Tumor cells can recruit dendritic cells expressing IDO1 into a tumor microenvironment, so that high expression of IDO1 also exists in various tumor tissues and draining lymph nodes of human beings, and the expression of IDO1 such as ovarian cancer, lung cancer, chronic lymphocytes, leukemia and the like plays an important regulation role in inhibiting T cell immunity and inducing tumor immune tolerance. The abnormally high expression of indoleamine 2, 3-dioxygenase is positively correlated with the prognosis of tumor poor. Abnormally high expression of indoleamine 2, 3-dioxygenase in tumors may be a major mechanism by which tumor cells escape immune surveillance.

Inhibition of indoleamine 2, 3-dioxygenase activity may activate the suppressed immune system to achieve the effect of inhibiting tumor growth, so that indoleamine 2, 3-dioxygenase inhibitor as an immune checkpoint inhibitor (immune checkpoint inhibitor) has attracted great interest in medicine. Tryptophan 2, 3-dioxygenase (TDO) is also aberrantly highly expressed in many types of tumors, and some tumors also exhibit both IDO and TDO positivity, so it is thought that inhibition of the TDO immune checkpoint may also serve the purpose of tumor therapy. Since normal liver cells express TDO, it is not clear whether TDO inhibitors will affect liver function and normal tryptophan metabolism, but TDO knock-outs are not abnormal in mouse models, suggesting that TDO inhibitors may not affect liver function and normal tryptophan metabolism. The mechanisms by which IDO and TDO cause immunosuppression are essentially the same, so IDO/TDO dual specific inhibitors, which would be suitable for patients with IDO positive, TDO positive, and IDO/TDO double positive, are also of interest to the medical community. However, when the body is infected and inflamed, the expression of IDO1 is obviously increased, and the high expression of indoleamine 2, 3-dioxygenase in the inflammation region can prevent excessive immune response and prevent excessive damage to cell tissues.

Many metabolites of the tryptophan kynurenine metabolic pathway are associated with schizophrenia, depression, neuronal degeneration and indoleamine 2, 3-dioxygenase inhibitors may also be useful in the treatment of these diseases. Kynurenine is converted to kynurenic acid, an NMDA antagonist, by catalysis by kynurenine aminotransferase, which is commonly found in higher kynurenic acid levels in the central nervous system of schizophrenic patients. Quinolinic acid has neurotoxicity and can cause apoptosis and neurodegeneration of nerve cells. Indoleamine 2, 3-dioxygenase is not only involved in tryptophan metabolism, but also in tryptophan metabolism, 5-hydroxytryptamine can be converted into 5-oxindole acetic acid under the catalytic action of indoleamine 2, 3-dioxygenase, and the decrease of 5-hydroxytryptamine can be one of factors causing depression.

The inhibitor aiming at IDO/TDO can liberate the defense system of the body and help T cells to better attack tumors, so that the inhibitor has the potential of treating a wide range of tumors, and the IDO/TDO inhibitor has a wide application prospect, but no IDO/TDO inhibitor is on the market so far, so that the finding and development of a novel efficient IDO inhibitor has important theoretical significance and application value. The current development of indoleamine 2, 3-dioxygenase inhibitors includes Indoxod, NLG-919 (IDO/TDO bispecific) by New Link, epacadostat (INCB 024360) by Incyte, and IDO or TDO inhibitors by BMS, pfizer, flexus, iomet, iteos, curadev, and the like.

In order to find a more medicinal and higher-inhibitory-activity small-molecule IDO/TDO inhibitor, the inventor finds that a group of ortho-carbonylamino-substituted benzene derivatives have high inhibitory activity on indoleamine 2, 3-dioxygenase (IDO) and/or tryptophan 2, 3-dioxygenase (TDO) after a series of researches, have very good exposure (AUC) in a drug animal model, have less in vitro cytotoxicity and have very good growth inhibition effect on a mouse B16F10 melanoma subcutaneous transplantation tumor model. The compounds can effectively inhibit the activity of IDO, and can be widely applied to treating or preventing diseases such as cancers or tumors.

Reference documents:

1.Austin,C.J.；Mizdrak,J.；Matin,A.；Sirijovski,N.；Kosim-Satyaputra,P.；Willows,R.D.；Roberts,T.H.；Truscott,R.J.；Polekhina,G.；Parker,M.W.；Jamie,J.F.,Optimised expression and purification of recombinant human indoleamine 2,3-dioxygenase.Protein Expr Purif 2004,37(2),392-8.

2.Littlejohn,T.K.；Takikawa,O.；Skylas,D.；Jamie,J.F.；Walker,M.J.；Truscott,R.J.,Expression and purification of recombinant human indoleamine 2,3-dioxygenase.Protein Expr Purif 2000,19(1),22-9.

3.Pham,K.N.；Yeh,S.R.,Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1.J Am Chem Soc 2018,140(44),14538-14541.

4.Weng,T.；Qiu,X.；Wang,J.；Li,Z.；Bian,J.,Recent discovery of indoleamine-2,3-dioxygenase 1inhibitors targeting cancer immunotherapy.Eur J Med Chem2018,143,656-669.

5.Yang,S.；Li,X.；Hu,F.；Li,Y.；Yang,Y.；Yan,J.；Kuang,C.；Yang,Q.,Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenase with therapeutic activity in Lewis lung cancer(LLC)tumor-bearing mice.J Med Chem 2013,56(21),8321-31.

6.Yue,E.W.；Douty,B.；Wayland,B.；Bower,M.；Liu,X.；Leffet,L.；Wang,Q.；Bowman,K.J.；Hansbury,M.J.；Liu,C.；Wei,M.；Li,Y.；Wynn,R.；Burn,T.C.；Koblish,H.K.；Fridman,J.S.；Metcalf,B.；Scherle,P.A.；Combs,A.P.,Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model.J Med Chem 2009,52(23),7364-7.

disclosure of Invention

The technical problem to be solved by the invention is to provide a compound which has a novel structure and strong activity and human-derived IDO and/or TDO inhibitory activity. The inventor finds that: the ortho-carbonyl amino disubstituted benzene derivatives are divided into open-loop and closed-loop, wherein a plurality of closed-loop lactone compounds are rapidly metabolized and opened into related open-loop compounds by esterase in vivo.

The ortho-carbonyl amino substituted benzene derivative has strong IDO inhibitory activity (IC with the strongest inhibitory activity) ₅₀ Is 10 ^-12 mol/L) and moderate TDO inhibitory activity, the compounds being selective for the inhibitory activity of IDO and TDO. The activity data of the compounds of the invention are compared with those of the comparative compounds and we conclude that the structural activity relationship is as follows:

a, in general, the IDO inhibitory activity of ring-opened compounds of the same substituent group is higher (about 100-fold stronger) than that of the corresponding ring-closed compounds.

In the general formula I, the S element is very important for maintaining the inhibiting activity of IDO, and the existence of the element S is the most ideal state of the framework. In contrast, when the position of element S is selected from O, N or C, the IDO inhibitory activity of the ring-opened and ring-closed compounds is almost absent.

c, only one CH can be present between the element S and the left aromatic ring, and only one CH must be present ₂ Absence or two or more CH ₂ In this case, the inhibitory activity of IDO was weak. However, this CH ₂ There may be small or flexible substituent groups.

d, R on the left side of the skeleton ₁ The group must be aromatic to have IDO inhibitory activity, R ₁ When the radicals are other than aromaticNo or weak IDO inhibitory activity. R is ₁ In the case of aromatic groups, the best choice of substituents is para-substituted and favored with lipophilic groups, and electron withdrawing groups slightly better than electron donating groups. However, after the long-chain alkyl is substituted on the aromatic group, the strong IDO inhibition activity can be still achieved by tolerating the hydrophilic group connected to the chain end.

e, R on the aromatic radical on the right side of the skeleton _2a 、R _2b 、R _2c 、R _2d The substituent groups tend to be small, fat-soluble groups.

f, for ring-opened compounds of formula IB, n may be selected from 0,1,2. Direct linkage of the carbonyl group to the benzene ring is preferred, but the presence of 1-2 CH's between the carbonyl group and the benzene ring is also permissible ₂ . The compounds with the end group of the chain being carboxylic acid, amide and ester all have IDO inhibitory activity.

Finally, the compounds have good drug forming property and growth inhibition effect on mice subcutaneous transplanted tumors, and can be used for preparing drugs for preventing and treating tumors related to IDO/TDO mediated immune evasion. The present invention has been completed based on the above findings.

Summary of The Invention

A compound according to any one of the first aspect of the invention, said compound being of formula (I) and stereoisomers thereof, and pharmaceutically acceptable salts thereof:

wherein:

when in use

And

the single dotted line therebetween is a chemical single bond;

is selected from

Selected from the group consisting of element O or element S;

selected from the group consisting of element C; n =0;

when in use

And

the single dashed line in between is absent;

is selected from

Selected from OR ₅ Or NR ₆ R ₇ ；

Is selected from

Or

n =0, 1 or 2;

R ₁ independently selected from phenyl, naphthyl, 5-14 membered aromatic heterocyclic group;

wherein the phenyl, naphthyl or 5-14 membered aromatic heterocyclic group is unsubstituted or substituted with 1,2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-8 Alkyl, substitutedOr unsubstituted C _2-8 Alkenyl, substituted or unsubstituted C _2-8 Alkynyl, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 3-to 8-membered heterocyclic group, substituted or unsubstituted 5-to 10-membered aromatic heterocyclic group, substituted or unsubstituted R ₈ -O-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -O-C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₈ -O-S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O) ₂ -O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -S(O) ₂ -N-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₉ -C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₁₀ R ₉ N-C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -O-C(O)-N-C _0-8 Alkylene-, - (meth) acrylic acid,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted C _2-8 An alkenyl group,Substituted or unsubstituted C _2-8 Alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-to 10-membered aromatic heterocyclic group, substituted or unsubstituted R ₈ -O-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -O-C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₈ -O-S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O) ₂ -O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -S(O) ₂ -N-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₉ -C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₁₀ R ₉ N-C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -O-C(O)-N-C _0-8 Alkylene-;

R ₃ 、R ₄ independently selected from hydrogen, deuterium, halogen, trifluoromethyl, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted C _2-8 Alkenyl, substituted or unsubstituted C _2-8 Alkynyl;

R ₅ 、R ₆ 、R ₇ independently selected from hydrogen, deuterium, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted C _2-8 Alkenyl, substituted or unsubstituted C _2-8 Alkynyl, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstitutedUnsubstituted naphthyl, substituted or unsubstituted 3-to 8-membered heterocyclic group, substituted or unsubstituted 5-to 10-membered aromatic heterocyclic group;

R ₈ 、R ₉ 、R ₁₀ independently selected from hydrogen, deuterium, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted C _2-8 Alkenyl, substituted or unsubstituted C _2-8 Alkynyl, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 3-to 8-membered heterocyclic group, substituted or unsubstituted 5-to 10-membered aromatic heterocyclic group;

said substituted substituent is selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, carboxamido, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _5-10 Aryl, 5-to 10-membered aromatic heterocyclic group, C _1-8 Alkyloxy, C _1-8 Alkyl carbonyl, C _1-8 Alkyl oxycarbonyl radical, C _1-8 Alkylcarbonyloxy, C _1-8 Alkylamido radical, C _1-8 Alkylaminocarbonyl radical, C _1-8 Alkyl ureido radical, C _1-8 Alkyloxycarbonylamino group, C _2-8 Alkenyloxy radical, C _2-8 Alkenylamido, C _2-8 Alkenyl ureido, C _2-8 Alkynyl oxy, C _2-8 Alkynyloxycarbonyl, C _2-8 Alkynyl ureido, C _5-10 Aryloxy radical, C _5-10 Arylamido, C _5-10 Aryloxycarbonylamino, 5-10 membered heterocyclyloxy, 5-10 membered heterocyclylamino, mono-C _1-8 Alkylamino or di-C _1-8 Alkylamino, di-C _2-8 Alkynyl amino, mono C _5-10 Arylamino, mono 5-to 10-membered aromatic heterocyclylamino;

the 5-to 10-membered aromatic heterocyclic group, the 5-to 14-membered aromatic heterocyclic group and the 3-to 8-membered heterocyclic group may contain 1, 2, 3 or 4 hetero atoms selected from N, O and S;

but does not contain the following compounds:

a compound according to any one of the first aspect of the invention, said compounds and pharmaceutically acceptable salts thereof, wherein preferred compounds are represented by general formula IA;

wherein:

selected from the group consisting of element O or element S;

wherein the phenyl, naphthyl or 5-14 membered aromatic heterocyclic group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted C _2-8 Alkenyl, substituted or unsubstituted C _2-8 Alkynyl, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 3-to 8-membered heterocyclic group, substituted or unsubstituted 5-to 10-membered aromatic heterocyclic group, substituted or unsubstituted R ₈ -O-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -O-C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₈ -O-S(O) ₂ -C _0-8 Alkylene- & ltwbr & gt,Substituted or unsubstituted R ₈ -S(O) ₂ -O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -S(O) ₂ -N-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₉ -C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₁₀ R ₉ N-C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -O-C(O)-N-C _0-8 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted C _2-8 Alkenyl, substituted or unsubstituted C _2-8 Alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-to 10-membered aromatic heterocyclic group, substituted or unsubstituted R ₈ -O-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -O-C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₈ -O-S(O) ₂ -C _0-8 Alkylene-, substituted or unsubstituted R ₈ -S(O) ₂ -O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-S(O) ₂ -C _0-8 Alkylene-, or alkylideneSubstituted or unsubstituted R ₉ R ₈ -S(O) ₂ -N-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ N-C(O)-C _0-8 Alkylene-, substituted or unsubstituted R ₉ -C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₁₀ R ₉ N-C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -O-C(O)-N-C _0-8 Alkylene-;

R ₃ 、R ₄ independently selected from hydrogen, deuterium, halogen, trifluoromethyl, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted C _2-8 Alkenyl, substituted or unsubstituted C _2-8 An alkynyl group;

R ₈ 、R ₉ 、R ₁₀ independently selected from hydrogen, deuterium, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted C _2-8 Alkenyl, substituted or unsubstituted C _2-8 Alkynyl, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted 5-to 10-membered arylheterocyclyl;

said substituted substituent is selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, carboxamido, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _5-10 Aryl, 5-to 10-membered aromatic heterocyclic group, C _1-8 Alkyloxy, C _1-8 Alkyl carbonyl, C _1-8 Alkyl oxycarbonyl radical, C _1-8 Alkylcarbonyloxy, C _1-8 Alkylamido radical, C _1-8 Alkylaminocarbonyl radical, C _1-8 Alkyl ureido radical, C _1-8 Alkyloxycarbonylamino, C _2-8 Alkenyloxy radical, C _2-8 Alkenylamido, C _2-8 Alkenyl ureido, C _2-8 Alkynyl oxy, C _2-8 Alkynyloxycarbonyl, C _2-8 Alkynyl ureido, C _5-10 Aryloxy radical, C _5-10 Arylamido, C _5-10 Aryloxycarbonylamino, 5-10 membered heterocyclyloxy, 5-10 membered heterocyclylamino, mono-C _1-8 Alkylamino or di-C _1-8 Alkylamino radical, di-C _2-8 Alkynyl amino, mono C _5-10 Arylamino, mono 5-to 10-membered aromatic heterocyclylamino;

but does not contain the following compounds:

the compounds according to any one of the first aspect of the present invention, said compounds and pharmaceutically acceptable salts thereof, characterized in that they are preferably

Selected from element O or element S;

wherein said phenyl, naphthyl, 5-14 membered heteroaromatic group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxy, carbamoyl, aminosulfonyl, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Alkyl radical, C _1-8 Alkoxy radical, X _g C _1-8 Alkyl radical, X _g C _1-8 Alkoxy radical, X _g C _2-8 Alkenyl radical, X _g C _2-8 Alkynyl, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstituted phenyl, R ₈ -C _1-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C _1-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-S (O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-S(O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -N(R ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -N (R) ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C (O) -N (R) ₉ )-C _0-8 Alkylene-, - (meth) acrylic acid,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, mercapto, amino, carboxylic acid group, carbamoyl, aminosulfonyl, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Alkyl radical, C _1-8 Alkoxy radical, X _g C _1-8 Alkyl radical, X _g C _1-8 Alkoxy radical, X _g C _2-8 Alkenyl radical, X _g C _2-8 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-8 Alkylene oxideRadical-, substituted or unsubstituted phenyl, R ₈ -C _0-8 alkylene-O-C _1-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-S (O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-S(O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -N(R ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -N (R) ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C (O) -N (R) ₉ )-C _0-8 Alkylene-;

R ₃ 、R ₄ independently selected from hydrogen, deuterium, fluorine, chlorine, X _g C _1-8 Alkyl radical, C _1-8 Alkyl radical, X _g C _2-8 Alkenyl radical, C _2-8 Alkenyl radical, X _g C _2-8 Alkynyl, C _2-8 An alkynyl group;

R ₈ is selected from C _1-8 Alkyl radical, X _g C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 <xnotran> , , , , , </xnotran>Substituted or unsubstituted pyridazine;

R ₉ 、R ₁₀ independently selected from hydrogen, deuterium, C _1-8 Alkyl radical, X _g C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 An alkynyl group;

the above-mentioned substituted substituent is selected from deuterium, halogen, hydroxyl group, mercapto group, amino group, cyano group, nitro group, azido group, methanesulfonyl group, isopropylsulfonyl group, benzenesulfonyl group, aminosulfonyl group, methanesulfonate group, isopropylsulfonate group, benzenesulfonate group, methoxy group, trifluoromethyl group, trifluoromethyloxy group, acetylamino group, carbamoyl group, methylamino group, dimethylamino group, diethylamino group, carboxylic acid group, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Alkoxy radical, C _5-10 Aryl, 5-10 membered aromatic heterocyclic group;

x is above _g Wherein X is selected from halogen: fluorine, chlorine, bromine or iodine; g is selected from 1, 2, 3, 4 or 5;

the 5-14 membered aromatic heterocyclic group and the 5-10 membered aromatic heterocyclic group may contain 1, 2, 3 or 4 heteroatoms selected from N, O and S;

but does not contain the following compounds:

Selected from the group consisting of element O or element S;

R ₁ independently selected from the following aromatic or heteroaromatic groups: phenyl, naphthyl, pyridyl, quinolyl, furyl, thienyl, isoxazolyl, benzoxazolyl, acridinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzofuryl, phenylAn imidazolyl group;

these aromatic or heteroaromatic groups are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid, carbamoyl, aminosulfonyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, X _g C _1-6 Alkyl radical, X _g C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, X _g C _2-6 Alkenyl radical, X _g C _2-6 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, R ₈ -C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-S(O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -N(R ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-6 Alkylene-, R ₈ -C _0-6 Alkylene oxideradical-O-C (O) -N (R) ₉ )-C _0-6 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, mercapto, amino, carboxylic acid group, carbamoyl, aminosulfonyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, X _g C _1-6 Alkyl radical, X _g C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-6 Alkylene-, substituted or unsubstituted phenyl, R ₈ -C _0-6 alkylene-O-C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-S(O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -N(R ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-6 Alkylene radical-、R ₈ -C _0-6 alkylene-O-C (O) -N (R) ₉ )-C _0-6 Alkylene-;

R ₃ 、R ₄ independently selected from hydrogen, deuterium, fluorine, chlorine, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, X _g C _1-6 Alkyl radical, X _g C _2-6 Alkenyl radical, X _g C _2-6 An alkynyl group;

R ₈ is selected from C _1-6 Alkyl radical, X _g C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine;

R ₉ 、R ₁₀ independently selected from hydrogen, deuterium, C _1-6 Alkyl radical, X _g C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 An alkynyl group;

said optionally substituted substituents are selected from the group consisting of deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy, phenyl, naphthyl, 5-6 membered aromatic heterocyclic group;

the 5-to 6-membered aromatic heterocyclic group may contain 1, 2, 3 or 4 heteroatoms selected from N, O, S;

but does not contain the following compounds:

the compounds according to any of the first aspect of the present invention, said compounds and pharmaceutically acceptable salts thereof, are characterized by being preferred

The compound is shown as a general formula IA1

R ₁ Independently selected from the following aromatic cyclic or heterocyclic groups: phenyl, naphthyl, pyridyl, quinolyl, furyl, thienyl, isoxazolyl, benzoxazolyl, acridinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzofuryl, benzimidazolyl;

these aromatic or heteroaromatic groups are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid, carbamoyl, aminosulfonyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, X _g C _1-6 Alkyl radical, X _g C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, X _g C _2-6 Alkenyl radical, X _g C _2-6 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, R ₈ -C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-S(O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -N(R ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -N (R) ₉ )-C _0-6 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid group, carbamoyl, aminosulfonyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, X _g C _1-6 Alkyl radical, X _g C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-6 Alkylene-, substituted or unsubstituted phenyl, R ₈ -C _0-6 alkylene-O-C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 Alkylene oxideradical-O-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-S(O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -N(R ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -N (R) ₉ )-C _0-6 Alkylene-;

R ₃ 、R ₄ independently selected from hydrogen, deuterium, fluorine, chlorine, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, X _g C _1-6 Alkyl radical, X _g C _2-6 Alkenyl radical, X _g C _2-6 Alkynyl;

above X _g Wherein X is selected from halogen: fluorine, chlorine, bromine or iodine; g is selected from 1, 2, 3, 4 or 5;

but does not contain the following compounds:

R ₁ Independently selected from the following aromatic or heteroaromatic groups: phenyl, naphthyl, pyridyl, quinolyl, furyl, thienyl, isoxazolyl, benzoxazolyl, acridinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzofuryl, benzimidazolyl;

these aromatic or heteroaromatic groups are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid, carbamoyl, aminosulfonyl, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkyl radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, X _g C _2-4 Alkenyl radical, X _g C _2-4 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, R ₈ -C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -O-C ₀₄ Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-S (O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-S(O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -N(R ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -N (R) ₉ )-C _0-4 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, mercapto, amino, carboxylic acid group, carbamoyl, aminosulfonyl, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkyl radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-4 Alkylene-, substituted or unsubstituted phenyl, R ₈ -C _0-4 alkylene-O-C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-S (O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-S(O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -N(R ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -N (R) ₉ )-C _0-4 Alkylene-;

R ₃ 、R ₄ independently selected from hydrogen, deuterium, fluorine, chlorine, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, X _g C _1-4 Alkyl radical, X _g C _2-4 Alkenyl radical, X _g C _2-4 An alkynyl group;

R ₈ is selected from C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine;

R ₉ 、R ₁₀ independently selected from hydrogen, deuterium, C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 An alkynyl group;

said optionally substituted substituents are selected from the group consisting of deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, phenyl, naphthyl, 5-6 membered aromatic heterocyclic group;

but does not contain the following compounds:

the compound according to any one of the first aspect of the present invention, said compound and pharmaceutically acceptable salts thereof, wherein preferably said compound is represented by formula IA2,

R _11a 、R _11b 、R _11c 、R _11d 、R _11e independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, sulfydryl, amino, cyano, nitro, azido methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, mesylate, and salt ethanesulfonate, propanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, acetylamino, carbamoyl, methylamino, dimethylaminoAmino, ethylamino, diethylamino, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, X _g C _2-4 Alkenyl radical, C _2-4 Alkynyl, X _g C _2-4 Alkynyl, HOC _1-4 Alkyl, NH ₂ C _1-4 Alkyl, substituted or unsubstituted phenyl, R ₈ -C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -N(R ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C _0-4 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, mesylate, ethylsulfonate, propylsulfonate, isopropylsulfonate, phenylsulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, substituted or unsubstituted phenyl;

R ₃ 、R ₄ independently selected from hydrogen, deuterium, fluorine, chlorine, X _g C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl;

R ₉ independently selected from hydrogen, deuterium, C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 An alkynyl group;

said substituted substituent is selected from the group consisting of deuterium, fluoro, chloro, bromo, iodo, hydroxy, mercapto, amino, cyano, nitro, azido, methylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, ethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, phenyl, naphthyl, 5-6 membered aromatic heterocyclic group;

but does not contain the following compounds:

the compound according to any one of the first aspect of the present invention, said compound and pharmaceutically acceptable salts thereof, wherein the preferred compound is represented by formula IA 3;

R _11a 、R _11b 、R _11c 、R _11d 、R _11e Independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, ethanesulfonate, propanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, ethylamino, diethylamino, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, X _g C _2-4 Alkenyl radical, C _2-4 Alkynyl, X _g C _2-4 Alkynyl, HOC _1-4 Alkyl, NH ₂ C _1-4 Alkyl, substituted or unsubstituted phenyl, R ₈ -C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -N(R ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C _0-4 Alkylene-, - (meth) acrylic acid,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, sulfydryl, amino, cyano, nitro, azido, methylsulfonyl ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenylsulfonyl aminosulfonyl, methanesulfonate, ethanesulfonate, Propyl sulfonate, isopropyl sulfonate, phenyl sulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, substituted or unsubstituted phenyl;

R ₃ 、R ₄ independently selected from hydrogen, deuterium, fluorine, chlorine, X _g C _1-4 Alkyl radical, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 An alkynyl group;

the above-mentioned substituted substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, ethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, phenyl, naphthyl, 5-6 membered aromatic heterocyclic group;

the 5-6 membered aromatic heterocyclic group may contain 1, 2, 3 or 4 heteroatoms selected from N, O, S;

but does not contain the following compounds:

the compound according to any one of the first aspect of the present invention, said compound and pharmaceutically acceptable salts thereof, wherein the preferred compound is represented by formula IB;

selected from OR ₅ Or NR ₆ R ₇ ；

Is selected from

Or

n =0, 1 or 2;

wherein said phenyl, naphthyl, 5-14 membered aromatic heterocyclic group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid, carbamoyl, aminosulfonyl, C _1-8 Alkyl radical, C _1-8 Alkoxy radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, X _g C _1-8 Alkyl radical, X _g C _1-8 Alkoxy radical, X _g C _2-8 Alkenyl radical, X _g C _2-8 Alkynyl, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstitutedPhenyl, R ₈ -C _1-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C _1-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-S (O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-S(O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -N(R ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -N (R) ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C (O) -N (R) ₉ )-C _0-8 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid group, carbamoyl, aminosulfonyl, C _1-8 Alkyl radical, C _1-8 Alkoxy radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, X _g C _1-8 Alkyl radical, X _g C _1-8 Alkoxy radical, X _g C _2-8 Alkenyl, X _g C _2-8 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-8 Alkylene-, substituted or unsubstituted phenyl, R ₈ -C _0-8 alkylene-O-C _1-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-S (O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -O-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-S(O) ₂ -C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-S (O) ₂ -N(R ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-C (O) -N (R) ₉ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-8 Alkylene-, R ₈ -C _0-8 alkylene-O-C (O) -N (R) ₉ )-C _0-8 Alkylene-;

R ₅ 、R ₆ 、R ₇ independently selected from hydrogen, deuterium, X _g C _1-8 Alkyl radical、C _1-8 Alkyl radical, X _g C _2-8 Alkenyl radical, C _2-8 Alkenyl radical, X _g C _2-8 Alkynyl, C _2-8 Alkynyl, substituted or unsubstituted C _3-8 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted phenyl C _1-4 Alkylene radical, C _1-4 alkyl-O-C _1-4 Alkylene radical, C _0-4 alkyl-CH ₂ ＝CH ₂ -C _1-4 An alkylene group;

R ₈ is selected from C _1-8 Alkyl radical, X _g C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine;

R ₉ 、R ₁₀ independently selected from hydrogen, deuterium, C _1-8 Alkyl radical, X _g C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl;

said substituted substituent is selected from deuterium, halogen, hydroxy, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Alkoxy radical, C _5-10 Aryl, 5-10 membered aromatic heterocyclic group;

but does not contain the following compounds:

a compound according to any one of the first aspect of the invention, preferably said compound and pharmaceutically acceptable salts thereof;

is selected from OR ₅ Or NR ₆ R ₇ ；

Is selected from

Or

n =0, 1 or 2;

These aromatic or heteroaromatic groups are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid, carbamoyl, aminosulfonyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, X _g C _1-6 Alkyl radical, X _g C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, X _g C _2-6 Alkenyl radical, X _g C _2-6 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, R ₈ -C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C _1-6 Alkylene radical-、R ₈ -C _0-6 alkylene-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-S(O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -N(R ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -N (R) ₉ )-C _0-6 Alkylene-, - (meth) acrylic acid,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, mercapto, amino, carboxylic acid group, carbamoyl, aminosulfonyl, X _g C _1-6 Alkyl radical, X _g C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-6 Alkylene-, substituted or unsubstituted phenyl, R ₈ -C _0-6 alkylene-O-C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-S(O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -N(R ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -N (R) ₉ )-C _0-6 Alkylene-;

R ₅ 、R ₆ 、R ₇ independently selected from hydrogen, deuterium, X _g C _1-6 Alkyl radical, C _1-6 Alkyl radical, X _g C _2-6 Alkenyl radical, C _2-6 Alkenyl radical, X _g C _2-6 Alkynyl, C _2-6 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstitutedPyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted phenyl C _1-4 Alkylene radical, C _1-4 alkyl-O-C _1-4 Alkylene radical, C _0-4 alkyl-CH ₂ ＝CH ₂ -C _1-4 An alkylene group;

above X _g Wherein X is selected from halogen: fluorine, chlorine, bromine or iodine; _g selected from 1, 2, 3, 4 or 5;

but does not contain the following compounds:

The compound according to any one of the first aspect of the invention, preferably said compound and pharmaceutically acceptable salts thereof,

characterized in that the compound is shown as a general formula IB1

Is selected from OR ₅ Or NR ₆ R ₇ ；

n =0, 1 or 2;

these aromatic or heteroaromatic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid, carbamoyl, aminosulfonyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, X _g C _1-6 Alkyl radical, X _g C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, X _g C _2-6 Alkenyl, X _g C _2-6 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, R ₈ -C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-S(O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -N(R ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -N (R) ₉ )-C _0-6 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxyl, mercapto, amino, carboxylic acid group, carbamoyl, aminosulfonyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, X _g C _1-6 Alkyl radical, X _g C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-6 Alkylene-, substituted or unsubstituted phenyl, R ₈ -C _0-6 alkylene-O-C _1-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-S (O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -O-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-S(O) ₂ -C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-S (O) ₂ -N(R ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-C (O) -N (R) ₉ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-6 Alkylene-, R ₈ -C _0-6 alkylene-O-C (O) -N (R) ₉ )-C _0-6 Alkylene-;

R ₅ 、R ₆ 、R ₇ independently selected from hydrogen, deuterium, X _g C _1-6 Alkyl radical, C _1-6 Alkyl radical, X _g C _2-6 Alkenyl radical, C _2-6 Alkenyl, X _g C _2-6 Alkynyl, C _2-6 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted phenyl C _1-4 Alkylene radical, C _1-4 alkyl-O-C _1-4 Alkylene radical, C _0-4 alkyl-CH ₂ ＝CH ₂ -C _1-4 An alkylene group;

R ₈ is selected from C _1-6 Alkyl radical, X _g C _1-6 Alkyl radical、C _2-6 Alkenyl radical, C _2-6 Alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine;

the 5-6 membered aromatic heterocyclic group may contain 1, 2, 3 or 4 heteroatoms selected from N, O and S.

