Compound for regulating β2 integrin and pharmaceutical composition thereof

Abstract

The present invention relates to a compound for regulating a β2 integrin, which has the following structure of formula I. The present invention further relates to a pharmaceutical composition containing the compound and the use of the compound.

Description

A compound for modulating β2 integrin and pharmaceutical composition thereof TECHNICAL FIELD

[0001] The present disclosure relates to the field of medicine, more particularly to a compound for modulating β2 integrin and its application in treating disorders such as tumors and autoimmune diseases. BACKGROUND

[0002] Integrins are a class of transmembrane receptors widely expressed on the cell membrane, which are involved in the interaction between cells and cells, and between cells and extracellular matrix (ECM). As a matrix molecule receptor, integrins receive extracellular molecular signals and transduce them into cells through signal pathways, affecting gene expression, thereby mediating cell adhesion and migration, cell survival, immune surveillance, coagulation, development and other physiological processes. Integrins are composed of α and β subunits through non-covalent bonds, both of which are type I transmembrane proteins, consisting of extracellular domain, single transmembrane domain and intracellular domain. The β2 integrin family protein, also known as β2 integrin, is a transmembrane heterodimeric adhesion receptor composed of α subunit and β2 (CD18) subunit. The β2 integrin subunit can form four corresponding protein molecules with different α subunits (CD11a, CD11b, CD11c and CD11d). These receptors can bind to multiple ligands such as iC3b, ICAM, LPS and fibrinogen, thereby participating in the adhesion, migration and phagocytosis of immune cells, cell matrix interaction and inflammatory diseases. More and more studies have shown that the β2 integrin family, especially CD11b / CD18, plays a very important role in the activation of the immune system and inflammatory diseases.

[0003] Integrin CD11b / CD18, also known as αMβ2, Mac-1, complement receptor 3 (CR3), is a multifunctional receptor highly expressed on the surface of innate immune cells such as neutrophils, macrophages, myeloid cells, dendritic cells, natural killer cells, MDSCs, etc., and also expressed on activated lymphocyte subsets (B cells, T cells, etc.). Under normal physiological conditions, CD11b participates in the regulation of the inflammatory response process and multiple signaling pathways. CD11b regulates the aggregation and activation of leukocytes at the inflammatory site by increasing the flow, adhesion and transendothelial migration ability of leukocytes, and promotes the phagocytosis of leukocytes to immune complexes and iC3b-coated pathogens; the combination of CD11b and iC3b can promote the production of anti-inflammatory factors such as interleukin IL-10 and transforming growth factor β, thereby inhibiting excessive inflammatory response and reducing tissue damage.

[0004] In addition, CD11b can reprogram resident innate immune cells (macrophages, dendritic cells, mast cells, etc.) in the inflammatory site tissues, inhibit the excessive activation of inflammatory response. CD11b can also regulate the migration of dendritic cells in lymphatic vessels, thereby affecting the T cell activation mediated by dendritic cells. CD11b regulates the proliferation and activation of T cells, promotes the aggregation of B cells to the inflammatory site and the production of protective antibodies, and these immune effects are beneficial to the body to eliminate pathogens and reduce pathological damage. CD11b can maintain B cell tolerance, inhibit the maturation and function of dendritic cells, and inhibit the differentiation of Th17. CD11b is also involved in the negative regulation of Toll-like receptor-mediated immune response and antibody IgG Fc receptor signaling pathway, and its abnormal regulation of the signaling pathway is closely related to the occurrence of human diseases, thereby potentially affecting the occurrence and progression of autoimmune and inflammatory diseases.

[0005] CD11b affects the secretion of various cytokines by regulating various immune cells, such as: CD11b agonists inhibit the secretion of IL-6, IL-12 and TNF-α induced by R837 and CpG1826 in bone marrow-derived macrophages; CD11b inhibits the secretion of IL-17 by inhibiting the differentiation of Th17 cells; CD11b reduces Tlr4-dependent pro-inflammatory signals in immune cells through AKT / FOXO3 / IFN-I signaling pathway, and inhibits IFN-I signal; CD11b promotes the production of chemotactic factors in lung resident myeloid cells through STAT6, thereby increasing the recruitment of Th2 cells and initiating the recruitment of eosinophils into the airway to amplify allergic inflammation, and the IL-4, IL-5 and IL13 secreted by Th2 cells are key drivers of allergic reactions. Biological agents targeting IL-6, IL-12, IL4, IL5, TNF-α, IL-17 and IFN have been approved to treat various autoimmune diseases, and therefore, the targeted therapy of CD11b has great potential in the treatment of various inflammatory and autoimmune diseases.

[0006] There is a need in the art to develop new compounds related to the activity of the beta2 integrin. SUMMARY

[0007] In a first aspect, the present disclosure provides a compound of formula (I)

[0008] or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically-labeled, pharmaceutically acceptable salts thereof.

[0009] In a second aspect, the present disclosure also provides a compound of formula (III)

[0010] or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically-labeled derivatives, pharmaceutically acceptable salts thereof.

[0011] In a third aspect, the present disclosure also relates to a pharmaceutical composition comprising the compound of the first and second aspects of the present disclosure, or a stereoisomer, a tautomer, a solvate, a hydrate, an active metabolite, an isotopically-labeled derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0012] In a fourth aspect, the present disclosure also relates to use of the compound of the first and second aspects of the present disclosure, or a stereoisomer, a tautomer, a solvate, a hydrate, an active metabolite, an isotopically-labeled derivative, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the third aspect of the present disclosure, in the manufacture of a medicament for treating a disorder associated with the activity of β2 integrin.

[0013] In a fifth aspect, the present disclosure also relates to use of the compound of the first and second aspects of the present disclosure, or a stereoisomer, a tautomer, a solvate, a hydrate, an active metabolite, an isotopically-labeled derivative, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the third aspect of the present disclosure, for treating a disorder associated with the activity of β2 integrin.

[0014] In a sixth aspect, the present disclosure also relates to a method of treating a disorder associated with the activity of β2 integrin, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first and second aspects of the present disclosure, or the pharmaceutical composition of the third aspect of the present disclosure.

[0015] In preferred embodiments, the disorder is selected from allergic diseases (e.g., allergic rhinitis, food allergy, asthma, etc.), acute gout, systemic lupus erythematosus, inflammatory bowel disease (IBD), rheumatoid arthritis, Sjogren’s syndrome, chronic kidney disease (e.g., IgA nephropathy, lupus nephritis, membranous nephropathy, etc.), lupus arthritis, autoimmune liver disease (e.g., autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis); atopic dermatitis, graft-versus-host disease (GVHD), alopecia areata, psoriasis, chronic spontaneous urticaria, Behcet’s disease, hidradenitis suppurativa, neointimal thickening associated with vascular injury, peritonitis, etc. BRIEF DESCRIPTION OF DRAWINGS

[0016] FIG. 1 shows the results of rat ankle joint diameter measured in a sodium urate-induced acute gouty arthritis model in rats;

[0017] FIG. 2 shows the results of rat left foot paw withdrawal pressure measured in a sodium urate-induced acute gouty arthritis model in rats;

[0018] Figure 3 shows the results of urine protein detection in mice in the MRL / lpr spontaneous systemic lupus erythematosus mouse model;

[0019] Figure 4 shows the results of anti-dsDNA antibody detection in mice in the MRL / lpr spontaneous systemic lupus erythematosus mouse model;

[0020] Figure 5 shows the results of BAFF content detection in mice in the MRL / lpr spontaneous systemic lupus erythematosus mouse model;

[0021] Figure 6 shows the results of the change in body weight of mice measured in a dextran sulfate sodium salt (DSS)-induced colitis mouse model;

[0022] Figure 7 shows the results of DAI of mice measured in a dextran sulfate sodium salt (DSS)-induced colitis mouse model;

[0023] Figure 8 shows the results of the colon length of mice measured in a dextran sulfate sodium salt (DSS)-induced colitis mouse model;

[0024] Figure 9 shows the results of the clinical score of foot lesions of rats in collagen type II-induced rheumatoid arthritis of rats;

[0025] Figure 10 shows the results of the foot volume of rats in collagen type II-induced rheumatoid arthritis of rats;

[0026] Figure 11 shows the effect of Example 84 on the body weight and saliva secretion of mice with Sjogren's syndrome, wherein a. the body weight of mice in each group (mean ± SD); b. the weight of saliva of mice in each group (mean ± SD); c. the ratio of the weight of saliva to the body weight of mice in each group (mean ± SD). *P < 0.05, **P < 0.01, ***P < 0.001, (G1, G3, G4, G5, G6 V.S.G2);

[0027] Figure 12 shows the effect of Example 84 on the kidney function of mice with Sjogren's syndrome, wherein a. the overnight urine creatinine (CREA) level of mice in each group (mean ± SD); b. the overnight urine albumin (UTP) level of mice in each group (mean ± SD). **P < 0.01, ***P < 0.001, ****P < 0.0001 (G1, G3, G4, G5, G6 V.S.G2);

[0028] Figure 13 shows the effect of the compound of Example on the body weight and liver and spleen indexes of mice with autoimmune hepatitis, wherein a. the body weight of mice in each group (mean ± SD); b. the liver index of mice in each group (mean ± SD); c. the spleen index of mice in each group (mean ± SD). **P < 0.01, ****P < 0.0001 (G1, G3, G4 V.S.G2).

[0029] Figure 14 shows the effect of the test compounds on liver function in autoimmune hepatitis mice, wherein a. Serum alanine aminotransferase (ALT) levels in mice of each group (mean ± SD); b. Serum aspartate aminotransferase (AST) levels in mice of each group (mean ± SD). *P < 0.01, **P < 0.001 (G1, G3, G4 V.S. G2).

[0030] Figure 15 shows photographs of the effect of different groups on IgE-induced passive cutaneous anaphylaxis in mice;

[0031] Figure 16 shows the effect of Example 84 on neutrophil infiltration peritonitis mice, wherein a. At the end of the experiment, the number of neutrophils in the ascites of mice of each group (mean ± SD); b. The amount of IL-6 secretion in the ascites of mice of each group (mean ± SD); c. The amount of TNF-α secretion in the ascites of mice of each group (mean ± SD). * P < 0.05, *** P < 0.001 (G1, G3, G4, G5 V.S. G2).

[0032] Figure 17 shows the effect of Example 84 on macrophage infiltration peritonitis mice, wherein a. At the end of the experiment, the number of macrophages in the ascites of mice of each group (mean ± SD); b. The amount of IL-6 secretion in the ascites of mice of each group (mean ± SD); c. The amount of TNF-α secretion in the ascites of mice of each group (mean ± SD). * P < 0.05, ** P < 0.01, *** P < 0.001 (G1, G3, G4 V.S. G2). DETAILED DESCRIPTION

[0033] The present disclosure will be further described in details by means of examples. The features and advantages of the present disclosure will become more apparent from these descriptions.

[0034] The term "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0035] Furthermore, the technical features involved in the different implementations of the present disclosure described below can be combined with each other as long as there is no conflict.

[0036] DEFINITIONS

[0037] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein in their entirety. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0038] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention herein. In this disclosure, it must be noted that, unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0039] Definitions of standard chemical terms can be found in literature, including Carey and Sundberg's "Advanced Organic Chemistry 4". th Ed, Vol A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacological methods, are employed. Unless specifically defined herein, the nomenclature and laboratory procedures and techniques related to chemistry such as analytical chemistry, organic synthetic chemistry, and medical and medicinal chemistry are known to those skilled in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation, drug delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transmission). For example, reaction and purification techniques can be performed using kits with instructions provided by the manufacturer, or according to methods known in the art, or according to methods described in this disclosure. In general, the foregoing techniques and steps can be performed by conventional methods well known in the art and described in various general or more specific documents, which are cited and discussed in this disclosure.

[0040] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0041] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent, as long as the valence of the designated atom is not normally and the resulting compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced, and oxo cannot be on an aromatic group.

[0042] When any variable (e.g., R) occurs more than one time in a constituent or

[0043] As used herein, C m～n means that the moiety has m to n carbon atoms. For example, the term "C 1～8 " means that the moiety has 1 to 8 carbon atoms, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms,... 8 carbon atoms. Thus, for example, "C 1～8 alkyl" means an alkyl group containing 1 to 8 carbon atoms, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,... octyl, and the like. The numerical ranges recited herein, such as "1 to 8", are used herein to describe small integer ranges. Thus, for example, "1 to 8 carbon atoms" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, or 8 carbon atoms. It will be appreciated that the upper and lower limits of these ranges can be combined to form further ranges. For example, "1 to 4 carbon atoms" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. It will also be appreciated that the upper and lower limits of these ranges can be combined to form further ranges. For example, "1 to 4 carbon atoms" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms.

[0044] The term "membered" means the number of skeletal atoms that make up a ring. For example, pyridine is a six-membered ring, and pyrrole is a five-membered ring.

[0045] In the present disclosure, each group can have the following definitions:

[0046] Hydrogen can be represented as -H (protium), and can be replaced with deuterium, tritium, and the like isotopes.

[0047] Halogen can include fluorine, chlorine, bromine, iodine.

[0048] As used herein, the term "alkyl" means a straight or branched chain aliphatic group having from 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, optionally having one, two, or three substituents. Preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl. A "C0" alkyl group (as in "C0-C3-alkyl") is a covalent bond. C 1～8The alkyl group can include methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, octyl, and the like.

[0049] deuterated C 1～8 alkyl, tritiated C 1～8 alkyl can mean that one or more, or even all, hydrogen atoms in the C 1～8 alkyl are replaced with deuterium, tritium, or the like isotope.

[0050] The term "alkoxy" as used herein means -Oalkyl, wherein the alkyl is as defined herein, including but not limited to -OCH3, -OCF3, -OEt, -OC(CH3)2CH3, and -OCH2CF3.C 1～8 alkoxy can mean -OC 1～8 alkyl, wherein the C 1～8 alkyl includes groups as previously defined; for example, C 1～8 The alkyl group can include methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, octyl, and the like.

[0051] C 1～8 haloalkyl can mean C 1～8 alkyl, wherein the C 1～8 alkyl, halogen includes groups as previously defined; for example, C 1～8 The haloalkyl group can include -CF3, and the like.