The compound according to any one of the first aspect of the present invention, preferably said compound and pharmaceutically acceptable salts thereof, characterized in that,

selected from OR ₅ Or NR ₆ R ₇ ；

n =0, 1 or 2;

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, hydroxy, mercapto, amino, carboxylic acid group, carbamoyl, aminosulfonyl, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkyl radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-4 Alkylene-, substituted or unsubstituted phenyl, R ₈ -C _0-4 alkylene-O-C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-S (O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-S(O) ₂ -C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -N(R ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C(O)-N(R ₁₀ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -N (R) ₉ )-C _0-4 Alkylene-;

R ₅ 、R ₆ 、R ₇ independently selected from hydrogen, deuterium, X _g C _1-4 Alkyl radical, C _1-4 Alkyl radical, X _g C _2-4 Alkenyl radical, C _2-4 Alkenyl radical, X _g C _2-4 Alkynyl, C _2-4 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted phenyl C _1-4 Alkylene radical, C _1-4 alkyl-O-C _1-4 Alkylene radical, C _0-4 alkyl-CH ₂ ＝CH ₂ -C _1-4 An alkylene group;

the 5-to 6-membered aromatic heterocyclic group may contain 1, 2, 3 or 4 heteroatoms selected from N, O and S.

The compound according to any one of the first aspect of the present invention, preferably said compound and pharmaceutically acceptable salts thereof, wherein the compound is represented by formula IB 2;

selected from OR ₅ Or NR ₆ R ₇ ；

n =0, 1 or 2;

R _12a 、R _12b 、R _12c 、R _12d 、R _12e independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, mesylate, ethylsulfonate, propylsulfonate, isopropylsulfonate, phenylsulfonate, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, X _g C _2-4 Alkenyl radical, C _2-4 Alkynyl, X _g C _2-4 Alkynyl, substituted or unsubstituted phenyl, R ₈ -C _1-4 Alkylene- & ltwbr & gt,R ₈ -C _0-4 alkylene-O-C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -N(R ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C _0-4 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkyloxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, substituted or unsubstituted phenyl;

R ₅ 、R ₆ 、R ₇ independently selected from hydrogen, deuterium, X _g C _1-4 Alkyl radical, C _1-4 Alkyl radical, X _g C _2-4 Alkenyl radical, C _2-4 Alkenyl, X _g C _2-4 Alkynyl, C _2-4 Alkynyl, substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted phenyl C _1-4 An alkylene group,C _1-4 alkyl-O-C _1-4 Alkylene radical, C _0-4 alkyl-CH ₂ ＝CH ₂ -C _1-4 An alkylene group;

the above-mentioned substituted substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Alkoxy, phenyl, naphthyl, 5-6 membered aromatic heterocyclic group;

The compounds, compounds and pharmaceutically acceptable salts thereof according to any one of the first aspect of the present invention are characterized in that preferred compounds are represented by formula IB 3;

Is selected from OR ₅ Or NR ₆ R ₇ ；

R _12a 、R _12b 、R _12c 、R _12d 、R _12e Independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, ethanesulfonate, propanesulfonate, isopropylsulfonate, benzenesulfonate, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl, X _g C _2-4 Alkenyl radical, C _2-4 Alkynyl, X _g C _2-4 Alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, R ₈ -C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -N(R ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C _0-4 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, sulfydryl, amino, cyano, nitro, azido, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, methanesulfonate, ethylsulfonate, propylsulfonate, isopropylsulfonate, phenylsulfonate, acetylamino, aminosulfonic acid, and the like Formyl, methylamino, dimethylamino, diethylamino, carboxylic acid radical, C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkyloxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, substituted or unsubstituted phenyl;

R ₅ 、R ₆ 、R ₇ independently selected from hydrogen, deuterium, X _g C _1-4 Alkyl radical, C _1-4 Alkyl radical, X _g C _2-4 Alkenyl radical, C _2-4 Alkenyl, X _g C _2-4 Alkynyl, C _2-4 Alkynyl, substituted or unsubstituted cyclopropane, substituted or unsubstituted cyclobutane, substituted or unsubstituted cyclopentane, substituted or unsubstituted cyclohexane, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted phenyl C _1-4 Alkylene radical, C _1-4 alkyl-O-C _1-4 Alkylene radical, C _0-4 alkyl-CH ₂ ＝CH ₂ -C _1-4 An alkylene group;

R ₉ independently selected from hydrogen, deuterium, C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl;

the substituted substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, sulfydryl, amino, cyano, nitro, azido, methylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, methylsulfonyl, isopropylsulfonate, phenylsulfonate, methoxy, trifluoromethyl Alkyl, trifluoromethyloxy, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid group, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 An alkoxy group;

the compound according to any one of the first aspect of the present invention, said compound and pharmaceutically acceptable salts thereof, wherein the preferred compound is represented by formula IB 4;

is selected from OR ₅ Or NR ₆ R ₇ ；

R _12a 、R _12b 、R _12c 、R _12d 、R _12e Independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, mesylate, ethylsulfonate, propylsulfonate, isopropylsulfonate, phenylsulfonate, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkoxy radical, C _2-4 Alkenyl, X _g C _2-4 Alkenyl radical, C _2-4 Alkynyl, X _g C _2-4 Alkynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, R ₈ -C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C _1-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -O-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-S (O) ₂ -N(R ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-O-C (O) -N (R) ₉ )-C _0-4 Alkylene-, R ₈ -C _0-4 alkylene-N (R) ₉ )-C _0-4 Alkylene- & ltwbr & gt,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, ethanesulfonate, propanesulfonate, isopropylsulfonate, benzenesulfonate, acetylamino, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, X _g C _1-4 Alkyl radical, C _1-4 Alkoxy radical, X _g C _1-4 Alkyloxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, substituted or unsubstituted phenyl;

said substituted substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetamido, carbamoyl, methylamino, dimethylamino, diethylamino, carboxylic acid, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 An alkoxy group;

but does not contain the following compounds:

the pharmaceutically acceptable salts described in the present invention are salts of the compounds of the present invention with an acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. Preferably hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid or trifluoroacetic acid.

A compound according to any one of the first aspect of the present invention, which is the subject compound of the present invention prepared in the examples (represented by structural formula or described by systematic name) and stereoisomers thereof, and pharmaceutically acceptable salts thereof. The compound according to any one of the first aspect of the invention, preferably it is a compound selected from the group consisting of:

meanwhile, in order to better investigate the relationship between the backbone of the compound of this patent and the IDO/TDO inhibitory activity, we prepared 25 comparative compounds (C-001 to C-025) as follows:

in a second aspect, the present invention provides a process for the preparation of a compound according to any one of the first aspect of the invention, comprising the steps of:

synthesis of Ring-opened Compound:

a. triphosgene (1 eq) was dissolved in 5 ml of anhydrous dichloromethane and kept at 0 ℃ in ice bath; slowly dropwise adding benzyl mercaptan (3 equivalents) into the reaction solution, then slowly dropwise adding anhydrous pyridine (3 equivalents) in anhydrous dichloromethane (1 ml), stirring the reaction solution in ice bath for 10 minutes, then returning to room temperature and stirring for about 2 hours, and detecting the end of the reaction by thin layer chromatography. The reaction intermediate is very active and is directly used in the next step.

b. Adding anthranilic acid (2 equivalents) into 5 ml of anhydrous dichloromethane, keeping an ice bath, adding N, N-diisopropylethylamine (4 equivalents), slowly dripping the solution a into the solution, removing the ice bath, heating and refluxing for about 2 hours, and detecting the completion of the reaction by thin layer chromatography. Extraction with dichloromethane (30 ml. Times.3) and water (30 ml), concentration of the organic phase and column chromatography gave the product.

Synthesis of the ring-closing compound:

the various corresponding ring-opened compounds, i.e. substituted 2- (((benzyl) thio) carbonyl) amino) benzoic acid (1 eq) were dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (1 eq) and 4-dimethylaminopyridine (trace) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml x 3 times) and water (30 ml), the organic phase was concentrated and separated by column chromatography to give the ring-closed final product.

In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.

The fourth aspect of the present invention provides the use of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention in the manufacture of a medicament for the treatment and or prevention of a disease or condition associated with excessive IDO/TDO activity or with excessive IDO/TDO expression. In one embodiment, the disease or condition associated with too high IDO/TDO activity or overexpression of IDO/TDO is a disease or condition selected from the group consisting of: a tumor.

The fourth aspect of the present invention also provides a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention for use in the preparation of a medicament for the treatment and/or prevention of a tumour.

The fourth aspect of the present invention also provides the use of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention in the manufacture of a medicament for use as an IDO/TDO inhibitor.

In a fifth aspect, the present invention provides a method of treating and/or preventing a disease or condition associated with IDO/TDO hyperactivity or IDO/TDO overexpression in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention. A method according to any of the fifth aspects of the invention, wherein said disease or condition associated with too high IDO/TDO activity or with overexpression of IDO/TDO is selected from tumours.

The fifth aspect of the present invention also provides a method of treating and/or preventing a tumour in a subject in need thereof, which comprises administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspect of the present invention.

A sixth aspect of the present invention provides a compound according to any one of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a disease or condition associated with IDO/TDO hyperactivity or IDO/TDO overexpression. A compound according to a sixth aspect of the invention, wherein said disease or condition associated with too high IDO/TDO activity or overexpression of IDO/TDO is selected from: a tumor.

The sixth aspect of the present invention also provides a compound according to any one of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of tumours.

Any aspect of the invention or any one of the aspects having features is equally applicable to any other aspect or any one of the other aspects as long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. In the present invention, for example, reference to "any one of the first aspect of the invention" is a reference to any one of the sub-aspects of the first aspect of the invention, and has similar meaning when referred to otherwise in a similar manner.

Detailed description of the invention:

various aspects and features of the disclosure are described further below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and it is intended that such terms and phrases be interpreted as having a more complete description and interpretation herein, unless otherwise expressly stated otherwise, unless expressly stated otherwise. The following are definitions of various terms used herein, which apply to the terms used throughout this application unless otherwise indicated in specific instances. Definitions for various groups of the compounds of the present invention are provided below and, unless otherwise defined, are used uniformly throughout the specification and claims.

As referred to herein, the term "alkyl" refers to an alkyl group having the indicated number of carbon atoms, which may be straight or branched chain, alkyl refers to a saturated aliphatic hydrocarbon group, e.g., the "C" group _1-8 Alkyl "refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8 carbon atoms and may include C _1-7 Alkyl radical, C _2-7 Alkyl radical, C _3-7 Alkyl radical, C _1-6 Alkyl radical, C _2-6 Alkyl radical, C _3-6 Alkyl radical, C _3-8 Alkyl radical, C _3-7 Alkyl radical, C _1-4 Alkyl, etc. to a sub-range<xnotran> , , , , , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- . </xnotran>

For example said "C _1-6 Alkyl "refers to an alkyl group having 1,2, 3, 4, 5, 6 carbon atoms and may include C _1-5 Alkyl radical, C _1-4 Alkyl radical, C _2-6 Alkyl radical, C _2-5 Alkyl radical, C _2-4 Alkyl radical, C _3-6 Alkyl radical, C _3-5 Alkyl radical, C _3-4 Alkyl, etc., and preferred specific groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 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, or various branched isomers thereof.

For example said "C _1-4 Alkyl refers to alkyl having 1,2, 3, 4 carbon atoms and may include C _1-3 Alkyl radical, C _1-2 Alkyl radical, C _2-4 Alkyl radical, C _2-3 Alkyl radical, C _3-4 Alkyl, etc., and preferred specific groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.

Alkyl groups may be substituted or unsubstituted, e.g. as described for "C _1-8 Alkoxy group "," C _1-6 Alkoxy group "," C _1-4 Alkoxy group "," C _1-8 Alkylcarbonyl group and C _1-8 Alkyloxycarbonyl group and C _1-8 Alkylcarbonyloxy group and C _1-8 Alkylamido group "," C _1-8 Alkylaminocarbonyl group and C _1-8 Alkyl ureido group "," C _1-8 Alkyloxycarbonylamino group "," C _1-8 C in alkylamino _1-8 Alkyl "refers to an alkyl group having 1,2, 3, 4, 5, 6, 7, 8 carbon atoms, and may include C _1-7 Alkyl radical, C _1-6 Alkyl radical, C _2-6 Alkyl radical, C _2-5 Alkyl radical, C _2-4 Alkyl radical, C _3-6 Alkyl radical, C _3-5 Alkyl radical, C _1-4 Alkyl, etc. When substituted, the substituent may be substituted with one or more substituent groups at any available point of attachment.

As referred to herein, the term "alkylene" refers to an alkyl group having the indicated number of carbon atoms, which may be a straight or branched chain alkyl group, where "alkyl" refers to a saturated aliphatic hydrocarbon group, as defined above. Alkylene groups are based on alkyl groups in which one hydrogen atom has been replaced by another group, and the substitution can occur at any available point of attachment. For example said "C _0-8 Alkylene "refers to an alkyl group having 0, 1,2, 3, 4, 5, 6, 7, 8 carbon atoms, but with one hydrogen atom in the alkyl chain being replaced by another group. For example methylene-, ethylene-, n-propylene-, isopropylene-, n-butylene-, isobutylene-, tert-butylene-, sec-butylene-, pentylene-, hexylene-, heptylene-, octylene-, 1-dimethylpropylene-, 1, 2-dimethylpropylene-, 2-dimethylpropylene-, 1-ethylpropylene-, 2-methylbutylene-, 3-methanemethylene Thiobutylene-, 1-ethyl-2-methylpropylene-, 1, 2-trimethylpropylene-, 1-dimethylbutylene-, 1, 2-dimethylbutylene-, 2-dimethylbutylene-, 1, 3-dimethylbutylene-, 2-ethylbutylene-, 2-methylpentylene-, 3-methylpentylene-, 4-methylpentylene-, 2, 3-dimethylbutylene-, 2-methylhexylene-, 3-methylhexylene-, 4-methylhexylene-, 5-methylhexylene-, 2, 3-dimethylpentylene-, 2, 4-dimethylpentylylene-, or mixtures thereof 2, 2-dimethylpentylene-, 3-dimethylpentylene-, 2-ethylpentylene-, 3-ethylpentylene-, 2, 3-dimethylhexylene-, 2, 4-dimethylhexylene-, 2, 5-dimethylhexylene-, 2-dimethylhexylene-, 3-dimethylhexylene-, 4-dimethylhexylene-, 2-ethylhexyl-, 3-ethylhexyl-, 4-ethylhexyl-, 2-methyl-2-ethylpentylene-, 2-methyl-3-ethylpentylene-or various branched isomers thereof.

Alkylene groups can be substituted or unsubstituted, and when substituted, like alkyl groups, the substituents can be substituted with one or more substituent groups at any available point of attachment.

As referred to herein, the term "X _g C _1-8 Alkyl group "," X _g C _1-6 Alkyl group "," X _g C _1-4 Alkyl group "," X _g C _1-8 Alkoxy group "," X _g C _1-6 Alkoxy group "," X _g C _1-4 Alkoxy ", X is selected from halogen: fluorine, chlorine, bromine or iodine, g being selected from 1, 2, 3, 4 or 5. Wherein "C _1-8 Alkyl group "," C _1-6 Alkyl group "," C _1-4 Alkyl group "," C _1-8 Alkoxy group "," C _1-6 Alkoxy group "," C _1-4 The specific explanation of alkoxy "is given in the above description of terms.

X _g C _1-8 Alkyl and X _g C _1-8 In the alkoxy radical, specifically designated as XC _1-8 Alkyl radical, X ₂ C _1-8 Alkyl radical, X ₃ C _1-8 Alkyl radical, X ₄ C _1-8 Alkyl radical, X ₅ C _1-8 Alkyl and XC _1-8 Alkoxy radical, X ₂ C _1-8 Alkoxy radical, X ₃ C _1-8 Alkoxy radical, X ₄ C _1-8 Alkoxy radical, X ₅ C _1-8 An alkoxy group; preference is given to XC _1-6 Alkyl radical, X ₂ C _1-6 Alkyl radical, X ₃ C _1-6 Alkyl radical, X ₄ C _1-6 Alkyl radical, X ₅ C _1-6 Alkyl and XC _1-6 Alkoxy radical, X ₂ C _1-6 Alkoxy radical, X ₃ C _1-6 Alkoxy radical, X ₄ C _1-6 Alkoxy radical, X ₅ C _1-6 An alkoxy group; comprising F ₃ C _1-6 Alkyl radical, br ₃ C _1-6 Alkyl, cl ₃ C _1-6 Alkyl radical, I ₃ C _1-6 Alkyl, F ₂ BrC _1-6 Alkyl, F ₂ ClC _1-6 Alkyl, F ₂ IC _1-6 Alkyl, FBr ₂ C _1-6 Alkyl, FCl ₂ C _1-6 Alkyl, FI ₂ C _1-6 Alkyl, clBr ₂ C _1-6 Alkyl, ICl ₂ C _1-6 Alkyl group, clI ₂ C _1-6 An alkyl group; f ₃ C _1-6 Alkoxy radical, br ₃ C _1-6 Alkoxy group, cl ₃ C _1-6 Alkoxy radical, I ₃ C _1-6 Alkoxy radical, F ₂ BrC _1-6 Alkoxy radical, F ₂ ClC _1-6 Alkoxy radical, F ₂ IC _1-6 Alkoxy radical, FBr ₂ C _1-6 Alkoxy, FCl ₂ C _1-6 Alkoxy, FI ₂ C _1-6 Alkyl, clBr ₂ C _1-6 Alkoxy, ICl ₂ C _1-6 Alkoxy, clI ₂ C _1-6 An alkoxy group;

More preferably F ₃ C _1-4 Alkyl, br ₃ C _1-4 Alkyl, cl ₃ C _1-4 Alkyl radical, I ₃ C _1-4 Alkyl, F ₂ BrC _1-4 Alkyl, F ₂ ClC _1-4 Alkyl, F ₂ IC _1-4 Alkyl, FBr ₂ C _1-4 Alkyl, FCl ₂ C _1-4 Alkyl, FI ₂ C _1-4 Alkyl, clBr ₂ C _1-4 Alkyl radical, ICl ₂ C _1-4 Alkyl group, clI ₂ C _1-4 An alkyl group; f ₃ C _1-4 Alkoxy, br ₃ C _1-4 Alkoxy, cl ₃ C _1-4 Alkoxy radical, I ₃ C _1-4 Alkoxy radical, F ₂ BrC _1-4 Alkoxy radical, F ₂ ClC _1-4 Alkoxy radical, F ₂ IC _1-4 Alkoxy radical, FBr ₂ C _1-4 Alkoxy radical, FCl ₂ C _1-4 Alkoxy, FI ₂ C _1-4 Alkyl, clBr ₂ C _1-4 Alkoxy, ICl ₂ C _1-4 Alkoxy, clI ₂ C _1-4 An alkoxy group;

most preferably F ₃ C、F ₃ CCH ₂ 、Br ₃ C、Br ₃ CCH ₂ 、Cl ₃ C、Cl ₃ CCH ₂ 、I ₃ C、I ₃ CCH ₂ 、F ₂ BrC、F ₂ BrCCH ₂ 、F ₂ ClC、F ₂ ClCCH ₂ 、F ₂ IC、F ₂ ICCH ₂ 、FBr ₂ C、FBr ₂ CCH ₂ 、FCl ₂ C、FCl ₂ CCH ₂ 、FI ₂ C、FI ₂ CCH ₂ 、ClBr ₂ C、ClBr ₂ CCH ₂ 、ICl ₂ C、ICl ₂ CCH ₂ 、ClI ₂ C、ClI ₂ CCH ₂ ；F ₃ CO、F ₃ CCH ₂ O、Br ₃ CO、Br ₃ CCH ₂ O、Cl ₃ CO、Cl ₃ CCH ₂ O、I ₃ CO、I ₃ CCH ₂ O、F ₂ BrCO、F ₂ BrCCH ₂ O、F ₂ ClCO、F ₂ ClCCH ₂ O、F ₂ ICO、F ₂ ICCH ₂ O、FBr ₂ CO、FBr ₂ CCH ₂ O、FCl ₂ CO、FCl ₂ CCH ₂ O、FI ₂ CO、FI ₂ CCH ₂ O、ClBr ₂ CO、ClBr ₂ CCH ₂ O、ICl ₂ CO、ICl ₂ CCH ₂ O、ClI ₂ CO、ClI ₂ CCH ₂ O；

As provided by the inventionAnd, the term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example said "C _2-8 Alkenyl "means a straight or branched chain alkenyl group containing 2 to 8 carbons. Such as ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-pentenyl, 3-dimethyl-1-butenyl, and the like. For example said "C _2-6 Alkenyl "means a straight or branched chain alkenyl group containing 2 to 6 carbons. For example said "C _2-4 Alkenyl "means a straight or branched chain alkenyl group containing 2 to 4 carbons. Alkenyl groups may be substituted or unsubstituted, when substituted, for example as described for "C _2-8 Alkenyloxy group and C _2-8 Alkenylamido group "," C _2-8 "C in" alkenylureido _2-8 Alkenyl ".

As referred to herein, the term "alkynyl" refers to an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon triple bond. For example said "C _2-8 Alkynyl "refers to straight or branched chain alkynyl groups containing 2-8 carbons. For example, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-pentynyl, 3-dimethyl-1-butynyl and the like. For example said "C _2-6 Alkynyl "refers to straight or branched chain alkynyl groups containing 2-6 carbons. For example said "C _2-4 Alkynyl "refers to straight or branched chain alkynyl groups containing 2-4 carbons. Alkynyl groups may be substituted or unsubstituted, and when substituted, for example, as described for "C _2-8 Alkynyl oxy group and C _2-8 Alkynyl oxycarbonyl group "," C _2-8 Alkynyl ureido "," C _2-8 "C" in alkynyl amino _2-8 Alkynyl ".

As referred to herein, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic, cyclic hydrocarbon substituent having the indicated number of ring carbon atoms. For example, mention of "C _3-8 When "cycloalkyl" is used, it means a cycloalkyl group having 3, 4, 5, 6, 7, 8 carbon atoms and may include C _3-7 Cycloalkyl radical, C _3-4 Cycloalkyl radical, C _4-6 Cycloalkyl, and the like.

Non-limiting examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptatrienyl, with cyclopropyl, cyclopentyl, cyclohexyl being further preferred.

Polycyclic cycloalkyl groups include spiro, fused, bridged cycloalkyl groups. "spirocycloalkyl" refers to a polycyclic group of single rings sharing a single carbon atom (called a spiro atom) and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spirocycloalkyl, di-spirocycloalkyl or multi-spirocycloalkyl, non-limiting examples of which include:

"fused-ring alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, non-limiting examples of fused ring alkyl groups including:

"bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the ring composition, there may be a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, non-limiting examples of which include:

The cycloalkyl rings may be fused to aryl, heteroaryl and heterocyclyl groups, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include:

cycloalkyl groups may be optionally substituted or unsubstituted, e.g. as described for "C _3-8 Cycloalkanoyloxycarbonyl group and C _3-8 Cycloalkylamido "," C _3-8 "C in" cycloalkylaminocarbonyl _3-8 Cycloalkyl "refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8 carbon atoms, and may include C _3-6 Cycloalkyl radical, C _3-5 Cycloalkyl, C _4-5 Cycloalkyl groups and the like, and preferred specific groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and further preferred are cyclopropyl, cyclopentyl, cyclohexyl.

<xnotran> , "" , , , , -O-O-, -O-S-, -S-S- , . </xnotran> Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, propylene oxide, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like.

Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group, or a multi-spiro heterocyclic group according to the number of spiro atoms shared between rings. Non-limiting examples of spiroheterocyclyl radicals include:

"fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, and the remaining ring atoms are carbon. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings, non-limiting examples of fused heterocyclic groups include:

"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system, wherein one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, and the remaining ring atoms are carbon. Depending on the ring composition, the ring may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, non-limiting examples of which include:

The heterocyclyl rings may be fused to aryl, arylheterocyclyl and cycloalkyl rings wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

as referred to herein, a "3-8 membered heterocyclyl" refers to a cyclic group containing from 3 to 8 ring atoms, including monocyclic or fused ring groups, wherein 1 or more ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur, the remaining ring atoms being carbon. These rings may also have one or more double bonds, but these rings do not have a completely conjugated pi-electron system. Including alkyl groups containing 3 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as 1, 3-glycidylalkyl, 1, 3-cycloaziridinyl, 1, 3-cyclothiodipropyl, 4, 5-tetrahydrooxazolyl; alkyl containing 4 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are tetrahydrofuranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl; alkyl containing 5 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, with particular groups such as piperidinyl, homopiperazinyl being preferred.

As referred to herein, "3-6 membered heterocyclyl" means a cyclic group containing 3 to 6 ring atoms, including monocyclic or fused ring groups, wherein 1 or more ring atoms are selected from heteroatoms of nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. These rings may also have one or more double bonds, but these rings do not have a completely conjugated pi-electron system. Including alkyl groups containing 3 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur.

Heterocyclyl may be optionally substituted or unsubstituted, with "3-8 membered heterocyclyl" as referred to herein in "3-8 membered heterocyclyloxy", "3-8 membered heterocyclylaminocarbonyl", "3-8 membered heterocyclylureido", referring to heterocycloalkyl containing 3-8 carbon atoms and 1 or more heteroatoms selected from nitrogen, oxygen, sulfur ", referring to cyclic heteroalkyl having the indicated number of ring atoms, including monocyclic or fused ring groups, having 3 to 8 ring atoms in the ring, wherein 1 to more ring atoms are selected from heteroatoms of nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon; these rings may also have one or more double bonds, but these rings do not have a completely conjugated pi-electron system; including alkyl groups containing 3 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, with preferred embodiments such as 1, 3-epoxypropyl, 1, 3-cycloaziridinyl, 1, 3-cyclothiopropanyl, 4, 5-tetrahydrooxazolyl; alkyl containing 4 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are tetrahydrofuranyl, pyrrolidinyl, morpholinyl, thiomorpholinyl; alkyl containing 5 carbon atoms and 1 to 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are piperidinyl, homopiperazinyl.

As referred to herein, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, as referred to herein as "C _5-10 Aryl "means an aryl group containing from 5 to 10 all carbons, examples of aryl include, but are not limited to, phenyl, naphthyl, and the like. The aryl ring may be fused to an arylheterocyclyl, heterocyclyl, or cycloalkyl ring, wherein attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be optionally substituted or unsubstituted, as mentioned in the present invention, "C _5-10 Aryloxy group "," C _5-10 Arylamido group "," C _5-10 Aryloxycarbonylamino group and (C) _5-10 "C in" arylamino _5-10 Aryl "means an aryl group containing 5 to 10 all carbons, examples of aryl include, but are not limited to, phenyl, naphthyl, and the like.

As referred to herein, the term "arylheterocyclyl" refers to a heterocyclic aromatic system containing 1 to 4 heteroatoms, including heteroatoms of nitrogen, oxygen and sulfur. As referred to herein, "5-6 membered aromatic heterocyclyl" means a heterocyclic aromatic system containing 5-6 ring atoms, "5-10 membered aromatic heterocyclyl" means a heterocyclic aromatic system containing 5-10 ring atoms, "5-14 membered aromatic heterocyclyl" means a heterocyclic aromatic system containing 5-14 ring atoms. Specific examples include aryl groups containing 1 carbon atom and 4 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as tetrazolyl; aryl containing 2 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as 1,2, 3-triazolyl, 1,2, 4-triazolyl, oxadiazolyl, thiadiazolyl; aryl containing 3 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred specific groups such as imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl; aryl containing 4 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, with preferred embodiments such as pyrrolyl, furyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl; aryl containing 5 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, preferred embodiments are e.g. pyridyl, preferably pyridyl; aryl containing 6 carbon atoms and 3 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are groups such as benzotriazolyl; aryl containing 7 carbon atoms and 2 heteroatoms selected from nitrogen, oxygen, sulfur, preferred embodiments are benzimidazolyl, benzpyrazolyl; aryl containing 8 carbon atoms and 1-2 heteroatoms selected from nitrogen, oxygen, sulfur, with preferred embodiments such as indolyl, benzofuranyl, benzothienyl, benzopyrazinyl, benzopyrimidinyl, and benzopyrazinyl; aryl containing 9 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, preferred embodiments are quinolinyl, isoquinolinyl; aryl containing 13 carbon atoms and 1 heteroatom selected from nitrogen, oxygen, sulfur, with particular preference being given to acridine.

The aromatic heterocyclic group may be optionally substituted or unsubstituted, and as referred to herein, the "5-to 10-membered aromatic heterocyclic group" in the "5-to 10-membered aromatic heterocyclic oxy group", "5-to 10-membered aromatic heterocyclic amido group", "5-to 10-membered aromatic heterocyclic amino group" means a heterocyclic aromatic system containing 5 to 10 ring atoms.

"independently selected" means that there is no correspondence or dependency between different individuals in the behavior of the substituent group selected, and that each individual independently selects a substituent group from the specified defined range. Such as deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, aminosulfonyl, methanesulfonate, isopropylsulfonate, benzenesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetylamino, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _5-10 Aryl, 5-to 10-membered aromatic heterocyclic group, C _1-8 Alkyl radicalOxy radical, C _1-8 Alkylcarbonyl group, C _1-8 Alkyl oxycarbonyl radical, C _1-8 Alkylcarbonyloxy, C _1-8 Alkylamido radical, C _1-8 Alkylaminocarbonyl radical, C _1-8 Alkyl ureido, C _1-8 Alkyloxycarbonylamino group, C _2-8 Alkenyloxy radical, C _2-8 Alkenylamido, C _2-8 Alkenyl ureido, C _2-8 Alkynyl oxy, C _2-8 Alkynyl oxycarbonyl radical, C _2-8 Alkynyl ureido, C _3-8 Cycloalkanoyloxycarbonyl group, C _3-8 Cycloalkyl amido radical, C _3-8 Cycloalkylaminocarbonyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylaminocarbonyl, 3-8 membered heterocyclylureido, C _5-10 Aryloxy radical, C _5-10 Arylamido, C _5-10 Aryloxycarbonylamino, 5-10 membered heterocyclyloxy, 5-10 membered heterocyclylamino, mono-C _1-8 Alkylamino or di-C _1-8 Alkylamino radical, di-C _2-8 Alkynyl amino, mono C _5-10 Arylamino, mono 5-to 10-membered aromatic heterocyclylamino; preferably deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, cyano, nitro, azido, methanesulfonyl, methanesulfonate, methoxy, trifluoromethyl, trifluoromethyloxy, acetamido, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _3-8 Cycloalkyl, phenyl, naphthyl, C _1-8 Alkyloxy, C _1-8 Alkyl oxycarbonyl radical, C _1-8 Alkylcarbonyl group, C _1-8 Alkylcarbonyloxy, C _1-8 Alkylamido radical, C _1-8 Alkylaminocarbonyl radical, C _1-8 Alkyl ureido, mono C _1-8 Alkylamino or di-C _1-8 Alkylamino radical, phenyl radical C _0-8 Alkylamino, phenoxy, phenoxycarbonyl, phenylcarbonyl, phenylcarbonyloxy, phenylamido, phenylaminocarbonyl, phenylureido.

"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.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents.

As referred to herein, the term "effective amount" refers to a dose that achieves treatment and/or prevention of a disease or disorder described herein in a subject.

As referred to herein, the term "pharmaceutical composition" may also refer to a "composition" which may be used to effect treatment and/or prevention of a disease or disorder described herein in a subject, particularly a mammal.

As referred to herein, the term "subject" may refer to a patient or other animal, particularly a mammal, e.g., a human, dog, monkey, cow, horse, etc., that receives a compound of formula I of the invention or a pharmaceutical composition thereof for the treatment and/or prevention of a disease or condition described herein.

As referred to herein, the term "disease and/or condition" refers to a physical condition of the subject that is associated with the disease and/or condition of the present invention. For example, a disease and/or condition described herein may refer to a physical condition, such as a physical condition exhibiting elevated blood glucose levels, or a disease condition, such as a disease condition characterized by hyperglycemia, diabetes, and the like. Physical and disease states are not distinguished herein or may be referred to one another, e.g., "hyperglycemic" and "hyperglycemia" may be used interchangeably.

As referred to herein, "%" refers to weight/weight percentages, particularly where solid matter is described, unless otherwise specified. Of course, in describing liquid materials, the "%" may refer to weight/volume percentages (for the case of solids dissolved in liquids) or may refer to volume/volume percentages (for the case of liquids dissolved in liquids).

As referred to herein, the term "pharmaceutically acceptable" when describing a "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of pharmaceutical value, e.g., a salt formed as an intermediate in order to effect chiral resolution, which salt may play a role in obtaining the final product of the invention, although such intermediate salt may not be directly administered to the subject.

In a further aspect, the invention relates to pharmaceutical compositions comprising as active ingredient a compound of the invention. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.

The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.

For tableting the compound of the present invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and cosolvent may be talc powder, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

The tablets may be further formulated as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered and multi-layered tablets.

To encapsulate the administration units, the active ingredient compounds of the invention can be mixed with diluents and cosolvents and the mixture placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The diluent, adhesive, wetting agent, disintegrating agent and cosolvent used for preparing the compound tablet can also be used for preparing capsules of the compound.

For preparing the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

For administration purposes, to enhance the therapeutic effect, the medicaments or pharmaceutical compositions of the invention may be administered by any known method of administration.

The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/Kg body weight, preferably from 0.1 to 100mg/Kg body weight, more preferably from 1 to 60mg/Kg body weight, and most preferably from 1 to 30mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.

Advantageous technical effects

All compounds of the present invention have novel chemical structures. Most of the compounds have strong in vitro IDO inhibitory activity (IC) ₅₀ <10 μ M), and wherein more than 70 compounds have IDO inhibitory activity in vitro IC ₅₀ Up to or less than 1 × 10 ^-6 mol/L. Among others, mention may be made of: 12 Compounds in vitro IDO inhibitory Activity IC ₅₀ Up to or less than 1 × 10 ^-8 mol/L;7 Compounds in vitro IDO inhibitory Activity IC ₅₀ Up to or less than 1 × 10 ^-9 mol/L; IC of 4 Compounds ₅₀ A value of 1X 10 or less ^-10 mol/L level, IC of 1 Compound ₅₀ A value of 1X 10 or less ^-11 The mol/L level is stronger than all IDO small-molecule inhibitors reported in the literature.

Moreover, such compounds, although also having a certain inhibitory effect on TDO activity in vitro, are relatively weak. In vitro TDO inhibitory Activity IC of 9 Compounds ₅₀ Up to or less than 1 × 10 ^-6 mol/L, and only 1 Compound in vitro TDO inhibitory Activity IC ₅₀ Up to or less than 1 × 10 ^-7 mol/L. Indicating that the compounds of the invention have selectivity of inhibition for IDO/TDO.

The tumor inhibition rate of the two selected compounds (IPK-003 and IPK-074) in a mouse B16F10 melanoma subcutaneous transplantation tumor model is more than 70 percent, and the treated mice do not show obvious blood toxicity and have very good exposure (AUC) in a drug animal model. The research content provides a class of IDO/TDO inhibitors with novel structures and strong activity, which can be used for preparing medicines for preventing and treating cancers or tumors and related diseases thereof.

Drawings

FIG. 1 plasma IPK-003 plasma concentration-time profiles in the plasma of mice following oral administration of IPK-074 (30 mg/kg) and intravenous injection of IPK-003 (3.16 mg/kg) in mice.

FIG. 2, tumor tissue size after subcutaneous transplantation of melanoma B16F10 in mice treated with IPK-003, IPK-074. Blank control group, cyclophosphamide group, IPK-074IP/30mg (intraperitoneal injection dose of 30 mg/kg), IPK-074IP/60mg (intraperitoneal injection dose of 60 mg/kg), IPK-074PO/30mg (oral injection dose of 30 mg/kg), IPK-074PO/60mg (oral injection dose of 60 mg/kg), IPK-003IP/30mg (intraperitoneal injection dose of 30 mg/kg), IPK-003IP/60mg (intraperitoneal injection dose of 60 mg/kg), IPK-003PO/30mg (oral injection dose of 30 mg/kg), and IPK-003PO/60mg (oral dose of 60 mg/kg).

FIG. 3, tumor weights after subcutaneous transplantation of melanoma B16F10 in mice treated with IPK-003 and IPK-074. Blank control group, cyclophosphamide group, IPK-074IP/30mg (intraperitoneal dose of 30 mg/kg), IPK-074IP/60mg (intraperitoneal dose of 60 mg/kg), IPK-074PO/30mg (oral dose of 30 mg/kg), IPK-074PO/60mg (oral dose of 60 mg/kg), IPK-003IP/30mg (intraperitoneal dose of 30 mg/kg), IPK-003IP/60mg (intraperitoneal dose of 60 mg/kg), IPK-003PO/30mg (oral dose of 30 mg/kg), and IPK-003PO/60mg (oral dose of 60 mg/kg). P <0.05, p <0.01, p <0.001, compared to the blank control group.

FIG. 4, change in body weight of mice treated with IPK-003 and IPK-074 after subcutaneous transplantation of melanoma B16F 10. Blank control group, cyclophosphamide group, IPK-074IP/30mg (intraperitoneal dose of 30 mg/kg), IPK-074IP/60mg (intraperitoneal dose of 60 mg/kg), IPK-074PO/30mg (oral dose of 30 mg/kg), IPK-074PO/60mg (oral dose of 60 mg/kg), IPK-003IP/30mg (intraperitoneal dose of 30 mg/kg), IPK-003IP/60mg (intraperitoneal dose of 60 mg/kg), IPK-003PO/30mg (oral dose of 30 mg/kg), and IPK-003PO/60mg (oral dose of 60 mg/kg). P <0.05 compared to the blank control group.

FIG. 5, IPK-003, IPK-074 the leukocyte content in the blood of mice after subcutaneous transplantation of melanoma B16F10 in mice. Blank control group, cyclophosphamide group, IPK-074IP/30mg (intraperitoneal dose of 30 mg/kg), IPK-074IP/60mg (intraperitoneal dose of 60 mg/kg), IPK-074PO/30mg (oral dose of 30 mg/kg), IPK-074PO/60mg (oral dose of 60 mg/kg), IPK-003IP/30mg (intraperitoneal dose of 30 mg/kg), IPK-003IP/60mg (intraperitoneal dose of 60 mg/kg), IPK-003PO/30mg (oral dose of 30 mg/kg), and IPK-003PO/60mg (oral dose of 60 mg/kg). P < 0.05) compared to blank control group.

FIG. 6, IPK-003, IPK-074 the lymphocyte content in the blood of mice after subcutaneous transplantation of melanoma B16F10 in mice. Blank control group, cyclophosphamide group, IPK-074IP/30mg (intraperitoneal injection dose of 30 mg/kg), IPK-074IP/60mg (intraperitoneal injection dose of 60 mg/kg), IPK-074PO/30mg (oral injection dose of 30 mg/kg), IPK-074PO/60mg (oral injection dose of 60 mg/kg), IPK-003IP/30mg (intraperitoneal injection dose of 30 mg/kg), IPK-003IP/60mg (intraperitoneal injection dose of 60 mg/kg), IPK-003PO/30mg (oral injection dose of 30 mg/kg), and IPK-003PO/60mg (oral dose of 60 mg/kg). P <0.05 compared to blank control group.

FIG. 7, content of monocytes in blood of mice treated with IPK-003, IPK-074 after subcutaneous transplantation of melanoma B16F10 in the mice. Blank control group, cyclophosphamide group, IPK-074IP/30mg (intraperitoneal injection dose of 30 mg/kg), IPK-074IP/60mg (intraperitoneal injection dose of 60 mg/kg), IPK-074PO/30mg (oral injection dose of 30 mg/kg), IPK-074PO/60mg (oral injection dose of 60 mg/kg), IPK-003IP/30mg (intraperitoneal injection dose of 30 mg/kg), IPK-003IP/60mg (intraperitoneal injection dose of 60 mg/kg), IPK-003PO/30mg (oral injection dose of 30 mg/kg), and IPK-003PO/60mg (oral dose of 60 mg/kg).

FIG. 8, IPK-003, IPK-074 the neutrophil level in the blood of mice after subcutaneous transplantation of melanoma B16F10 in the mice. Blank control group, cyclophosphamide group, IPK-074IP/30mg (intraperitoneal dose of 30 mg/kg), IPK-074IP/60mg (intraperitoneal dose of 60 mg/kg), IPK-074PO/30mg (oral dose of 30 mg/kg), IPK-074PO/60mg (oral dose of 60 mg/kg), IPK-003IP/30mg (intraperitoneal dose of 30 mg/kg), IPK-003IP/60mg (intraperitoneal dose of 60 mg/kg), IPK-003PO/30mg (oral dose of 30 mg/kg), and IPK-003PO/60mg (oral dose of 60 mg/kg).

Detailed Description

1. Synthesis of Compounds

The synthesis procedure of the patented ring-opened compound (example 1-example 73) was carried out with slight modifications depending on the final product:

a. Triphosgene (1 eq) was dissolved in 5 ml of anhydrous dichloromethane and kept at 0 ℃ in ice bath; benzyl mercaptan (3 equivalents) is slowly dripped into the reaction liquid, then anhydrous pyridine (3 equivalents) solution of anhydrous dichloromethane (1 ml) is slowly dripped, the reaction liquid is stirred for 10 minutes in ice bath, then the stirring is carried out for about 2 hours at room temperature, and the reaction is detected to be finished by thin layer chromatography. The reaction intermediate is very active and is directly used in the next step.

Example 1:2- (((benzylthio) carbonyl) amino) benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; benzyl mercaptan (269 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, followed by anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) and then the reaction mixture was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was terminated by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (199 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the mixture was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (262 mg, 63% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.77(s,1H),11.38(s,1H),8.26(d,J＝8.4Hz,1H),7.97(d,J＝7.9Hz,1H),7.61(t,J＝7.8Hz,1H),7.38(d,J＝7.2Hz,2H),7.32(t,J＝7.4Hz,2H),7.25(t,J＝7.2Hz,1H),7.18(t,J＝7.5Hz,1H),4.22(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝170.11,165.20,140.66,138.65,134.85,131.69,129.25(2C),129.00(2C),127.66,123.57,120.38,116.89,33.80.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₅ H ₁₄ O ₃ NS,288.06889；found,288.06815

Example 2:2- (((((3' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees centigrade in ice bath; 3-trifluoromethyl benzyl mercaptan (288 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction was stirred in an ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (349 μ l, 2 mmol) was added, and then the solution a was slowly dropped into the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Column chromatography was carried out directly on a stirred sample (petroleum ether: ethyl acetate: acetic acid = 100).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.78(s,1H),11.40(s,1H),8.23(d,J＝8.4Hz,1H),7.97(d,J＝7.9Hz,1H),7.75(s,1H),7.70(d,J＝7.5Hz,1H),7.59(dt,J＝15.2,7.4Hz,3H),7.18(t,J＝7.6Hz,1H),4.31(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝170.04,164.92,140.55,137.41,134.81,133.45,131.67,130.10,129.41,125.78,124.39,123.69,120.47,117.13,115.80,33.16.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₆ H ₁₃ F ₃ NO ₃ S,356.05628；found,356.05582.

Example 3:2- (((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 4-trifluoromethyl benzyl mercaptan (288 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction was stirred in an ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100).

¹ H NMR(400MHz,DMSO-d6):δ＝13.75(s,1H),11.40(s,1H),8.22(d,J＝8.4Hz,1H),7.97(dd,J＝7.9,1.3Hz,1H),7.69(d,J＝8.2Hz,2H),7.61(d,J＝8.1Hz,3H),7.18(t,J＝7.6Hz,1H),4.30(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝170.06,164.85,143.92,140.50,134.80,131.68,130.04(2C),126.07,125.83(2C),123.70,123.37,120.50,117.14,33.19.HRMS(ESI):m/z calculated for C ₁₆ H ₁₃ F ₃ NO ₃ S[M+H] ⁺ :354.04063；found,354.03885.

Example 4:2- ((((4' -methylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees under ice bath; 4-methylbenzyl mercaptan (207 mg, 1.5 mmol) was slowly added dropwise to the reaction, and then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in an ice bath for 10 minutes, the reaction solution was stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 198 mg of the product in 66% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.80(s,1H),11.38(s,1H),8.26(d,J＝8.1Hz,1H),7.97(dd,J＝7.9,1.5Hz,1H),7.63–7.59(m,1H),7.25(d,J＝7.9Hz,2H),7.17(t,J＝7.6Hz,1H),7.12(d,J＝7.9Hz,2H),4.17(s,2H),2.26(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.15,165.28,140.74,136.84,135.49,134.86,131.70,129.55(2C),129.17(2C),123.51,120.31,116.76,33.61,21.16.HRMS(ESI):m/z calculated for C ₁₆ H ₁₆ NO ₃ S[M+H] ⁺ 302.08454；found,302.08426.

Example 5:2- ((((3' -cyanobenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 3-cyanobenzylthiol (223 mg, 1.5 mmol) was slowly added dropwise to the reaction, and then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in ice bath for 10 minutes, the reaction solution was stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 184 mg of the product in 59% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.77(s,1H),11.38(s,1H),8.22(d,J＝8.3Hz,1H),7.97(dd,J＝7.9,1.4Hz,1H),7.83(s,1H),7.76–7.70(m,2H),7.63–7.59(m,1H),7.54(t,J＝7.8Hz,1H),7.18(t,J＝7.6Hz,1H),4.26(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.09,164.85,140.79,140.52,134.79,134.26,132.76,131.68,131.44,130.26,123.69,120.51,119.11,117.09,111.88,32.97.HRMS(ESI):m/z calculated for C ₁₆ H ₁₃ N ₂ O ₃ S[M+H] ⁺ 313.06414；found,313.06168.

Example 6:2- ((((4' -chlorobenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 4-chlorobenzyl mercaptan (238 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100) to give 207 mg of a white solid, 64% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.79(s,1H),11.38(s,1H),8.23(d,J＝8.3Hz,1H),7.97(d,J＝9.3Hz,1H),7.61(t,J＝8.6Hz,1H),7.43–7.35(m,4H),7.18(t,J＝7.6Hz,1H),4.20(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.06,165.01,140.55,137.97,134.81,132.22,131.67,131.11(2C),128.92(2C),123.64,120.43,117.03,33.01.HRMS(ESI):m/z calculated for C ₁₅ H ₁₃ ClNO ₃ S[M+H] ⁺ :322.02972；found,322.02992.

Example 7:2- ((((4' -methoxybenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; 4-methoxybenzyl mercaptan (334 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction mixture was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and then detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. Anthranilic acid (199 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the mixture was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (326 mg, 71% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.75(s,1H),11.36(s,1H),8.27(d,J＝8.4Hz,1H),7.97(d,J＝8.4Hz,1H),7.61(t,J＝7.8Hz,1H),7.29(d,J＝8.5Hz,2H),7.17(t,J＝7.8Hz,1H),6.87(d,J＝8.5Hz,2H),4.16(s,2H),3.72(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝170.13,165.36,158.89,140.75,134.85,131.68,130.44(2C),130.34,123.46,120.28,116.69,114.38(2C),55.53,33.37.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₆ H ₁₆ O ₄ NS:318.07946；found:318.07880

Example 8:2- (((((4' - (trifluoromethoxy) benzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 4-Trifluoromethoxybenzylthiol (312 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.81(s,1H),11.40(s,1H),8.24(d,J＝8.4Hz,1H),8.00–7.94(m,1H),7.61(t,J＝8.5Hz,1H),7.51(d,J＝8.6Hz,2H),7.32(d,J＝8.3Hz,2H),7.18(t,J＝7.6Hz,1H),4.24(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.07,164.99,147.80,140.54,138.49,134.81,131.67,131.13(2C),129.27,123.65,121.57(2C),120.45,117.06,32.89.HRMS(ESI):m/z calculated for C ₁₆ H ₁₃ F ₃ NO ₄ S[M+H] ⁺ :372.05119；found,372.05072.

Example 9:2- ((((4' -fluorobenzyl) thio) amino) benzoic acid

a. Triphosgene (214.83 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane and maintained at zero degrees centigrade in ice bath. 4-fluorobenzylthiol (308.14 mg, 2.17 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate/petroleum ether = 10%).

b. Anthranilic acid (200 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (475 μ l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.80(s,1H),11.39(s,1H),8.24(dd,J＝1.1,8.4Hz,1H),7.97(dd,J＝1.7,8.0Hz,1H),7.61(ddd,J＝1.7,7.4,8.7Hz,1H),7.47–7.32(m,2H),7.30–7.03(m,3H),4.21(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.17,165.17,140.69,135.08,135.05,134.88,131.73,131.24(2C),123.61,120.41,116.91,115.89(2C),33.03.HRMS(ESI):m/z calculated for C ₁₅ H ₁₃ FNO ₃ S[M+H] ⁺ 306.05908；found,306.05947.

Example 10:2- ((((4' -bromobenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 4-bromobenzylthiol (304 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 219 mg of the product in 60% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.78(s,1H),11.38(s,1H),8.23(d,J＝8.4Hz,1H),7.97(dd,J＝7.9,1.2Hz,1H),7.65–7.57(m,1H),7.51(d,J＝8.3Hz,2H),7.34(d,J＝8.3Hz,2H),7.20–7.16(m,1H),4.19(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.11,165.00,140.61,138.40,134.82,131.86(2C),131.69,131.46(2C),123.61,120.76,120.41,116.95,33.10.HRMS(ESI):m/z calculated for C ₁₅ H ₁₃ BrNO ₃ S[M+H] ⁺ 365.97940,found 365.97894.

Example 11 (((4' -phenylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; [1,1' -biphenyl ] -4-methanethiol (300 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, and then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Column chromatography was performed directly on the stirred sample (petroleum ether: ethyl acetate: acetic acid = 100).

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.81(s,1H),11.41(s,1H),8.27(d,J＝8.2Hz,1H),7.98(dd,J＝7.9,1.5Hz,1H),7.63(dd,J＝9.8,7.9Hz,5H),7.46(t,J＝8.3Hz,4H),7.35(t,J＝7.3Hz,1H),7.18(t,J＝7.5Hz,1H),4.26(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.09,165.18,140.64,140.24,139.54,137.96,134.83,131.68,129.84(2C),129.40(2C),127.91,127.30(2C),127.08(2C),123.58,120.38,116.93,33.49.HRMS(ESI):m/z calculated for C ₂₁ H ₁₈ NO ₃ S[M+H] ⁺ :364.10019；found,364.09991.

Example 12 (((2 ',5' -difluorobenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 2, 5-difluorobenzylthiol (240 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 174 mg of the product in 54% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.78(s,1H),11.38(s,1H),8.21(d,J＝8.2Hz,1H),7.97(dd,J＝7.9,1.5Hz,1H),7.65–7.57(m,1H),7.35–7.22(m,2H),7.22–7.13(m,2H),4.22(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.08,164.50,158.11,140.48,134.81,131.68,127.66,123.73,120.54,117.96,117.42,117.15,116.38,115.83,27.29.HRMS(ESI):m/z calculated for C ₁₅ H ₁₂ F ₂ NO ₃ S[M+H] ⁺ 324.05005,found324.04962.

Example 13 (((2 ',5' -dichlorobenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 2, 5-dichlorobenzyl mercaptan (290 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100) to obtain 231 mg of a white solid with a yield of 65%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.83(s,1H),11.39(s,1H),8.21(d,J＝8.4Hz,1H),8.02–7.93(m,1H),7.65–7.57(m,2H),7.53(d,J＝8.6Hz,1H),7.41(dd,J＝8.5,2.5Hz,1H),7.19(t,J＝7.6Hz,1H),4.27(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.01,164.48,140.38,138.17,134.81,132.36,132.11,131.66,131.58,131.26,129.59,123.78,120.59,115.80,31.76.HRMS(ESI):m/z calculated for C ₁₅ H _l2 NO ₃ S[M+H] ⁺ :355.99095；found,355.99033.

Example 14 (((2 '-chloro-4' -fluorobenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees under ice bath; 2-chloro-4-fluorobenzylthiol (265 mg, 1.5 mmol) was slowly added dropwise to the reaction, and then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in an ice bath for 10 minutes, the stirring was resumed at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. The reaction was dried by rotary column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.81(s,1H),11.38(s,1H),8.22(d,J＝8.0Hz,1H),7.97(dd,J＝8.0,1.5Hz,1H),7.65–7.56(m,2H),7.49(dd,J＝8.8,2.6Hz,1H),7.24–7.17(m,2H),4.28(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.06,164.65,160.56,140.48,134.81,134.43,133.15,131.68,123.71,120.49,117.36,117.11,115.17,114.96,31.40.HRMS(ESI):m/z calculated for C ₁₅ H ₁₂ ClFNO ₃ S[M+H] ⁺ 340.02050,found 340.02005.

Example 15 (((2 ',3',4',5',6' -pentafluorobenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 2,3,4,5, 6-pentafluorobenzyl mercaptan (321 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.77(s,1H),11.36(s,1H),8.16(d,J＝8.3Hz,1H),7.96(dd,J＝7.9,1.5Hz,1H),7.61(t,J＝8.7Hz,1H),7.19(t,J＝7.6Hz,1H),4.34(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ169.95,163.65,160.35,147.56,141.87,140.17,137.41,134.77,131.64,129.41,123.98,120.75,115.80,110.75,28.87.HRMS(ESI):m/z calculated for C ₁₅ H ₉ F ₅ NO ₃ S[M+H] ⁺ :378.02178；found,378.02094.

Example 16 Oxybis (2- (4' -methylenebenzyl) thio) carbonyl) amino) benzoic acid)

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; ((oxybis (methylene)) bis (4, 1-phenyl)) dimethylmercaptan (629 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, followed by anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction mixture was stirred in an ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and then detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. Anthranilic acid (397 mg, 2.9 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (1011 μ l, 5.8 mmol) was added, and then the solution a was slowly added dropwise to the solution, ice bath was removed, heating and refluxing were performed for about 2 hours, and the reaction was detected to be completed by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave a white solid powder (276 mg, 31% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.78(s,2H),11.38(s,2H),8.25(d,J＝8.3Hz,2H),7.98(d,J＝7.9Hz,2H),7.61(t,J＝7.8Hz,2H),7.38(br,8H),7.18(t,J＝7.6Hz,2H),4.73(s,4H),4.22(s,4H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝170.11(2C),165.10(2C),140.63(2C),138.96(2C),137.05(2C),134.84(2C),131.68(2C),129.54(8C),123.60(2C),120.41(2C),116.92(2C),46.37(2C),33.45(2C).HRMS(ESI):m/z[M+H] ⁺ calculated for C ₃₂ H ₂₉ O ₇ N ₂ S ₂ :617.14107；found:617.14052

Example 17- ((((4' - (methylsulfonyl) methylene) benzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; n- (4- (mercaptomethyl) benzyl) methanesulfonamide (231 mg, 1.5 mmol) was slowly added dropwise to the reaction, followed by the addition of a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) slowly, the reaction was stirred in an ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100) to obtain 177 mg of a white solid with a yield of 45%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.70(s,1H),11.39(s,1H),8.33–8.19(m,1H),7.98(dd,J＝8.0,1.6Hz,1H),7.51(q,J＝8.9,7.6Hz,1H),7.36(d,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,2H),7.17(td,J＝7.6,1.2Hz,1H),4.21(s,2H),4.13(d,J＝6.3Hz,2H),2.85(s,3H).HRMS(ESI):m/z calculated for C ₁₇ H ₁₈ N ₂ O ₅ S ₂ [M+H] ⁺ :395.07299；found,395.07108.

Example 18- ((((4' - (((4 "-trifluoromethyl-phenyl) acetoxy) methylene) benzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; 4- (mercaptomethyl) benzyl-2- (4- (trifluoromethyl) phenyl) acetate (737 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction mixture was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and then detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. Anthranilic acid (199 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (262 mg, 36% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝11.64(s,1H),8.25(d,J＝8.3Hz,1H),7.98(d,J＝7.1Hz,1H),7.68(d,J＝8.0Hz,2H),7.59(t,J＝7.3Hz,1H),7.51(d,J＝7.8Hz,2H),7.37(d,J＝8.0Hz,2H),7.30(d,J＝7.9Hz,2H),7.16(t,J＝7.5Hz,1H),5.10(s,2H),4.21(s,2H),3.87(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝171.01,170.08,165.02,140.68,139.66,138.74,137.43,135.35,134.51,131.69,130.88(2C),129.34(2C),128.70(2C),125.64(2C),124.01,123.46,120.22,115.82,66.20,33.47,27.87.HRMS(ESI):m/z[M+Na] ⁺ calculated for C ₂₅ H ₂₀ O ₅ NF ₃ NaS:526.09065；found:526.09119

Example 19 ((benzylthio) carbonyl) amino) -4-methoxybenzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; benzyl mercaptan (269 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, followed by anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) and then the reaction mixture was stirred in ice bath for 10 minutes, then the mixture was stirred at room temperature for about 2 hours, and then TLC detection (ethyl acetate: petroleum ether) =10% reaction was completed.

b. 2-amino-4-methoxybenzoic acid (242 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (478. Mu.l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (257 mg, 56% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.49(s,1H),11.72(s,1H),7.94(d,J＝8.9Hz,1H),7.93(d,J＝2.5Hz,1H),7.41-7.22(m,5H),6.74(dd,J＝8.9,2.5Hz,1H),4.23(s,2H),3.82(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝170.16,165.32,164.23,142.84,138.52,133.65,129.23(2C),129.02(2C),127.68,109.31,104.74,103.16,56.04,33.79.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₆ H ₁₆ O ₄ NS:318.07946；found:318.07872

Example 20 (((4' -methoxybenzyl) thio) carbonyl) amino) -4-methoxy-benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; (4-methoxyphenyl) methyl mercaptan (334 mg, 2.17 mmol) was slowly added dropwise to the reaction solution, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in ice bath for 10 minutes, the reaction solution was stirred at room temperature for about 2 hours, and the reaction was terminated by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 2-amino-4-methoxybenzoic acid (242 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (478. Mu.l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (352 mg, 70% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.50(s,1H),11.64(s,1H),7.94(m,2H),7.29(d,J＝8.4Hz,2H),6.88(d,J＝8.4Hz,2H),6.74(d,J＝8.9Hz,1H),4.17(s,2H),3.82(s,3H),3.73(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝170.16,165.52,164.26,158.93,142.88,133.66,130.46(2C),130.22,114.42(2C),109.28,108.40,104.73,56.05,55.56,33.38.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₇ H ₁₈ O ₅ NS:348.09002；found:348.08899

Example 21 (((4' -methoxybenzyl) thio) carbonyl) amino) -4- (trifluoromethyl) benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; (4-methoxyphenyl) methyl mercaptan (334 mg, 2.17 mmol) was slowly added dropwise to the reaction solution, then a solution of anhydrous pyridine (175 μ l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was terminated by thin layer chromatography (ethyl acetate: petroleum ether) = 10%.

b. 2-amino-4-trifluoromethylbenzoic acid (297 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (478. Mu.l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝11.45(s,1H),8.58(s,1H),8.15(d,J＝8.2Hz,1H),7.51(d,J＝8.2Hz,1H),7.29(d,J＝8.6Hz,2H),6.87(d,J＝8.6Hz,2H),4.18(s,2H),3.72(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝169.07,166.29,158.96,140.90,134.01,132.93,130.51(2C),130.14,125.19,120.67,119.77,116.70,114.43(2C),55.55,33.46.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₇ H ₁₅ O ₃ NF ₃ S:386.06684；found:386.06799

Example 22- ((((benzyl) thio) carbonyl) amino) -4- (trifluoromethyl) benzoic acid

b. 2-amino-4-trifluoromethylbenzoic acid (297 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (478. Mu.l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (185 mg, 36% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝14.33(s,1H),11.51(s,1H),8.57(s,1H),8.16(d,J＝8.2Hz,1H),7.53(d,J＝8.2Hz,1H),7.42-7.16(m,5H),4.24(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝168.99,165.99,140.87,138.50,133.71,132.88,129.26(2C),129.02(2C),127.69,125.30,121.56,119.67,116.61,33.80.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₆ H ₁₃ O ₃ NF ₃ S:356.05628；found:356.05529

Example 23-fluoro-6- (((((4' -methoxybenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; p-methoxybenzylthiol (231 mg, 1.5 mmol) was slowly added dropwise to the reaction, and then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in an ice bath for 10 minutes, the stirring was resumed at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 6-Fluoroanthranilic acid (155 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 223 mg of a white solid in 66% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.62(s,1H),10.58(s,1H),7.51(q,J＝3.8Hz,2H),7.30–7.24(m,2H),7.08(ddd,J＝10.0,6.0,3.3Hz,1H),6.90–6.81(m,2H),4.11(s,2H),3.73(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ166.06,165.90,161.96,158.83,138.60,133.21,130.48(2C),130.42,119.37,114.36,114.07(2C),112.36,55.53,33.12.HRMS(ESI):m/z calculated for C ₁₆ H ₁₅ O ₄ NFS[M+H] ⁺ 336.07003；found,336.07068

Example 24 2-fluoro-6- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; to trifluoromethyl benzyl mercaptan (288 mg, 1.5 mmol) was slowly added dropwise to the reaction, followed by anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 6-Fluoroanthranilic acid (155 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 202 mg of a white solid in 54% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.55(s,1H),10.63(s,1H),7.68(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,2H),7.54–7.43(m,2H),7.14–7.06(m,1H),4.24(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ165.84,165.68,161.96,144.20,138.36,133.19,130.06(2C),128.03,125.89,123.44,119.71,114.80(2C),112.88,33.01.HRMS(ESI):m/z calculated for C ₁₆ H ₁₂ O ₃ NF ₄ S[M+H] ⁺ 374.04685；found,374.04559.