[0052] The term "alkenyl" as employed herein refers to an unsaturated straight or branched chain aliphatic group having one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and optionally substituted with one, two, or three substituents. Preferred alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0053] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched-chain aliphatic group having one or more carbon-carbon triple bonds, having 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and optionally substituted with one, two, or three substituents. Preferred alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0054] Unless otherwise defined, the term "cycloalkyl" as used herein means a non-aromatic, saturated or unsaturated, monocyclic or polycyclic C3-Ci2hydrocarbon ring, preferably C3-C8, more preferably C3-C6, and most preferably C3-C5, which is optionally substituted with one, two, or three substituents. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, and substituted cyclohexyl. 12 Unless otherwise defined, the term "cycloalkyl" as used herein means a non-aromatic, saturated or unsaturated, monocyclic or polycyclic C3-Ci2hydrocarbon ring, preferably C3-C8, more preferably C3-C6, and most preferably C3-C5, which is optionally substituted with one, two, or three substituents. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, and substituted cyclohexyl. 3～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C3-C6, C3-C5, C3-C4, C3-C3, C3-C2, C3-C1, C4-C6, C4-C5, C4-C4, C4-C3, C4-C2, C4-C1, C5-C6, C5-C5, C5-C4, C5-C3, C5-C2, C5-C1, C6-C6, C6-C5, C6-C4, C6-C3, C6-C2, or C6-C1. 3～8 Cycloalkyl can include cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, and the like.

[0055] C 3～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C 1～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C 3～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C 1～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C 3～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C 1～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C 3～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C 1～8 Cycloalkyl can mean a non-aromatic, saturated carbon ring, including single carbon rings (having one ring) and double carbon rings (having two rings), for example, C

[0056] "Aryl" means a monocyclic or polycyclic aromatic hydrocarbon, including, for example, phenyl, naphthyl, and phenanthryl. 6～20 Aryl can include a monocyclic aryl, a bicyclic aryl, or a polycyclic aryl, for example, can include phenyl, biphenyl, naphthyl, phenanthryl, anthryl, azulenyl, and the like. Unless otherwise indicated, "aryl," "C6or C 10 Aryl can include a monocyclic aryl, a bicyclic aryl, or a polycyclic aryl, for example, can include phenyl, biphenyl, naphthyl, phenanthryl, anthryl, azulenyl, and the like. Unless otherwise indicated, "aryl," "C6or C

[0057] ​"Heterocyclyl" or "heterocyclic" groups are ring structures having from about 3 to 12 atoms in the ring structure, wherein the ring structure has one or more heteroatoms selected from N, O, S, etc. One or more positions of the heterocyclyl group are optionally substituted. The nitrogen of the heterocyclyl group is likewise optionally substituted independently with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Preferred heterocyclyl groups include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepinyl, oxepinyl, thiepinyl, oxazepinyl, piperidinyl, etc. In certain preferred embodiments, the heterocyclyl group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocycles include, but are not limited to, tetrahydroquinoline and dihydrobenzofuran.

[0058] The term "heteroaryl" as used herein refers to a group having from 5 to 14 ring-forming atoms, preferably 5, 6, 9, or 10 ring-forming atoms, having 6, 10, or 14 shared π-electrons in a cyclic arrangement, and having 1 to 3 heteroatoms in each ring in addition to carbon atoms. The term "heteroaryl" also means to include monocyclic or bicyclic groups. For example, the heteroaryl group can be pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. "Heteroaralkyl" or "heteroarylalkyl" includes a heteroaryl group attached to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroaralkyl groups comprise a C1-C6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring-forming atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl.

[0059] For simplicity, reference to "n-m membered" heterocyclyl or heteroaryl groups means a heterocyclyl or heteroaryl group having from "n" to "m" ring-forming atoms, where "n" and "m" are integers. Thus, for example, a 5-6 membered-heterocyclyl group is a 5 or 6 membered ring having at least one heteroatom and includes pyrrolidinyl (5 membered ring) and piperidinyl (6 membered ring); a 6 membered-heteroaryl group includes, for example, pyridyl and pyrimidinyl.

[0060] Hydroxyl can be represented as -OH.

[0061] Mercapto can be represented as -SH.

[0062] Carboxyl can be represented as -COOH.

[0063] Ester can be represented as -COOR', R' can be C 1～8 Alkyl, for example C 1～8 Alkyl-substituted ester can be represented as -COOC 1～8 Alkyl, wherein C 1～8 Alkyl includes groups as defined previously.

[0064] Acyl can be represented as -COR', R' can be C 1～8 Alkyl, for example C 1～8 Alkyl-substituted acyl can be represented as -COC 1～8 Alkyl, wherein C 1～8 Alkyl includes groups as defined previously.

[0065] Amino can be represented as -NH2, -NHR' or -N(R')2, R' can be C 1～8 Alkyl, for example C 1～8 Alkyl-substituted amino can be represented as -NHC 1～8 Alkyl or -N(C 1～8 Alkyl)2, wherein C 1～8 Alkyl includes groups as defined previously.

[0066] Amido can be represented as -CO amino, wherein amino is as defined previously.

[0067] Sulfonyl can be represented as -S(O)2R', R' can be C 1～8 Alkyl, for example C 1～8 Alkyl-substituted sulfonyl can be represented as -S(O)2C 1～8 Alkyl, wherein C 1～8 Alkyl includes groups as defined previously.

[0068] Cyano can be represented as -CN.

[0069] Oxo can be represented as (=O).

[0070] Thioxo can be represented as (=S).

[0071] In the foregoing definitions, when the number of carbon atoms varies, the above definitions vary only according to the number of carbon atoms, without affecting the definition of the type of group; for example, "C 1～5 Alkyl" can include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, and the like, all of which are included in the definition of "C 1～8 Alkyl" as defined previously, with the number of carbon atoms being 1-5.

[0072] As used herein, the term "acyloxy" means -OC(O)alkyl, wherein the alkyl group is as described herein. Examples of acyloxy substituents used in the present disclosure include: -OC(O)CH3, -OC(O)CH(CH3)2, and -OC(O)(CH2)3CH3.

[0073] As used herein, the term "N-acylamino" means N(H)C(O)alkyl, wherein the alkyl group is as described herein. Examples of N-acylamino substituents used in the present disclosure include: -N(H)C(O)CH3, N(H)C(O)CH(CH3)2, and N(H)C(O)(CH2)3CH3.

[0074] As used herein, the term "aryloxy" means -Oaryl, wherein the aryl group is phenyl, naphthyl, pyridyl or biphenyl, optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxyalkyl, alkoxy, trifluoromethyl, acyloxy, amino, N-acylamino, hydroxy, nitro, cyano, halogen, protected hydroxyl and amine.

[0075] As used herein, the term "heteroatom" means oxygen, nitrogen, sulfur, silicon and phosphorus.

[0076] As used herein, the term "halogen" means a substituent selected from the group consisting of bromo, iodo, chloro and fluoro.

[0077] As used herein, the term "treatment" and its derivatives, means both prophylactic and therapeutic treatment.

[0078] All publications, including but not limited to patents and patent applications, cited in this specification, are hereby incoφorated by reference in their entirety.

[0079] As used herein, the term "protected hydroxyl" or "protected -OH, -NH2" means the relevant group in an alcohol, carboxylic acid, amine or amide which can be protected by a conventional protecting group in the art. Compounds containing protected hydroxyl or amine groups are also useful as pharmaceutically active compounds of the present disclosure.

[0080] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0081] In general, crystallization produces solvates of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the disclosure with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the disclosure can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the disclosure can be true solvates, while in other instances, the compounds of the disclosure merely retain adventitious water or are a mixture of water plus some adventitious solvent.

[0082] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group can or can not be substituted and that the description includes substituted aryl groups and aryl groups with no substituents.

[0083] "Pharmaceutical composition" refers to a formulation of a compound of the disclosure and a medium generally accepted for the delivery of compounds to mammals, e.g., humans. Such medium includes all pharmaceutically acceptable carriers, diluents or excipients thereof.

[0084] "Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening, diluting, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor.

[0085] "Stereoisomers" refer to compounds which have the same bond sequence and hence the same connectivity but differ in the orientation of atoms in space. The disclosure contemplates various stereoisomers and mixtures thereof including "enantiomers", which refers to two stereoisomers whose mirror images cannot be superimposed on one another.

[0086] The compounds of the present disclosure (i.e., compounds of structure (I)), or pharmaceutically acceptable salts thereof, can contain one or more geometrically asymmetric centers and can therefore give rise to stereoisomers, such as enantiomers, diastereomers, and other stereoisomeric forms, which are defined in absolute terms as (R)- or (S)-, or as (D)- or (L)-, depending on the absolute configuration of asymmetric carbon atoms. Embodiments therefore include all such possible isomers, as well as, their racemic and optically pure forms. Optional levo- and dextro-, (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemic form (or salt or derivative thereof) using, for example, chiral high pressure liquid chromatography. When the compounds described herein contain olefinic double bonds, other geometric isomers are possible, and these are intended to be encompassed by the scope of the compounds. Likewise, all tautomeric forms are also intended to be included.

[0087] Embodiments of the present disclosure include all modes and conformationally restricted states of the atopic isomers of the compounds of the invention. Also included are atropisomers, which are stereoisomers that result from restricted rotation about a single bond, where the energy difference due to steric strain or other contributing factors creates a high enough rotational barrier to allow separation of individual conformers. As an example, certain compounds of the present disclosure can exist as a mixture of atropisomers, or be purified or enriched to exist as one atropisomer.

[0088] In some embodiments, the compounds of structure (I) are mixtures of enantiomers or diastereomers. In other embodiments, the compounds of structure (I) are substantially one enantiomer or diastereomer.

[0089] “Tautomer” refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. Embodiments therefore include tautomers of the disclosed compounds.

[0090] Compounds

[0091] The present disclosure relates to compounds of formula (I)

[0092] or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically-labeled derivatives, pharmaceutically acceptable salts thereof;

[0093] wherein R1is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C2-6 alkenyl, C 3-6 cycloalkyl or C 2-6 alkynyl;

[0094] R2is selected from cyano, -C(=O)OR 21 , substituted with m R B C 2-6 alkenyl, substituted with m R B C 2-6 alkynyl, substituted with m R B phenyl, or, pyridyl, substituted with m R B ;

[0095] R 21 is selected from hydrogen, C 20 alkyl, optionally substituted with R 1-6 , or C 20 aryl, optionally substituted with R 6-12 , wherein R 20 is selected from halogen, hydroxy, C 6-12 aryl, heteroaryl containing 1-3 heteroatoms selected from N, S and O, or heterocyclyl containing 1-3 heteroatoms selected from N, S and O;

[0096] R B are each independently selected from protium, deuterium, tritium, halogen, cyano, hydroxy, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

[0097] m is 0, 1, 2, 3, 4 or 5;

[0098] R3and R4are each independently selected from fluorine, protium, deuterium or tritium;

[0099] R 10 is selected from hydrogen, halogen or C 1-6 alkyl;

[0100] R A has the structure of Formula II, wherein —— indicates the position of R A attached to the phenyl ring;

[0101] In Formula II, R5and R6are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C(=O)R 51 , -C(=O)OR 51or -S(=O)2R 52 , provided that R5and R6are not simultaneously -C(=O)R 51 , -C(=O)OR 51 , and -S(=O)2R 52 ; or, R5and R6together with the N atom to which they are attached form a 5-8 membered N-containing heterocyclyl group optionally substituted with R 61 ;

[0102] R7is -OR 71 or -NR 72 R 73 ;

[0103] R 11 is selected from hydrogen or C 1-6 alkyl; or, R 11 and R5together with the atoms to which they are attached form a 5-8 membered N-containing heterocyclyl group optionally substituted with R 61 ;

[0104] or, when R A is located at the para position of the *C atom on the phenyl ring to which R A is attached, R 11 and R 10 together with the C atom to which they are attached form a 5-6 membered cyclic group;

[0105] x is 0 or 1 ;

[0106] when x is 1, R8and R9are each independently selected from hydrogen or C 1-6 alkyl; or, R8and R 11 together with the C atom to which they are attached form a C 3-6 cycloalkyl group;

[0107] R 51 and R 52 are each independently hydrogen, C 50 alkyl optionally substituted with R 1-6 , or C 50 aryl optionally substituted with R 6-12 , wherein R 50 is selected from halogen, hydroxyl, NH2, C 6-12 aryl, heteroaryl containing 1-3 heteroatoms selected from N, S and O, or heterocyclyl containing 1-3 heteroatoms selected from N, S and O;

[0108] R 61 is hydrogen, oxo, hydroxyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0109] R 71 is hydrogen or C 1-6 alkyl;

[0110] R 72 and R 73 are each independently hydrogen or C 1-6 alkyl; or, R 72 and R 73 together with the N atom to which they are attached form a 5-6 membered cyclic group.

[0111] In a preferred embodiment, R A is located at the para position relative to the *C atom to which R A is attached, i.e., the compounds of the disclosure have the following structure of Formula I-1

[0112] wherein each of the groups in Formula I-1 is as defined in Formula I.

[0113] In the above compounds of Formula I and Formula I-1, in one embodiment, R1is hydrogen or C 1-3 alkyl, e.g., methyl; preferably, R1is hydrogen.

[0114] In the above compounds of Formula I and Formula I-1, in one embodiment, R2is of the following structure:

[0115] wherein the dash indicates the point of attachment of R2to the **C atom in Formula I and Formula I-1;

[0116] R B is each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxy;

[0117] m is the number of R B and can be 0, 1, 2, 3, 4, or 5, and in particular can be 0, 1, or 2, and in particular can be 0 or 1.

[0118] In the above compounds of Formula I and Formula I-1, in one embodiment, R2is wherein R B is hydrogen, halogen, or C 1-3 alkoxy.

[0119] In the above compounds of Formula I and Formula I-1, in one embodiment, R2is wherein R B is protium, deuterium, or F. In this embodiment, R Bmay be deuterium, i.e. R2is deuterophenyl. In this embodiment, R B may be F, i.e. R2is monofluorophenyl.

[0120] In the above compounds of formula I and formula I-1, in one embodiment, R3and R4are hydrogen or deuterium. In one embodiment, R3and R4are both hydrogen. In one embodiment, at least one of R3and R4may be deuterium, or both can be deuterium, i.e. the compounds of formula I and formula I-1 are the corresponding deuterated compounds.

[0121] In the above compounds of formula I and formula I-1, in one embodiment, R7is OH.

[0122] In the above compounds of formula I and formula I-1, in one embodiment, R 10 is hydrogen.

[0123] In the above compounds of formula I and formula I-1, in one embodiment, x is 0, i.e. the structure is directly attached to the phenyl ring.

[0124] In one embodiment of the compounds of formula I-1,

[0125] R5is hydrogen,

[0126] R6is -C(=O)R 51 or -S(=O)2R 52 ,

[0127] wherein R 51 and R 52 are each independently hydrogen, C 50 alkyl optionally substituted with R 1-6 , or C 50 aryl optionally substituted with R 6-12 , wherein R 50 is selected from halogen, hydroxy or C 6-12 aryl. In one embodiment of the compounds of formula I-1, x can further be 0.

[0128] In one embodiment of the compounds of formula I-1, R5is hydrogen and R6is -S(=O)2R 52 ,

[0129] wherein R 52 is C 50 alkyl optionally substituted with R 1-6 , or C 50 aryl optionally substituted with R 6-12 , wherein R 50 is selected from halogen, hydroxy or C 6-12 aryl. Preferably, R52 is phenyl.

[0130] In one embodiment of the compound of formula I-1, R5is hydrogen, R6is -C(=O)R 51 ,

[0131] wherein R 51 is C 1-6 alkyl or C 1-6 haloalkyl, for example methyl, trifluoromethyl, ethyl, isopropyl or tert-butyl. Preferably, R 51 is tert-butyl.

[0132] In one embodiment of the compound of formula I-1, namely R A is located in para position to the *C atom of the phenyl ring to which R A is attached; in this case, R5and R6together with the N atom to which they are attached form a 5-8 membered N-containing heterocyclyl group, which is optionally substituted with R 61 ;

[0133] Preferably, the heterocyclyl group has one of the following structural formulae:

[0134] The above heterocyclyl group is optionally substituted with one or more R 61 , wherein R 61 is hydrogen, oxo, hydroxyl, halogen or C 1-6 alkyl. Preferably, R5and R6together with the N atom to which they are attached form one of the following structural formulae:

[0135] In another aspect, the present disclosure provides a compound of formula (III)

[0136] or a stereoisomer, a tautomer, a solvate, a hydrate, an active metabolite, an isotopically-labeled derivative, a pharmaceutically acceptable salt thereof;

[0137] wherein R1is selected from hydrogen (including protium, deuterium or tritium), halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 3-6 cycloalkyl or C 2-6 alkynyl;

[0138] R3and R4are each independently selected from fluorine, hydrogen (including protium, deuterium or tritium);

[0139] R 10 is selected from hydrogen (including protium, deuterium or tritium), halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0140] R D For the following L1 or L2

[0141] or

[0142] In L1, R L1 Selected from hydrogen (including protium, deuterium, or tritium), halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, or -(CR L11 R L12 ) p -R L0 ;

[0143] Where p is 0, 1, 2 or 3;

[0144] R L11 and R L12 Each is independently selected from hydrogen (including protium, deuterium, or tritium), halogens, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-6 alkoxy, or C 1-6 Halogenated alkoxy groups;

[0145] R L0 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, optionally substituted with R L10 C 3-6 Cycloalkyl, optionally substituted with R L10 C 6-12 Aryl, optionally substituted with R L10 It contains 1-3 heteroatoms selected from N, S, and O, with optional substitutions of R. L10 5-10 membered heterocyclic groups containing 1-3 heteroatoms selected from N, S, and O, -NR L13 R L14 -OR L13 -OC(=O)R L15 , -N(R L16 )C(=O)R L15 Or -S(=O)2R L15 ;

[0146] Among them, R L13 and RL14 Each is independently selected from hydrogen and C. 1-3 Alkyl, C 1-3 Halogenated alkyl, -(CR L11 R L12 ) s OC(=O)R L25 , -(CR L11 R L12 ) s C(=O)R L25 , or -(CR L11 R L12 ) s S(=O)2R L25 ;; or, R L13 and R L14 Together with the N atoms they are attached to, they form 3-10 membered rings; s can be 0, 1, 2, 3, or 4.

[0147] R L15 Each is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, optionally substituted with R L10 C 3-6 Cycloalkyl, optionally substituted with R L10 C 6-12 Aryl, optionally substituted with R L10 It contains 1-3 heteroatoms selected from N, S, and O, with optional substitutions of R. L10 A 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, with optional substitutions including R. L10 C 3-6 cycloalkyl C 1-6 Alkyl groups, optionally substituted with R L10 C 6-12 Aryl C 1-6 Alkyl groups, optionally substituted with R L10 5-10 membered heteroaryl C containing 1-3 heteroatoms selected from N, S and O 1-6 Alkyl, or optionally substituted with R L10 C containing 1-3 heteroatoms selected from N, S, and O, consisting of 5-10 membered heterocyclic groups. 1-6 alkyl;

[0148] R L16 Independently selected from hydrogen (including protium, deuterium, or tritium), C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, or C 3-6 Halogenated cycloalkyl groups;

[0149] R L10 Independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups;

[0150] In L2, R L2 Selected from hydrogen (including protium, deuterium, or tritium), halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, or -(CR L21 R L22 ) q -R L20 u can be 0, 1, or 2;

[0151] q can be 0, 1, 2, or 3;

[0152] R L20 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, optionally substituted with R L30 C 3-6 Cycloalkyl, optionally substituted with R L30 C 6-12 Aryl, optionally substituted with R L30 It contains 1-3 heteroatoms selected from N, S, and O, with optional substitutions of R. L30 5-10 membered heterocyclic groups containing 1-3 heteroatoms selected from N, S, and O, -NR L23 R L24 -OC(=O)R L25 , -N(R L23 )C(=O)R L25 Or -S(=O)2R L25 ;

[0153] R L21 and R L22 Each is independently selected from hydrogen (including protium, deuterium, or tritium), halogens, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-6 alkoxy, or C1-6 Halogenated alkoxy groups;

[0154] R L23 and R L24 Each is independently selected from hydrogen (including protium, deuterium, or tritium), C 1-3 Alkyl, C 1-3 Halogenated alkyl, -(CR L21 R L22 ) t OC(=O)R L25 , -(CR L21 R L22 ) t C(=O)R L25 , or -(CR L21 R L22 ) t S(=O)2R L25 Or, R L23 and R L24 Together with the N atoms they are attached to, they form 3-10 membered rings; t is 0, 1, 2, 3, or 4.

[0155] R L25 Independently selected from hydrogen (including protium, deuterium, or tritium), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, optionally substituted with R L30 C 3-6 Cycloalkyl, optionally substituted with R L30 C 6-12 Aryl, optionally substituted with R L30 It contains 1-3 heteroatoms selected from N, S, and O, with optional substitutions of R. L30 A 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, with optional substitutions including R. L30 C 3-6 cycloalkyl C 1-6 Alkyl groups, optionally substituted with R L30 C 6-12 Aryl C 1-6 Alkyl groups, optionally substituted with R L30 5-10 membered heteroaryl C containing 1-3 heteroatoms selected from N, S and O 1-6 Alkyl, or optionally substituted with R L30 C containing 1-3 heteroatoms selected from N, S, and O, consisting of 5-10 membered heterocyclic groups. 1-6 alkyl;

[0156] R L30 Independently selected from halogen, cyano, C 1-6 Alkyl, C1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 haloalkenyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 2-6 alkynyl or C 2-6 haloalkynyl;

[0157] R A having the structure of Formula II, wherein the dash indicates the bond to the phenyl ring; A position on the phenyl ring;

[0158] In Formula II, R5and R6are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C(=O)R 51 , -C(=O)OR 51 , or -S(=O)2R 52 , provided that R5and R6are not simultaneously -C(=O)R 51 , -C(=O)OR 51 , and -S(=O)2R 52 ; or, R5and R6together with the N atom to which they are attached form a 5-8 membered N-containing heterocyclyl group optionally substituted with R 61 ;

[0159] R7is -OR 71 or -NR 72 R 73 ;

[0160] R 11 is selected from the group consisting of hydrogen (including protium, deuterium, or tritium) or C 1-6 alkyl; or, R 11 and R5together with the atoms to which they are attached form a 5-8 membered N-containing heterocyclyl group optionally substituted with R 61 ;

[0161] or, when R A is located at the para position of the *C atom on the phenyl ring to which R A is attached, R 11 and R 10 together with the C atom to which they are attached form a 5-6 membered cyclic group;

[0162] x is 0 or 1 ;

[0163] when x is 1, R8and R9are each independently selected from the group consisting of hydrogen (including protium, deuterium, or tritium) or C 1-6 alkyl; or, R8and R 11Together with the C atoms they are attached to, they form C 3-6 cycloalkyl;

[0164] R 51 and R 52 Each is independently hydrogen (including protium, deuterium, or tritium), optionally substituted with R. 50 C 1-6 Alkyl, or optionally substituted with R 50 C 6-12 Aryl, wherein R 50 Selected from halogens, hydroxyl groups, NH2, C 6-12 Aryl, heteroaryl containing 1-3 heteroatoms selected from N, S and O, or heterocyclic group containing 1-3 heteroatoms selected from N, S and O;

[0165] R 61 Hydrogen (including protium, deuterium, or tritium), oxo, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, or C 1-6 Halogenated alkoxy groups;

[0166] R 71 It is hydrogen or C 1-6 alkyl;

[0167] R 72 and R 73 Each is independently hydrogen (including protium, deuterium, or tritium) or C. 1-6 Alkyl; or, R 72 and R 73 Together with the N atoms they are attached to, they form 5-6 membered cyclic groups.

[0168] In one implementation, R A Located in R A The *C atom superscripted on the benzene ring is at the para position, meaning the compound disclosed herein has the following formula III-1.

[0169] Among them, each substituent, for example R1, R3, R4, R D R5, R6, R7, R8, R9, R 10 R 11 The definitions of x, etc., are as shown in Formula III. It should be noted that the definitions of the relevant groups mentioned in Formula I, Formula I-1, and Formula III also apply to the same groups in Formula III-1.

[0170] In the above compounds of Formula III and Formula III-1, in one embodiment, R3and R4are hydrogen (including protium, deuterium, or tritium). In one embodiment, R3and R4are both hydrogen. In one embodiment, at least one of R3and R4may be deuterium, or both can be deuterium, i.e., the compounds of Formula III and Formula III-1 are the corresponding deuterated compounds.

[0171] In the above compounds of Formula III and Formula III-1, in one embodiment, R D is the following L3

[0172] wherein,

[0173] R L2 is hydrogen (including protium, deuterium, or tritium) or -(CH2) q -R L20 ; when R L2 is -(CH2) q -R L20 , it is located at the 3- or 4-position of the phenyl ring;

[0174] R L20 is a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, S, and O optionally substituted with R L30 ;

[0175] R L30 is independently selected from halogen, C 1-3 alkyl, or C 1-3 haloalkyl;

[0176] q is 0 or 1.

[0177] In the above compounds of Formula III and Formula III-1, in one embodiment, R L2 is -(CH2)q-R L20 , R L20 is one of the following structural formulas:

[0178] Preferably, R L2 is located at the 4-position of the phenyl ring.

[0179] In the above compounds of Formula III and Formula III-1, in one embodiment, R L2 is hydrogen (including protium, deuterium, or tritium).

[0180] In the above compounds of Formula III and Formula III-1, in one embodiment, R 10 is hydrogen (including protium, deuterium, or tritium), halogen, C 1-6 alkoxy, or C 1-6haloalkoxy; for example, hydrogen (including protium, deuterium or tritium), halogen, F or C 1-6 alkoxy such as methoxy, ethoxy. 1-3 alkoxy such as methoxy, ethoxy.

[0181] For the above compounds of formula III and III-1, R 10 may be located in meta- or ortho-position to the *C atom of the phenyl ring to which it is attached, preferably in meta-position. In these embodiments, R 10 may be hydrogen (including protium, deuterium or tritium), halogen, C 10 alkyl, or C 1-6 alkyl optionally substituted with R 1-6 haloalkoxy; for example, hydrogen (including protium, deuterium or tritium), F or C 1-6 alkoxy such as methoxy, ethoxy. 1-3 alkoxy such as methoxy, ethoxy.

[0182] In one embodiment of the above compounds of formula III and III-1, R5is hydrogen,

[0183] R6is -C(=O)R 51 or -S(=O)2R 52 ,

[0184] wherein R 51 and R 52 are each independently hydrogen, C 50 alkyl optionally substituted with R 1-6 alkyl, or C 50 aryl optionally substituted with R 6-12 alkyl, or C 50 aryl; 6-12

[0185] R7is -OR 71 ;

[0186] R 11 is hydrogen;

[0187] R 71 is hydrogen or C 1-6 alkyl such as C 1-3 alkyl such as methyl, ethyl, propyl or isopropyl;

[0188] x is 0.

[0189] Further, R6is -C(=O)R 51 ,

[0190] wherein R 51 is C 1-6 alkyl or C 1-6 alkyl.haloalkyl, for example methyl, trifluoromethyl, ethyl, isopropyl or tert-butyl, in particular tert-butyl.

[0191] Further, R7is -OH.

[0192] It should be noted that the compounds of the present disclosure have chiral centers, and thus the present disclosure includes compounds of various chiral configurations, such as R-configuration compounds or S-configuration compounds, racemates (typically a mixture of R-configuration compounds and S-configuration compounds), meso forms, and the like, all within the scope of the present disclosure.

[0193] In one embodiment, the compound is selected from one of the following compounds or a pharmaceutically acceptable salt thereof:

[0194] The above compounds refer to chiral compounds, such as compounds of R configuration and compounds of S configuration, as well as racemates. For example, the above compounds 1, 2, 4, 7-13, 18-21, 23-45, 52-83 refer to compounds having a specific chiral configuration (R configuration or S configuration), and compounds 3, 5-6, 14-17, 22, 46-51, 84-85, and 86-119 are racemates (mixtures of R configuration compounds and S configuration compounds). It is noted that the corresponding enantiomeric compounds of the above compounds 1, 2, 4, 7-13, 18-21, 23-45, 52-83, as well as racemates (mixtures of R configuration compounds and S configuration compounds) are also within the scope of the present disclosure. For example, compound 1 is a compound of S configuration, and the corresponding R configuration compound and racemate (mixture of R configuration compound and S configuration compound) are also within the scope of the present disclosure, and the same applies to other compounds 2, 4, 7-13, 18-21, 23-45, 52-83. Likewise, compounds 3, 5-6, 14-17, 22, 46-51, 84-85, and 86-123 are racemates (mixtures of R configuration compounds and S configuration compounds), and the respective compounds of specific chiral configuration (R configuration and / or S configuration) are also within the scope of the present disclosure. For example, compound 3 is a racemate (mixture of R configuration compound and S configuration compound), and the R configuration and / or S configuration compound is also within the scope of the present disclosure, and the same applies to other compounds 5-6, 14-17, 22, 46-51, 84-85, and 86-123.