Example 25-fluoro-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 5-Fluoroanthranilic acid (155 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 224 mg of a white solid in 60% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.96(s,1H),11.15(s,1H),8.16(dd,J＝9.2,5.1Hz,1H),7.72–7.62(m,3H),7.60(d,J＝8.1Hz,2H),7.49(td,J＝8.6,3.2Hz,1H),4.28(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.64,165.04,156.41,143.95,136.59,130.78(2C),130.03,125.86,123.37,123.28,121.57,120.17,117.56(2C),33.12.HRMS(ESI):m/z calculated for C ₁₆ H ₁₂ O ₃ NF ₄ S[M+H] ⁺ 374.04685；found,374.04596.

Example 26 4-fluoro-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees under ice bath; to trifluoromethyl benzyl mercaptan (288 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction was stirred in an ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 4-Fluoroanthranilic acid (155 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 235 mg of a white solid in 63% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.94(s,1H),11.64(s,1H),8.10–8.03(m,2H),7.69(d,J＝8.2Hz,2H),7.61(d,J＝8.1Hz,2H),7.03(td,J＝8.4,2.6Hz,1H),4.32(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ169.47,165.47,164.19,143.67,142.60,134.57,130.06(2C),128.09,126.05,125.84,113.09(2C),110.75,107.03,33.22.HRMS(ESI):m/z calculated for C ₁₆ H ₁₂ O ₃ NF ₄ S[M+H] ⁺ 374.04685；found,374.04648.

Example 27-chloro-6- (((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 4-trifluoromethyl benzyl mercaptan (288 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 2-amino-6-chlorobenzoic acid (172 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, heating and refluxing were carried out for about 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100) to give 253 mg of a white solid in 65% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.60(s,1H),10.27(s,1H),7.68(d,J＝8.2Hz,2H),7.56(d,J＝8.1Hz,2H),7.46–7.35(m,3H),4.20(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ166.24,156.96,147.13,144.42,144.32,137.03,136.17,135.42,129.97(2C),129.47,125.77(2C),115.04,108.63,32.84.HRMS(ESI):m/z calculated for C ₁₆ H ₁₂ ClF ₃ NO ₃ S[M+H] ⁺ :390.01730；found,390.01767.

Example 28-chloro-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 4-Trifluoromethylbenzylthiol (288 mg, 1.5 mmol) was slowly added dropwise to the reaction, and then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in an ice bath for 10 minutes, the stirring was resumed at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 2-amino-5-chlorobenzoic acid (171 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for 2 hours and the reaction was detected by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 230 mg of the product, 59% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.31(s,1H),8.21(d,J＝9.0Hz,1H),7.90(d,J＝2.6Hz,1H),7.70–7.66(m,3H),7.61(d,J＝8.1Hz,2H),4.30(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):168.81,165.18,150.05,139.15,134.00,130.40(2C),130.08,125.89(2C),122.56,122.61,119.39,119.17,111.61,33.24.HRMS(ESI):m/z calculated for C ₁₆ H ₁₂ ClF ₃ NO ₃ S[M+H] ⁺ 390.01730；found 390.01773.

Example 29-bromo-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees under ice bath; 4-trifluoromethyl benzyl mercaptan (288 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 2-amino-5-bromobenzoic acid (216 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. The reaction solution was dried by rotary column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.33(s,1H),8.15(d,J＝8.8Hz,1H),8.03(s,1H),7.79(d,J＝8.8Hz,1H),7.69(d,J＝7.8Hz,2H),7.60(d,J＝7.8Hz,2H),4.29(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):168.69,165.13,143.81,139.54,137.16,133.66,130.06(2C),128.38,125.87(2C),123.36,122.77,119.59,115.11,33.22.HRMS(ESI):m/z calculated for C ₁₆ H ₁₂ BrF ₃ NO ₃ S[M+H] ⁺ 433.96679；found,433.96915.

Example 30-bromo-6- (((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-6-bromobenzoic acid (216 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100).

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.60(s,1H),10.25(s,1H),7.68(d,J＝8.1Hz,2H),7.56(d,J＝8.3Hz,3H),7.42–7.33(m,2H),4.20(s,2H). ¹³ C NMR(101MHz,DMSO):δ166.95,166.26,157.34,147.12,146.99,144.51,144.33,137.19,131.29,129.96(2C),129.47,125.76(2C),115.63,32.83.HRMS(ESI):m/z calculated for C ₁₆ H ₁₂ BrF ₃ NO ₃ S[M+H] ⁺ :433.96679；found,433.96622.

Example 31 2-methoxy-6- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (214.83 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane and maintained at zero degrees centigrade in ice. 4-trifluoromethyl benzyl mercaptan (416.64 mg, 2.17 mmol) was slowly added dropwise to the reaction, followed by anhydrous pyridine (175. Mu.l, 2.17 mmol) in dichloromethane (1 ml) and the reaction was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours and checked by thin layer chromatography (ethyl acetate/petroleum ether = 10%) for reaction.

b. 2-amino-6-methoxybenzoic acid (242.15 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (475. Mu.l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave 340 mg of white solid powder as a 61% product.

¹ H NMR(400MHz,Chloroform-d)δ12.15(s,1H),11.58(s,1H),8.42–8.25(m,1H),7.68–7.43(m,5H),6.76(d,J＝8.4Hz,1H),4.23(s,2H),4.10(d,J＝1.3Hz,3H).HRMS(ESI):m/z calculated for 386.06570 C ₁₇ H ₁₅ F ₃ NO ₄ S；found,386.06684

Example 32-methoxy-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. Adding 2-amino-5-methoxybenzoic acid (167 mg, 1 mmol) into 5 ml of anhydrous dichloromethane, keeping an ice bath, adding N, N-diisopropylethylamine (258 mg, 2 mmol), slowly dripping the solution a into the solution, removing the ice bath, heating and refluxing for about 2 hours, and detecting the completion of the reaction by thin layer chromatography. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100) to obtain 222 mg of a white solid with a yield of 58%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.78(s,1H),10.98(s,1H),8.04(d,J＝9.0Hz,1H),7.69(d,J＝8.1Hz,2H),7.60(d,J＝8.0Hz,2H),7.42(d,J＝3.1Hz,1H),7.21(dd,J＝9.1,3.1Hz,1H),4.27(s,2H),3.77(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ169.38,164.50,155.21,144.12,133.44,130.00(2C),127.96,126.08,125.84(2C),123.02,120.52,119.74,115.28,55.93,33.10.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ F ₃ NO ₄ S[M+H] ⁺ :386.06684；found,386.06573.

Example 33 4-methoxy-2- (((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-4-methoxybenzoic acid (167 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, heating and refluxing were carried out for about 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100) to obtain 242 mg of a white solid, yield 63%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.55(s,1H),11.65(s,1H),7.95(d,J＝8.9Hz,1H),7.90(d,J＝2.5Hz,1H),7.71(d,J＝8.2Hz,2H),7.62(d,J＝8.2Hz,2H),6.76(dt,J＝8.9,2.0Hz,1H),4.31(s,2H),3.82(s,3H). ¹³ C NMR(101MHz,DMSO):δ170.13,164.97,164.24,143.79,142.71,133.66,130.03(2C),128.97,125.89(2C),123.36,109.40,108.54,104.86,56.06,33.20.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ F ₃ NO ₄ S[M+H] ⁺ :386.06684；found,386.06543.

Example 34 3-methoxy-2- (((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-3-methoxybenzoic acid (167 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. The reaction solution was dried and separated by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 219 mg of the product, yield 57%.

¹ H NMR(400MHz,CD ₃ OD):δ7.58(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.44(dd,J＝7.7,1.3Hz,1H),7.29(t,J＝8.0Hz,1H),7.23(dd,J＝8.3,1.2Hz,1H),4.22(s,2H),3.85(s,3H). ¹³ C NMR(101MHz,CD ₃ OD):169.95,168.42,155.66,145.07,130.45(2C),129.99,127.95,126.84,126.33(2C),124.39,123.02,118.15,116.18,56.63,34.02.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ F ₃ NO ₄ S[M+H] ⁺ 386.06684；Found,386.06723.

Example 35-methyl-6- (((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-6-methylbenzoic acid (151 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 232 mg of the product in 63% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.20(s,1H),10.14(s,1H),7.68(d,J＝8.2Hz,2H),7.57(d,J＝8.2Hz,2H),7.35–7.27(m,2H),7.12(d,J＝7.2Hz,1H),4.20(s,2H),2.35(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):169.04,159.48,147.63,142.98,136.31,130.33,129.97,129.48(2C),128.18,126.45,125.75(2C),113.779,109.17,27.66,22.18.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ F ₃ NO ₃ S[M+H] ⁺ 370.07193；Found,370.07199.

Example 36-methyl- (2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-5-methylbenzoic acid (151 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for 2 hours and the reaction was detected by thin layer chromatography to be complete. The reaction solution was dried by rotary column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.68(s,1H),11.28(s,1H),8.10(d,J＝8.4Hz,1H),7.78(s,1H),7.70(d,J＝8.2Hz,2H),7.61(d,J＝8.2Hz,2H),7.43(d,J＝8.4Hz,1H),4.29(s,2H),2.30(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.05,164.57,144.01,138.12,135.25,132.91,131.68,130.03(2C),128.02,126.08,125.86(2C),120.63,117.22,33.16,20.64.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ F ₃ NO ₃ S[M+H] ⁺ 370.07193；Found,370.07288.

Example 37: 4-methyl-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-4-methylbenzoic acid (151 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 221 mg of the product in 60% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.65(s,1H),11.45(s,1H),8.11(s,1H),7.87(d,J＝8.1Hz,1H),7.69(d,J＝8.1Hz,2H),7.61(d,J＝8.1Hz,2H),7.00(d,J＝8.1Hz,1H),4.29(s,2H),2.35(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.19,164.73,145.50,143.99,140.73,131.69,130.03(2C),128.38,125.87(2C),124.40,123.37,120.50,113.98,33.21,22.02.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ F ₃ NO ₃ S[M+H] ⁺ 370.07193；Found,370.07318.

Example 38:4- (trifluoromethyl) -2- (((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-4-trifluoromethylbenzoic acid (297.25 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (475. Mu.l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ )δ14.33(s,1H),11.62(s,1H),8.53(d,J＝1.7Hz,1H),8.15(d,J＝8.3Hz,1H),7.70(d,J＝8.2Hz,2H),7.62(d,J＝8.1Hz,2H),7.57–7.46(m,1H),4.32(s,2H). ¹³ C HRMS(ESI):m/z calculated for C ₁₇ H ₁₂ F ₆ NO ₃ S[M+H] ⁺ 424.17981；found,424.04366

Example 39: 4-nitro-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-4-nitrobenzoic acid (263.9 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (475. Mu.l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(500MHz,DMSO-d ₆ ):δ11.49(s,1H),9.00(d,J＝2.4Hz,1H),8.17(d,J＝8.7Hz,1H),7.97(d,J＝8.6Hz,1H),7.77–7.57(m,4H),4.34(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.58,165.90,150.57,143.69,140.70,133.15,130.29(2C),129.88,128.13,126.00,125.69,125.29(2C),117.92,33.24.HRMS(ESI):m/z calculated for C ₁₆ H ₁₂ F ₃ N ₂ O ₅ S[M+H] ⁺ 401.03912；found,401.04135

Example 40:5- (2 '-methyl) phenyl-2- (((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

b. 4-amino-2 '-methyl [1,1' -biphenyl ] -3-carboxylic acid (227 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the above solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for 2 hours and checked by thin layer chromatography for completion of the reaction. The reaction solution was dried by spinning and separated by column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.41(s,1H),8.29(d,J＝8.6Hz,1H),7.88(d,J＝2.2Hz,1H),7.70(d,J＝8.2Hz,2H),7.65–7.60(m,3H),7.31–7.20(m,4H),4.32(s,2H),2.23(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):169.92,164.94,143.97,140.13,139.29,136.42,135.24,131.73,130.96,130.60,130.06(2C),129.92,128.37,128.15,126.62,126.09,125.88(2C),120.51,117.16,33.22,20.55.HRMS(ESI)：m/z calculated for C ₂₃ H ₁₉ F ₃ NO ₃ S[M+H] ⁺ 446.10323；Found，446.10199.

Example 41:5- (2 '-trifluoromethyl) phenyl-2- (((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees under ice bath; 4-Trifluoromethylbenzylthiol (288 mg, 1.5 mmol) was slowly added dropwise to the reaction, and then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in an ice bath for 10 minutes, the stirring was resumed at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 4-amino-3 '- (trifluoromethyl) -1,1' -biphenyl-3-carboxylic acid (281 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, heating and refluxing were performed for 2 hours, and the reaction was detected to be complete by thin layer chromatography. The reaction solution was dried by spinning and separated by column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ14.03(s,1H),11.45(s,1H),8.35(d,J＝8.7Hz,1H),8.26(d,J＝1.9Hz,1H),8.06–7.95(m,3H),7.76–7.68(m,4H),7.63(d,J＝8.1Hz,2H),4.33(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):169.86,165.05,143.87,140.31,140.12,133.62,133.15,131.05,130.67,130.51,130.07(2C),129.74,128.40,126.08,126.01,125.89(2C),124.70,123.31,121.20,117.82,33.25.HRMS(ESI)：m/z calculated for C ₂₃ H ₁₆ F ₆ NO ₃ S[M+H] ⁺ 500.07496；Found，500.07770.

Example 42:2- ((((4' -methoxybenzyl) thio) carbonyl) amino) -5- (trifluoromethoxy) benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane maintained at 0 ℃ in ice bath; 4-methoxybenzyl mercaptan (334 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction mixture was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and then detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. 2-amino-4-trifluoromethoxybenzoic acid (320 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (478. Mu.l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, heating and refluxing were performed for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (220 mg, 38% yield).

¹ H NMR(400MHz,CDCl ₃ ):δ＝11.32(s,1H),8.57(d,J＝8.9Hz,1H),7.92(s,1H),7.38(d,J＝8.9Hz,1H),7.29(d,J＝8.3Hz,2H),6.84(d,J＝8.3Hz,2H),4.18(s,2H),3.79(s,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝169.36,166.21,158.83,140.24,

129.98(2C),129.70,127.35,127.21,123.93,121.29,116.00,114.00(2C),113.95,

55.24,33.87.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₇ H ₁₅ O ₅ NF ₃ S:402.06175；

found:402.06213

Example 43:3, 5-dimethyl-2- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-3, 5-dimethylbenzoic acid (165 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100) to obtain 233 mg of a white solid with a yield of 61%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ12.80(s,1H),9.82(s,1H),7.66(s,2H),7.55(d,J＝6.1Hz,2H),7.44(s,1H),7.27(s,1H),4.18(s,2H),2.29(s,3H),2.13(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ160.50,147.81,147.10,144.70,139.52,138.04,134.79,132.99,129.83(2C),129.47(2C),126.60,125.68,124.80,32.73,20.79,18.28.HRMS(ESI):m/z calculated for C ₁₈ H ₁₇ F ₃ NO ₃ S[M+H] ⁺ :384.08758；found,384.08688.

Example 44:3, 4-dimethyl-2- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-3, 4-dimethylbenzoic acid (165 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 207 mg of the product in 54% yield.

¹ H NMR(400MHz,CD ₃ OD):δ7.71(d,J＝8.0Hz,1H),7.59(d,J＝8.6Hz,2H),7.54(d,J＝8.6Hz,2H),7.18(d,J＝8.0Hz,1H),4.23(s,2H),2.35(s,3H),2.15(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):191.04,148.13,143.90,143.50,130.08(2C),127.92,126.61,126.08,125.77(2C),123.38,122.00,118.22,114.71,32.02,21.21,13.19.HRMS(ESI):m/z calculated for C ₁₈ H ₁₇ F ₃ NO ₃ S[M+H] ⁺ 384.08758；Found,384.08997.

Example 45:4, 5-dimethoxy-2- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-4, 5-di-methoxybenzoic acid (285.65 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (475. Mu.l, 2.90 mmol) was added, and then the above solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100).

¹ H NMR(400MHz,DMSO-d ₆ )δ13.56(s,1H),11.52(s,1H),7.95(s,1H),7.83–7.51(m,4H),7.41(s,1H),4.30(s,2H),3.79(d,J＝24.8Hz,6H).HRMS(ESI):m/z calculated for C ₁₈ H ₁₇ F ₃ NO ₅ S[M+H] ⁺ 416.07687；found,416.07740

Example 46:4, 5-difluoro-2- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid

b. 4, 5-Difluoroanthranilic acid (173 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 240 mg of a white solid in 61% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ14.17(s,1H),11.44(s,1H),8.22(dd,J＝13.1,7.5Hz,1H),7.94(dd,J＝11.2,9.0Hz,1H),7.69(d,J＝8.1Hz,2H),7.61(d,J＝8.1Hz,2H),4.31(s,2H). ¹³ C NMR(126MHz,DMSO-d ₆ ):δ168.39,165.52,153.56,151.55,143.67,138.01,130.06(2C),128.40,125.87,123.62,120.27,114.37(2C),109.53,33.21.HRMS(ESI):m/z calculated for C ₁₆ H ₁₁ O ₃ NF ₅ S[M+H] ⁺ 392.03743；found,392.03699.

Example 47:4, 5-difluoro-2- (((((4' -methoxybenzyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; p-methoxybenzyl mercaptan (231 mg, 1.5 mmol) was slowly added dropwise to the reaction, followed by anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in an ice bath for 10 minutes, the reaction solution was stirred at room temperature for about 2 hours and then checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. 4, 5-Difluoroanthranilic acid (173 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, after which the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was detected by thin layer chromatography to be complete. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 245 mg of a white solid in 69% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ14.21(s,1H),11.40(s,1H),8.26(dd,J＝13.2,7.4Hz,1H),7.94(dd,J＝11.2,9.1Hz,1H),7.29(d,J＝8.8Hz,2H),6.92–6.80(m,2H),4.18(s,2H),3.72(d,J＝1.2Hz,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.42,166.00,158.93,155.57,143.49,138.08,130.47(2C),130.09,120.09,114.40(2C),114.15,109.30,55.54,33.39.HRMS(ESI):m/z calculated for C ₁₆ H ₁₄ O ₄ NF ₂ S[M+H] ⁺ 354.06061；found,354.06018.

Example 48:4, 5-dichloro-2- (((((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid

b. 2-amino-4, 5-dichlorobenzoic acid (206 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the solution was heated under reflux for 2 hours and the reaction was detected by thin layer chromatography to be complete. The reaction solution was dried by rotary column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.41(s,1H),8.45(s,1H),8.07(d,J＝1.5Hz,1H),7.69(d,J＝8.1Hz,2H),7.61(d,J＝8.1Hz,2H),4.31(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):168.27,165.62,143.65,139.75,136.82,132.71,130.09(2C),128.11,125.88(2C),125.35,123.36,121.81,117.77,33.28.HRMS(ESI):m/z calculated for C ₁₆ H ₁₁ Cl ₂ F ₃ NO ₃ S[M+H] ⁺ 423.97833；found,423.97479.

Example 49:2- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid methyl ester

b. Anthranilate (151 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the mixture was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography was performed directly on the sample (petroleum ether: ethyl acetate: acetic acid = 100) to obtain 211 mg of a white solid, yield 57%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.81(s,1H),7.96(dd,J＝8.3,1.0Hz,1H),7.88(dd,J＝7.9,1.6Hz,1H),7.69(d,J＝8.1Hz,2H),7.64–7.59(m,3H),7.23(td,J＝7.7,1.1Hz,1H),4.28(s,2H),3.81(s,3H). ¹³ C NMR(101MHz,DMSO):δ167.92,165.23,144.08,139.03,134.43,130.99,130.02(2C),128.30,125.78(2C),124.38,123.37,122.06,119.30,52.90,33.10.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ F ₃ NO ₃ S[M+H] ⁺ :370.07193；found,370.07101.

Example 50 methyl 5-chloro-2- ((((((4' -methoxybenzyl) thio) carbonyl) amino) benzoate

Methyl 2-amino-5-chlorobenzoate (185 mg, 1 mmol) was dissolved in 10 ml of anhydrous dichloromethane, N-diisopropylethylamine (258 mg, 2 mmol) and triphosgene (148 mg, 0.5 mmol) were slowly added under ice-bath, reacted at room temperature for 2 hours, and the organic phase was spin-dried. 10 ml of anhydrous dichloromethane and N, N-diisopropylethylamine (258 mg, 2 mmol) were added thereto, and p-methoxybenzyl mercaptan (231 mg, 1.5 mmol) was slowly added thereto under ice-bath, followed by reaction at room temperature for 3 hours. The organic phase was spin dried and column chromatographed (ethyl acetate: petroleum ether = 1).

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.70(s,1H),7.98(d,J＝8.8Hz,1H),7.84(s,1H),7.69(d,J＝8.8Hz,1H),7.35–7.17(m,2H),6.94–6.78(m,2H),4.15(s,2H),3.82(s,3H),3.73(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):166.77,166.01,158.89,137.95,134.04,130.46(2C),130.37,130.20,127.87,123.83,120.91,114.36(2C),55.54,53.22,33.31.HRMS(ESI):m/z calculated for C ₁₇ H ₁₇ ClNO ₄ S[M+H] ⁺ 366.05613；found,366.05475.

Example 51 methyl 2-fluoro-6- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoate

2-fluoro-6- ((((4- (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-024, 373 mg, 1 mmol) and anhydrous methanol (35 mg, 1.1 mmol) were dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 209 mg of white solid, 54% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.54(s,1H),7.69(d,J＝8.1Hz,2H),7.61–7.49(m,3H),7.24(d,J＝8.2Hz,1H),7.13(t,J＝9.3Hz,1H),4.22(s,2H),3.71(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.68,167.95,153.51,139.82,134.32,130.93(2C),129.91,129.66,125.63,121.77,118.50(2C),107.10,106.81,52.82,30.76.HRMS(ESI):m/z calculated for C ₁₇ H ₁₄ O ₃ NF ₄ S[M+H] ⁺ 388.06250；found,388.06204.

Example 52 allyl 2- (((benzylmercapto) carbonyl) amino) benzoate

Allyl-2-aminobenzoate hydrochloride (213 mg, 1 mmol) was dissolved in 10 ml of anhydrous dichloromethane, N-diisopropylethylamine (387 mg, 3 mmol) and triphosgene (148 mg, 0.5 mmol) were slowly added under ice bath, reacted at room temperature for 2 hours, and the organic phase was spin-dried. Then, 10 ml of anhydrous dichloromethane and N, N-diisopropylethylamine (258 mg, 2 mmol) were added, and benzylmercaptan (186 mg, 1.5 mmol) was slowly added under ice bath to react at room temperature for 3 hours. The organic phase was dried by spin-drying and column chromatography (ethyl acetate: petroleum ether =1 = 20) to give 183 mg of white powder, 56% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ11.13(s,1H),8.52(dd,J＝8.6,1.0Hz,1H),8.06(dd,J＝8.0,1.7Hz,1H),7.55–7.51(m,1H),7.42–7.36(m,2H),7.35–7.27(m,2H),7.28–7.21(m,1H),7.12–7.02(m,1H),6.07–5.97(m,1H),5.42(dq,J＝17.2,1.4Hz,1H),5.32(dq,J＝17.2,1.4Hz,1H),4.82(dt,J＝5.7,1.4Hz,2H),4.24(s,2H). ¹³ C NMR(101MHz,CDCl ₃ ):δ167.67,165.80,141.34,134.75,131.56,130.84,129.38,128.84(2C),128.56(2C),127.23,122.39,120.12,118.86,114.48,65.90,34.32.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₈ H ₁₈ NO ₃ S:328.10019,found:328.09982.

Example 53 phenyl 2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoate

2- (((4- (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (I-1-3, 355 mg, 1 mmol) and phenol (104 mg, 1.1 mmol) were dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether =1 = 20) to give 257 mg of a white solid in 60% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.69(s,1H),8.04(dd,J＝7.9,1.6Hz,1H),7.78(dd,J＝8.3,1.3Hz,1H),7.69(dd,J＝7.3,1.5Hz,1H),7.64(d,J＝8.2Hz,2H),7.57(d,J＝8.2Hz,2H),7.45(t,J＝7.8Hz,2H),7.36–7.28(m,2H),7.26(dd,J＝8.5,1.3Hz,2H),4.27(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ165.92,165.72,150.83,144.06,138.55,134.58,131.32,130.00(2C),129.94(2C),127.99,126.50,125.77(2C),124.97,124.34,123.17,122.35(2C),120.96,33.03.HRMS(ESI):m/z calculated for C ₂₂ H ₁₇ O ₃ NF ₃ S[M+H] ⁺ 432.08758；found,432.08664.

Example 54 benzyl 2- (((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoate

2- (((4- (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-003, 355 mg, 1 mmol) and benzyl alcohol (119 mg, 1.1 mmol) were dissolved in dry dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, column chromatographed (ethyl acetate: petroleum ether =1 = 20) to give 276 mg of white solid in 62% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.77(s,1H),7.95–7.88(m,2H),7.69–7.57(m,5H),7.46–7.33(m,5H),7.23(td,J＝7.6,1.2Hz,1H),5.28(s,2H),4.26(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ167.22,165.29,144.09,138.92,136.07,134.45,131.07,130.03(2C),128.95(2C),128.66,128.62(2C),125.82(2C),124.54,122.28,119.70,49.06,33.08.HRMS(ESI):m/z calculated for C ₂₃ H ₁₉ O ₃ NF ₃ S[M+H] ⁺ 446.10323；found,446.10410.

Example 55 [ 2- (((benzylmercapto) carbonyl) amino) benzoic acid phenethyl ester ]

2- (((benzylthio) carbonyl) amino) benzoic acid (IPK-001, 287 mg, 1 mmol) was dissolved in 10 mL of anhydrous dichloromethane, N, N-diisopropylethylamine (258 mg, 2 mmol), 2- (7-oxabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (456 mg, 1.2 mmol), and phenethyl alcohol (146 mg, 1.2 mmol) were added and stirred at room temperature overnight. Extraction with water (5 ml × 3), spin-drying of the organic phase, and column chromatography (ethyl acetate: petroleum ether =1 = 20) gave 293 mg of a white powder in 75% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.77(s,1H),8.02–7.97(m,1H),7.82(dd,J＝7.9,1.6Hz,1H),7.65–7.56(m,1H),7.38–7.31(m,3H),7.31–7.21(m,8H),4.44(t,J＝6.8Hz,2H),4.20(s,2H),3.01(t,J＝6.8Hz,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ167.42,165.54,139.37,138.76,138.39,134.54,129.85,129.34(2C),129.23(2C),128.95(2C),128.87(2C),127.60,126.90,124.18,121.83,118.79,66.19,34.64,33.72.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₂₃ H ₂₂ NO ₃ S:392.13149；found,392.13095.

Example 56 (((4' -trifluoromethyl) benzylmercapto) carbonyl) amino) benzoyl (methoxyethyl) amine

2- ((((4-trifluoromethyl) benzylthio) carbonyl) amino) benzoic acid (IPK-003, 355 mg, 1 mmol) was dissolved in 10 ml of anhydrous dichloromethane, and N, N-diisopropylethylamine (258 mg, 2 mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (456 mg, 1.2 mmol) and 2-methoxyethylamine (90 mg, 1.2 mmol) were added and stirred at room temperature overnight. Extraction with water (5 ml × 3), spin-drying of the organic phase, and column chromatography (ethyl acetate: petroleum ether =1 = 20) gave 280mg of white powder in 67% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.85(s,1H),8.85(t,J＝5.0Hz,1H),8.18(dd,J＝8.3,1.0Hz,1H),7.78(dd,J＝7.9,1.4Hz,1H),7.68(d,J＝8.2Hz,2H),7.60(d,J＝8.1Hz,2H),7.53–7.48(m,1H),7.17(td,J＝7.7,1.2Hz,1H),4.28(s,2H),3.48–3.38(m,4H),3.26(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.69,164.52,144.09,143.03,139.02,132.81,130.01(2C),128.71,128.32,126.08,125.84(2C),123.52,120.78,70.54,58.39,39.47,33.13.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₉ H ₂₀ F ₃ N ₂ O ₃ S:413.11412；found,413.11374.

Example 57 (((4' -trifluoromethyl) benzylmercapto) carbonyl) amino) benzoyl (cyclopropyl) amine

2- ((((4-trifluoromethyl) benzylthio) carbonyl) amino) benzoic acid (IPK-003, 355 mg, 1 mmol) was dissolved in 10 ml of anhydrous dichloromethane, and N, N-diisopropylethylamine (258 mg, 2 mmol), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (456 mg, 1.2 mmol) and cyclopropylamine (68 mg, 1.2 mmol) were added and stirred at room temperature overnight. Extraction with water (5 ml × 3), spin-drying of the organic phase, and column chromatography (ethyl acetate: petroleum ether =1 = 20) gave 279 mg of white powder in 70% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝11.83(s,1H),8.74(s,1H),8.15(d,J＝8.3Hz,1H),7.73–7.55(m,5H),7.49(dd,J＝11.3,4.3Hz,1H),7.18–7.10(m,1H),4.28(s,2H),2.89–2.79(m,1H),0.73–0.66(m,2H),0.59(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝169.98,164.54,144.17,138.85,132.78,130.06(2C),129.51,128.87,128.02,125.85,123.52(2C),120.83,120.72,33.14,23.58,6.18(2C).HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₉ H ₁₈ F ₃ N ₂ O ₂ S:395.10356；found,395.10301.