[0195] Pharmaceutically acceptable salt or ester or pharmaceutically acceptable salt or ester

[0196] As used herein, the term "pharmaceutically acceptable salt or ester or pharmaceutically acceptable salt or ester" refers to any pharmaceutically acceptable salt or ester that can be prepared from a compound of the disclosure, including salts formed from acidic and basic functional groups such as nitrogen groups of one of the compounds of the disclosure. Illustrative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, acid phosphate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt or ester" also includes salts prepared from a compound of the disclosure having an acidic functional group, such as a carboxyl functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, organic amines, such as unsubstituted or hydroxyl-substituted mono-, di- or trialkyl amines; dicyclohexylamine; tributylamine; pyridine; morpholine; N,N-methyl-ethylamine; diethylamine; triethylamine; mono-, di- or tri-(2-hydroxy-lower alkyl) amines, such as mono-, di- or tri-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tri-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids, such as arginine, lysine, N,N,N-trimethylglycine, and the like. Moreover, where compounds (I) and salts thereof produce tautomers, any tautomers are included in the disclosure, and compounds (I) and salts thereof can be in any of a solvate, hydrate, non-solvate, and non-hydrate. In one embodiment, the class of acids used for salt formation includes inorganic acids and organic acids. Inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid; organic acids include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, oxalic acid.

[0197] Compounds of Formula (I) are included in the pharmaceutical compositions of the disclosure and are used in the methods of the disclosure. If a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example, methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate, maleate, and the like for -OH, which are known in the art to improve solubility or hydrolysis properties, to serve as sustained release or prodrug dosage forms.

[0198] Therapeutic / prophylactic administration and compositions of the disclosure

[0199] Because of their activity, the compounds of the present disclosure are advantageously useful in veterinary and human medicine. As described above, the compounds of the present disclosure are useful in the treatment or prevention of a disease in an animal in need thereof.

[0200] The present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure or stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically-labeled, pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient.

[0201] The compounds of the present disclosure have β2 integrin (particularly CD11b / CD18) agonistic activity, particularly CD11b agonistic activity, capable of modulating the function of β2 integrin. It is known that agonists can inhibit the expression of proinflammatory cytokines (e.g. IL-6) in leukocytes by phosphorylating Akt. Thus, the activity of agonists can be characterized by the activity of inhibiting IL-6 expression.

[0202] The present disclosure relates to the use of a compound of the present disclosure or stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically-labeled, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for the treatment of a disorder associated with β2 integrin activity.

[0203] The present disclosure relates to the use of a compound of the present disclosure or stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically-labeled, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for the treatment of a disorder associated with β2 integrin activity.

[0204] The present disclosure also relates to a method of treating a disorder associated with β2 integrin activity, comprising administering to an individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure.

[0205] As described above, the compounds or compositions of the present disclosure can be used to treat a disorder associated with β2 integrin activity. There are many diseases or conditions associated with the activity of β2 integrin. For example, it can play a role in a variety of autoimmune diseases, and can also play a role in a variety of tumor therapies.

[0206] In one embodiment, the disorder is selected from allergic diseases (e.g., allergic rhinitis, food allergies, asthma, etc.), acute gout, systemic lupus erythematosus, inflammatory bowel disease (IBD), rheumatoid arthritis, Sjogren's syndrome, chronic kidney disease (e.g., IgA nephropathy, lupus nephritis, membranous nephropathy, etc.), lupus arthritis, autoimmune liver disease (e.g., autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis); atopic dermatitis, graft versus host disease (GVHD), alopecia areata, psoriasis, chronic spontaneous urticaria, Behcet's disease, hidradenitis suppurativa, neointimal thickening associated with vascular injury, peritonitis, etc.

[0207] The compounds or compositions of the disclosure can be administered orally or parenterally. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal, intranasal, intrapulmonary, rectal, and topical routes, among others. Parenteral administration can be performed by continuous infusion over a selected time period.

[0208] The phrase "therapeutically effective amount" when used in connection with the compounds of the disclosure means an amount effective to treat or prevent a disease. The phrase "therapeutically effective amount" when used in connection with other therapeutic agents means an amount effective to make the other therapeutic agent effective. The term "effective amount" and its derivatives as used herein means that amount of a drug or pharmaceutical agent that elicits the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher or clinician. The term "therapeutically effective amount" and its derivatives also means any amount that improves a treatment, heals, prevents, or ameliorates a disease, condition, or side effect, or reduces the rate of advancement of a disease or condition, compared to the corresponding patient not receiving the amount of the drug. The term also includes amounts effective to enhance normal physiological function.

[0209] The phrases "treat," "treatment," and the like, contemplate an alleviation or cessation of a disease or symptoms thereof. In one embodiment, treatment includes inhibition, e.g., a reduction in the overall frequency of disease or symptoms events.

[0210] The term "animal" includes mammals, including, but not limited to, cows, monkeys, baboons, chimpanzees, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, and humans. In one embodiment, the mammal is a murine, canine, porcine, simian, and human.

[0211] The examples and formulations provided below further illustrate and demonstrate the compounds of the present disclosure and methods of making and testing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and formulations. In the following examples, and throughout the specification and claims, molecules shown in a particular chiral isomer form represent a single enantiomer of the molecule, having a single stereocenter but molecules shown in a particular chiral isomer form exist as racemic mixtures where the molecule has more than one stereocenter; molecules shown in a particular chiral isomer form can also be obtained by resolution of a racemic form (or a racemic form of a salt or derivative) using conventional techniques such as chiral high pressure liquid chromatography (HPLC) and fractional crystallization, among others.

[0212] Synthesis of intermediates

[0213] Preparation of Intermediate 1:

[0214] Step A: Synthesis of 2-(but-2-yn-1-yl)isoindoline-1,3-dione

[0215] Into a reaction flask was added compound 1-bromobut-2-yn (10.0 g, 75.7 mmol, 1.0 eq.) and DMF (50 mL), potassium phthalimide salt (15.0 g, 83.3 mmol, 1.1 eq) was added, heated to 80 °C, stirred overnight. TLC control reaction end, cooled, added 200 mL water, solid precipitated, filtered, filter cake oven dried to give 2-(but-2-yn-1-yl)isoindoline-1,3-dione (13.5 g, 90%) as a white solid.

[0216] 1 HNMR (400 MHz, DMSO-d6): δ 7.83-7.93 (m, 4H), 4.30-4.33 (m, 2H), 1.76 (s, 3H).

[0217] Step B: Synthesis of but-2-yn-1-amine hydrochloride

[0218] Into a reaction flask was added 2-(but-2-yn-1-yl)isoindoline-1,3-dione (13.5 g, 67.8 mmol, 1 eq.) and methanol (135 mL), then hydrazine hydrate (4.67 g, 74.6 mmol, 1.1 eq, 80%) was added dropwise, heated to 70 °C under N2protection, stirred overnight. LCMS control reaction end, cooled, filtered, filtrate adjusted to Ph = 4-5 with concentrated hydrochloric acid, filtered, filtrate rotary dried, added ethanol to slurry, filtered, filtrate rotary dried again, slurry with petroleum ether again, filtered to give but-2-yn-1-amine hydrochloride (4.5 g, 62%) as a yellowish solid.

[0219] 1 HNMR (400 MHz, D20): δ 3.65 (s, 2H), 1.73 (s, 3H).

[0220] Step C: Synthesis of 3-(but-2-yn-1-yl)-2-thioxothiohydantoin

[0221] Butyl-2-yne-1 -amine hydrochloride (4.5 g, 42.4 mmol, 1.0 eq.) was dissolved in DME (180 mL), bis(carboxymethyl)trithiocarbonate (55 mg, 0.245 mmol, 1.0 eq.) and triethylamine (8.6 g, 84.8 mmol, 2.0 eq) were added and heated to 90 °C, stirred for 1 h. LCMS checked for completion of reaction, cooled, filtered, filtrate was evaporated, column chromatography gave the desired product (5.3 g, 68%) as yellowish solid.

[0222] 1 HNMR (400 MHz, CDCh): δ 4.70 (s, 2H), 4.03 (s, 2H), 1.80 (s, 3H).

[0223] Preparation of Intermediate 2: 2-(4-oxo-2-thioxothiohydantoin-3-yl)acetonitrile

[0224] 2-Aminoacetonitrile (200 mg, 2.17 mmol) was added to DME (5 mL), bis(carboxymethyl)trithiocarbonate (491 mg, 2.17 mmol), TEA (440 mg, 4.34 mmol) were added sequentially, under nitrogen protection, the reaction was heated to 90 °C for 10 min under microwave condition. The solvent was evaporated and the product was purified by column chromatography (65 mg).

[0225] 1 HNMR (400 MHz, Methanol-d4): δ 5.33 (s, 2H), 4.77 (s, 2H).

[0226] Example 1: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiohydantoin-5- ylidene)methyl)furan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0227] Step A: (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid

[0228] A reaction vial was charged with (S)-3-(4-bromophenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (500.0 mg, 1.45 mmol), (5-formylfuran-2- yl)boronic acid (304.8 mg, 2.18 mmol), Pd(PPh3)4(80.0 mg, 0.069 mmol), Pd(dppf)Cl2(40.0 mg, 0.055 mmol), sodium carbonate (2.31 g, 21.79 mmol), then DME (11.0 mL), water (11.0 mL) was added, and the vial was purged with nitrogen three times. The reaction was stirred at 50 °C for 3 h. The reaction was cooled to room temperature, water (10 mL) and EA (30 mL) were added, and the mixture was stirred in an ice bath. 1M HCl was added dropwise until the pH was 3-4. The mixture was separated, and the aqueous phase was extracted with EA (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 620 mg.

[0229] 1 HNMR (400 MHz, CDC13): δ 9.65 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 3.7 Hz, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 6.84 (d, J = 3.7 Hz, 1H), 5.05 (d, J = 8.0 Hz, 1H), 4.65 (q, J = 6.5 Hz, 1H), 3.20 (dd, J = 13.7, 5.8 Hz, 2H), 1.44 (s, 9H).

[0230] Step B: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0231] A reaction vial was charged with (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)propanoic acid (250.0 mg, 0.70 mmol), 3-benzyl-2- thioxothiazolidin-4-one (155.3 mg, 0.70 mmol), ammonium acetate (80.4 mg, 1.04 mmol), then dioxane (10.0 mL), acetic acid (0.5 mL) was added, and the vial was purged with nitrogen three times. The reaction was stirred at 100 °C for 2 h. The reaction was checked by LCMS. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was slurried with EA to give the target product 550 mg.

[0232] 1HNMR (400 MHz, DMSO-d6): δ 12.61 (s, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.73 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 3.8 Hz, 1H), 7.38 - 7.26 (m, 6H), 7.17 (d, J = 8.4 Hz, 1H), 5.26 (s, 2H), 4.15 (td, J = 9.6, 4.5 Hz, 1H), 3.14 - 2.82 (m, 2H), 1.32 (s, 9H).

[0233] Example 2: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0234] Following the procedure described in Example 1, substituting (S)-3-(4- bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid with (R)-3-(4- bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid gave the title compound (80 mg, 95%).

[0235] LC-MS: LC-MS (m / z) [M-H]- = 563.33.

[0236] Example 3: (Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-methylpropanoic acid

[0237] Step A: 2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid methyl ester

[0238] Compound 2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (2.3 g, 1.0 eq.) was weighed into a reaction flask, methanol (30 mL) was added, and thionyl chloride (7 mL, 8.0 eq.) was added dropwise with ice bath cooling. The reaction was allowed to proceed at 60 °C overnight. LCMS was used to monitor the reaction. The starting material was consumed and the desired molecular weight was detected. The solvent was concentrated, and the product was purified by petroleum ether slurry to give the target product 2.3 grams in 93.5% yield.

[0239] 1 HNMR (400 MHz, Methanol-d4): δ 7.05 - 6.99 (m, 2H), 6.83 - 6.77 (m, 2H), 3.85 (s, 3H), 3.21 (d, J = 14.3 Hz, 1H), 3.02 (d, J = 14.4 Hz, 1H), 1.61 (s, 3H).

[0240] Step B: 2-((tert-Butoxycarbonyl)amino)-3-(4-hydroxyphenyl)-2-methylpropanoic acid methyl ester

[0241] Take 2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid methyl ester (2.2 g, 1.0 eq.) in a reaction bottle, add anhydrous DMF (12 mL), triethylamine (2.02 g, 1.9 eq.), (Boc)20 (3.44 g, 1.5 eq.), react at room temperature overnight. LCMS monitors the target molecular weight, water and ethyl acetate extraction, anhydrous sodium sulfate drying of organic phase, concentration of solvent, column purification to get 1.6 grams of target product, yield 49.2%.

[0242] 1 HNMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 6.97 (s, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.3 Hz, 2H), 3.59 (s, 3H), 3.07 (d, J = 13.9 Hz, 1H), 2.79 (d, J = 13.4 Hz, 1H), 1.40 (s, 9H), 1.16 (s, 3H).

[0243] Step C: 2-((tert-Butoxycarbonyl)amino)-2-methyl-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoic acid methyl ester

[0244] Take 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)-2-methylpropanoic acid methyl ester (500 mg, 1.0 eq.) in a reaction tube, add anhydrous DCM (10 mL), under nitrogen protection, triethylamine (325 mg, 2.0 eq.) at -78°C, Tf20 (549 mg, 1.2 eq.), react at -78°C for 1 hour. TLC and LCMS monitor the reaction, LCMS monitors the target molecular weight, water is added to destroy the ice bath, extracted with dichloromethane three times, the organic phase is dried with anhydrous sodium sulfate, the solvent is concentrated, and column purification to get 300 mg of target compound, yield 42.0%.

[0245] 1 HNMR (400 MHz, CDCl3): δ 7.24-7.12 (m, 4H), 5.18 (s, 1H), 3.79 (s, 3H), 3.48 (d, J = 12.5 Hz, 1H), 3.29 (d, J = 13.6 Hz, 1H), 1.58 (d, J = 6.2 Hz, 3H), 1.49 (s, 9H).