Example 58 ((benzylmercapto) carbonyl) amino) benzoylphenethylamine

2- (((benzylthio) carbonyl) amino) benzoic acid (IPK-001, 287 mg, 1 mmol) was dissolved in 10 mL of anhydrous dichloromethane, N, N-diisopropylethylamine (258 mg, 2 mmol), 2- (7-oxabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (456 mg, 1.2 mmol), and phenethylamine (145 mg, 1.2 mmol) were added and stirred at room temperature overnight. Extraction with water (5 ml × 3), spin-drying of the organic phase, and column chromatography (ethyl acetate: petroleum ether =1 = 20) gave 280 mg of white powder in 72% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.75(s,1H),8.89(t,J＝5.1Hz,1H),8.21(d,J＝8.3Hz,1H),7.71(d,J＝7.3Hz,1H),7.51(t,J＝7.4Hz,1H),7.37(d,J＝7.2Hz,2H),7.34–7.13(m,9H),4.20(s,2H),3.49(d,J＝6.6Hz,2H),2.85(t,J＝7.3Hz,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.58,164.88,139.76,139.15,138.89,132.79,129.25(2C),129.18(2C),129.00(2C),128.84(2C),128.59,127.63,126.67,123.41,120.69,120.55,41.27,35.24,33.74.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₂₃ H ₂₃ N ₂ O ₂ S:391.14748；found,391.14697.

Example 59 methyl 2- ((((4' - (trifluoromethyl) phenyl) thio) carbonyl) amino) phenylacetate

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; 4-trifluoromethyl benzyl mercaptan (417 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction mixture was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. Methyl o-aminophenylacetate (239 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml/3 times) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (422 mg, 76% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝9.90(s,1H),7.68(d,J＝8.2Hz,2H),7.57(d,J＝8.2Hz,2H),7.33-7.24(m,3H),7.24-7.13(m,1H),4.20(s,2H),3.67(s,2H),3.51(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝171.51,165.68,144.62,136.57,131.66,130.44,129.95(2),128.04,127.83,126.85,126.72,125.67(2),123.41,52.02,37.08,32.83.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₈ H ₁₇ O ₃ NF ₃ S:384.08758；found:384.08694

Example 60 (((4' - (trifluoromethyl) phenyl) thio) carbonyl) amino) phenylacetic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; trifluoromethyl benzyl mercaptan (417 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, then anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction mixture was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and then detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. O-aminophenylacetic acid (219 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (478. Mu.l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml/3 times) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (299 mg, 56% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝7.55(d,J＝8.1Hz,2H),7.43(d,J＝7.6Hz,2H),7.19-7.33(m,4H),4.17(s,2H),3.68(s,2H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝175.54,162.37,142.03,135.20,131.22,129.37,129.24(2C),128.72,128.11,125.55(2C),125.41,122.71,120.04,37.89,33.86.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₇ H ₁₅ O ₃ NF ₃ S:370.07193；found:370.07089

Example 61-methoxy-2- ((((((1 '- (3 "- (trifluoromethyl) phenyl) -1' -methyl) methylene) thio) carbonyl) amino) benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; 1- (3- (trifluoromethyl) phenyl) ethanethiol (447 mg, 2.17 mmol) is slowly added dropwise to the reaction solution, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) is slowly added dropwise, the reaction solution is stirred in ice bath for 10 minutes, then the reaction solution is stirred at room temperature for about 2 hours, and then the reaction solution is stirred for about 10% by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction is finished.

b. 2-amino-4-methoxybenzoic acid (242 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (478. Mu.l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (329 mg, 57% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.81(s,1H),10.93(s,1H),8.03(d,J＝9.1Hz,1H),7.76(m,2H),7.60(m,2H),7.41(s,1H),7.20(d,J＝9.0Hz,1H),4.80(q,J＝6.9Hz,1H),3.76(s,3H),1.69(d,J＝7.0Hz,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝169.46,164.10,155.12,145.11,133.54,131.93,130.14,129.49,125.97,124.52,124.27,122.82,120.61,119.36,115.29,55.92,43.42,22.55.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₈ H ₁₇ O ₄ NF ₃ S:400.08249；found:400.08130

Example 62 (((((1 '- (4 "-bromophenyl) -1' -propyl) methylene) thio) carbonyl) amino) benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; benzyl mercaptan 1- (4-bromobenzene) butyl mercaptan (529 mg, 2.17 mmol) was slowly added dropwise to the reaction solution, then anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and then detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. Anthranilic acid (199 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave a white solid powder (425 mg, 72% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.76(s,1H),11.34(s,1H),8.21(d,J＝8.3Hz,1H),7.96(d,J＝7.9Hz,1H),7.58(t,J＝7.9Hz,1H),7.52(d,J＝8.4Hz,2H),7.35(d,J＝8.5Hz,2H),7.15(t,J＝7.6Hz,1H),4.53(t,J＝7.8Hz,1H),1.98–1.85(m,2H),1.38–1.13(m,2H),0.87(t,J＝7.3Hz,3H). ¹³ C NMR(126MHz,DMSO-d ₆ ):δ＝170.12,164.53,142.00,140.63,134.82,131.84(2C),131.68,130.31(2C),123.50,120.68,120.22,116.70,48.22,37.91,20.67,13.82.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₈ H ₁₉ O ₃ NBrS:408.02635；found:408.02753

Example 63 (((((5 '-chlorothien-2' -yl) methylene) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; (5-chlorothien-2-yl) methanethiol (246 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. Column chromatography separation (petroleum ether: ethyl acetate: acetic acid = 100) directly by stirring to give 217 mg of a white solid in 66% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.75(s,1H),11.37(s,1H),8.23(s,1H),7.97(s,1H),7.62(s,1H),7.19(s,1H),6.93(s,2H),4.37(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.08,164.82,141.31,140.47,134.87,131.74,127.93,127.18,126.92,123.85,120.68,117.33,28.92.HRMS(ESI):m/z calculated for C ₁₃ H ₁₁ ClNO ₃ S ₂ [M+H] ⁺ 327.98634；found,327.98520.

Example 64 methyl 2- ((((pyridine-4' -methylene) thio) carbonyl) amino) benzoate

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; 4-mercaptomethylpyridine (271 mg, 2.17 mmol) was slowly added dropwise to the reaction solution, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. Methyl anthranilate (219 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml × 3) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate = 100) gave a white solid powder (359 mg, 82% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝10.81(s,1H),8.51(d,J＝6.0Hz,2H),7.92(d,J＝8.3Hz,1H),7.88(d,J＝7.9Hz,1H),7.61(t,J＝7.8Hz,1H),7.38(d,J＝6.0Hz,2H),7.24(t,J＝7.6Hz,1H),4.19(s,2H),3.80(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝167.97,165.12,150.18(2C),148.07,138.88,134.41,131.08,124.52,124.28(2C),122.25,119.73,32.47.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₅ H ₁₅ O ₃ N ₂ S:303.07979；found:303.08029

Example 65 2- ((((naphthalen-2' -ylmethylene) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees under ice bath; 2-Naphthalenethiol (261 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 182 mg of the product, 54% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.77(s,1H),11.41(s,1H),8.27(d,J＝8.3Hz,1H),7.97(dd,J＝7.9,1.4Hz,1H),7.89–7.87(m,4H),7.64–7.58(m,1H),7.54–7.46(m,3H),7.19–7.15(dd,J＝11.6,4.4Hz,1H),4.39(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.12,165.16,140.66,136.19,134.84,133.30,132.58,131.69,128.71,128.07,128.03,127.63,127.52,126.83,126.47,123.59,120.42,116.93,34.11.HRMS(ESI):m/z calculated for C ₁₉ H ₁₆ NO ₃ S[M+H] ⁺ 338.08454；found,338.08420.

Example 66 (((acridin-9' -ylmethylene) thio) carbonyl) amino) benzoic acid

a. Triphosgene (214.83 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane and maintained at zero degrees centigrade in ice. Acridine-9-methyl mercaptan (488.25 mg, 2.17 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (175 μ l, 2.17 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate/petroleum ether = 10%).

b. 2-aminobenzoic acid (198.65 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (475 μ l, 2.90 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the end of the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave 338 mg of white solid powder in 60% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.72(s,2H),8.23(d,J＝8.2Hz,2H),7.92(d,J＝7.9Hz,2H),7.79–7.69(m,3H),7.54(d,J＝8.4Hz,1H),7.25(t,J＝7.7Hz,3H),7.15(d,J＝8.2Hz,1H),5.75(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ177.22,167.42,160.39,147.30,141.86,141.34,137.39,133.91(2C),131.98,129.12,126.46(2C),123.97,121.45(2C),120.93,117.79(2C),115.79,65.49,30.46.HRMS m/z calculated for 389.09544C ₂₂ H ₁₇ N ₂ O ₃ S[M+H] ⁺ ,389.10913

Example 67 (((5 '- (trifluoromethyl) furan-2' -yl) methylene) thio) carbonyl) amino) benzoic acid

a. Triphosgene (215 mg, 0.7 mmol) was dissolved in 10 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; (5- (trifluoromethyl) furan-2-yl) methanethiol (440 mg, 2.4 mmol) is slowly added dropwise to the reaction, then a solution of anhydrous pyridine (255 mg, 3.2 mmol) in dichloromethane (5 ml) is slowly added dropwise, the reaction solution is stirred in ice bath for 10 minutes, then the stirring is resumed for about 2 hours at room temperature, and the reaction is detected by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (221 mg, 1.6 mmol) was added to 10 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (255 g, 3.2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) afforded 350 mg, 63% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.76(s,1H),11.39(s,1H),8.20(d,J＝7.8Hz,1H),7.97(dd,J＝7.9,1.5Hz,1H),7.67–7.57(m,1H),7.22–7.17(m,1H),7.15(d,J＝2.1Hz,1H),6.56(d,J＝3.2Hz,1H),4.34(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ169.99,164.00,155.72,140.31,139.65,134.78,131.66,123.88,122.40,120.67,

117.43,114.75,109.81,26.06.HRMS(ESI):m/z calculated for C ₁₄ H ₁₁ O ₄ NF ₃ S[M+H] ⁺ ,346.03485；found,346.03554

Example 68 (((4' - (trifluoromethyl) benzyl) thio) thioacyl) amino) benzoic acid

2-aminobenzoic acid (200 mg, 1.45 mmol) and carbon disulfide (220 mg, 2.90 mmol) were dissolved in dioxane (20 ml), triethylamine (526 μ l, 3.62 mmol) was slowly added dropwise under ice bath, and after stirring for 5 hours additional 4-trifluoromethylbenzyl bromide (414 mg, 1.74 mmol) was added and stirred at room temperature overnight, and column chromatography was performed (petroleum ether: ethyl acetate: acetic acid =100: 10) to give 345 mg of a white solid in 64% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.38(s,1H),12.05(s,1H),7.95(dd,J＝1.7,7.8Hz,2H),7.70(d,J＝8.1Hz,2H),7.67–7.57(m,3H),7.41(td,J＝1.2,7.6Hz,1H),4.67(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ196.57,182.30,168.05,142.64,140.00,133.29,131.43,130.18(2C),128.37,127.16,126.71,125.76(2C),123.62,38.45.HRMS(ESI):m/z calculated for C ₁₆ H ₁₃ F ₃ NO ₂ S ₂ [M+H] ⁺ 372.03363；found,372.0261

Example 69 (((4' -fluorobenzyl) thio) thioacyl) amino) benzoic acid

2-aminobenzoic acid (200 mg, 1.45 mmol) and carbon disulfide (220 mg, 2.90 mmol) were dissolved in dioxane (20 ml), triethylamine (526 μ l, 3.62 mmol) was slowly added dropwise under ice bath, after stirring for 5 hours 4-fluorobenzyl bromide (329 mg, 1.74 mmol) was added with stirring at room temperature overnight, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave 301 mg of white solid in 65% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.37(s,1H),11.99(s,1H),8.08–7.88(m,2H),7.62(td,J＝1.6,7.8Hz,1H),7.50–7.33(m,3H),7.20–7.07(m,2H),4.54(s,2H). ¹³ C NMR(126MHz,DMSO-d ₆ ):δ196.86,168.16,168.13,162.82,160.88,140.06,133.44,131.48,131.41(2C),127.02,126.47,115.81(2C),38.45.HRMS(ESI):m/z calculated for C ₁₅ H ₁₃ FNO ₂ S ₂ [M+H] ⁺ 322.03665；found,322.03662

Example 70 ((((4' -methoxybenzyl) thio) thioacyl) amino) benzoic acid

2-aminobenzoic acid (200 mg, 1.45 mmol) and carbon disulfide (220 mg, 2.90 mmol) were dissolved in dioxane (20 ml), triethylamine (526 μ l, 3.62 mmol) was slowly added dropwise under ice bath, after stirring for 5 hours 4-methoxybenzyl bromide (348 mg, 1.74 mmol) was added and stirred at room temperature overnight, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.39(s,1H),11.99(s,1H),8.04(d,J＝8.1Hz,1H),7.94(dd,J＝1.6,7.8Hz,1H),7.62(td,J＝1.7,7.8Hz,1H),7.38(td,J＝1.2,7.6Hz,1H),7.34–7.26(m,2H),6.92–6.85(m,2H),4.48(s,2H),3.73(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ197.11,168.17,159.00,140.08,133.26,131.39,130.73(2C),128.44,126.91,126.37,124.97,114.41(2C),55.54,39.03.HRMS(ESI):m/z calculated for C ₁₆ H ₁₆ NO ₃ S ₂ [M+H] ⁺ 334.05664；found,334.05661

Example 71

b. 2-aminobenzamide (197.2 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (475. Mu.l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave 318 mg of white solid powder in 62% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ12.28(s,1H),8.36(s,1H),8.25(d,J＝8.3Hz,1H),7.90–7.75(m,2H),7.69(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.57–7.47(m,1H),7.15(t,J＝7.6Hz,1H),4.28(s,2H). ¹³ C NMR(126MHz,DMSO-d ₆ ):δ171.15,164.42,144.04,139.74,133.15,130.04(2C),129.18,128.29,127.97,125.80,123.27,119.23(2C),56.48,49.0.HRMS(ESI):m/z calculated for C ₁₆ H ₁₄ F ₃ N ₂ O ₂ S[M+H] ⁺ 355.07187,found 355.07226

Example 72:2- ((((((4' -trifluoromethyl) benzyl) thio) carbonyl) amino) benzoylmethylamine

b. 2-amino-N-methylbenzamide (217.5 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (475. Mu.l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave 326 mg of white solid powder in 61% yield.

¹ H NMR(500MHz,DMSO-d ₆ )δ11.98(s,1H),8.79(d,J＝5.3Hz,1H),8.20(d,J＝8.4Hz,1H),7.89–7.39(m,6H),7.16(t,J＝7.7Hz,1H),4.28(s,2H),3.32(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ169.00,164.46,144.09,139.07,132.73,130.00(2C),128.50,125.84,123.47(2C),120.65,120.34,110.12,107.33,33.11,26.74.HRMS(ESI):m/z calculated for C ₁₇ H ₁₆ F ₃ N ₂ O ₂ S[M+H] ⁺ ,369.06033；found,369.08063

Example 73: 2-methoxy-6- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid ethyl ester

2-methoxy-6- ((((4- (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (DX-YG-044, 385 mg, 1 mmol) and absolute ethanol (44 mg, 1.1 mmol) were dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 330 mg of a white solid in 80% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.08(s,1H),7.67(d,J＝8.0Hz,2H),7.55(d,J＝8.1Hz,2H),7.39(t,J＝8.2Hz,1H),6.94(dd,J＝8.2,15.6Hz,2H),4.17(s,2H),4.11(q,J＝7.1Hz,2H),3.77(s,3H),1.14(t,J＝7.1Hz,3H). ¹³ C NMR(101MHz,DMSO-d6):δ165.67,165.16,157.55,144.52,136.17,131.49,130.60(2C),129.13,127.88,125.68(2C),123.66,118.92,118.15,109.65,61.03,56.56,32.82.HRMS(ESI):m/z calculated for C ₁₉ H ₁₉ F ₃ NO ₄ S[M+H] ⁺ 414.09665,found 414.0908

The procedure for the synthesis of the cyclized compounds (example 74-example 135) was carried out with slight modifications in the final product:

Example 74:2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-003, 355 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and the organic phase was separated by column chromatography (ethyl acetate: petroleum ether = 1).

¹ H NMR(400MHz,DMSO-d6):δ8.04(dd,J＝7.8,1.2Hz,1H),7.93–7.87(m,1H),7.77(d,J＝8.3Hz,2H),7.71(d,J＝8.3Hz,2H),7.59–7.51(m,2H),4.55(s,2H). ¹³ C NMR(101MHz,DMSO)δ162.35,158.57,146.43,142.43,137.60,130.56(2C),128.75,128.62,128.25,125.89(2C),125.78,123.32,116.20,34.57.HRMS(ESI):m/z calculated for C ₁₆ H ₁₁ F ₃ NO ₂ S[M+H] ⁺ :338.04571；found,338.04553.

Example 75:2- ((3' -cyanobenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((3' -cyanobenzyl) thio) carbonyl) amino) benzoic acid (IPK-005,156 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 98 mg of white solid in 67% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.06-7.99(m,2H),7.93-7.86(m,2H),7.74(d,J＝7.7Hz,1H),7.57-7.51(m,3H),4.50(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):162.32,158.54,146.41,139.33,137.56,134.69,133.29,131.70,130.12,128.72,128.19,125.79,119.08,116.19,111.80,34.26.HRMS(ESI):m/z calculated for C ₁₆ H ₁₁ N ₂ O ₂ S[M+H] ⁺ 295.05357；found,295.05432.

Example 76:2- ((3' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((3' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-002,355 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 253 mg of white solid in 63% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.03(d,J＝7.6Hz,1H),7.93(s,1H),7.92–7.87(m,1H),7.86(d,J＝7.5Hz,1H),7.68–7.49(m,4H),4.54(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ162.40,158.54,146.42,139.09,137.59,133.93,129.98,129.30,128.76,128.23,126.52,125.71,124.62,123.96,116.21,34.55.HRMS(ESI):m/z calculated for C ₁₆ H ₁₁ F ₃ NO ₂ S[M+H] ⁺ :338.04571；found,338.04578.

Example 77:2- ((4' -phenylbenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((4' -phenylbenzyl) thio) carbonyl) amino) benzoic acid (IPK-011, 363 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether =1 20) gave 283 mg of a white solid in 82% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.05(d,J＝7.7Hz,1H),7.90(t,J＝7.5Hz,1H),7.58(m,J＝31.0,15.2,8.1Hz,8H),7.45(t,J＝7.6Hz,2H),7.35(t,J＝7.3Hz,1H),4.52(s,2H). ¹³ C NMR(101MHz,DMSO):δ162.66,158.63,146.52,140.13,139.89,137.62,136.23,130.32(2C),129.40(2C),128.75,128.18,127.96,127.28(2C),127.09(2C),125.89,116.15,35.00.HRMS(ESI):m/z calculated for C ₂₁ H ₁₆ NO ₂ S[M+H] ⁺ :346.08963；found,346.08963.

Example 78- ((4' - (trifluoromethoxy) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((4' - (trifluoromethoxy) benzyl) thio) carbonyl) amino) benzoic acid (IPK-008, 371 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and the organic phase was separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 287 mg of a white solid in 81% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.04(dd,J＝7.8,1.4Hz,1H),7.94–7.87(m,1H),7.66(d,J＝8.6Hz,2H),7.61–7.50(m,2H),7.34(d,J＝8.4Hz,2H),4.50(s,2H). ¹³ C NMR(101MHz,DMSO):δ165.76,162.49,158.60,146.47,137.60,136.94,131.67(2C),131.26,128.75,128.22,125.89,121.50(2C),116.21,34.30.HRMS(ESI):m/z calculated for C ₁₆ H ₁₁ F ₃ NO ₃ S[M+H] ⁺ :354.04063；found,354.04031.

Example 79 2- ((4' -chlorobenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((((4' -chlorobenzyl) thio) carbonyl) amino) benzoic acid (IPK-006, 322 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and the organic phase was separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 255 mg of white solid in 84% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.07–8.02(m,1H),7.92–7.87(m,1H),7.55(dt,J＝7.8,3.7Hz,4H),7.40(d,J＝8.5Hz,2H),4.45(s,2H). ¹³ C NMR(101MHz,DMSO):δ162.47,158.59,146.46,137.61,136.38,132.60,131.60(2C),128.89(2C),128.74,128.21,125.88,116.16,34.46.HRMS(ESI):m/z calculated for C ₁₅ H ₁₁ ClNO ₂ S[M+H] ⁺ :304.01913；found,304.01935.

EXAMPLE 80 2- (4' -Fluorobenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((4' -fluorophenyl) thio) amino) benzoic acid (IPK-009,305 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether =1 20) gave 235 mg of a white solid in 82% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.04(d,J＝7.9Hz,1H),7.89(d,J＝7.4Hz,1H),7.74–7.41(m,4H),7.16(t,J＝8.7Hz,2H),4.46(d,J＝2.9Hz,2H).HRMS(ESI):m/z calcd C ₁₅ H ₁₁ FNO ₂ S[M+H] ⁺ 288.04892；found,288.04890

Example 81- ((4' -Bromobenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((((4' -bromobenzyl) thio) carbonyl) amino) benzoic acid (IPK-010, 183 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to afford 114 mg of a white solid in 50% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.04(dd,J＝7.8,0.9Hz,1H),7.92–7.86(m,1H),7.58–7.46(m,6H),4.44(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):162.45,158.57,146.44,137.58,136.79,131.93(2C),131.18(2C),128.73,128.19,125.86,121.15,116.12,34.52.HRMS(ESI):m/z calculated for C ₁₅ H ₁₁ BrNO ₂ S[M+H] ⁺ 347.96884；found,347.96921.

Example 82- ((4' -methylbenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((((4' -methylbenzyl) thio) carbonyl) amino) benzoic acid (IPK-004, 150 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to afford 99 mg of a white solid in 70% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.03(dd,J＝7.8,1.1Hz,1H),7.92–7.86(m,1H),7.57–7.48(m,2H),7.38(d,J＝7.9Hz,2H),7.14(d,J＝7.9Hz,2H),4.42(s,2H),2.26(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ162.68,158.59,146.51,137.58,137.30,133.68,129.61(2C),129.55(2C),128.71,128.11,125.83,116.05,35.15,21.16.HRMS(ESI):m/z calculated for C ₁₆ H ₁₄ NO ₂ S[M+H] ⁺ 284.07398,found 284.07361.

Example 83- ((4' -methoxybenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((4' -methoxybenzene) thio) carbonyl) amino) benzoic acid (IPK-007, 317 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether =1 20) gave 254 mg of a white solid in 85% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.12(d,J＝8.1Hz,1H),7.76(t,J＝7.6Hz,1H),7.50(d,J＝8.1Hz,1H),7.42(t,J＝7.6Hz,1H),7.37(d,J＝8.6Hz,2H),6.86(d,J＝8.6Hz,2H),4.37(s,2H),3.79(s,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝163.08,159.18,158.75,146.81,136.74,130.39(2C),128.75,127.70,127.27,125.57,115.70,114.08(2C),55.26,35.45.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₆ H ₁₄ O ₃ NS:300.06889；found:300.06793

Example 84- ((2 ',5' -difluorobenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((2 ',5' -difluorobenzyl) thio) carbonyl) amino) benzoic acid (IPK-012, 162 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 93 mg of a white solid in 61% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.04(dd,J＝7.8,1.4Hz,1H),7.90(td,J＝8.1,1.4Hz,1H),7.58–7.49(m,3H),7.29(td,J＝9.2,4.6Hz,1H),7.23–7.16(m,1H),4.47(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ189.78,172.03,161.18,155.86,148.39,136.20,134.45,131.75,130.37,129.66,125.31,117.55,117.34,115.44,29.78.HRMS(ESI):m/z calculated for C ₁₅ H ₁₀ F ₂ NO ₂ S[M+H] ⁺ 306.03948；found,306.03979.

Example 85- ((2 ',5' -dichlorobenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((2 ',5' -dichlorobenzyl) thio) carbonyl) amino) benzoic acid (IPK-013, 356 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 249 mg of white solid, 74% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.04(dd,J＝7.9,1.4Hz,1H),7.95–7.89(m,1H),7.85(d,J＝2.5Hz,1H),7.60–7.50(m,3H),7.41(dd,J＝8.6,2.5Hz,1H),4.53(s,2H). ¹³ C NMR(101MHz,DMSO):δ162.03,158.48,146.38,137.62,136.65,132.66,132.10,132.02,131.51,129.87,128.79,128.28,125.75,116.30,33.12.HRMS(ESI):m/z calculated for C ₁₅ H ₁₀ Cl ₂ NO ₂ S[M+H] ⁺ :337.98038；found,337.97961.

Example 86- ((2 '-chloro-4' -fluorobenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((((2 '-chloro-4' -fluorobenzyl) thio) carbonyl) amino) benzoic acid (IPK-014, 169 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 111 mg of a white solid, 69% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.04(dd,J＝7.8,1.1Hz,1H),7.93–7.87(m,1H),7.81–7.78(m,1H),7.59(d,J＝8.0Hz,1H),7.60–7.48(m,2H),7.22(td,J＝8.5,2.6Hz,1H),4.53(s,2H).

¹³ C NMR(101MHz,DMSO-d ₆ ):δ163.16,162.15,160.70,158.49,146.38,137.57,133.80,130.81,128.73,128.24,125.89,117.13,116.15,114.87,32.86.HRMS(ESI):m/z calculated for C ₁₅ H ₁₀ ClFNO ₂ S[M+H] ⁺ 322.00993；found,322.01028.

Example 87- ((2 ',3',4',5',6' -pentafluorobenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((2 ',3',4',5',6' -pentafluorobenzyl) thio) carbonyl) amino) benzoic acid (IPK-015, 377 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 221 mg of a white solid, 62% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.03(d,J＝9.0Hz,1H),7.91(t,J＝7.7Hz,1H),7.53(t,J＝8.1Hz,1H),7.44(d,J＝8.0Hz,1H),4.57(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ190.90,189.10,171.36,161.31,158.37,146.27,137.68,136.19,134.41,128.79,125.54,123.98,115.80,110.74,23.73.HRMS(ESI):m/z calculated for C ₁₅ H ₇ F ₅ NO ₂ S[M+H] ⁺ :360.01122；found,360.01041.

Example 88- ((4' - (hydroxymethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

Reacting 2-thio-4H-benzo [ d ]][1,3]Oxazin-4-one (200 mg, 1.12 mmol), potassium iodide (186 mg, 1.12 mmol), 4-hydroxymethylbromobenzyl (246 mg, 1.23 mmol) and potassium carbonate (308 mg, 2.23 mmol) were dissolved in a mixed solution of anhydrous dichloromethane (20 ml) and anhydrous N, N-dimethylformamide (2 ml), and stirred at room temperature for 2 hours. Extraction with dichloromethane (30 ml × 3 times) and water (30 ml), concentration of the organic phase, column chromatography (ethyl acetate: petroleum ether = 20) gave a white solid (251 mg, 75%). ¹ H NMR(400MHz,CDCl ₃ ):δ＝8.12(d,J＝7.9Hz,1H),7.77(t,J＝7.7Hz,1H),7.53–7.39(m,4H),7.33(d,J＝8.1Hz,2H),4.67(s,2H),4.40(s,2H),1.85(s,1H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝162.84,158.70,146.75,140.48,136.79,135.33,129.41(2C),128.77,127.35,127.27(2C),125.58,115.68,64.92,35.53.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₆ H ₁₄ O ₃ NS:300.06889；found:300.06827

EXAMPLE 89 Oxybis (2- ((4' -methylenebenzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one)

Oxybis (2- (4' -methylenebenzyl) thio) carbonyl) amino) benzoic acid) (IPK-016, 616 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (416 mg, 2.02 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether =1 = 20) to give 325 mg of white solid in 56% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.13(d,J＝7.9Hz,2H),7.76-7.80(m,2H),7.50(d,J＝8.0Hz,2H),7.41-7.47(m,6H),7.36(d,J＝8.2Hz,4H),4.57(s,4H),4.40(s,4H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝162.74(2C),158.65(2C),146.74(2C),137.04(2C),136.81(2C),136.38(2C),129.59(4C),128.92(4C),128.82(2C),127.41(2C),125.60(2C),115.72(2C),45.77(2C),35.38(2C).HRMS(ESI):m/z[M+Na] ⁺ calculated for C ₃₂ H ₂₄ O ₅ N ₂ NaS ₂ :603.10188；found:603.10235

Example 90- ((4' - ((tert-Butyloxycarbonylamino) methylene) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

To a solution of anthranilic acid (137 mg, 1 mmol) and N, N-diisopropylethylamine (258 mg, 2 mmol) in dry dichloromethane (20 ml) was added chlorotrimethylsilane (217 mg, 2 mmol) in portions followed by thiophosgene (126 mg, 1.1 mmol added dropwise over 20 minutes). After stirring at room temperature for a further 4 hours, methanol was added and the mixture was evaporated to dryness. The residue was stirred in ice/water (40 mL), the resulting yellow powder was collected by filtration, dissolved with potassium iodide (166 mg, 1 mmol) p-trifluoromethylbenzyl bromide (263 mg, 1.2 mmol) and potassium carbonate (276 mg, 2 mmol) in a mixed solution of anhydrous dichloromethane (20 mL) and DMF (2 mL), stirred at room temperature for 2 hours, extracted with dichloromethane (30 mL × 3 times) and water (30 mL), the organic phase was concentrated, and separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 207 mg of white solid in 52% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ8.13(dd,J＝7.7,1.8Hz,1H),7.77(ddd,J＝8.1,7.3,1.6Hz,1H),7.50(d,J＝7.5Hz,1H),7.44(d,J＝8.7Hz,2H),7.41(d,J＝1.3Hz,2H),7.26–7.22(m,1H),4.39(s,2H),4.29(s,2H),1.45(s,9H). ¹³ C NMR(101MHz,CDCl ₃ ):δ162.87,158.70,155.83,146.77,138.61,136.79,135.04,129.47(2C),128.80(2C),127.78,127.35,125.60,115.72,79.57,44.31,35.51,28.39(3C).HRMS(ESI):m/z calculated for C ₂₁ H ₂₂ N ₂ O ₄ S[M+H] ⁺ :399.13730；found,399.13593.

Example 91- ((4' - (aminomethylene) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one hydrochloride

2- ((4' - ((tert-Butyloxycarbonylamino) methylene) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one (IPK-090, 200 mg, 0.50 mmol) was dissolved in dry DCM (10 mL), and a dioxane solvent of hydrochloric acid (4 mol per liter, 10 mL) was stirred at room temperature for 30 minutes and then suction filtered to give 155mg of a white solid in 93% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ11.36(s,1H),8.23(dd,J＝8.4,1.0Hz,1H),8.05(dd,J＝7.9,1.1Hz,1H),7.91(ddd,J＝8.1,7.3,1.6Hz,1H),7.46(d,J＝8.2Hz,2H),7.43(d,J＝3.6Hz,2H),7.25–7.09(m,1H),4.95(s,2H),4.48(s,2H),4.22(s,2H).HRMS(ESI):m/z calculated for C ₁₆ H ₁₅ N ₂ O ₂ S[M+H] ⁺ :299.08487；found,299.08536.