[0246] Step D: 2-((tert-butoxycarbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)-2- methylpropanoic acid methyl ester

[0247] Take 2-((tert-butoxycarbonyl)amino)-2-methyl-3-(4-(((trifluoromethyl)sulfonyl)oxy) phenyl)propanoic acid methyl ester (400 mg, 1.0 eq) in a reaction tube, add 1,4- dioxane (12 mL), water (3 mL), 5-formyl-2-furanboronic acid (152 mg, 1.2 eq), DIPEA (600 mg, 5.1 eq), Pd(PPh3)2Cl2(60 mg, 0.09 eq), under nitrogen protection at 70 °C for 2 h. TLC and LCMS monitor the reaction, LCMS monitor the molecular weight, add water and extract with ethyl acetate three times, dry the organic phase with anhydrous sodium sulfate, concentrate the solvent, and purify by column to obtain 250 mg of the target compound with a yield of 71.2%.

[0248] 1 HNMR (400 MHz, CDC13): δ 9.65 (s, 1H), 7.80-7.71 (m, 2H), 7.33 (d, J = 3.7 Hz, 1H), 7.21-7.15 (m, 2H), 6.83 (d, J = 3.7 Hz, 1H), 5.21 (s, 1H), 3.79 (s, 3H), 3.57-3.39 (m, 1H), 3.27 (d, J = 13.4 Hz, 1H), 1.65 (d, J = 12.1 Hz, 3H), 1.50 (s, 9H).

[0249] Step E: 2-((tert-butoxycarbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)-2- methylpropanoic acid

[0250] Take 2-((tert-butoxycarbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)-2- methylpropanoic acid methyl ester (250 mg, 1.0 eq) in a reaction bottle, add tetrahydrofuran (4 mL), water (2 mL), methanol (2 mL), and LiOH (108 mg, 4.0 eq) under ice bath, and react at room temperature for 5 hours. LCMS monitors the completion of the reaction. Add water and ethyl acetate, adjust the pH to 5-6 with 2M hydrochloric acid under ice bath, extract with ethyl acetate three times, dry the organic phase with anhydrous sodium sulfate, concentrate the solvent to obtain 180 mg of the target compound with a yield of 74.7%.

[0251] 1HNMR (400 MHz, CDC13): δ 9.65 (s, 1H), 7.75 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 3.7 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 3.7 Hz, 1H), 5.15 (s, 1H), 3.37 (d, J = 12.9 Hz, 2H), 1.61 (s, 3H), 1.52 (s, 9H).

[0252] Step F: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)-2- methylpropanoic acid

[0253] To the reaction flask was added 2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)-2-methylpropanoic acid (130 mg, 1.0 eq.), 1,4- dioxane (6 mL), acetic acid (0.6 mL), 3-benzyl-2-thioxothiazolidin-4-one (78 mg, 1.0 eq.), ammonium acetate (26 mg, 1.0 eq.), and the reaction was allowed to react at 100 °C for 2 hours. LCMS monitored the product molecular weight, the solvent was concentrated, and 280 mg of crude was sent for prep purification, which resulted in 117 mg of the target product with a yield of 58.1%.

[0254] 1 HNMR (400 MHz, DMSO-d6): δ 7.79 (d, J = 8.1 Hz, 2H), 7.73 (s, 1H), 7.40 (d, J = 3.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 2.3 Hz, 3H), 7.33-7.26 (m, 4H), 6.80 (s, 1H), 5.26 (s, 2H), 2.99 (d, J = 14.0 Hz, 2H), 1.43 (s, 9H), 1.23 (d, J = 7.5 Hz, 3H).

[0255] Step G: (Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)-2-methylpropanoic acid

[0256] To a reaction flask was added (Z)-3-(4-(5-((3-phenyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-((tert- butoxycarbonyl)amino)-2-methylpropanoic acid (115 mg, 1.0 eq.), hydrogen chloride dioxane solution (4.0 M, 1.0 mL), and allowed to react at room temperature for 1 h. LCMS confirmed complete conversion of starting material, concentrated the solvent, slurried with acetonitrile and lyophilized to give 20 mg of the target product in 21.0% yield.

[0257] 1 HNMR (400 MHz, Methanol-d4): δ 7.88 (d, J = 8.0 Hz, 2H), 7.62 (s, 1H), 7.47-7.37 (m, 4H), 7.37-7.27 (m, 3H), 7.20 (d, J = 3.8 Hz, 1H), 7.14 (d, J = 3.8 Hz, 1H), 5.34 (s, 2H), 3.41 (s, 1H), 3.17 (d, J = 14.1 Hz, 1H), 1.67 (s, 3H).

[0258] Example 4: (R,Z)-2-(4-(5-((4-oxo-3-((phenyl-4-d)methyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-neopentylaminoacetic acid

[0259] Step A: 2-(phenyl-4-d)-1,3-dioxolane

[0260] 2-(4-bromophenyl)-1,3-dioxolane (7 g, 30.6 mmol) was dissolved in anhydrous THF (70 mL), protected by nitrogen, and cooled to -70 °C. n-butyllithium (13.5 mL, 34 mmol) was added dropwise, and the mixture was stirred at -70 °C for 30 min. Then, a THF solution (10 mL) of D2O (1.2 g, 61.2 mmol) was added dropwise at -70 °C. After the addition was completed, the mixture was slowly warmed to 25 °C and stirred for 2 h. TLC monitoring showed that the reaction was complete. The reaction was quenched with water (350 mL), and extracted with EA (350 mL). The organic phase was washed with saturated brine (350 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The target compound (3.7 g, 79% yield) was obtained by column chromatography.

[0261] 1 HNMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 5.82 (s, 1H), 4.17-3.99 (m, 4H).

[0262] Step B: Benzaldehyde-4-d

[0263] Dissolve 2-(phenyl-4-d)-1,3-dioxolane (3.7 g, 24.5 mmol) in DCM (150 mL), add FeCl3.H2O (33 g, 122.4 mmol), then keep 25 °C for 2 h; TLC monitor the reaction complete, add water (150 mL) to quench, extract with DCM (100 mL), wash with saturated brine (150 mL) once, dry over anhydrous sodium sulfate, concentrate to get the crude product; purify by column chromatography to get the target compound (2 g, yield 75%).

[0264] 1 HNMR (400 MHz, CDC13): δ 10.03 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.2 Hz, 2H).

[0265] Step C: (Phenyl-4-d)methanol

[0266] Dissolve benzaldehyde-4-d (1.5 g, 14 mmol) in MeOH (20 mL), add NaBH4(0.8 g, 21 mmol) portionwise under ice bath, then keep 25 °C for 2 h. TLC monitor the reaction complete, directly concentrate to dryness, then add 1 N aqueous HC1 to adjust pH = 4-5, then extract with EA (50 mL), wash with saturated brine (50 mL) once, dry over anhydrous sodium sulfate, concentrate to get the crude product 1.4 g, which is used directly for the next step reaction.

[0267] Step D: 1-(Bromomethyl)phenyl-4-d

[0268] Dissolve (phenyl-4-d)methanol (1.4 g, 12.8 mmol) in DCM (20 mL), add PBr3(4.2 g, 15.4 mmol) portionwise under ice bath, then keep 25 °C for 2 h. TLC monitor the reaction complete, add water (50 mL) to quench, extract with DCM (50 mL), wash with saturated brine (50 mL) once, dry over anhydrous sodium sulfate, concentrate to get the crude product; purify by column chromatography to get the target compound (1.2 g, yield 51%).

[0269] 1 HNMR (400 MHz, CDC13): δ 7.33 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.43 (s, 2H).

[0270] Step E: 2-((Phenyl-4-d)methyl)isoindoline-1,3-dione

[0271] Dissolve 1-(bromomethyl)phenyl-4-d (1.2 g, 7.02 mmol) in ACN (20 mL), add potassium phthalimide (1.6 g, 8.4 mmol), then raise to 100 °C for 10 h; TLC monitor the complete reaction of raw materials, after cooling to remove the white solid, the filtrate concentrated to get the crude product, column purification to get the target compound (1.1 g, yield 66%).

[0272] 1 HNMR (400 MHz, CDC13): δ 7.87-7.81 (m, 2H), 7.73-7.67 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 4.85 (s, 2H).

[0273] Step F: (phenyl-4-d)methanamine

[0274] Dissolve 2-((phenyl-4-d)methyl)isoindoline-1,3-dione (500 mg, 2.1 mmol) in 1.4-dioxane (10 mL), add hydrazine hydrate (0.53 g, 10.5 mmol), then raise to 100 °C for 2 h. A large amount of white solid precipitated, TLC monitor the complete reaction of raw materials, LCMS confirmation; after cooling to remove the white solid, the filtrate was concentrated to dryness, then add water (20 mL) and DCM (20 mL) to extract, dry over anhydrous sodium sulfate, concentrated to get the crude product 200 mg directly used in the next step reaction.

[0275] Step G: 3-((phenyl-4-d)methyl)-2-thioxothiohydantoin

[0276] Dissolve (phenyl-4-d)methanamine (200 mg, 1.82 mmol), (biscarbomethyl)trithiocarbonate (836 mg, 3.7 mmol) and TEA (374 mg, 3.7 mmol) in DME (5 mL), raise to 90 °C microwave reaction for 20 min. TLC monitor the complete reaction of raw materials, the reaction was cooled to dryness directly, large plate purification to get the target compound (140 mg, yield 34%).

[0277] 1 HNMR (400 MHz, CDC13): δ 7.43 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.19 (s, 2H), 3.98 (s, 2H).

[0278] Step H: (R)-2-(4-hydroxyphenyl)-2-tert-butylaminoacetic acid methyl ester

[0279] Into a reaction flask was placed (R)-2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride (0.50 g, 2.30 mmol), tetrahydrofuran / water (15 mL / 10 mL), K2CO3(0.51 g, 3.68 mmol), nitrogen was replaced for three times, cooling to 0 °C, dropwise added tert-butyryl chloride (0.31 g, 2.53 mmol), after dropwise addition was completed, reaction was carried out at room temperature for half an hour, LCMS monitoring, the raw material was completely reacted, the reaction liquid was added to 40 mL of water, 30 mL of ethyl acetate was extracted three times, the combined organic phase was washed with 100 mL of brine, dried over anhydrous sodium sulfate and concentrated to give the target compound (0.62 g, yield 83%).

[0280] LC-MS (m / z) [M+1]+ = 266.1.

[0281] Step I: (R)-2-tert-butyrylamino-2-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetic acid methyl ester

[0282] Into a reaction flask was placed (R)-2-(4-hydroxyphenyl)-2-tert-butyrylaminoacetic acid methyl ester (0.61 g, 2.32 mol), DCM (50 mL), pyridine (0.18 g, 6.96 mmol), nitrogen was replaced for three times, dropwise added trifluoromethanesulfonic anhydride (0.98 g, 3.48 mmol) at 0 °C, after dropwise addition was completed, reaction was carried out at room temperature for half an hour. LCMS monitoring, the raw material was completely reacted, the reaction system was diluted with DCM, washed with water and brine respectively, dried over anhydrous sodium sulfate and concentrated to give the target compound (0.63 g, crude yield 72%).

[0283] LC-MS (m / z) [M+1]+ = 398.1.

[0284] Step G: (R)-2-(4-(5-formylfuran-2-yl)phenyl)-2-tert-butyrylaminoacetic acid methyl ester

[0285] Into a reaction vial, was placed (R)-methyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-tert-butylcarbamate (300 mg, 0.76 mmol), dioxane (20 mL), water (4.0 mL), 5-formylfuran-2-boronic acid (157 mg, 1.12 mmol), K3PO4(0.48 g, 2.26 mmol), SPhos (38 mg, 0.056 mmol), Pd(OAc)2(12.7 mg, 0.056 mmol), the reaction was purged with nitrogen for 3 times, and reacted at 80 °C for 2 h. The reaction was monitored by LCMS. The reaction mixture was diluted with EA, washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give the title compound (200 mg, yield 78%).

[0286] LC-MS (m / z): [M+1]+= 344.1.

[0287] Step K: (R)-2-(4-(5-formylfuran-2-yl)phenyl)-2-tert-butylcarbamic acid

[0288] Into a reaction vial, was placed (R)-methyl 2-(4-(5-formylfuran-2-yl)phenyl)-2-tert-butylcarbamate (200 mg, 1 eq), THF / H2O (20 mL / 10 mL), LiOH H2O (38 mg, 1.5 eq), and the reaction was reacted at room temperature for half an hour. The reaction was monitored by LCMS. The reaction mixture was concentrated, acidified with 1N HCl to pH≈2, and extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, and concentrated to give the title compound (190 mg, yield 100%).

[0289] LC-MS (m / z): [M+1]+= 330.1.

[0290] 1 HNMR (400MHz, DMSO-d6): δ 9.61 (s, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.91-7.81 (m, 2H), 7.66 (d, J = 3.7 Hz, 1H), 7.59-7.48 (m, 2H), 7.29 (d, J = 3.7 Hz, 1H), 5.44 (d, J = 7.5 Hz, 1H), 1.14 (s, 9H).

[0291] Step L: (R,Z)-2-(4-(5-((4-oxo-3-((phenyl-4-d)methyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-tert-butylcarbamic acid

[0292] Into a reaction vial was placed 3-((phenyl-4-d) methyl)-2- thioxotetrahydrothiazol-4-one (70 mg, 0.31 mmol), (R)-2-(4-(5-formylfuran-2- yl)phenyl)-2-pivalamidoacetic acid (102 mg, 0.31 mmol), ammonium acetate (37 mg, 0.47 mmol), AcOH (5 mL), the reaction vial was purged with nitrogen for 3 times, and then the reaction was heated at 120 °C for 2 h. The reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was cooled to room temperature, and then added to water / methanol (20 mL / 4 mL). The mixture was stirred and filtered. The filter cake was washed with methanol (10 mL), and then dried to give the title compound (91.2 mg, 55% yield).

[0293] 1 HNMR (400 MHz, CDC13): δ 12.95 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.87-7.85 (m, 2H), 7.74 (s, 1H), 7.61-7.59 (m, 2H), 7.42-7.40 (m, 1H), 7.36-7.31 (m, 5H), 5.44 (d, J = 7.5 Hz, 1H), 5.26 (s, 2H), 1.16 (s, 9H).

[0294] Example 5: (Z)-2-amino-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)acetic acid

[0295] Step A: 2-((tert-butoxycarbonyl)amino)-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid

[0296] Into a reaction vial was placed 2-(4-bromophenyl)-2-((tert- butoxycarbonyl)amino)acetic acid (1.0 g, 3.03 mmol), 5-formylfuran-2- boronic acid (635.6 mg, 4.54 mmol), SPhos (76 mg, 0.10 mmol), Pd(OAc)2(75 mg, 0.10 mmol), K3PO4(4.82 g, 45.43 mmol), toluene (27 mL), water (3 mL), and then the reaction vial was purged with nitrogen for 3 times. The reaction was heated at 60 °C overnight. The reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was cooled to room temperature, and then added to 10% citric acid to pH = 2. The mixture was extracted with EA (20 mL x 2), and then the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (500 mg).

[0297] Step B: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)acetic acid

[0298] To the reaction flask was added (Z)-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-((tert- butoxycarbonyl)amino)acetic acid (240 mg, 0.39 mmol), trifluoroacetic acid (5.0 mL), and the reaction stirred at room temperature for 2 hours. The reaction was complete by LCMS, and the reaction was quenched, concentrated under reduced pressure, washed with EA, and dried under vacuum to yield the target product 210 mg.

[0299] 1 HNMR (400 MHz, DMSO-d6): δ 12.84 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.74 (s, 1H), 7.60 (t, J = 7.4 Hz, 3H), 7.41 (d, J = 3.8 Hz, 1H), 7.39-7.27 (m, 6H), 5.26 (s, 2H), 5.16 (d, J = 8.2 Hz, 1H), 1.40 (s, 9H).

[0300] Step C: (Z)-2-amino-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)acetic acid

[0301] To the reaction flask was added (Z)-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-((tert- butoxycarbonyl)amino)acetic acid (240 mg, 0.39 mmol), trifluoroacetic acid (5.0 mL), and the reaction stirred at room temperature for 2 hours. The reaction was complete by LCMS, and the reaction was quenched, concentrated under reduced pressure, washed with EA, and dried under vacuum to yield the target product 210 mg.

[0302] 1 HNMR (400 MHz, DMSO-d6): δ 12.84 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.74 (s, 1H), 7.60 (t, J = 7.4 Hz, 3H), 7.41 (d, J = 3.8 Hz, 1H), 7.39-7.27 (m, 6H), 5.26 (s, 2H), 5.16 (d, J = 8.2 Hz, 1H), 1.40 (s, 9H).

[0303] Example 6: (Z)-2-acetamido-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-methylpropanoic acid

[0304] Step A: 2-amino-3-(4-(5-formylfuran-2-yl)phenyl)-2-methylpropanoic acid

[0305] To the reaction flask was added 2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)-2-methylpropanoic acid (180 mg, 1.0 eq. from Example 3), hydrogen chloride dioxane solution (4.0 M, 1.4 mL), and the reaction was allowed to proceed for 1 hour at room temperature. The reaction was monitored by LCMS and the starting material was consumed. The solvent was concentrated and the crude product was purified by trituration to give 140 mg of the target compound.

[0306] 1 HNMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 8.44 (s, 3H), 7.86 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 3.8 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 3.8 Hz, 1H), 3.23 (s, 1H), 3.14 (d, J = 13.8 Hz, 1H), 1.51 (s, 3H).

[0307] Step B: 2-acetamido-3-(4-(5-formylfuran-2-yl)phenyl)-2-methylpropanoic acid

[0308] To the reaction flask was added 2-amino-3-(4-(5-formylfuran-2-yl)phenyl)-2- methylpropanoic acid (160 mg, 1.0 eq.), DMF (5 mL), and triethylamine (207 mg, 3.5 eq.) was added dropwise while the reaction was maintained in an ice bath. Acetic anhydride (84 mg, 1.4 eq.) was added dropwise while the reaction was maintained in an ice bath. The reaction was allowed to proceed for 1 hour. The reaction was monitored by LCMS and the starting material was consumed. The product molecular weight was observed. Water and ethyl acetate were added and the pH was adjusted to 5-6 with 2 M hydrochloric acid. The organic phase was extracted three times with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated and the product was purified by column chromatography to give 120 mg of the target compound in 65.0% yield.

[0309] 1HNMR (400 MHz, DMSO-d6): δ 12.27 (s, 1H), 9.60 (s, 1H), 7.90-7.76 (m, 3H), 7.66 (d, J = 3.7 Hz, 1H), 7.34-7.16 (m, 3H), 2.99 (d, J = 13.1 Hz, 1H), 1.83 (s, 3H), 1.21 (s, 3H).

[0310] Step C: (Z)-2-acetamido-3-(4-(5-((3-benzyl-4-oxo-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)-2-methylpropanoic acid

[0311] To the reaction flask was added 2-acetamido-3-(4-(5-formylfuran-2-yl)phenyl)-2- methylpropanoic acid (120 mg, 1.0 eq.), acetic acid (4 mL), 3-benzyl-2- thioxothiazolidin-4-one (84 mg, 1.0 eq.), ammonium acetate (29 mg, 1.0 eq.), 120 °C for 2 hours. LCMS monitored the product molecular weight. Solvents such as n-hexane, ethyl acetate were slurried to purify, to get 165 mg of target product, 83.3% yield.

[0312] 1 HNMR (400 MHz, DMSO-d6): δ 12.27 (s, 1H), 9.60 (s, 1H), 7.90-7.76 (m, 3H), 7.66 (d, J = 3.7 Hz, 1H), 7.34-7.16 (m, 3H), 2.99 (d, J = 13.1 Hz, 1H), 1.83 (s, 3H), 1.21 (s, 3H).

[0313] Example 7: (S,Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)propanoic acid

[0314] A reaction flask was charged with (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (550 mg, 0.974 mmol; from Example 1), trifluoroacetic acid (5.0 mL, 0.177 mmol), and the reaction stirred at room temperature for 30 min. The reaction was checked by LCMS and was complete. The trifluoroacetic acid was removed under reduced pressure, and the reaction was diluted with dioxane (30 mL) and stirred for 10 min. The reaction was filtered, washed with MTBE, and dried under vacuum to give the title compound 250 mg.

[0315] 1 HNMR (400 MHz, TFA-d / DMSO-d6): δ 7.94 (dd, J = 20.7, 8.0 Hz, 2H), 7.70 (d, J = 3.9 Hz, 1H), 7.55 - 7.43 (m, 4H), 7.36 (p, J = 6.7 Hz, 3H), 7.20 (d, J = 3.7 Hz, 1H), 7.02 (dd, J = 13.5, 3.8 Hz, 1H), 5.50 (s, 2H), 4.78 (dd, J = 8.8, 4.9 Hz, 1H), 3.79 - 3.70 (m, 1H), 3.52 (dd, J = 15.0, 6.9 Hz, 1H).

[0316] Example 8: (S,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(2-hydroxy-2-methylpropanamido)acetic acid

[0317] Step A: (S)-2-(2-acetyloxy-2-methylpropanamido)-2-(4-hydroxyphenyl) ethyl acetate

[0318] To a reaction flask was added (S)-2-amino-2-(4-hydroxyphenyl)ethyl acetate hydrochloride (2.0 g, 9.22 mmol), triethylamine (2.4 g, 23.5 mmol), dichloromethane (30 mL), and the reaction was stirred at 0 °C. A solution of 1-chloro-2-methyl-1- oxopropan-2-yl acetate (1.6 g, 9.76 mmol) in 5 mL of dichloromethane was added dropwise to the reaction at 0 °C under a nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h. The reaction was checked by LCMS and was complete. The reaction was concentrated and purified by column chromatography (PE:EA = 4:1) to give 800 mg of the title compound A8-24-1 in 29% yield.

[0319] LC-MS: (ES+): m / z 310.1 [M+1]+.

[0320] Step B: (S)-2-(2-acetyloxy-2-methylpropanamide)-2-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetic acid methyl ester

[0321] Into a reaction bottle was added (S)-2-(2-acetyloxy-2-methylpropanamide)-2-(4- hydroxyphenyl)acetic acid methyl ester (800 mg, 2.59 mmol), triethylamine (786 mg, 7.77 mmol), dichloromethane (20 mL), after the addition was completed, a 5 mL dichloromethane solution of compound triflic anhydride (1.1 g, 3.89 mmol) was added dropwise under nitrogen protection at -70 degrees, the reaction system was reacted at -70 degrees for 1 hour. LCMS monitoring showed that the raw material was completely reacted, the system was warmed to room temperature, 30 mL of water was added, dichloromethane was extracted 3 times, and the organic phase was combined and concentrated to obtain 1.0 g of the target compound crude product.

[0322] LC-MS: (ES+): m / z 442.0 [M+1]+.

[0323] Step C: (S)-2-(2-acetyloxy-2-methylpropanamide)-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid methyl ester

[0324] Into a reaction bottle was added (S)-2-(2-acetyloxy-2-methylpropanamide)-2-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetic acid methyl ester (1.0 g, 2.27 mmol), DIEA (878 mg, 6.81 mmol) and 5-formyl-2-furanboronic acid (477 mg, 3.41 mmol), Pd(PPh3)Cl2 (161 mg, 0.23 mmol), dioxane / water (10 mL / 2 mL), after the addition was completed, the reaction system was replaced with nitrogen three times, and was warmed to 80°C for reaction for three hours. LCMS monitoring showed that the raw material was completely reacted, the system was cooled to room temperature, the solvent was concentrated, and column chromatography purification (PE:EA=3:1) gave 250 mg of the target compound, with a yield of 28%.

[0325] LC-MS: (ES+): m / z 442.0 [M+1]+.

[0326] Step D: (S)-2-(4-(5-formylfuran-2-yl)phenyl)-2-(2-hydroxy-2-methylpropanamide)acetic acid

[0327] To a reaction flask was added (S)-2-(2-acetyloxy-2-methylpropanamide)-2-(4-(5- formylfuran-2-yl)phenyl)acetate (250 mg, 0.646 mmol), LiOH (42 mg, 0.970 mmol), THF / H2O (6 mL / 2 mL), after addition was complete, the reaction was allowed to react at 25 °C for 2 h. LCMS was used to monitor the reaction completeness, the reaction mixture was concentrated to remove the solvent, the water phase was adjusted to pH 4 with 1M aqueous HC1 solution, extracted with ethyl acetate for 3 times, combined the organic phase, concentrated to get 180 mg of the target compound, yield 84%.

[0328] LC-MS: (ES+): m / z 332.1 [M+1]+.

[0329] Step E: (S,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(2-hydroxy-2-methylpropanamido)acetic acid

[0330] To a reaction flask was added (S)-2-(4-(5-formylfuran-2-yl)phenyl)-2-(2-hydroxy-2- methylpropanamido)acetic acid (180 mg, 0.544 mmol), NH4OAc (64 mg, 0.816 mmol) and 3-benzyl-2-thioxotetrahydrothiazol-4-one (121 mg, 0.544 mmol), acetic acid (6 mL), after addition was complete, the reaction was allowed to react at 120 °C for 1 h. LCMS was used to monitor the reaction completeness, the reaction mixture was allowed to cool to room temperature, added 30 mL of water, extracted with ethyl acetate for 3 times, combined the organic phase, concentrated to get the crude product, the crude product was slurried with methanol (30 mL), the filter cake was concentrated to dryness to get 96 mg of the target compound, yield 33%.

[0331] 1 H NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 8.10 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 3.8 Hz, 1H), 7.39 - 7.20 (m, 6H), 5.66 (s, 1H), 5.35 (d, J = 7.2 Hz, 1H), 5.26 (s, 2H), 1.28 (s, 3H), 1.24 (s, 3H).

[0332] Example 9: (S,Z)-2-amino-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)acetic acid

[0333] Following the procedure of Example 5, replacing 2-(4-bromophenyl)-2-((tert- butoxycarbonyl)amino)acetic acid with (S)-2-(4-bromophenyl)-2-((tert- butoxycarbonyl)amino)acetic acid gave 30 mg of the target product in 78% yield.

[0334] 1 HNMR (400 MHz, DMSO-d6): δ 8.80 (s, 3H), 7.94 (d, J = 8.1 Hz, 2H), 7.75 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.41 (s, 2H), 7.33 (hept, J = 7.3, 6.7 Hz, 5H), 5.26 (s, 2H), 5.13 (s, 1H).

[0335] Example 10: (R,Z)-2-amino-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)acetic acid

[0336] Following the procedure of Example 5, replacing 2-(4-bromophenyl)-2-((tert- butoxycarbonyl)amino)acetic acid with (R)-2-(4-bromophenyl)-2-((tert- butoxycarbonyl)amino)acetic acid gave 104 mg of the target product in 81% yield.

[0337] 1 HNMR (400 MHz, DMSO-d6): δ 8.80 (s, 3H), 7.94 (d, J = 8.1 Hz, 2H), 7.75 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.41 (s, 2H), 7.33 (hept, J = 7.3, 6.7 Hz, 5H), 5.26 (s, 2H), 5.13 (s, 1H).

[0338] Example 11: (R,Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)propanoic acid

[0339] To (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2- yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (500 mg, 1.0 eq; from Example 2) in a 25 mL single neck flask, add hydrochloric acid in dioxane (4 M, 10 mL), stir at room temperature for 1 h, monitor the reaction by LCMS, when the reaction is complete, spin dry, then add water (20 mL) and acetonitrile (5 mL) to slurry, filter to get solid 382 mg in 86% yield.

[0340] LC-MS (m / z) [M-H] - = 463.1.

[0341] 1 HNMR (400MHz, DMSO-d6): δ 8.37 (dd, J = 18.5, 5.5 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.74 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 3.7 Hz, 1H), 7.38-7.25 (m, 5H), 5.26 (s, 2H), 4.28 (dd, J = 6.5, 2.9 Hz, 1H), 3.18 (h, J = 7.7, 7.0 Hz, 2H).

[0342] Example 12: (Z)-2-acetylamino-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)-2-methylpropanoic acid

[0343] Referring to Example 6, 2-((tert-butoxycarbonyl)amino)-3-(4-(5-formylfuran-2- yl)phenyl)-2-methylpropanoic acid is replaced by (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)-2-methylpropanoic acid to obtain the target product 185 mg in a yield of 72.3%.

[0344] 1 HNMR (400MHz, DMSO-d6): δ 12.39 (s, 1H), 7.85-7.78 (m, 3H), 7.74 (s, 1H), 7.41 (d, J = 3.8 Hz, 1H), 7.38-7.35 (m, J = 6.9, 1.3 Hz, 1H), 7.34-7.32 (m, 4H), 7.30 (dd, J = 8.4, 6.8 Hz, 3H), 5.26 (s, 2H), 3.37 (d, J = 13.2 Hz, 1H), 3.02 (d, J = 13.1 Hz, 1H), 1.85 (s, 3H), 1.22 (s, 3H).