Example 92- ((4' - (methanesulfonamido methylene) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((4' - (methylsulfonyl) methylene) benzyl) thio) carbonyl) amino) benzoic acid (IPK-017, 167 mg, 0.5 mmol) and N, N-diisopropylethylamine (194 mg, 1.5 mmol) were dissolved in anhydrous dichloromethane, followed by dropwise addition of methanesulfonyl chloride (86 mg, 0.75 mmol), stirring at room temperature for 4 hours, extraction with dichloromethane (30 ml × 3 times) and water (30 ml), concentration of the organic phase, column chromatography (ethyl acetate: petroleum ether =1 = 20) to give 109 mg of a white solid in 58% yield.

¹ H NMR(400MHz,DMSO-d6):δ8.07–8.03(m,1H),7.93–7.87(m,1H),7.58–7.53(m,2H),7.53–7.50(m,2H),7.49(s,1H),7.31(d,J＝8.2Hz,2H),4.46(s,2H),4.13(d,J＝6.3Hz,2H),2.85(s,3H). ¹³ C NMR(101MHz,DMSO):δ162.60,158.64,146.52,138.16,137.63,135.87,129.76(2C),128.75,128.26(2C),128.19,125.88,116.15,46.17,40.34,35.04.HRMS(ESI):m/z calculated for C ₁₇ H ₁₇ N ₂ O ₄ S ₂ [M+H] ⁺ :377.06242；found,377.06268.

Example 93:2- ((4' -trifluoromethylphenyl) methylenecarboxamidemethylene) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((4 '- (aminomethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one (80.00 mg, 0.24 mmol), 2- (4' - (trifluoromethyl) phenyl) acetic acid (53.66 mg, 0.26 mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.00 mg, 0.29 mmol), triethylamine (99.60. Mu.l, 0.72 mmol) were dissolved in dry 10 ml of N, N-dimethylformamide and stirred at room temperature. Detecting the disappearance of the raw materials by thin layer chromatography. After 10 ml of water was added in ice bath and extracted three times with 10 ml of ethyl acetate, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated to give 90 mg of white solid with a yield of 78%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝8.81(t,J＝5.7Hz,1H),8.05(dd,J＝7.8,1.4Hz,1H),7.93–7.88(m,1H),7.66(d,J＝8.1Hz,2H),7.56(dd,J＝7.9,7.1Hz,2H),7.51(dd,J＝6.8,4.7Hz,2H),7.46(d,J＝8.1Hz,2H),7.21(d,J＝8.1Hz,2H),4.45(s,2H),4.25(d,J＝5.9Hz,2H),3.61(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝169.91,162.65,158.66,146.53,141.80,139.27,137.64,135.41,130.40(2C),129.71(2C),128.76,128.20,127.89(2C),127.43,125.88,125.49(2C),123.55,116.15,42.41,42.36,35.06.HRMS(ESI):m/z[M+H] ⁺ calculate for C ₂₅ H ₂₀ F ₃ N ₂ O ₃ S:485.11412；found:485.11359

Example 94:2- ((4' -trifluoromethylphenyl) methylenecarbonyloxymethylene) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((((4' - (((4 "-trifluoromethyl-phenyl) acetoxy) methylene) benzyl) thio) carbonyl) amino) benzoic acid (IPK-018, 503 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 325 mg of white solid in 67% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.13(d,J＝7.9Hz,1H),7.78(t,J＝7.7Hz,1H),7.58(d,J＝8.1Hz,2H),7.50(d,J＝8.0Hz,1H),7.45(m,3H),7.39(d,J＝8.1Hz,2H),7.28(d,J＝8.0Hz,2H),5.12(s,2H),4.40(s,2H),3.72(s,2H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝170.57,165.67,158.70,146.80,141.78,136.83,131.82,129.70(2C),129.45(2C),129.11(2C),128.82,128.59,128.55(2C),127.42,125.52,122.68,120.20,115.70,66.48,40.99,35.41.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₂₅ H ₁₉ O ₄ NF ₃ S:486.09814；found:486.09845

Example 95:2- (benzylthio) -7-methoxy-4H-benzo [ d ] [1,3] oxazin-4-one

2- (((benzylthio) carbonyl) amino) -4-methoxybenzoic acid (IPK-019, 317 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 248 mg of a white solid in 83% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.02(d,J＝8.8Hz,1H),7.44(d,J＝7.0Hz,2H),7.38–7.31(m,2H),7.31-7.27(m,1H),6.96(dd,J＝8.8,2.5Hz,1H),6.90(d,J＝2.5Hz,1H),4.41(s,2H),3.93(s,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝166.48,163.90,158.39,149.17,135.86,130.49,129.15(2C),128.71(2C),127.78,116.16,108.41,107.67,55.86,35.78.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₆ H ₁₄ O ₃ NS:300.06889；found:300.06824

Example 96:2- (benzylsulfanyl) -7- (trifluoromethyl) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((benzyl) thio) carbonyl) amino) -4- (trifluoromethyl) benzoic acid (IPK-022, 355 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 232 mg of white solid, 69% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.21(d,J＝8.3Hz,1H),7.60(s,1H),7.47(d,J＝8.3Hz,1H),7.42-7.34(m,2H),7.31(t,J＝8.1Hz,3H),5.50(s,2H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝183.38,163.47,141.72,137.35,134.21,129.29(2C),128.96,128.68,128.22,126.42(2C),122.32,120.25,115.13,48.91.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₆ H ₁₁ O ₂ NF ₃ S:338.04571；found:338.04529

Example 97:2- ((4-methoxybenzyl) thio) -6-fluoro-4H-benzo [ d ] [1,3] oxazin-4-one

2-fluoro-6- ((((4' -methoxybenzyl) thio) carbonyl) amino) benzoic acid (IPK-023, 335 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 212 mg of a white solid in 67% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.89(td,J＝8.2,5.7Hz,1H),7.46–7.28(m,4H),6.93–6.86(m,2H),4.41(s,2H),3.73(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ164.12,162.81,160.17,159.29,148.24,138.67,131.05(2C),128.49,122.00,114.93,114.49(2C),105.84,55.62,35.01.HRMS(ESI)m/z calculated for C ₁₆ H ₁₃ O ₃ NFS[M+H] ⁺ 318.05947；found,318.05704

Example 98:2- ((4' -methoxybenzyl) thio) -7-methoxy-4H-benzo [ d ] [1,3] oxazin-4-one

4-methoxy-2- ((((4' -methoxybenzyl) thio) carbonyl) amino) benzoic acid (IPK-020, 347 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1).

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.02(d,J＝8.8Hz,1H),7.36(d,J＝8.8Hz,2H),6.96(d,J＝8.6Hz,1H),6.90(s,1H),6.87(d,J＝8.6Hz,2H),4.37(s,2H),3.93(s,3H),3.80(s,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝166.47,164.03,159.19,158.44,149.21,130.47(2C),130.36,127.65,116.12,114.11(2C),108.42,107.64,55.85,55.27,35.40.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₇ H ₁₆ O ₄ NS:330.07946；found:330.07880

Example 99:2- ((4' -methoxybenzyl) thio) -7- (trifluoromethyl) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((4' -methoxybenzyl) thio) carbonyl) amino) -4- (trifluoromethyl) benzoic acid (IPK-021, 385 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 195 mg of a white solid, 53% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.24(d,J＝8.2Hz,1H),7.77(s,1H),7.63(d,J＝8.2Hz,1H),7.36(d,J＝8.7Hz,2H),6.87(d,J＝8.7Hz,2H),4.39(s,2H),3.80(s,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝165.11,159.32,157.59,147.00,137.92,130.39(2C),129.78,127.23,124.31,123.39,122.99,118.23,114.17(2C),55.27,35.65.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₇ H ₁₃ O ₃ NF ₃ S:368.05628；found:368.05545

Example 100:2- ((4' -methoxybenzyl) thio) -6- (trifluoromethoxy) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((4' -methoxybenzyl) thio) carbonyl) amino) -5- (trifluoromethoxy) benzoic acid (IPK-042, 401 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 126 mg of white solid in 33% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝7.95(d,J＝2.2Hz,1H),7.60(d,J＝2.2Hz,1H),7.56(s,1H),7.36(d,J＝8.7Hz,2H),6.87(d,J＝8.6Hz,2H),4.37(s,2H),3.79(s,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝163.90,159.27,157.73,145.31,130.38(2C),130.00,129.41,127.61,127.37,120.13,116.67,114.13(2C),113.76,55.26,35.56.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₇ H ₁₃ O ₄ NF ₃ S:384.05119；found:384.05151

Example 101: 5-methoxy-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2-methoxy-6- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-031, 385 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (194 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 297 mg of a white solid, 81% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.93–7.53(m,5H),7.21–6.91(m,2H),4.51(s,2H),3.90(d,J＝0.9Hz,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ162.89,161.10,154.39,148.41,142.46,138.31,130.70(2C),130.31,127.36,125.75(2C),117.54,110.49,104.55,56.86,34.45.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ F ₃ NO ₃ S[M+H] ⁺ 368.05719,found 368.05628

Example 102: 6-methoxy-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

5-methoxy-2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-032, 385 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 203 mg of white solid in 55% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.78–7.66(m,4H),7.55–7.45(m,2H),7.42(d,J＝2.7Hz,1H),4.52(s,2H),3.86(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ159.68,158.61,142.47,140.72,130.53,128.61,128.29,127.59,125.94,125.76(2C),123.32,116.87(2C),109.51,56.36,34.52.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ F ₃ NO ₃ S[M+H] ⁺ :368.05628；found,368.05521.

Example 103- (4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

4-methoxy-2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-033, 385 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 218 mg of white solid in 59% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.95(d,J＝8.8Hz,1H),7.79–7.68(m,4H),7.09(d,J＝11.3Hz,1H),7.04(d,J＝2.4Hz,1H),4.54(s,2H),3.93(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ166.67,163.26,158.10,148.83,142.36,130.66,130.57(2C),128.68,128.36,125.79(2C),123.34,116.63,108.48,56.65,34.53.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ F ₃ NO ₃ S[M+H] ⁺ :368.05628；found,368.05603.

Example 104- (8-methoxy-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

3-methoxy-2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-034,192 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 101 mg of a white solid in 55% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.83(d,J＝8.1Hz,2H),7.69(d,J＝8.1Hz,2H),7.57(dd,J＝7.6,1.5Hz,1H),7.52(dd,J＝8.2,1.5Hz,1H),7.49–7.43(m,1H),4.51(s,2H),3.97(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):160.98,158.65,153.36,142.54,136.41,130.87(2C),128.51,128.26,126.06,125.61(2C),119.43,118.89,116.91,56.88,34.72.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ F ₃ NO ₃ S[M+H] ⁺ 368.05628,Found 368.05496.

Example 105 [ 5-fluoro-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2-fluoro-6- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-024, 373 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 220 mg of a white solid in 62% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.89(td,J＝8.3,5.7Hz,1H),7.76(d,J＝8.2Hz,2H),7.71(d,J＝8.3Hz,2H),7.42–7.29(m,2H),4.54(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ163.63,162.71,160.07,148.03,142.36,138.59,132.63,130.58(2C),128.32,125.78,121.96,114.98(2C),105.81,34.53.HRMS(ESI):m/z calculated for C ₁₆ H ₁₀ O ₂ NF ₄ S[M+H] ⁺ 356.03629,found 356.03638.

Example 106 [ 6-fluoro-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one ]

5-fluoro-2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-025, 373 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 mL), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 mL. Times.3) and water (30 mL), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 214 mg of a white solid, 61% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.81–7.72(m,4H),7.69(d,J＝8.1Hz,2H),7.63(dd,J＝9.9,4.6Hz,1H),4.53(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ161.72,159.27,157.98,143.34,142.38,130.57(2C),128.60,126.02,125.71,125.48,125.24,117.77,114.02(2C),34.55.HRMS(ESI):m/z calculated for C ₁₆ H ₁₀ O ₂ NF ₄ S[M+H] ⁺ 356.03629；found,356.03510.

Example 107-fluoro-2- (4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

4-fluoro-2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-026, 373 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 225 mg of white solid in 63% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.10(ddd,J＝8.6,6.1,2.2Hz,1H),7.77(d,J＝8.0Hz,2H),7.70(dd,J＝8.5,2.0Hz,2H),7.45–7.34(m,2H),4.53(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.91,164.28,157.66,148.78,142.23,131.92,130.64(2C),128.77,125.72,116.17,113.13,113.11(2C),112.09,34.68.HRMS(ESI)m/z calculated for C ₁₆ H ₁₀ O ₂ NF ₄ S[M+H] ⁺ 356.03629,found 356.03583.

Example 108- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one 5-chloro-2

2-chloro-6- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-027, 390 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 214 mg of a white solid, 58% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.81(t,J＝8.1Hz,1H),7.76(d,J＝8.4Hz,2H),7.71(d,J＝8.5Hz,2H),7.58(dd,J＝8.0,1.0Hz,1H),7.50(dd,J＝8.1,1.0Hz,1H),4.54(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ163.33,155.22,148.77,142.37,137.27,134.60,130.57(2C),130.18,128.31,125.76(2C),125.27,123.32,114.08,34.51.HRMS(ESI):m/z calculated for C ₁₆ H ₁₀ ClF ₃ NO ₂ S[M+H] ⁺ :372.00674；found,372.00650.

Example 109 [ 6-chloro-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one ]

5-chloro-2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-028, 194 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 117 mg of a white solid, 63% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.99(d,J＝2.3Hz,1H),7.92(dd,J＝8.7,2.3Hz,0H),7.76(d,J＝8.2Hz,2H),7.70(d,J＝8.2Hz,2H),7.59(d,J＝8.7Hz,1H),4.54(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):162.98,157.55,145.15,142.23,137.28,131.87,130.55(2C),128.69,127.92,127.53,125.72(2C),123.28,117.75,34.63.HRMS(ESI):m/z calculated for C ₁₆ H ₁₀ ClF ₃ NO ₂ S[M+H] ⁺ 372.00674,found 372.00711.

Example 110-bromo-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2-bromo-6- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-030, 424 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 233 mg of a white solid in 56% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.79–7.65(m,6H),7.53(d,J＝8.7Hz,1H),4.53(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ163.05,155.59,148.74,142.36,137.43,133.85,130.56(2C),128.63,125.89,125.72(2C),123.31,122.79,115.30,34.48.HRMS(ESI):m/z calculated for C ₁₆ H ₁₀ BrF ₃ NO ₂ S[M+H] ⁺ :415.95622；found,415.95517.

Example 111

5-bromo-2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-029, 217 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 139 mg of a white solid, 67% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.11(d,J＝2.3Hz,1H),8.04(dd,J＝8.6,2.3Hz,1H),7.76(d,J＝8.2Hz,2H),7.70(d,J＝8.2Hz,2H),7.51(d,J＝8.6Hz,1H),4.55(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):163.07,157.43,145.47,142.27,140.08,130.57(2C),130.54,128.35,128.08,126.01,125.73(2C),119.85,118.14,34.63.HRMS(ESI):m/z calculated for C ₁₆ H ₁₀ BrF ₃ NO ₂ S[M+H] ⁺ 415.95622,found415.95541.

Example 112- (5-methyl-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2-methyl-6- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-035, 184 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 112 mg of a white solid, 64% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.76–7.72(m,3H),7.70(d,J＝8.5Hz,2H),7.37(d,J＝7.9Hz,1H),7.33(d,J＝7.5Hz,1H),4.52(s,2H),2.65(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):161.95,157.68,147.76,142.59,142.52,136.64,130.52(2C),130.43,128.30,125.75(2C),123.96,123.32,114.48,34.50,22.42.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ F ₃ NO ₂ S[M+H] ⁺ 352.06136,Found 352.06088.

Example 113-methyl-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

5- (2- (((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-036, 184 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 mL), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 mL. Times.3) and water (15 mL), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 109 mg of a white solid in 62% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.85-7.83(m,1H),7.76(d,J＝8.3Hz,2H),7.69-7.73(m,3H),7.47(d,J＝8.2Hz,1H),4.54(s,2H),2.42(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ161.33,158.61,144.38,142.43,138.57,138.15,130.54(2C),128.63,128.15,126.02,125.75(2C),125.73,115.79,34.54,21.03.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ F ₃ NO ₂ S[M+H] ⁺ 352.06136,Found 352.06226.

Example 114- (7-methyl-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

4-methyl-2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-037, 184 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 109 mg of a white solid in 62% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.96(dd,J＝8.0,2.0Hz,1H),7.80(d,J＝7.8Hz,2H),7.75(d,J＝7.3Hz,2H),7.43(s,1H),7.39(d,J＝8.0Hz,1H),4.57(s,2H),2.54(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):162.44,158.45,148.86,146.47,142.45,130.50(2C),129.38,128.60,128.31,125.78(2C),125.75,123.32,113.41,34.53,21.96.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ F ₃ NO ₂ S[M+H] ⁺ 352.06136,Found 352.06204.

Example 115- (8-methyl-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

To a solution of 2-amino-3-methylbenzoic acid (151 mg, 1 mmol) and N, N-diisopropylethylamine (258 mg, 2 mmol) in dry dichloromethane (20 ml) was added chlorotrimethylsilane (217 mg, 2 mmol) in portions followed by thiophosgene (126 mg, 1.1 mmol added dropwise over 20 minutes). After stirring at room temperature for a further 4 hours, methanol was added and the mixture was evaporated to dryness. The residue was stirred in ice/water (40 mL), the resulting yellow powder was collected by filtration, dissolved with potassium iodide (166 mg, 1 mmol) and p-trifluoromethylbenzyl bromide (263 mg, 1.2 mmol) and potassium carbonate (276 mg, 2 mmol) in a mixed solution of anhydrous dichloromethane (20 mL) and DMF (2 mL), stirred at room temperature for 2 hours, extracted with dichloromethane (30 mL × 3 times) and water (30 mL), the organic phase was concentrated, and separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 241 mg of a white solid, 69% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.87(d,J＝7.7Hz,1H),7.74(q,J＝8.4Hz,5H),7.40(t,J＝7.7Hz,1H),4.57(s,2H)，2.47(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ161.43,158.88,144.75,142.65,138.12,134.32,130.25(2C),128.57,127.62,126.30,125.75(2C),123.33,116.00,34.69,17.28.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ F ₃ NO ₂ S[M+H] ⁺ :352.06136；found,352.06122.

Example 116- (trifluoromethyl) -2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

4- (trifluoromethyl) -2- ((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-038, 423 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (194 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 345 mg of a white solid in 85% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.17(d,J＝8.2Hz,1H),8.01–7.53(m,6H),4.52(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ164.37,157.82,156.00,146.80,142.44,136.57,130.81(2C),130.68(2C),128.72,125.85,125.81,124.01,122.91,105.17,34.65.HRMS(ESI):m/z calculated for C ₁₇ H ₁₀ F ₆ NO ₂ S[M+H] ⁺ 406.03531,found 406.03309.

Example 117- ((4 '- (trifluoromethyl) benzyl) thio) -6- (3' - (trifluoromethyl) phenyl) -4H-benzo [ d ] [1,3] oxazin-4-one

5- (2 "-trifluoromethyl) phenyl-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid (IPK-041, 249 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml. Times.3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 142 mg of white solid in 59% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.34–8.28(m,2H),8.09(s,2H),7.80–7.76(m,3H),7.72–7.68(m,3H),7.67(d,J＝8.4Hz,1H),4.57(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):162.87,158.44,146.16,142.38,139.56,138.07,136.07,131.42,130.74,130.58(2C),130.29,128.67,126.68,126.60,125.78(2C),125.27,123.82,123.33,123.25,116.77,34.63.HRMS(ESI):m/z calculated for C ₂₃ H ₁₄ F ₆ NO ₂ S[M+H] ⁺ 482.06440,Found 482.06650.

Example 118- (o-tolyl) -2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

5- (2 "-methyl) phenyl-2- ((((4' -trifluoromethylbenzyl) thio) carbonyl) amino) benzoic acid (IPK-040, 222 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml. Times.3) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 105 mg of a white solid in 49% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.91–7.88(m,2H),7.79(d,J＝8.2Hz,2H),7.72(d,J＝8.2Hz,2H),7.63(d,J＝8.1Hz,1H),7.35–7.24(m,3H),4.57(s,2H),2.24(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):162.47,158.55,145.32,142.50,140.99,139.70,138.33,135.26,131.07,130.57(2C),129.99,128.63,128.55,128.35,126.72,126.04,125.85,125.78(2C),116.14,34.59,20.48.HRMS(ESI):m/z calculated for C ₂₃ H ₁₇ F ₃ NO ₂ S[M+H] ⁺ 428.09266,Found 428.09515.

Example 119-6-chloro-8-methyl-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

5-chloro-3-methyl-2- ((((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (403 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 242 mg of white solid in 63% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.84–7.80(m,2H),7.75(d,J＝8.4Hz,2H),7.71(d,J＝7.2Hz,2H),4.57(s,2H),2.46(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ162.08,157.95,143.72,142.51,137.43,113.42,137.15,131.21,130.29(2C),128.28,125.75(2C),124.98,117.61,34.72,17.07.HRMS(ESI):m/z calculated for C ₁₇ H ₁₂ O ₂ NClF ₃ S[M+H] ⁺ 386.02239,found 386.02158.

Example 120-dichloro-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

4, 5-dichloro-2- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-048, 212 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 136 mg of a white solid in 67% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ8.18(s,1H),7.62-7.60(m,3H),7.57(s,2H),4.41(s,2H). ¹³ C NMR(101MHz,CDCl ₃ ):146.88,140.72,131.77,128.75,127.30,120.79,119.65,119.29,118.96(2C),117.21,115.97(2C),113.44,107.44,43.58.HRMS(ESI):m/z calculated for C ₁₆ H ₉ Cl ₂ F ₃ NO ₂ S[M+H] ⁺ 405.96777,found 405.96698.

Example 121-difluoro-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

4, 5-difluoro-2- ((((4' -methoxybenzyl) thio) carbonyl) amino) benzoic acid (IPK-046, 391 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 234 mg of a white solid, 63% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.08(t,J＝9.2Hz,1H),7.80–7.67(m,5H),4.52(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ163.63,157.18,154.46,147.88,144.80,142.25,130.66(2C),128.64(2C),125.74,123.58,116.77,114.76,113.62,34.60.HRMS(ESI):m/z calculated for C ₁₆ H ₉ O ₂ NF ₅ S[M+H] ⁺ 374.02687,found 374.02664.

Example 122, 6,8-difluoro-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

3, 5-difluoro-2- ((((4' -methoxybenzyl) thio) carbonyl) amino) benzoic acid (353 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 202 mg of a white solid in 54% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.94(ddd,J＝10.3,9.0,2.8Hz,1H),7.75(d,J＝8.2Hz,2H),7.73–7.65(m,3H),4.53(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ163.03,158.55,157.03,154.49,142.35,132.76,130.68(2C),128.41(2C),125.73,123.37,119.18,112.91,110.26,34.75.HRMS(ESI):m/z calculated for C ₁₆ H ₉ O ₂ NF ₅ S[M+H] ⁺ 374.02687,found 374.02576.

Example 123, 6,7-dimethoxy-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

4, 5-dimethoxy-2- ((((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-045, 415 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (194 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 341 mg of a white solid in 86% yield.

¹ H NMR(400MHz,Chloroform-d)δ7.59(t,J＝3.1Hz,4H),7.44(d,J＝0.8Hz,1H),6.90(d,J＝0.8Hz,1H),4.43(s,2H),3.98(dd,J＝0.8,20.0Hz,6H). ¹³ C NMR(126MHz,DMSO-d ₆ ):δ161.00,158.28,157.01,149.20,142.96,142.36,130.71,130.50(2C),125.82(2C),124.86,119.69,107.89,107.58,56.70,56.45,34.40.HRMS(ESI):m/z calculated for C ₁₈ H ₁₅ F ₃ NO ₄ S[M+H] ⁺ 398.06607,found 398.06684

Example 124-dimethyl-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

3, 5-dimethyl-2- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-043, 383 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 245 mg of a white solid in 67% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.73(q,J＝8.3Hz,4H),7.66(s,1H),7.58(s,1H),4.55(s,2H),2.44(s,3H),2.36(s,3H). ¹³ C NMR(101MHz,DMSO):δ160.40,158.95,142.77,142.68,139.24,137.42,134.13,133.11,130.26(2C),128.56,126.03,125.78(2C),115.70,34.66,21.03,17.17.HRMS(ESI):m/z calculated for C ₁₈ H ₁₅ F ₃ NO ₂ S[M+H] ⁺ :366.07701；found,366.07657.

Example 125, 7,8-dimethyl-2- ((4' - (trifluoromethyl) benzyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

3, 4-dimethyl-2- (((((4' - (trifluoromethyl) benzyl) thio) carbonyl) amino) benzoic acid (IPK-044, 191 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 113 mg of white solid in 62% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.79–7.73(m,3H),7.71(d,J＝8.5Hz,2H),7.33(d,J＝8.0Hz,1H),4.58(s,2H),2.40(s,3H),2.38(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):161.05,158.98,147.17,144.34,142.62,132.69,130.18(2C),129.46,128.27,125.79(2C),125.68,123.33,113.64,34.67,21.13,13.28.HRMS(ESI):m/z calculated for C ₁₈ H ₁₅ F ₃ NO ₂ S[M+H] ⁺ 366.07701,Found 366.07651.

Example 126- ((pyridin-4' -methyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2-thio-4H-benzo [ d ] [1,3] oxazin-4-one (200 mg, 1.12 mmol), potassium iodide (186 mg, 1.12 mmol), 4-bromomethylpyridine (210 mg, 1.23 mmol) and potassium carbonate (308 mg, 2.23 mmol) were dissolved in a mixed solution of anhydrous dichloromethane (20 ml) and anhydrous N, N-dimethylformamide (2 ml) and stirred at room temperature for 2 hours. Extraction with dichloromethane (30 ml × 3 times) and water (30 ml), concentration of the organic phase, column chromatography (ethyl acetate: petroleum ether = 20) gave a white solid (190 mg, 63%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝8.52(d,J＝5.4Hz,2H),8.03(d,J＝7.7Hz,1H),7.89(t,J＝7.7Hz,1H),7.51-7.54(m,4H),4.46(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝162.23,158.61,150.13(2C),146.59,146.40,137.59,128.75,128.26,125.88,124.67(2C),116.20,33.89.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₄ H ₁₁ O ₂ N ₂ S:271.05357；found:271.05359

Example 127 [ 2- ((naphthalen-2' -ylmethyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one ]

2- ((((naphthalen-2' -ylmethyl) thio) carbonyl) amino) benzoic acid (IPK-065,168 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 102 mg of a white solid in 64% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.06-8.03(m,2H),7.92-7.89(m,4H),7.64-7.60(m,2H),7.54-7.49(m,3H),4.64(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):162.58,158.64,146.53,137.61,134.45,133.22,132.72,128.73,128.63,128.50,128.16,128.12,128.01,127.73,126.84,126.61,125.88,116.16,35.59.HRMS(ESI):m/z calculated for C ₁₉ H ₁₄ NO ₂ S[M+H] ⁺ 320.07398,found 320.07422.

Example 128- ((quinolin-8' -methyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2-thio-1, 2-dihydro-4H-benzo [ d ] [1,3] oxazin-4-one (134.38 mg, 0.75 mmol), potassium iodide (124.60 mg, 0.75 mmol) and potassium carbonate (207.00 mg, 1.50 mmol) were dissolved in 10 ml of N, N-dimethylformamide, 8-bromomethylquinoline (200.00 mg, 0.90 mmol) was dissolved in 5 ml of N, N-dimethylformamide, and then the mixture was slowly dropped into the above mixed solution, followed by stirring at room temperature. And detecting the disappearance of the raw materials by thin layer chromatography. After adding 15 ml of water under ice bath and extracting with 15 ml of ethyl acetate three times, respectively, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (ethyl acetate: petroleum ether =1 20) to obtain 150 mg of a yellow solid with a yield of 62.44%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝9.00(dd,J＝4.2,1.7Hz,1H),8.42(dd,J＝8.3,1.7Hz,1H),8.04(ddd,J＝6.9,4.6,1.3Hz,2H),7.97(dd,J＝8.3,1.3Hz,1H),7.94–7.89(m,1H),7.65–7.52(m,4H),5.03(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝163.38,158.72,150.59,146.63,146.06,137.61,137.14,134.67,130.78,128.81,128.75,128.56,128.09,126.78,125.92,122.30,116.12,31.72.HRMS(ESI):m/z[M+H] ⁺ calculate for C ₁₈ H ₁₃ N ₂ O ₂ S:321.06922；found:321.05688

EXAMPLE 129- ((acridin-9' -ylmethyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((acridin-9' -ylmethyl) thio) carbonyl) amino) benzoic acid (IPK-066, 388 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (194 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.65–8.54(m,2H),8.19(dd,J＝1.2,8.7Hz,2H),8.06(dd,J＝1.5,7.9Hz,1H),7.98–7.87(m,3H),7.74(ddd,J＝1.3,6.5,8.9Hz,2H),7.64(dd,J＝1.1,8.2Hz,1H),7.56(td,J＝1.2,7.6Hz,1H),5.61(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ162.08,158.48,148.62,146.42,139.39,137.67,137.29,130.86(2C),130.36(2C),128.86,128.34,127.10(2C),125.85,125.36(2C),124.64,116.24,103.97,27.57.HRMS(ESI):m/z calculated for C ₂₂ H ₁₅ F ₃ N2O ₂ S[M+H] ⁺ 371.08487,found 371.08542

Example 130- (((5 '- (trifluoromethyl) furan-2' -yl) methyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((5 '- (trifluoromethyl) furan-2' -yl) methyl) thio) carbonyl) amino) benzoic acid (IPK-067, 345 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and separated by column chromatography (ethyl acetate: petroleum ether = 1).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.05(dd,J＝7.8,1.5Hz,1H),7.90(td,J＝7.7,1.2Hz,1H),7.55(dd,J＝17.0,8.1Hz,2H),7.17(d,J＝3.4Hz,1H),6.74(d,J＝3.5Hz,1H),4.60(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ161.63,158.49,154.38,146.35,139.78,137.60,128.76,128.35,125.91,119.46,116.23,114.74,110.87,27.58.HRMS(ESI):m/z calculated for C ₁₄ H ₉ O ₃ NF ₃ S[M+H] ⁺ ,328.01166；found,328.02497.

Example 131 ((5 '-Chlorothien-2' -yl) methyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((((5 '-chlorothien-2' -yl) methyl) thio) carbonyl) amino) benzoic acid (IPK-063, 327 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 208 mg of a white solid, 67% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.04(d,J＝7.8Hz,1H),7.91(t,J＝7.8Hz,1H),7.62–7.49(m,2H),7.06(d,J＝3.8Hz,1H),6.95(d,J＝3.8Hz,1H),4.62(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ162.55,158.56,146.32,139.29,137.77,128.89,128.40,128.38,128.28,126.75,125.86,116.17,30.51.HRMS(ESI):m/z calculated for C ₁₃ H ₉ ClNO ₂ S ₂ [M+H] ⁺ 309.97577；found,309.97540.

Example 132 6-methoxy-2- ((1 '-methyl-1' - (3 "-trifluoromethylphenyl) -methylene) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

5-methoxy-2- ((((((1 '- (3 "- (trifluoromethyl) phenyl) -1' -methyl) methylene) thio) carbonyl) amino) benzoic acid (IPK-061, 399 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 236 mg of a white solid in 62% yield.

¹ H NMR(400MHz,CDCl ₃ )：δ＝7.77(s,1H),7.68(d,J＝7.6Hz,1H),7.52(d,J＝7.7Hz,1H),7.46(m,2H),7.40(d,J＝8.9Hz,1H),7.35–7.30(m,1H),5.01(q,J＝7.2Hz,1H),3.87(s,3H),1.80(d,J＝7.2Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝159.34,158.95,158.55,143.17,141.07,130.73,130.55,129.09,127.04,126.06,124.69,124.47,122.62,116.36,108.75,55.88,44.75,21.64.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₈ H ₁₅ O ₃ NF ₃ S:382.07193；found:382.07175

Example 133- ((1 '-methyl-1' - (3 "-bromophenyl) -methylene) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((((1 '- (4 "-bromophenyl) -1' -propyl) methylene) thio) carbonyl) amino) benzoic acid (IPK-062, 407 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 322 mg of a white solid, 83% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.10(d,J＝8.0Hz,1H),7.77–7.72(m,1H),7.46–7.42(m,3H),7.40(d,J＝7.5Hz,1H),7.33(d,J＝8.5Hz,2H),4.79(m,1H),2.13–1.86(m,2H),1.49–1.28(m,2H),0.97–0.93(m,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝162.28,158.69,146.75,140.26,136.72,131.60(2C),129.65(2C),128.75,127.34,125.54,121.38,115.67,49.59,37.64,20.62,13.57.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₈ H ₁₇ O ₂ NBrS:390.01579；found:390.01456

Example 134- ((4' -fluorobenzyl) thio) -4-H-benzo [ d ] [1,3] thiazin-4-one

2- (((((4' -fluorobenzyl) thio) thiocarbonyl) amino) benzoic acid (IPK-069, 305 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (194 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 297 mg of white solid in 81% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.06(dd,J＝1.6,7.9Hz,1H),7.95(ddd,J＝1.7,7.2,8.6Hz,1H),7.82(dd,J＝1.2,8.1Hz,1H),7.64–7.48(m,3H),7.23–7.10(m,2H),4.63(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ182.62,162.33,147.71,137.30,133.63,131.92,131.84(2C),130.29,128.93,125.14,119.11,115.94(2C),34.44.HRMS(ESI):m/z calculated for C ₁₅ H ₁₁ FNOS ₂ [M+H] ⁺ 304.02664,found 304.02606

Example 135- ((4' -methoxybenzyl) thio) -4-H-benzo [ d ] [1,3] thiazin-4-one

2- (((((4' -methoxybenzyl) thio) thiocarbonyl) amino) benzoic acid (IPK-070, 334 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (194 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 258 mg of white solid in 82% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.08(dd,J＝1.6,7.9Hz,1H),7.97(ddd,J＝1.7,7.2,8.7Hz,1H),7.84(dd,J＝1.2,8.1Hz,1H),7.61(ddd,J＝1.3,7.2,8.2Hz,1H),7.52–7.36(m,2H),6.96–6.80(m,2H),4.60(s,2H),3.72(s,3H). ¹³ C NMR(126MHz,DMSO-d ₆ ):δ182.63,162.52,159.14,147.71,137.19,131.03(2C),130.21,128.75,128.67,125.04,119.04,114.41(2C),55.53,34.93.HRMS(ESI):m/z calculated for C ₁₆ H ₁₄ NO ₂ S ₂ [M+H] ⁺ 316.04517,found 316.04605

Synthesis of comparative Compounds

The procedure for the synthesis of the ring-opened compounds (comparative examples 1 to 16) was carried out with slight modifications depending on the final product:

a. triphosgene (1 eq) was dissolved in 5 ml of anhydrous dichloromethane and kept at 0 ℃ in ice bath; benzyl mercaptan (3 equivalents) is slowly dripped into the reaction liquid, then anhydrous pyridine (3 equivalents) solution of anhydrous dichloromethane (1 ml) is slowly dripped, the reaction liquid is stirred for 10 minutes in ice bath, then the stirring is carried out for about 2 hours at room temperature, and the reaction is detected to be finished by thin layer chromatography. The reaction intermediate is very active and is directly put into the next step.

Comparative example 1

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; propanethiol (165 mg, 2.17 mmol) was slowly added dropwise to the reaction solution, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and then detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. Anthranilic acid (199 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml/3 times) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100.

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.73(s,1H),11.36(s,1H),8.26(d,J＝7.9Hz,1H),7.97(d,J＝7.9Hz,1H),7.59(t,J＝7.9Hz,1H),7.15(t,J＝7.6Hz,1H),2.91(t,J＝7.3Hz,2H),1.56-1.65(m,2H),0.94(t,J＝7.3Hz,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝170.19,165.71,140.89,134.87,131.70,123.36,120.16,116.54,31.81,23.64,13.51.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₁ H ₁₄ O ₃ NS:240.06889；found:240.06839

Comparative example 2- ((((4 ',4',4' -trifluorobutyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees under ice bath; 4, 4-trifluorobutane-1-thiol (171 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. The reaction solution was dried by column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 1) to give 172 mg of the product, 56% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.78(s,1H),11.40(s,1H),8.25(d,J＝8.3Hz,1H),7.98(d,J＝7.9Hz,1H),7.61(t,J＝7.9Hz,1H),7.18(t,J＝7.5Hz,1H),3.02(t,J＝7.1Hz,2H),2.44–2.31(m,2H),1.89–1.77(m,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):170.21,165.25,140.79,140.72,134.88,131.71,123.57,120.36,116.83,41.72,28.69,23.24.HRMS(ESI):m/z calculated for C ₁₂ H ₁₃ F ₃ NO ₃ S[M+H] ⁺ 308.05628,found 308.05484.

Comparative example 3

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 2-phenethyl mercaptan (207 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.79(s,1H),11.36(s,1H),8.27(d,J＝8.4Hz,1H),7.98(dd,J＝7.9,1.6Hz,1H),7.64–7.57(m,1H),7.34–7.25(m,4H),7.17(td,J＝7.7,1.2Hz,2H),3.23–3.16(m,2H),2.91(t,J＝7.6Hz,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.13,165.48,140.75,140.37,134.85,131.67,129.03(2C),128.88(2C),126.86,123.45,120.29,116.70,33.23,31.26.HRMS(ESI):m/z calculated for C ₁₆ H ₁₆ NO ₃ S[M+H] ⁺ :302.08454；found,302.08441.

Comparative example 4

a. Triphosgene (214.83 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane and maintained at zero degrees centigrade in ice. Benzyl alcohol (234.36 mg, 2.17 mmol) was slowly added dropwise to the reaction, followed by slowly adding a solution of anhydrous pyridine (175 μ l, 2.17 mmol) in dichloromethane (1 ml), the reaction was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate/petroleum ether = 10%).

b. 2-aminobenzoic acid (198.65 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (475 μ l, 2.90 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave 255 mg of white solid powder in 65% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.68(s,1H),10.80(s,1H),8.28(dd,J＝1.1,8.5Hz,1H),7.97(dd,J＝1.7,8.0Hz,1H),7.60(ddd,J＝1.7,7.3,8.7Hz,1H),7.49–7.25(m,5H),7.11(ddd,J＝1.2,7.4,8.3Hz,1H),5.18(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.22,153.20,141.53,136.78,134.88,131.81,129.14(2C),128.94,128.81(2C),122.49,118.72,116.09,39.84.HRMS(ESI):m/z calculated for C ₁₅ H ₁₄ NO ₄ [M+H] ⁺ 272.09485,found 272.09173

Comparative example 5

a. Triphosgene (214.83 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane and maintained at zero degrees centigrade in ice. 3-trifluoromethyl benzyl alcohol (381.92 mg, 2.17 mmol) was slowly added dropwise to the reaction, after which a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction was stirred in ice bath for 10 minutes, the reaction was returned to room temperature and stirred for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate/petroleum ether = 10%).

b. 2-aminobenzoic acid (198.65 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (475 μ l, 2.90 mmol) was added, then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave 305 mg of white solid powder in 62% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ13.72(s,1H),10.86(s,1H),8.26(dd,J＝1.1,8.5Hz,1H),7.98(dd,J＝1.7,8.0Hz,1H),7.80(d,J＝2.0Hz,1H),7.74(dd,J＝7.3,11.8Hz,1H),7.68–7.56(m,3H),7.28–6.99(m,1H),5.28(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.12,153.00,144.53,141.28,138.24,134.79,131.73,131.42,130.14,129.51,125.33,125.02,122.56,118.76,116.24,62.54.HRMS(ESI):m/z calculated for C ₁₆ H ₁₃ F ₃ NO ₄ [M+H] ⁺ 340.07855,found 340.07912

Comparative example 6 methyl 2- (((3' - (trifluoromethyl) benzyloxy) carbonyl) amino) benzoate

2- ((((3- (trifluoromethyl) benzyl) oxy) carbonyl) amino) benzoic acid (C-005, 340 mg, 1 mmol) and anhydrous methanol (35.2 mg, 1.1 mmol) were dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12.2 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 275 mg of a white solid in 78% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.34(s,1H),8.11(dd,J＝1.1,8.5Hz,1H),7.92(dd,J＝1.6,8.0Hz,1H),7.80(s,1H),7.78–7.69(m,2H),7.69–7.58(m,2H),7.17(td,J＝1.2,7.7Hz,1H),5.28(s,2H),3.83(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.23,153.28,140.38,138.31,134.78,131.29,131.09,130.30,130.09,129.57,125.05,125.00,123.20,120.09,115.36,53.05,52.85.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ F ₃ NO ₄ [M+H] ⁺ 354.09433,found 354.09477

Comparative example 7 (((4' - (trifluoromethyl) benzyl) oxy) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; p-trifluoromethylbenzyl alcohol (264 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 205 mg of a white solid in 51% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.71(s,1H),10.88(s,1H),8.34–8.19(m,1H),7.99(dd,J＝7.9,1.7Hz,1H),7.77(d,J＝8.1Hz,2H),7.65(d,J＝8.1Hz,2H),7.63–7.57(m,1H),7.12(t,J＝7.6Hz,1H),5.29(s,2H). ¹³ C NMR(126MHz,DMSO-d ₆ ):δ170.17,152.99,141.64,141.32,134.80,131.76(2C),129.18,128.85(2C),125.88,125.73,122.56,118.73,116.22,65.81.HRMS(ESI):m/z calculated for C ₁₆ H ₁₃ O ₄ NF ₃ [M+H] ⁺ 340.07912,found 340.07718

Comparative example 8 (((4' -fluorobenzyl) oxy) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; p-fluorobenzyl alcohol (189 mg, 1.5 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, the reaction solution was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 234 mg of a white solid in 81% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.67(s,1H),10.81(s,1H),8.28(dd,J＝8.5,1.2Hz,1H),7.98(dd,J＝7.9,1.7Hz,1H),7.60(ddd,J＝8.7,7.3,1.7Hz,1H),7.52–7.46(m,2H),7.26–7.19(m,2H),7.14–7.09(m,1H),5.17(s,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.24,163.73,153.15,141.53,134.84,133.05,131.80,131.15(2C),122.46,118.70,116.07,115.74(2C),66.10.HRMS(ESI):m/z calculated for C ₁₅ H ₁₃ O ₄ NF[M+H] ⁺ 290.08231,found 290.09781.

Comparative example 9 (((3 ',5' -difluorobenzyl) oxy) carbonyl) amino) benzoic acid

a. Triphosgene (148 mg, 0.5 mmol) was dissolved in 3 ml of anhydrous dichloromethane, maintained at zero degrees under ice bath; 3,5-difluorobenzyl alcohol (216 mg, 1.5 mmol) was slowly added dropwise to the reaction, and then a solution of anhydrous pyridine (119 mg, 1.5 mmol) in dichloromethane (1 ml) was slowly added dropwise, and after the reaction solution was stirred in an ice bath for 10 minutes, the stirring was resumed at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. Column chromatography was performed directly on a stirred sample column (petroleum ether: ethyl acetate: acetic acid = 100) to give 228 mg of a white solid in 74% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.69(s,1H),10.81(s,1H),8.26(dd,J＝8.5,1.1Hz,1H),7.98(dd,J＝8.0,1.7Hz,1H),7.63–7.42(m,3H),7.30(ddt,J＝8.4,4.0,1.7Hz,1H),7.12(td,J＝7.8,1.0Hz,1H),5.16(s,2H). ¹³ C NMR(126MHz,DMSO-d ₆ ):δ170.14,152.98,148.84,141.35,134.79,134.47,131.74(2C),125.66,122.51,118.74,117.99,116.18,65.48.HRMS(ESI):m/z calculated for C ₁₅ H ₁₂ O ₄ NF ₂ [M+H] ⁺ 308.07289,found 308.07437.

Comparative example 10-fluoro-2- ((((4' - (trifluoromethyl) phenyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (214.83 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane and maintained at zero degrees centigrade in ice. 4-trifluoromethylthiophenol (386.26 mg, 2.17 mmol) was slowly added dropwise to the reaction, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in dichloromethane (1 ml) was slowly added dropwise, after the reaction was stirred in ice bath for 10 minutes, the reaction was left to stir at room temperature for about 2 hours, and the reaction was checked by thin layer chromatography (ethyl acetate/petroleum ether = 10%).

b. 2-amino-5-fluorobenzoic acid (224.75 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, ice bath was maintained, N-diisopropylethylamine (475. Mu.l, 2.90 mmol) was added, after which the solution a was slowly added dropwise to the solution, the ice bath was removed, heating and refluxing were carried out for about 2 hours, and the reaction was detected by thin layer chromatography to be complete. Extraction with dichloromethane (30 ml × 3) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid = 100) gave 281 mg of a white solid powder in 54% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ11.36(s,1H),8.03–7.45(m,6H),7.18(dd,J＝4.4,8.9Hz,1H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ159.67,159.64,158.96,157.04,147.25,138.60(2C),125.33,125.14,118.08,118.01(2C),114.55,111.99,111.91.HRMS(ESI):m/z calculated for C ₁₅ H ₁₀ F ₄ NO ₃ S[M+H] ⁺ 360.03281,found 360.03120

Comparative example 11

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; 4-fluorobenzenethiol (278 mg, 2.17 mmol) is slowly added dropwise to the reaction solution, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) is slowly added dropwise, the reaction solution is stirred in ice bath for 10 minutes, then stirring is resumed for about 2 hours at room temperature, and detection is carried out by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction is finished.

b. Anthranilic acid (199 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the mixture was heated under reflux for about 2 hours, and the reaction was detected by thin layer chromatography. Extraction with dichloromethane (30 ml/3 times) and (water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (181 mg, 43% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.76(s,1H),11.35(s,1H),8.22(d,J＝8.4Hz,1H),7.97(d,J＝8.4Hz,1H),7.72-7.65(m,2H),7.60(t,J＝7.9Hz,1H),7.39-7.32(m,2H),7.19(t,J＝7.9Hz,1H). ¹³ C NMR(101MHz,DMSO):δ＝160.29,147.58,141.88,137.41,131.29(2C),130.91,129.42,123.99,117.22(2C),116.44,115.81,110.75.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₄ H ₁₁ O ₃ NFS:292.04382；found:292.04309

Comparative example 12:2- (((((4-methoxyphenyl) thio) carbonyl) amino) benzoic acid

a. Triphosgene (216 mg, 0.73 mmol) was dissolved in 4 ml of anhydrous dichloromethane, maintained at 0 ℃ in ice bath; 4-Methoxyphenylthiol (304 mg, 2.17 mmol) was slowly added dropwise to the reaction mixture, then a solution of anhydrous pyridine (175. Mu.l, 2.17 mmol) in anhydrous dichloromethane (1 ml) was slowly added dropwise, the reaction mixture was stirred in ice bath for 10 minutes, then stirred at room temperature for about 2 hours, and then detected by thin layer chromatography (ethyl acetate: petroleum ether) =10% reaction was completed.

b. Anthranilic acid (199 mg, 1.45 mmol) was added to 5 ml of anhydrous dichloromethane, an ice bath was maintained, N-diisopropylethylamine (478 μ l, 2.90 mmol) was added, and after that, the solution a was slowly added dropwise to the solution, the ice bath was removed, and the reaction was detected by thin layer chromatography after heating under reflux for about 2 hours. Extraction with dichloromethane (30 ml/3 times) and water (30 ml), concentration of the organic phase, column chromatography (petroleum ether: ethyl acetate: acetic acid =100: 10) gave a white solid powder (158 mg, 36% yield).

¹ H NMR(400MHz,DMSO-d ₆ ):δ＝13.70(s,1H),11.31(s,1H),8.25(d,J＝8.4Hz,1H),7.96(d,J＝8.4Hz,1H),7.58(t,J＝7.8Hz,1H),7.53(d,J＝8.6Hz,2H),7.16(t,J＝7.8Hz,1H),7.04(d,J＝8.6Hz,2H),3.81(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ＝169.92,165.32,161.25,140.64,137.83(2C),134.80,131.69,123.64,120.12,117.96,116.80,115.68(2C),55.87.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₅ H ₁₄ O ₄ NS:304.06381；found:304.06354

Comparative example 13:2- (3' -Benzylpyrureido) benzoic acid methyl ester

Methyl anthranilate (151 mg, 1 mmol), benzyl isocyanate (133 mg, 1 mmol), and N, N-diisopropylethylamine (258 mg, 2 mmol) were added to 10 ml of anhydrous tetrahydrofuran, reacted at 60 ℃ for 10 hours, the reaction solution was spin-dried, the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 149 mg of white powder, 52% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ9.84(s,1H),8.37(dd,J＝8.5,0.6Hz,1H),8.03(t,J＝5.6Hz,1H),7.90(dd,J＝8.0,1.6Hz,1H),7.54–7.47(m,1H),7.37–7.29(m,4H),7.28–7.22(m,1H),7.03–6.96(m,1H),4.29(d,J＝5.8Hz,2H),3.86(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.20,155.17,143.09,140.53,134.47,130.93,128.76(2C),127.74(2C),127.22,120.89,120.10,114.63,52.70,43.34.HRMS(ESI):m/z calculated for C ₁₆ H ₁₇ N ₂ O ₃ [M+H] ⁺ 285.12337,found 285.12271.

Comparative example 14:2- (3' -Benzylheido) -4-methoxybenzoic acid methyl ester

Methyl 2-amino-4-methoxybenzoate (181 mg, 1 mmol), benzyl isocyanate (133 mg, 1 mmol) and N, N-diisopropylethylamine (258 mg, 2 mmol) were added to 10 ml of anhydrous tetrahydrofuran, reacted at 60 ℃ for 10 hours, the reaction solution was spin-dried, the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1).

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.11(s,1H),8.12(d,J＝2.6Hz,2H),7.86(d,J＝8.9Hz,1H),7.36–7.30(m,4H),7.25(d,J＝6.8Hz,1H),6.57(dd,J＝8.9,2.6Hz,1H),4.29(d,J＝5.8Hz,2H),3.83(s,3H),3.78(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ168.03,164.16,155.15,145.46,140.51,132.84,128.76(2C),127.72(2C),127.22,107.59,106.73,103.76,55.78,52.37,43.30.HRMS(ESI):m/z calculated for C ₁₇ H ₁₉ N ₂ O ₄ [M+H] ⁺ 315.13393,found 315.13354.

Comparative example 15:2- (3' - (4 "- (trifluoromethyl) phenyl) propionamido) benzoic acid methyl ester

2- (3- (4- (trifluoromethyl) phenyl) propionamido) benzoic acid (C-016, 337 mg, 1 mmol) and anhydrous methanol (35 mg, 1.1 mmol) are dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) are added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase is concentrated, and the mixture is separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 226 mg of white solid, 64% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.55(s,1H),8.20(dd,J＝8.4,1.2Hz,1H),7.89(dd,J＝8.0,1.6Hz,1H),7.64(d,J＝8.0Hz,2H),7.62–7.56(m,1H),7.50(d,J＝8.0Hz,2H),7.18(t,J＝7.6Hz,1H),3.82(s,3H),3.03(t,J＝7.5Hz,2H),2.76(t,J＝7.5Hz,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.72,168.04,146.35,140.02,134.40,131.89,131.00,129.71(2C),127.55,125.67(2C),123.70,121.72,118.31,52.85,38.43,30.83.HRMS(ESI):m/z calculated for C ₁₈ H ₁₇ O ₃ NF ₃ [M+H] ⁺ 352.11550,found352.11530.

Comparative example 16:2- (3 '- (4' - (trifluoromethyl) phenyl) propionamido) benzoic acid

a. 3- (4-trifluoromethylphenyl) propionic acid (240 mg, 1.1 mmol) was dissolved in 3 ml of anhydrous dichloromethane and kept at zero degrees under ice bath; oxalyl chloride (140 mg, 1.1 mmol) was slowly added dropwise to the reaction, two drops of DMF were added dropwise and then stirring was continued for 1 hour, after the reaction solution was stirred in ice bath for 10 minutes, stirring was resumed for about 2 hours at room temperature, and the reaction was detected by thin layer chromatography (ethyl acetate: petroleum ether = 10%).

b. Anthranilic acid (137 mg, 1 mmol) was added to 5 ml of anhydrous dichloromethane, the ice bath was maintained, N-diisopropylethylamine (258 mg, 2 mmol) was added, and then the solution a was slowly added dropwise to the solution, the ice bath was removed, the solution was heated under reflux for 2 hours, and the reaction was checked by thin layer chromatography. Column chromatography separation (petroleum ether: ethyl acetate: acetic acid = 100) directly by stirred-sample column gave 219 mg of a white solid in 65% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ13.57(s,1H),11.11(s,1H),8.46(dd,J＝8.5,1.1Hz,1H),7.96(dd,J＝8.0,1.7Hz,1H),7.64(d,J＝8.0Hz,2H),7.60–7.54(m,1H),7.50(d,J＝8.0Hz,2H),7.18–7.08(m,1H),3.03(t,J＝7.6Hz,2H),2.78(t,J＝7.6Hz,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.68,169.99,146.36,141.20,134.54,131.93,131.61(2C),129.71(2C),125.69,123.96,123.17,120.56,117.10,38.73,30.73.HRMS(ESI):m/z calculated for C ₁₇ H ₁₅ O ₃ NF ₃ [M+H] ⁺ 338.09985,found 338.09872.

The procedure for the synthesis of the ring-closing compounds (comparative example 17 to comparative example 25) was carried out with slight modifications according to the final product:

Comparative example 17:2- ((4' -fluorophenyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((4-fluorophenyl) thio) carbonyl) amino) benzoic acid (C-011, 291 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 169 mg of a white solid in 62% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝7.98(d,J＝8.2Hz,1H),7.52-7.42(m,2H),7.31(t,J＝7.6Hz,1H),7.19–7.10(m,2H),6.72(t,J＝7.6Hz,1H),6.66(d,J＝8.2Hz,1H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝191.16,164.80,162.31,148.45,137.67(2C),134.79,130.12,123.12,117.24,117.17,116.50(2C),116.29.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₄ H ₉ O ₂ NFS:274.03325；found:274.03333

Comparative example 18:2- ((4' -methoxyphenyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((4-methoxyphenyl) thio) carbonyl) amino) benzoic acid (C-012, 303 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether =1 20) gave 157 mg of a white solid in 55% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.10(d,J＝7.9Hz,1H),7.71(t,J＝7.8Hz,1H),7.57(d,J＝8.7Hz,2H),7.41-7.33(m,2H),6.98(d,J＝8.7Hz,2H),3.86(s,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝163.12,161.28,158.81,146.93,137.24(2C),136.67,132.34,128.67,127.37,125.92,116.53,115.05(2C),55.41.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₅ H ₁₂ O ₃ NS:286.05324；found:286.05316

Comparative example 19:2- (Phenethylthio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- (((phenethylthio) carbonyl) amino) benzoic acid (C-003, 301 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.05(d,J＝8.0Hz,1H),7.93–7.86(m,1H),7.56-7.51(m,2H),7.35-7.31(m,4H),7.27-7.20(m,1H),3.44-3.40(m,2H),3.08-3.04(m,2H). ¹³ C NMR(101MHz,DMSO-D ₆ ):δ162.96,158.75,146.67,140.15,137.58,129.19(2C),128.95(2C),128.71,128.08,126.99,125.90,116.18,35.02,32.81.HRMS(ESI):m/z calculated for C ₁₆ H ₁₄ NO ₂ S[M+H] ⁺ :284.07398；found,284.07364.

Comparative example 20

2- (((propylthio) carbonyl) amino) benzoic acid (C-001,239 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 123 mg of a white solid in 56% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ＝8.12(d,J＝8.1Hz,1H),7.75(t,J＝7.7Hz,1H),7.45(d,J＝8.1Hz,1H),7.41(t,J＝7.7Hz,1H),3.15(t,J＝7.2Hz,2H),1.77-1.87(m,2H),1.08(t,J＝7.2Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ ):δ＝163.59,158.89,146.91,136.68,128.68,127.11,125.55,115.65,33.39,22.33,13.30.HRMS(ESI):m/z[M+H] ⁺ calculated for C ₁₁ H ₁₂ O ₂ NS:222.05833；found:222.05815

Comparative example 21- ((4 ',4',4' -trifluorobutyl) thio) -4H-benzo [ d ] [1,3] oxazin-4-one

2- ((((4, 4-trifluorobutyl) thio) carbonyl) amino) benzoic acid (C-002,153 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 ml), dicyclohexylcarbodiimide (104 mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (15 ml × 3 times) and water (15 ml), the organic phase was concentrated, and column chromatographed (ethyl acetate: petroleum ether = 1) to give 97 mg of a white solid in 67% yield.

¹ H NMR(400MHz,CDCl ₃ ):δ8.14(dd,J＝7.9,1.4Hz,1H),7.80–7.74(m,1H),7.48–7.41(m,2H),3.24(t,J＝7.1Hz,2H),2.36–2.23(m,2H),2.11(dt,J＝9.9,7.3Hz,2H). ¹³ C NMR(101MHz,CDCl ₃ ):δ162.66,158.58,146.64,136.82,128.79,127.45,125.63,115.69,99.90,32.75,30.15,21.88.HRMS(ESI):m/z calculated for C ₁₂ H ₁₁ F ₃ NO ₂ S[M+H] ⁺ 290.04571,found 290.04520.

Comparative example 22

2- (3- (4- (trifluoromethyl) phenyl) propionamido) benzoic acid (C-016, 337 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 ml), dicyclohexylcarbodiimide (208 mg, 1.01 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added, stirred at room temperature for 1 hour, extracted with dichloromethane (30 ml × 3 times) and water (30 ml), the organic phase was concentrated, and column chromatography (ethyl acetate: petroleum ether = 1) gave 217 mg of white solid in 68% yield.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.10(dd,J＝8.2,1.6Hz,1H),7.91(td,J＝7.7,1.6Hz,1H),7.65(d,J＝8.1Hz,2H),7.60(ddd,J＝8.1,6.4,1.3Hz,2H),7.56(d,J＝8.0Hz,2H),3.17(t,J＝7.7Hz,2H),3.08–3.01(m,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ162.20,159.65,146.36,145.80,137.41,130.06(2C),129.84,129.04,128.46(2C),126.87,125.75,125.67,117.19,35.21,31.16.HRMS(ESI):m/z calculated for C ₁₇ H ₁₃ O ₂ NF ₃ [M+H] ⁺ 320.08929,found 320.08948.

Comparative example 23

Methyl 2- (3-benzylureido) benzoate (C-013, 142 mg, 0.5 mmol) was added to 0.5 ml of concentrated sulfuric acid and reacted for half an hour at room temperature. The solution was made acidic with a saturated solution of sodium bicarbonate, extracted with ethyl acetate (20 ml × 3), the organic phases were combined, the organic phases were spin-dried, and separated by column chromatography (ethyl acetate: petroleum ether = 1) to give 62 mg of a white powder with a yield of 49%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.53(t,J＝5.9Hz,1H),7.91–7.87(m,1H),7.70–7.63(m,1H),7.36(dt,J＝13.1,7.5Hz,4H),7.26(t,J＝7.0Hz,1H),7.22–7.14(m,2H),4.50(d,J＝6.0Hz,2H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ170.01,159.99,154.86,139.08,137.21,128.83(2C),128.75,128.61,127.77(2C),127.50,124.42,123.56,44.48.HRMS(ESI):m/z calculated for C ₁₅ H ₁₃ N ₂ O ₂ [M+H] ⁺ 253.09715,found253.09671.

Comparative example 24

Methyl 2- (3-benzylureido) -4-methoxybenzoate (C-014, 157 mg, 0.5 mmol) was added to 0.5 ml of concentrated sulfuric acid and reacted at room temperature for half an hour. The solution was made acidic with a saturated solution of sodium hydrogencarbonate, extracted with ethyl acetate (20 ml × 3), the organic phases were combined, the organic phases were spin-dried, and column chromatography separation (ethyl acetate: petroleum ether = 1) gave 64 mg of a white powder with a yield of 45%.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.52(s,1H),7.79(d,J＝8.8Hz,1H),7.38–7.33(m,4H),7.27(d,J＝6.6Hz,1H),6.75(dd,J＝8.8,2.4Hz,1H),6.65(d,J＝1.8Hz,1H),4.50(s,2H),3.84(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ ):δ166.60,159.44,155.45,153.49,139.09,130.36,128.86(2C),127.67(2C),127.50,113.04,106.14,106.06,56.21,44.40.HRMS(ESI):m/z calculated for C ₁₆ H ₁₅ N ₂ O ₃ [M+H] ⁺ 283.10772,found283.10724.

Comparative example 25-chloro-2- ((4' - (trifluoromethyl) benzyl) thio) quinazolin-4 (3H) -one

6-chloro-2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (100 mg, 0.47 mmol), potassium iodide (86 mg, 0.52 mmol), 4-trifluoromethylbromobenzyl (135 mg, 0.56 mmol) and triethylamine (130. Mu.L, 0.94 mmol) were dissolved in anhydrous dichloromethane (20 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched by addition of water (30 ml), extracted with dichloromethane (30 ml. Times.3 times) and the organic phase Na ₂ SO ₄ Dried, concentrated by filtration, and isolated by column chromatography (ethyl acetate: petroleum ether =1 = 20) to give a white solid (55 mg, 31.54%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ12.80(s,1H),7.93(d,J＝2.3Hz,1H),7.77(dd,J＝8.7,2.3Hz,1H),7.72(d,J＝8.1Hz,2H),7.66(d,J＝8.2Hz,2H),7.61(d,J＝8.7Hz,1H),4.56(s,2H).HRMS(ESI):m/z calculated for C ₁₆ H ₁₁ ON ₂ ClF ₃ S[M+H] ⁺ 371.02272,found 371.02301.