[0345] Example 13: (R,Z)-3-(3-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan- 2-yl)phenyl)-2-acetylamino propanoic acid

[0346] Referring to Example 6, the target compound can be synthesized to obtain 87 mg.

[0347] LC-MS: (ES-): m / z 507.1 [M+1]+.

[0348] Example 14: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(2,2,2-trifluoroacetamido)acetic acid

[0349] Step A: 2-amino-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid

[0350] To 2-((tert-butoxycarbonyl)amino)-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid (1.6 g, 1.0 eq; from example 5) was added hydrochloric acid in dioxane (4 M, 20 mL) and allowed to react at room temperature for 2 h. TLC monitoring of the reaction completion, the organic phase was dried and slurry with 20 mL of ethyl acetate to get 1.1 g of solid, 84% yield.

[0351] 1 HNMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.98 (s, 3H), 8.06-7.93 (m, 2H), 7.74-7.59 (m, 3H), 7.38 (d, J = 3.7 Hz, 1H), 4.78 (s, 1H).

[0352] Step B: 2-(4-(5-formylfuran-2-yl)phenyl)-2-(2,2,2-trifluoroacetamido)acetic acid

[0353] To 2-amino-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid (300 mg, 1.0 eq) was dissolved in 3 mL of DCM, TFAA (512.0 mg, 2.0 eq) was added and allowed to react at room temperature for 1.0 h. LC-MS monitoring of the reaction completion, the reaction mixture was directly dried and taken to the next step.

[0354] LC-MS (m / z) [M+H] + = 341.99.

[0355] Step C: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(2,2,2-trifluoroacetamido)acetic acid

[0356] Take 2-(4-(5-formylfuran-2-yl)phenyl)-2-(2,2,2-trifluoroacetamido)acetic acid (300.0 mg, 1.0 eq), 3-benzyl-2-thioxothiazetidin-4-one (215.9 mg, 1.1 eq), ammonium acetate (81.3 mg, 1.2 eq) and acetic acid (105.6 mg, 2.0 eq) in a 50 mL Schlenk tube, add 10 mL 1,4-dioxane, warm to 60°C for 30 min; monitor the reaction by LCMS, and dry the system after the reaction is completed to obtain 153 mg of the target product with a yield of 32%.

[0357] LC-MS (m / z) [M+H] + = 546.85.

[0358] 1 HNMR (400MHz, DMSO-d6): δ 13.34 (s, 1H), 10.26 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.74 (s, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 3.7 Hz, 1H), 7.37 (d, J = 3.8 Hz, 1H), 7.36-7.25 (m, 5H), 5.53 (d, J = 7.0 Hz, 1H), 5.25 (s, 2H).

[0359] Example 15: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-((benzyloxy carbonyl)amino)acetic acid

[0360] Referring to Example 14, replace TFAA with benzyloxy carbonyl succinimide to obtain 80 mg of the target product with a yield of 50%.

[0361] 1 HNMR (400MHz, DMSO-d6): δ 8.14 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.38-7.30 (m, 12H), 5.24 (d, J = 17.3 Hz, 3H), 5.07 (s, 2H).

[0362] Example 16: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(dimethylamino)acetic acid

[0363] Step A: 2-bromo-2-(4-bromophenyl)acetic acid methyl ester

[0364] Into a reaction tube was placed 2-(4-bromophenyl)acetic acid methyl ester (9.8 g, 1.0 eq.), 180 mL of chloroform, NBS (11.4 g, 1.5 eq.), and the reaction was stirred at 60 °C for 2 h under nitrogen. The reaction was monitored by TLC and was complete. The reaction was allowed to cool to room temperature and the solvent was removed by concentration. The residue was purified by silica gel column to give 5.4 g of the desired product.

[0365] 1 HNMR (400 MHz, CDC13): δ 7.56-7.49 (m, 2H), 7.45 (d, J = 8.6 Hz, 2H), 5.32 (s, 1H), 3.82 (s, 3H).

[0366] Step B: 2-(4-bromophenyl)-2-(dimethylamino)acetic acid methyl ester

[0367] Into a reaction tube was placed 2-bromo-2-(4-bromophenyl)acetic acid methyl ester (2.7 g, 1.0 eq.), 25 mL of THF, potassium carbonate (1.8 g, 1.5 eq.), and dimethylamine (1.0 g, 1.0 eq.), and the reaction was stirred at room temperature for 1 h. The reaction was extracted with water and ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column to give 2.3 g of the product, which was used in the next reaction.

[0368] 1 HNMR (400 MHz, CDC13): δ 7.53-7.47 (m, 2H), 7.37-7.30 (m, 2H), 3.85 (s, 1H), 3.71 (s, 3H), 2.25 (s, 6H).

[0369] Step C: 2-(dimethylamino)-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid methyl ester

[0370] Into a reaction tube was placed 2-(4-bromophenyl)-2-(dimethylamino)acetic acid methyl ester (100 mg, 1.0 eq.), 1.5 mL of glycol dimethyl ether, 5-formyl-2-furanboronic acid (57 mg, 1.1 eq.), 1.5 mL of aqueous sodium carbonate, Pd(dppf)Cl2(9 mg, 0.03 eq.), Pd(PPh3)4(18 mg, 0.04 eq.), and the reaction was stirred at 60 °C for 2 h under nitrogen. The reaction was monitored by LCMS. The product was detected by LCMS and the reaction was extracted with water and ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column to give 80 mg of the product.

[0371] 1 HNMR (400 MHz, CDC13): δ 9.68 (s, 1H), 7.88-7.80 (m, 2H), 7.60-7.52 (m, 2H), 7.34 (d, J = 3.7 Hz, 1H), 6.87 (d, J = 3.8 Hz, 1H), 3.95 (s, 1H), 3.74 (s, 3H), 2.29 (s, 6H).

[0372] Step D: 2-(dimethylamino)-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid methyl ester

[0373] To the reaction flask was added 2-(dimethylamino)-2-(4-(5-formylfuran-2- yl)phenyl)acetic acid methyl ester (300 mg, 1.0 eq.), 6 mL tetrahydrofuran, 3 mL methanol, 3 mL water, sodium hydroxide (105 mg, 2.5 eq.), 50 °C for 1 h. LCMS monitored the reaction was complete, adjusted to weakly acidic with 2M HC1, concentrated the solvent to get 320 mg of crude. Used directly for the next step.

[0374] Step E: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(dimethylamino)acetic acid

[0375] To the reaction flask was added 2-(dimethylamino)-2-(4-(5-formylfuran-2- yl)phenyl)acetic acid methyl ester (300 mg, 1.0 eq.), 6 mL tetrahydrofuran, 3 mL methanol, 3 mL water, sodium hydroxide (105 mg, 2.5 eq.), 50 °C for 1 h. LCMS monitored the reaction was complete, adjusted to weakly acidic with 2M HC1, concentrated the solvent to get 320 mg of crude. Used directly for the next step.

[0376] 1 HNMR (400 MHz, DMSO-d6): δ 7.88 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 3.8 Hz, 1H), 7.38-7.27 (m, 6H), 5.26 (s, 2H), 4.22 (s, 1H), 2.48 (s, 6H).

[0377] Example 17: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(4-methylpiperazin-l-yl)acetic acid

[0378] Referring to Example 16, replace dimethylamine with 1 -methylpiperazine to obtain 70 mg of the target compound.

[0379] 1 HNMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.75 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 3.8 Hz, 1H), 7.40-7.26 (m, 6H), 5.26 (s, 2H), 4.32 (s, 1H), 3.38 (t, J = 14.4 Hz, 3H), 3.03 (d, J = 15.4 Hz, 4H), 2.87 (d, J = 12.6 Hz, 1H), 2.78 (d, J = 2.7 Hz, 3H).

[0380] Example 18: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(2-hydroxy-2-methylpropanamido)acetic acid

[0381] Referring to Example 8, replace (S)-methyl 2-amino-2-(4-hydroxyphenyl)acetate hydrochloride with (R)-methyl 2-amino-2-(4-hydroxyphenyl)acetate hydrochloride to obtain the target product 203 mg.

[0382] 1 HNMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 8.11 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 4.5 Hz, 1H), 7.38-7.24 (m, 6H), 5.66 (s, 1H), 5.36 (d, J = 7.3 Hz, 1H), 5.25 (s, 2H), 1.28 (s, 3H), 1.24 (s, 3H).

[0383] Example 19: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoic acid

[0384] Step A: (R)-isopropyl 2-amino-3-(4-bromophenyl)propanoate hydrochloride

[0385] Into a reaction vial was placed (R)-2-amino-3-(4-bromophenyl)propionic acid (1.0 g, 4.10 mmol), isopropanol (20.0 mL), and an ice bath was used to stir the reaction. To this was added a solution of thionyl chloride (0.89 mL, 12.29 mmol) dropwise. The reaction was allowed to stir at 80 °C overnight. The reaction was checked by LCMS and found to be substantially complete. The reaction was allowed to cool to room temperature and was concentrated under reduced pressure. This resulted in 1.5 g of the desired compound which was used directly in the next step.

[0386] Step B: (R)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid isopropyl ester

[0387] Into a reaction vial was placed (R)-2-amino-3-(4-bromophenyl)propionic acid isopropyl ester hydrochloride (1.0 g, 4.65 mmol), THF (15.0 mL), water (15.0 mL), and an ice bath was used to stir the reaction. To this was added sodium carbonate (1.72 g, 16.27 mmol) followed by Boc anhydride (1.60 mL, 6.97 mmol). The reaction was allowed to stir at room temperature for 3 h. The reaction was checked by TLC and LCMS and found to be substantially complete. The reaction was quenched with saturated brine (20 mL) and EA (50 mL) was added. The phases were allowed to separate and the aqueous phase was extracted with additional EA (2 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This resulted in 1.5 g of the desired compound which was purified by column chromatography. The overall yield for the two steps was 94.8%.

[0388] 1 HNMR (400 MHz, CDC13): δ 7.43 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 5.11-4.93 (m, 2H), 4.58-4.43 (m, 1H), 3.15-2.95 (m, 2H), 1.44 (s, 9H), 1.23 (dd, J = 9.9, 6.3 Hz, 6H).

[0389] Step C: (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)propionic acid isopropyl ester

[0390] A reaction flask was charged with (R)-3-(4-bromophenyl)-2-((tert- butoxycarbonyl)amino)propionic acid isopropyl ester (1.40 g, 3.62 mmol), 5- formyl-2-furanboronic acid (760.5 mg, 5.44 mmol), Pd(PPh3)4(100.0 mg), Pd(dppf)Cl2(100.0 mg), sodium carbonate (5.76 g, 54.36 mmol), DME (27.0 mL), water (27.0 mL), nitrogen was replaced for 3 times, stirred at 50 °C for 3 hours. LCMS tested the reaction was complete. Reduced to room temperature, water (50 mL), EA (50 mL), stirred for 5 minutes, transfer to separatory funnel and let phase separation, the aqueous phase was extracted with EA 2 times, 50 mL each time, combined organic phase, saturated brine (50 mL) washing, anhydrous sodium sulfate drying, reduced pressure concentration, column chromatography purification (PE:EA = 3:1) to get 820 mg of target product, yield 56.4%.

[0391] 1 HNMR (400 MHz, CDC13): δ 9.66 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 3.7 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 3.7 Hz, 1H), 5.19-4.92 (m, 2H), 4.65-4.47 (m, 1H), 3.27-3.00 (m, 2H), 1.44 (s, 9H), 1.24 (dd, J = 8.5 Hz, 6.3 Hz, 6H).

[0392] Step D: (R)-2-amino-3-(4-(5-formylfuran-2-yl)phenyl)propionic acid isopropyl ester

[0393] A reaction flask was charged with (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)propionic acid isopropyl ester (600.0 mg, 1.50 mmol), HCl / dioxane solution (4.0 M, 7.5 mL), stirred at room temperature for 2 hours. LCMS tested the reaction was complete, reduced pressure concentration, methyl tert-butyl ether washing, vacuum drying to get 450.0 mg of target compound, yield 89.1%.

[0394] Step E: (R)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)propionic acid isopropyl ester

[0395] Into a reaction vial was placed (R)-isopropyl 2-amino-3-(4-(5-formylfuran-2- yl)phenyl)propanoate hydrochloride (200.0 mg, 0.59 mmol), DMF (4.0 mL), and triethylamine (0.33 mL, 2.37 mmol) and stirred in an ice bath for 10 minutes. CbzCl (0.13 mL, 0.89 mmol) was added and the reaction was stirred in an ice bath for 2 hours. The reaction was checked by LCMS and was found to be substantially complete. Water (0.5 mL) was added and the reaction was concentrated under reduced pressure. Purification by column chromatography provided 110.0 mg of the desired compound in 42.7% yield.

[0396] Step F: (R)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-formylfuran-2- yl)phenyl)propanoic acid

[0397] Into a reaction vial was placed (R)-isopropyl 2-amino-3-(4-(5-formylfuran-2- yl)phenyl)propanoate hydrochloride (200.0 mg, 0.59 mmol), DMF (4.0 mL), and triethylamine (0.33 mL, 2.37 mmol) and stirred in an ice bath for 10 minutes. CbzCl (0.13 mL, 0.89 mmol) was added and the reaction was stirred in an ice bath for 2 hours. The reaction was checked by LCMS and was found to be substantially complete. Water (0.5 mL) was added and the reaction was concentrated under reduced pressure. Purification by column chromatography provided 110.0 mg of the desired compound in 42.7% yield.

[0398] 1 HNMR (400 MHz, CDC13): δ 9.66 (s, 1H), 7.75 (d, J = 7.9 Hz, 2H), 7.41-7.31 (m, 6H), 7.26 (d, J = 7.9 Hz, 3H), 6.83 (d, J = 3.7 Hz, 1H), 5.12 (d, J = 4.5 Hz, 2H), 4.78-4.69 (m, 1H), 3.33-3.12 (m, 2H).

[0399] Step G: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoic acid

[0400] A reaction vial was charged with (R)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)propanoic acid (65.0 mg, 0.17 mmol), 3-benzyl-2- thioxothiochromen-4-one (44.3 mg, 0.20 mmol), ammonium acetate (25.5 mg, 0.33 mmol), and acetic acid (2.0 mL) was added. The reaction was stirred at 100 °C for 2 h. The reaction was checked by LCMS and was complete. The reaction was allowed to cool to room temperature and stirred with water (5 mL) for 10 min. The reaction was filtered, rinsed with water (5 mL), rinsed with acetonitrile (5 mL), and rinsed with petroleum ether (5 mL) and dried under vacuum to give 36.0 mg of the desired product in 36.4% yield.