2. Determination of biological Activity and stability of Compounds

Experimental example 1: test of inhibitory Activity of Compounds against human IDO and TDO

Human indoleamine 2, 3-dioxygenase (IDO) recombinant proteins were derived from the dawn topic group and the specific procedures are described in the references of the present invention (Protein Expr Purif 2004,37 (2), 392-8, protein Expr Purif 2000,19 (1), 22-9 j Med Chem 2013,56 (21), 8321-J Med Chem 2009,52 (23), 7364-7). An IDO or TDO reaction system was prepared, i.e., a final reaction of 100. Mu.l containing 100mM potassium phosphate solution (pH 6.5), 40mM ascorbic acid (neutralized with sodium hydroxide), 200. Mu.g/ml catalase, 20. Mu.M methylene blue, a certain concentration of L-tryptophan and a test compound was added, and the test compound was finally added. In the IDO assay, the final concentration of L-tryptophan was 800. Mu.M, and the concentration of hIDO protein was 0.05. Mu.M. In the TDO reaction system, the concentration of L-tryptophan was 1mM and the concentration of hTDO protein was 0.1 mM. After the reaction was carried out at 37 ℃ for 45 minutes, 20. Mu.l of 30% trichloroacetic acid was added to terminate the reaction. Then putting the reacted 96-well plate into 65 ℃ water for reaction for 1 minute, and finally adding 100 mu l of 2% (w/v) p-dimethylaminobenzaldehyde acetic acid solution into the reaction solution after the solution is cooled. The absorbance at 492nM was measured with a microplate reader. The inhibition rate is calculated as (blank control group absorbance-absorbance value of the compound to be detected)/blank control group absorbance 100%, after the inhibition rate is calculated, graphPad is used for calculating IC ₅₀ . The reference compounds used were NLG919, INCB024360, which can be referred to in the literature.

The experimental results are as follows:

table 1: results of the inhibitory Activity of Compounds on IDO and TDO

Table 2: determination of the IDO/TDO inhibitory Activity of comparative Compounds

Numbering	IDO/μM	TDO/μM
			C-001	>100	>100
C-002	78
			C-003	69	>100
C-004	>100	>100
			C-005	>100	>100
C-006	>100	>100
			C-007	>100	>100
C-008	>100	>100
			C-009	>100	>100
C-010	38.6	>100
			C-011	>100
C-012	94.8
			C-013	>100	>100
C-014	>100	>100
			C-015	>100	>100
C-016	>100	>100
			C-017	>100
C-018	91.3
			C-019	86.2	>100
C-020	>100	>100
			C-021	>100
C-022	>100	>100
			C-023	>100	>100
C-024	>100	>100
			C-025	>100
NLG919	0.064	0.085
			INCB024360	0.023

The experimental conclusion is that: specific results are shown in table 1. We selected 118 compounds of the invention and determined their inhibitory activity against IDO/TDO. And most compounds have strong in-vitro IDO inhibitory activity (IC) ₅₀ <10 μ M), of which 74 compounds had in vitro IDO inhibitory activity IC ₅₀ Up to or less than 1 μ M. Among others, mention may be made of: 12 Compounds in vitro IDO inhibitory Activity IC ₅₀ Up to or less than 1 × 10 ^-8 mol/L;7 Compounds in vitro IDO inhibitory Activity IC ₅₀ Up to or less than 1 × 10 ^- ⁹ mol/L; IC of 4 Compounds ₅₀ A value of 1X 10 or less ^-10 mol/L level, IC of 1 Compound ₅₀ A value of 1X 10 or less ^-11 The mol/L level is stronger than all IDO small-molecule inhibitors reported in the literature. Secondly, these patented compounds also have some inhibitory effect on TDO activity in vitro, but the inhibitory activity against IDO is much weaker. In vitro TDO inhibitory Activity IC of 9 Compounds of the invention ₅₀ Up to or less than 1 × 10 ^-6 mol/L, and only 1 Compound in vitro TDO inhibitory Activity IC ₅₀ Up to or less than 1 × 10 ^-7 mol/L. It can be seen that the compounds of the present invention have selectivity for the in vitro inhibitory activity of IDO/TDO.

At the same time, we also determined the inhibitory activity of 25 compounds for structural comparison on IDO/TDO. These comparative compounds exhibited very weak IDO/TDO inhibitory activity in vitro. IC of inhibitory activity of 25 selected compounds on IDO ₅₀ Are all greater than 3 × 10 ^-5 IC of inhibitory Activity of mol/L, and of only 6 Compounds on IDO ₅₀ At 3-10X 10 ^-5 mol/L. The inhibitory activity of 25 compounds on TDO is more than 1 x 10 ^-4 mol/L, the comparative compound has very weak effect on IDO/TDOThe inhibitory activity of (3).

Experimental example 2: screening of compounds for in vitro toxicity against several tumor cells

Mu.l of cells (human colorectal cancer cell HCT-116, human liver cancer cell HepG2, human breast cancer cell MCF-7, human lung cancer cell A549, and human glioma cell U251) were seeded in a 96-well plate at a cell concentration of 2000/well, 100. Mu.l of a medium solution of the test compound at a final concentration of 50. Mu.M was added to each well the next day, 20. Mu.l of MTT solution (5 mg/ml) was added to each well after the cell culture was continued at 37 ℃ for 96 hours, and after the cell culture was continued for 4 hours in the incubator, the supernatant was carefully discarded. Then 200. Mu.l of dimethyl sulfoxide solution was added to each well and the mixture was placed on a shaker to dissolve the crystals sufficiently. Finally, the absorbance of 560nM was measured by a microplate reader. The inhibition rate was calculated as (absorbance of solvent control-absorbance of test compound group)/absorbance of solvent control x 100%. The reference compound used was the literature-available Taxol, which is very active using IC ₅₀ And (4) showing.

Table 3: cytotoxicity assays of compounds on five tumor cell lines.

-, indicates an inhibitory activity of less than 50%.

And (4) conclusion: the specific results are shown in Table 3. We selected 100 compounds of the invention to determine their cytotoxicity against five common tumor cell lines. All compounds at a concentration of 10. Mu.M failed to completely inhibit the growth of five tumor cells. IC of cytotoxicity of 88 Compounds against five tumors ₅₀ All are greater than 10 μ M, only 12 compounds are activatedAt a concentration of 10. Mu.M, over 50% of the cytostatic activity of some cell lines could be detected, which may be the cytotoxicity of certain specific chemical groups themselves. Overall, such compounds are less cytotoxic in vitro. This is also consistent with and suggests a mechanism by which such small molecules act as small molecule inhibitors of IDO/TDO immunomodulatory proteins to combat tumors, rather than to treat tumors by cytotoxicity.

Experimental example 3: physical and chemical properties of two compounds (IPK-003 and IPK-074)

The physical and chemical properties of the compounds IPK-074 (closed loop) and IPK-003 (open loop) were selected for the study.

3.1, IPK-074 quality research results

Physicochemical Properties of IPK-074

(1) And appearance: white crystalline loose powder.

(2) Solubility: the results are shown in Table 4.

Table 4: solubility determination of IPK-074

Solvent(s)	Solubility in water	Determination of solubility in Water by HPLC
			Water (I)	Insoluble or almost insoluble	0.85μg/mL
0.1M hydrochloric acid solution	Insoluble or almost insoluble	Undetected
			pH 7.4 aqueous solution	Insoluble or almost insoluble	Not detected out
Methanol	Slightly soluble
			Ethanol	Slightly soluble
Acetonitrile	Dissolution
			Petroleum ether	Slightly soluble
Methylene dichloride	Is easy to dissolve
			Chloroform	Is easy to dissolve
DMSO	Is easy to dissolve

(3) Melting point DSC-TG method: at 90.2 ℃.

(4) And the oil-water distribution coefficient LogP is 4.62 determined by liquid chromatography.

(5) IPK-074 by HPLC

0.5mg/mL IPK-074 was assayed by high performance liquid chromatography (C18 column, gradient elution) in acetonitrile for a retention time of 24.6 minutes. And (4) calculating by a normalization method, wherein no impurity is detected in the sample.

(6) IPK-074 test for influencing factors

IPK-074 was exposed to 60 ℃ under 5000lx light at RH92.5% relative humidity for 12 days. The results are given in Table 5 below.

Table 5: effect factor research result of IPK-074

Conclusion of physicochemical properties: IPK-074 is stable basically when placed under the conditions of illumination, high temperature and high humidity for 12 days.

3.2 quality study result of IPK-003

(1) Melting point DSC-TG test: 166.0 ℃.

(2) HPLC measurement

The chromatographic parameters are the same as IPK-074, and the detection wavelength is 260nm (the maximum absorption wavelength of IPK-003).

(3) And sample measurement

IPK-003 retention time was 11.6 minutes as determined by HPLC using acetonitrile solution. The purity of IPK-003 was 99.90% as calculated by normalization.

(4) Influence factor test

Exposed for 12 days at 60 deg.C under 5000lx light and relative humidity RH 92.5%. The results are given in Table 6 below.

Table 6: research result of influence factors of IPK-003

The research conclusion of the physical and chemical properties is as follows: the IPK-003 is placed under the conditions of illumination, high temperature and high humidity for 12 days, and the sample is basically stable. 2 impurities less than 0.1% are generated at high temperature, and the product is basically stable.

Experimental example 4: mouse oral drug generation characteristic and bioavailability research of compound IPK-074

We selected two compounds IPK-074 and IPK-003, studied the pharmacokinetic profile of plasma in mice after oral administration of IPK-074 and intravenous injection of IPK-003, and calculated the bioavailability. The experimental animal is an ICR mouse, the weight of the experimental animal is 20-22 g, and the ICR mouse is provided by Beijing Wintolite laboratory animals Limited company. The early stage experiment shows that: after IPK-074 was mixed with mouse plasma, IPK-074 was rapidly and completely converted to IPK-003 in plasma.

Experimental methods

(1) Establishment of a plasma sample standard curve

IPK-003 was dissolved in DMSO to make a 31.6mg/mL solution, which was diluted with acetonitrile containing an internal standard (YHP 836, 0.2. Mu.g/mL) to working solutions of concentrations 0.05, 0.1, 0.25, 0.5, 1, 2, 4, 8, 16, 20 ng/mL. mu.L of blank plasma was added with 40. Mu.L of working solution and 80. Mu.L of acetonitrile containing an internal standard (YHP 836, 0.2. Mu.g/mL), mixed and spun, and centrifuged (14000 rpm. Times.5 min) twice, and 5. Mu.L of supernatant was collected for LC/MS/MS analysis.

(2) Plasma pharmacokinetic study of mice after oral administration of IPK-074 and intravenous injection of IPK-003

IPK-074 powder was formulated as a 3mg/mL suspension with 0.5% CMC for oral administration, and a DMSO solution of IPK-003 (31.6 mg/mL) was formulated as a 0.316mg/mL solution (containing 5% DMSO) with 20% cyclodextrin for tail vein injection. 16 mice were divided into 2 groups, 10 oral groups, 6 intravenous groups. Fasting is carried out for 12h before administration, and water is freely drunk. The experiment adopts a sectional blood sampling method. Mice were bled from orbital

venous plexus

5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, 24h after oral administration, 2, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, 24h after intravenous administration, 20 μ L plasma was isolated, 60 μ L acetonitrile containing an internal standard (YHP 836,0.2 μ g/mL) was added, centrifuged (14000 rpm × 5 min) twice after vortexing, and 5 μ L supernatant was taken for LC/MS analysis.

(3) LC/MS/MS conditions

A chromatographic column: zomax C18 (50 mm. Times.2.1mm, 3.5 μm); column temperature: at the temperature of 37 ℃ and the like,

mobile phase: IPK-003 acetonitrile/water gradient; flow rate: 0.3mL/min; MRM anion mode detection m/z 356 → 58.5 (IPK-003), m/z 463 → 463 (internal standard YHP 836).

(4) Data analysis

Plasma pharmacokinetic parameters were calculated using WinNonlin software.

And (3) calculating the bioavailability: f (%) = (D intravenous × AUC oral)/(D oral × AUC intravenous) × 100%

Results of the experiment

(1) Plasma sample standard curve

According to LC/MS/MS spectrums of all samples, the peak area ratio of IPK-003 to an internal standard is a vertical coordinate, the concentration of IPK-003 is a horizontal coordinate, correlation analysis is carried out, the correlation relation between the concentration of IPK-003 and the area ratio of chromatographic peaks in a plasma sample is good in the concentration range of 0.05-20 mu g/mL, and the correlation coefficient is greater than 0.99.

(2) Plasma pharmacokinetic study of mice orally administered IPK-074 and intravenously injected IPK-003

Plasma IPK-003 blood concentration-time data after oral administration of IPK-074 and intravenous injection of IPK-003 in mice are shown in table 7, table 8 and fig. 1, and pharmacokinetic parameters calculated by using WinNonlin software are shown in table 8.

After mice take IPK-074 (30 mg/kg) orally, the blood peak time of metabolite IPK-003 is 0.5 h, C _max 22.7. Mu.g/mL, t _1/2 1.12h, AUC (0-t) 68.5 h/. Mu.g/mL. Mice were injected intravenously with IPK-003 (3.16 mg/kg, corresponding to a 1/10 oral dose), t _1/2 0.86h, AUC (0-t) 6.36 h. Mu.g/mL. Mice were orally administered IPK-074 (30 mg/kg) with a bioavailability of 107.7% calculated as IPK-003.

Table 7: plasma IPK-003 blood concentration after oral administration of IPK-074 (30 mg/kg) in mice

BLQ lower than lowest detected value

Table 8: blood concentration of mice injected with IPK-003 (3.16 mg/kg) intravenously

BLQ lower than minimum detection value

Table 9: plasma pharmacokinetic parameters of mice after oral administration of IPK-074 (30 mg/kg) and intravenous injection of IPK-003 (3.16 mg/kg)

The experimental results are as follows: the compound IPK-074 showed good oral pharmacokinetic properties in mice, which were orally administered IPK-074 (30 mg/kg) with a bioavailability of 107.7% calculated as IPK-003.

Experimental example 5: acute toxicity test of Compound IPK-074

The purpose of the test is to evaluate the possible toxic reaction condition after IPK-074 is orally administered to Kunming mice once, and provide animal test data for subsequent toxicity research and clinical research. The test animal is female/male Kunming mouse with weight of 16-18 g, provided by Beijing Hua Fukang biotech GmbH.

Test method

(1) IPK-074 (1000 mg/kg) group: 250mg of IPK-074 was weighed out accurately, and the mixture was milled and added to 5mL0.5% CMC-equivalent solution to prepare 50mg/mL (equivalent to 1000 mg/kg). Each animal is orally administered at a dose of 0.4mL/20g, ready to use.

(2) The mice were divided into two cages according to sex, 6 mice per group of female/male mice were tested, IPK-074 was orally administered once, and animals were continuously observed for 6 hours after administration, from the day after administration, 1 time each day in the morning and afternoon. At the end of the observation period (day 7), all animals were euthanized and gross anatomical observations were performed.

Observation time: the observation is carried out beside a cage after the day of drug administration, the observation is recorded for at least 1 time every 15 minutes within 1 hour, and the observation is carried out for at least 1 time every 1 hour within 1-6 hours; for animals with no obvious abnormal response, the observation was completed after 6 hours. Observations include, but are not limited to: mental state, behavioral activities, skin, fur, eyes, ears, nose, abdomen, external genitalia, anus, limbs, feet, respiration, etc. General clinical observation frequency and time: the test period was observed twice daily (once in the morning and afternoon). And (4) observing the content: including but not limited to dead or dying conditions, mental states, behavioral activities, eating conditions, hair, glandular secretions, stool characteristics, etc., of the animal.

(3) Animal body weight recording after dosing the body weight was monitored daily before dosing (day one) and 6 days after dosing.

Analysis of results

During the test period, all the animals are euthanized according to the planned time without death or dying phenomenon. The results of the clinical observations are shown in tables 10 and 11. As shown in Table 9, no abnormal reaction was observed in any of the animals during the experiment. Animal body weight individual data are shown in table 11. During the test, the weight average of each animal in each administration group at each time point showed an increasing trend.

Table 10: clinical observations individual data

-: indicating no anomaly.

Table 11: body weight individual data (grams)

The experimental results are as follows: during the test period, no death or dying phenomenon of the animals is observed. The clinical observation of the test animals is good, and no abnormal reaction is found. The gross anatomy observation shows that no obvious abnormality is found in the organ tissues of each animal. Under the test condition, after IPK-074 is orally administered to Kunming mice for a single time, the dosage is 1000mg/kg, no death of the mice and no obvious systemic toxicity reaction are seen, and the maximum tolerance dose is more than 1000mg/kg.

Experimental example 6: in vivo pharmacodynamic study of IDO inhibitors

The in vivo antitumor effect of the IDO inhibitors IPK-074 and IPK-003 on the mouse B16F10 melanoma subcutaneous transplantation tumor is evaluated on a mouse subcutaneous transplantation tumor model, and the toxicity of the compounds is preliminarily observed. Positive drugs: cyclophosphamide (CTX). Experimental animals: c57BL/6 mice, weighing 18-20g, SPF grade, female, were provided by Beijing Sibefu laboratory animals, inc.

Experimental methods

(1) The mouse B16F10 tumor solution is inoculated to the right armpit of a C57BL/6 mouse under a sterile condition. After 12 days, well-grown tumor tissue was aseptically harvested, minced, ground, filtered, diluted with physiological saline to a cell concentration of 2.5X 10 ⁷ one/mL, 0.2 mL/mouse was inoculated in the right underarm of C57BL/6 mice. Animals were randomly grouped the day after inoculation, 7 animals per group, weighed and dosed, and test compound was dosed 1 time per day for 19 consecutive doses. Animals were sacrificed after taking the blood from the canthus after weighing on day 20, and tumor tissues were stripped and weighed for photography. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect strength by using the tumor inhibition rate. The inner canthus blood was used to test the number of each cell type in the five categories of test blood.

(2) Grouping: blank control group, positive drug control group-Cyclophosphamide (CTX) 100mg/kg, IPK-074 group 30mg/kg (intraperitoneal injection, IP), IPK-074 group 60mg/kg (intraperitoneal injection), IPK-074 group 30mg/kg (oral, PO), IPK-074 group 60mg/kg (oral), IPK-003 group 30mg/kg (intraperitoneal injection), IPK-003 group 60mg/kg (intraperitoneal injection), IPK-003 group 30mg/kg (oral), IPK-003 group 60mg/kg (oral).

(3) And the preparation of the positive medicine-cyclophosphamide: 25mg of cyclophosphamide was accurately weighed, and dissolved in 5mL physiological saline to 5mg/mL, and each animal was administered intraperitoneally at a rate of 0.4mL/20g per body weight.

The preparation of the compound to be tested comprises accurately weighing the compound, adding 2 drops (about 50 mu L) of Tween 80, uniformly grinding, and adding physiological saline to a concentration of 3 mg/kg. Each animal is administered intraperitoneally or orally at a dose of 0.4mL/20g, i.e., 60mg/kg, based on body weight. Diluting twice to obtain 30mg/kg.

(4) Computing method

Tumor proliferation inhibition rate TGI (%): TGI = (1-T/C) × 100. (T: tumor weight in treatment group; C: tumor weight in negative control group).

Table 12: IDO inhibitor with in vivo antitumor effect on mouse B16F10 melanoma

IP-intraperitoneal OP-oral administration

Tt test,*P<0.01,**P<0.01,***P<0.001

NA is not applicable

And (4) experimental conclusion: the drug effects of IPK-003 and IPK-074 are reflected by the tumor weight, the tumor weight is weighed when animals are treated, and the effect of the compounds to be tested on mouse melanoma B16F10 is shown in figure 2, figure 3 and table 12. In a mouse B16F10 melanoma model, oral administration and intraperitoneal administration of IDO small-molecule inhibitors IPK-074 and IPK-003 can generate a certain anti-tumor effect, wherein the oral administration has a tumor inhibition rate of 71.8% when the IPK-074 is administrated at a dose of 30mg/kg, and the intraperitoneal injection has a tumor inhibition rate of 60% when the IPK-003 is administrated at a dose of 30mg/kg. See table 12 for details. The safety of IPK-003 and IPK-074 is high, and the weight of the mice is measured on the day of treatment. Mice in each group of IPK-003 and IPK-074 did not significantly lose weight compared to the control group. The specific results are shown in FIG. 4 and Table 12. This also suggests that two small molecule inhibitors of IPK-003 and IPK-074 inhibit tumor growth by modulating the immune system, rather than killing tumor cells by cytotoxicity.

Blood index: neither compounds IPK-074 nor IPK-003 significantly changed the level of leukocytes (FIG. 5), lymphocytes (FIG. 6), monocytes (FIG. 7) and neutrophils (FIG. 8) in the blood. The specific results are shown in FIGS. 5-8.

Claims

1. A compound having the general formula (I):

wherein:

when the temperature is higher than the set temperature

And

when the single dotted line between them is a chemical single bond;

is selected from

Selected from element O or element S;

is selected from the elements C; n =0;

when in use

And

the single dashed line in between is absent;

is selected from

Selected from OR ₅ Or NR ₆ R ₇ ；

Is selected from

Or

n =0, 1 or 2;

wherein the phenyl, naphthyl or 5-14 membered aromatic heterocyclic group is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from halogen, cyano, nitro, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted R ₈ -C(O)-O-C _0-8 Alkylene-, substituted or unsubstituted R ₉ -C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -O-C(O)-N-C _0-8 Alkylene-, - (meth) acrylic acid,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted phenyl;

R ₃ 、R ₄ independently selected from hydrogen, substituted or unsubstituted C _1-8 An alkyl group;

R ₅ 、R ₆ 、R ₇ independently selected from hydrogen, substituted or unsubstituted C _1-8 Alkyl, substituted orUnsubstituted C ₃ Cycloalkyl, substituted or unsubstituted phenyl;

R ₈ 、R ₉ independently selected from hydrogen, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted phenyl;

the substituted substituent is selected from halogen, hydroxyl, amino, cyano, nitro, methoxy, trifluoromethyl and trifluoromethyloxy;

the 5-14 membered aromatic heterocyclic group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S;

but does not contain the following compounds:

2. the compound of claim 1, wherein the compound is of formula IA;

wherein:

selected from the group consisting of element O or element S;

wherein phenyl, naphthyl or 5-14 membered aromatic heterocyclic group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, cyano, nitro, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted R ₉ -C(O)-N(R ₈ )-C _0-8 Alkylene-, substituted or unsubstituted R ₉ R ₈ -O-C(O)-N-C _0-8 Alkylene-, - (meth) acrylic acid,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted C _1-8 Alkyl, substituted or unsubstituted phenyl; r is ₃ 、R ₄ Independently selected from hydrogen, substituted or unsubstituted C _1-8 An alkyl group;

but does not contain the following compounds:

3. the compound according to any one of claims 1-2, and pharmaceutically acceptable salts thereof,

selected from element O or element S;

wherein the phenyl, naphthyl and 5-14-membered aromatic heterocyclic group are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from halogen, cyano, nitro and C _1-8 Alkyl radical, X _g C _1-8 Alkyl, substituted or unsubstituted phenyl,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, halogen, cyano, nitro, C _1-8 Alkyl radical, X _g C _1-8 Alkyl, substituted or unsubstituted phenyl;

R ₃ 、R ₄ independently selected from hydrogen, C _1-8 An alkyl group;

but does not contain the following compounds:

4. the compound and pharmaceutically acceptable salts thereof according to claim 3,

selected from element O or element S;

the aromatic ring group or aromatic heterocyclic group is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from halogen, cyano, nitro, C _1-6 Alkyl, substituted or unsubstituted phenyl,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, halogen, cyano, nitro, C _1-6 Alkyl radical, X _g C _1-6 Alkyl, substituted or unsubstituted phenyl;

R ₃ 、R ₄ independently selected from hydrogen, C _1-6 An alkyl group;

But does not contain the following compounds:

5. the compound and pharmaceutically acceptable salts thereof according to claim 4,

the compound is shown as a general formula IA1

these aromatic or heteroaromatic groups are unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from halogen, cyano, nitro, C _1-6 Alkyl radical, X _g C _1-6 Alkyl, substituted or unsubstituted phenyl,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, halogen, cyano, nitro, C _1-6 Alkyl radical, X _g C _1-6 Alkyl, substituted or unsubstituted phenyl; r ₃ 、R ₄ Independently selected from hydrogen, C _1-6 An alkyl group;

but does not contain the following compounds:

6. The compound and pharmaceutically acceptable salts thereof according to claim 5,

the aromatic or heteroaromatic groups are unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, cyano, nitro, azido, C _1-4 Alkyl radical, X _g C _1-4 Alkyl, substituted or unsubstituted phenyl,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, halogen, cyano, nitro, C _1-4 Alkyl radical, X _g C _1-4 Alkyl, substituted or unsubstituted phenyl;

R ₃ 、R ₄ independently selected from hydrogen, C _1-4 An alkyl group;

but does not contain the following compounds:

7. the compound according to any one of claims 1-2, and pharmaceutically acceptable salts thereof,

The compound is shown as a general formula IA2

R _11a 、R _11b 、R _11c 、R _11d 、R _11e Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, X _g C _1-4 Alkyl, substituted or unsubstituted phenyl,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, X _g C _1-4 Alkyl, substituted or unsubstituted phenyl; r ₃ 、R ₄ Independently selected from hydrogen, C _1-4 An alkyl group;

the substituted substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethyloxy and methoxy;

but does not contain the following compounds:

8. the compound of claim 4 and pharmaceutically acceptable salts thereof, wherein the compound is of formula IA 3;

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, X _g C _1-4 Alkyl, substituted or unsubstituted phenyl;

R ₃ 、R ₄ independently selected from hydrogen, C _1-4 An alkyl group;

the substituted substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, trifluoromethyl and trifluoromethyl methoxy;

but does not contain the following compounds:

9. the compound of claim 1 and pharmaceutically acceptable salts thereof, wherein the compound is represented by formula IB;

is selected from OR ₅ Or NR ₆ R ₇ ；

Is selected from

Or

n =0, 1 or 2;

R ₃ 、R ₄ independently selected from hydrogen, C _1-8 An alkyl group; r is ₅ 、R ₆ 、R ₇ Independently selected from hydrogen, X _g C _1-8 Alkyl radical, C _1-8 Alkyl, substituted or unsubstituted C ₃ Cycloalkyl, substituted or unsubstituted phenyl; the substituted substituent is selected from halogen, hydroxyl, amino, cyano, nitro, methoxy, trifluoromethyl and trifluoromethyloxy;

but does not contain the following compounds:

10. a compound according to claim 9 and pharmaceutically acceptable salts thereof;

selected from OR ₅ Or NR ₆ R ₇ ；

Is selected from

Or alternatively

n =0, 1 or 2;

R ₁ aromatic ring radical independently selected fromOr an aromatic heterocyclic group: phenyl, naphthyl, pyridyl, quinolyl, furyl, thienyl, isoxazolyl, benzoxazolyl, acridinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzofuryl, benzimidazolyl;

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, halogen, cyano, nitro, X _g C _1-6 Alkyl, substituted or unsubstituted phenyl;

R ₃ 、R ₄ independently selected from hydrogen, C _1-6 An alkyl group; r ₅ 、R ₆ 、R ₇ Independently selected from hydrogen, X _g C _1-6 Alkyl radical, C _1-6 Alkyl, substituted or unsubstituted C ₃ A cycloalkyl group;

but does not contain the following compounds:

11. the compound of claim 9 and pharmaceutically acceptable salts thereof, wherein the compound is represented by formula IB 2;

selected from OR ₅ Or NR ₆ R ₇ ；

n =0, 1 or 2;

R _12a 、R _12b 、R _12c 、R _12d 、R _12e independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C _1-4 Alkyl radical, X _g C _1-4 Alkyl, substituted or unsubstituted phenyl,

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, X _g C _1-4 An alkyl group;

R ₃ 、R ₄ independently selected from hydrogen, C _1-4 An alkyl group; r ₅ 、R ₆ 、R ₇ Independently selected from hydrogen, X _g C _1-4 Alkyl radical, C _1-4 Alkyl, substituted or unsubstituted C ₃ Cycloalkyl, substituted or unsubstituted phenyl; the substituted substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, methoxy, trifluoromethyl and trifluoromethyloxy; x is above _g Wherein X is selected from halogen: fluorine, chlorine, bromine or iodine; g is selected from 1, 2, 3, 4 or 5.

12. The compound of claim 11 and pharmaceutically acceptable salts thereof, wherein the compound is represented by formula IB 3;

Selected from OR ₅ Or NR ₆ R ₇ ；

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C _1-4 Alkyl radical, X _g C _1-4 Alkyl, substituted or unsubstituted phenyl; r is ₃ 、R ₄ Independently selected from hydrogen, C _1-4 An alkyl group; r ₅ 、R ₆ 、R ₇ Independently selected from hydrogen, C _1-4 Alkyl, substituted or unsubstituted cyclopropane, substituted or unsubstituted phenyl; the substituted substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitromethoxy, trifluoromethyl and trifluoromethyloxy;

x is above _g Wherein X is selected from halogen: fluorine, chlorine, bromine or iodine; g is selected from 1, 2, 3, 4 or 5.

13. The compound of claim 10 and pharmaceutically acceptable salts thereof, wherein the compound is represented by formula IB 4;

is selected from OR ₅ Or NR ₆ R ₇ ；

R _2a 、R _2b 、R _2c 、R _2d Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C _1-4 Alkyl radical, X _g C _1-4 An alkyl group;

R ₃ 、R ₄ independently selected from hydrogen, X _g C _1-4 Alkyl radical, C _1-4 An alkyl group; r is ₅ 、R ₆ 、R ₇ Independently selected from hydrogen X _g C _1-4 Alkyl radical, C _1-4 Alkyl, substituted or unsubstituted cyclopropane, substituted or unsubstituted phenyl;

The substituted substituent is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, nitro, methoxy, trifluoromethyl and trifluoromethyloxy;

but does not contain the following compounds:

14. a compound according to any one of claims 1 to 13, and pharmaceutically acceptable salts thereof, selected from the following compounds:

15. a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1 to 14, and pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.

16. Use of a compound according to any one of claims 1 to 14 and pharmaceutically acceptable salts thereof or a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the treatment and/or prevention of diseases or conditions associated with excessive IDO and/or TDO activity or with IDO and/or TDO overexpression.

17. Use of a compound according to any one of claims 1 to 14, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the treatment of cancer.

18. The use according to claim 17, wherein the cancer is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, lymphoma, leukemia or melanoma.