[0401] 1 HNMR (400 MHz, DMSO-d6): δ 12.86 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.48-7.39 (m, 3H), 7.39-7.16 (m, 11H), 5.26 (s, 2H), 4.97 (s, 2H), 4.28-4.17 (m, 1H), 3.19-2.86 (m, 2H).

[0402] Example 20: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(1,1-dioxidothiomorpholino)propanoic acid

[0403] Step A: 1-chloro-2-((2-chloroethyl)sulfonyl)ethane

[0404] A reaction vial was charged with 2,2'-sulfonylbis(ethan-1-ol) (2.5 g, 0.016 mol), sulfurous acid chloride (11.57 g, 0.097 mol), pyridine (2.6 g, 0.032 mol) was dissolved in toluene (50 mL) and the mixture was heated to 110 °C and stirred for 3 h. The reaction was quenched with water (50 ml) and the aqueous phase was extracted with ethyl acetate (30 mL*3) and the combined organic phase was concentrated to give a yellow oil (3 g, yield 98%) which was used directly in the next step.

[0405] 1 HNMR (400 MHz, CDCl3): δ 3.94 (t, J = 6.8 Hz, 4H), 3.55 (t, J = 6.8 Hz, 4H).

[0406] Step B: (S)-methyl 3-(4-bromophenyl)-2-(1,1-dioxidothiomorpholino)propanoate

[0407] To a solution of (S)-methyl 3-(4-bromophenyl)-2-(1,1-dioxidothiomorpholino)propanoate (400 mg, 1.00 mmol) in dioxane / H2O (8 mL / 2 mL) was added DIEA (394 mg, 3.00 mmol), 5-formyl-2-furanboronic acid (187 mg, 1.32 mmol) at room temperature. The reaction was purged with nitrogen for three times, then Pd(PPh3)2Cl2 (71 mg, 0.10 mmol) was added. The reaction was heated to 80 °C and stirred for 2 h. The reaction was cooled to room temperature, water (20 mL) was added. The aqueous phase was extracted with EtOAc (30 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, concentrated to give the crude product (320 mg, yield 81 %) which was used directly in the next step.

[0408] LC-MS: (ES+): m / z 376.0 [M+1]+.

[0409] Step C: (S)-methyl 2-(1,1-dioxidothiomorpholino)-3-(4-(5-formylfuran-2- yl)phenyl)propanoate

[0410] To a solution of (S)-methyl 3-(4-bromophenyl)-2-(1,1-dioxidothiomorpholino)propanoate (400 mg, 1.00 mmol) in dioxane / H2O (8 mL / 2 mL) was added DIEA (394 mg, 3.00 mmol), 5-formyl-2-furanboronic acid (187 mg, 1.32 mmol) at room temperature. The reaction was purged with nitrogen for three times, then Pd(PPh3)2Cl2 (71 mg, 0.10 mmol) was added. The reaction was heated to 80 °C and stirred for 2 h. The reaction was cooled to room temperature, water (20 mL) was added. The aqueous phase was extracted with EtOAc (30 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, concentrated to give the crude product (320 mg, yield 81 %) which was used directly in the next step.

[0411] LC-MS: (ES+): m / z 392.1 [M+1]+.

[0412] Step D: (S)-2-(1,1-dioxidothiomorpholino)-3-(4-(5-formylfuran-2- yl)phenyl)propanoic acid

[0413] To a solution of (S)-methyl 2-(l, l-dioxidothiomorpholino)-3-(4-(5- formylfuran-2-yl)phenyl)propanoate (200 mg, 0.51 mmol) in THF / H20 (5 mL / 5 mL) was added LiOH (130 mg, 2.55 mmol) at room temperature, the reaction was heated to 50 °C and stirred for 1 h. The reaction was poured into 20 mL water, then adjusted to pH 4 with 1 M hydrochloric acid, the aqueous phase was extracted with EA (30 mL*3), the combined organic phase was washed with saturated brine (30 mL), concentrated to give the crude product (200 mg) which was used directly in the next step.

[0414] LC-MS: (ES-): m / z 378.1 [M+l]+.

[0415] Step E: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(l, l-dioxidothiomorpholino)propanoic acid

[0416] To a solution of (S)-methyl 2-(l, l-dioxidothiomorpholino)-3-(4-(5- formylfuran-2-yl)phenyl)propanoate (200 mg, 0.53 mmol) in dioxane / acetic acid (10 mL / 0.3 mL) was added NH4OAc (62 mg, 0.79 mmol), 3-benzyl-2- thioxotetrahydrothiazol-4-one (120 mg, 0.53 mmol) at room temperature, the reaction was heated to 100 °C and stirred for 1 h. After the reaction was completed, water (50 mL) was added and extracted with EA (30 mL*3), the combined organic phase was washed with saturated brine (30 mL), concentrated, the residue was purified by prep-TL to give the target compound (120 mg, yield 38%).

[0417] 1 HNMR (400 MHz, DMSO-d6): d 12.72 (s, 1H), 7.84-7.70 (m, 3H), 7.53-7.25 (m, 9H), 5.26 (s, 2H), 3.69 (t, J = 7.6 Hz, 1H), 3.24-3.14 (m, 2H), 3.11-2.86 (m, 8H).

[0418] Example 21: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(l, l-dioxidothiomorpholino)propanoic acid

[0419] The title compound 40 mg, yield 27% was obtained according to the procedures described in Reference Example 20 by replacing (S)-methyl 2-amino-3-(4-bromophenyl)propanoate with (R)-methyl 2-amino-3-(4-bromophenyl)propanoate.

[0420] 1 HNMR (400 MHz, DMSO-d6): δ 12.63 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 4.0 Hz, 1H), 7.37-7.25 (m, 6H), 5.26 (s, 2H), 3.69 (t, J = 7.6 Hz, 1H), 3.18 (t, J = 8.0 Hz, 2H), 3.08-2.85 (m, 8H).

[0421] Example 22: (Z)-2-amino-6-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

[0422] Step A: 2-amino-6-bromo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile

[0423] Weigh 6-bromo-3,4-dihydronaphthalen-2(1H)-one (300 mg, 1.33 mmol) and AlCl3 (177.70 mg, 1.33 mmol) into DCM (1.0 mL), drop TMSCN (158.67 mg, 1.60 mmol) under nitrogen protection, and react at room temperature for 4 h. Add NH3methanol solution (4 mL) and stir overnight. Monitor by LCMS. Dry to get the crude product, and purify by column to get 110 mg of the target compound, with a yield of 32.9%.

[0424] LC-MS (m / z): [M+H]+= 252.90.

[0425] Step B: 2-amino-6-bromo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

[0426] Weigh 2-amino-6-bromo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile (310 mg, 1.23 mmol) into HCl (8.0 M, 7.7 mL), and reflux for 5 h. Dry the reaction solution directly to get the crude product, and purify by column to get 246 mg of the target compound, with a yield of 71%.

[0427] LC-MS (m / z): [M+H]+= 271.89.

[0428] Step C: 6-bromo-2-((tert-butoxy carbonyl)amino)-l,2,3,4-tetrahydronaphthalene-2- carboxylic acid

[0429] Weigh 2-amino-6-bromo-l,2,3,4-tetrahydronaphthalene-2-carboxylic acid (310 mg, 1.15 mmol) into THF (3.0 mL) and H2O (3.0 mL), add Boc anhydride (0.290 mL, 1.26 mmol) and anhydrous sodium carbonate (182.45 mg, 1.72 mmol), stir for 2 h, monitor the reaction completion by LCMS, spin dry THF and wash the aqueous phase with petroleum ether, adjust the aqueous phase pH = 5.5, add EA to extract, dry over anhydrous sodium sulfate, spin dry the solvents to get 188 mg of the target compound with a yield of 63%.

[0430] LC-MS (m / z): [M]+ = 371.4.

[0431] Step D: 2-((tert-butoxy carbonyl)amino)-6-(5-formylfuran-2-yl)-l,2,3,4- tetrahydronaphthalene-2-carboxylic acid

[0432] Weigh 6-bromo-2-((tert-butoxy carbonyl)amino)-l,2,3,4-tetrahydronaphthalene-2- carboxylic acid (240.0 mg, 0.89 mmol), 5-formyl-2-furanboronic acid (124.30 mg, 0.89 mmol), Pd(dppf)Cl2(130.02 mg, 0.18 mmol) and Na2CO3(282.50 mg, 2.67 mmol) into dioxane: water = 5: 1 (5 mL + 1 mL), protect under nitrogen, react at 80 °C for 2 h, monitor the reaction completion by LCMS. Purification by preparation to get 160 mg of the target compound with a yield of 46.7%.

[0433] Step E: 2-amino-6-(5-formylfuran-2-yl)-l,2,3,4-tetrahydronaphthalene-2-carboxylic acid

[0434] Into a 50 mL single neck flask, add 2-((tert-butoxy carbonyl)amino)-6-(5- formylfuran-2-yl)-l,2,3,4-tetrahydronaphthalene-2-carboxylic acid (160 mg, 0.42 mmol), then add trifluoroacetic acid (0.62 mL, 8.4 mmol), after the addition is complete, stir at room temperature for 1 h, test the reaction completion by LCMS, concentrate under reduced pressure to get 110 mg of the target product with a yield of 95%.

[0435] LC-MS (m / z): [M+H]+ = 286.0.

[0436] Step F: (Z)-2-amino-6-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

[0437] Into a 50 mL single necked flask was placed 2-amino-6-(5-formylfuran-2-yl)- 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (60.0 mg, 0.21 mmol) dissolved in acetic acid (4.0 mL), 3-benzyl-2-thioxotetrahydrothiazol-4-one (46.96 mg, 0.21 mmol) was added, followed by ammonium acetate (32.42 mg, 0.42 mmol). After the addition was complete, the system was purged with nitrogen three times. It was stirred at 120 °C for 2 h. LCMS showed the reaction was complete. It was cooled to room temperature. Water was added first, followed by acetonitrile to slurry the product. This resulted in 16 mg of product. Yield: 4.85 %.

[0438] LC-MS (m / z): [M-H]"= 489.

[0439] 1 HNMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.46-7.23 (m, 8H), 5.26 (s, 2H), 2.98-2.74 (m, 4H), 2.19-2.07 (m, 1H), 1.94-1.83 (m, 1H).

[0440] Example 23: (R,Z)-2-(4-(5-((4-oxo-3-(phenylmethane-d2)-2- thioxotetrahydrothiazol-5-yl)methyl)furan-2-yl)phenyl)-2-pivaloylaminoacetic acid

[0441] Step A: phenylmethane-d2-amine

[0442] Into a reaction flask was placed LiAI D4 (800 mg, 19.0 mmol), THF (20 mL), a solution of benzamide (800.0 mg, 6.60 mmol) in 10 mL THF was added dropwise at 0 °C, the system was warmed to 70 °C for 2 h. The reaction was monitored by LCMS. The system was cooled to 0 °C, 0.8 mL water, 0.8 mL 15% sodium hydroxide aqueous solution, 2.4 mL water were added dropwise, the system was warmed to room temperature and anhydrous sodium sulfate was added, stirred for 30 min, diluted with 50 mL DCM, filtered, the mother liquor was concentrated to give the target compound (700 mg colorless oil).

[0443] LC-MS (m / z) [M+1]+ = 110.3.

[0444] Step B: 3-(phenylmethyl-d2)-2-thioxothiolidine-4-one

[0445] To a reaction flask was added phenylmethane-d2-amine (650.0 mg, 5.96 mmol), diethyl ether (10.0 mL), and a solution of CS2(453 mg, 5.96 mmol) in 2 mL of ether was added dropwise at 0 °C. The solution was stirred at 0 °C for 1 h; a large amount of solid precipitated, which was filtered and dried. The solid was dissolved in 15 mL of ethanol, and bromoacetic acid (414 mg, 2.98 mmol) was added. The solution was heated to 85 °C and stirred for 5 h. The solution was cooled to room temperature and poured into 50 mL of water. The solution was extracted with 30 mL of ethyl acetate three times and concentrated. The residue was purified by column chromatography to give 300 mg of a light yellow solid.

[0446] LC-MS (m / z) [M-1]+ = 224.1.

[0447] Step C: (R,Z)-2-(4-(5-((4-oxo-3-(phenylmethyl-d2)-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0448] To a reaction flask was added 3-(phenylmethyl-d2)-2-thioxothiolidine-4-one (180 mg, 0.799 mmol), AcOH (10 mL), (R)-2-(4-(5-formylfuran-2-yl)phenyl)-2- pivalamidoacetic acid (263 mg, 0.799 mmol; from Example 4), ammonium acetate (93 mg, 1.20 mmol), and the solution was stirred at 100 °C for 1 h. The reaction was monitored by LCMS. The reaction was cooled and poured into 50 mL of water. The solution was filtered and the solid was washed with 30 mL of methanol to give compound A8-50 (123 mg).

[0449] 1 HNMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.72 (s, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.42-7.21 (m, 7H), 5.46 (d, J = 7.4 Hz, 1H), 1.16 (s, 9H).

[0450] Example 24: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-pivaloylalanine

[0451] Referring to Example 1, 6 mg of the target product was synthesized with a yield of 18%.

[0452] LC-MS (m / z) [M-H]- = 475.3.

[0453] Example 25: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(phenylsulfonamido)propanoic acid

[0454] Step A: (R)-3-(4-bromophenyl)-2-(phenylsulfonamido)propanoic acid

[0455] Into a reaction flask was added (R)-2-amino-3-(4-bromophenyl)propanoic acid (1.0 g, 4.015 mmol), water (20 mL), and aqueous sodium hydroxide solution (1.21 mol / L, 10 mL). After the reaction system was clarified, benzene sulfonyl chloride (0.776 mL, 6.022 mmol) was added dropwise. After the addition was completed, the reaction was allowed to proceed at room temperature for 2 hours. A sample was taken, and TLC was used to monitor the completion of the reaction of the starting material. Ethyl acetate was added and washed twice. After the separation of the phases, the aqueous phase was adjusted to pH 2 with 2M hydrochloric acid solution, and extracted with ethyl acetate three times. The combined organic phase was dried and concentrated to dryness to obtain 800 mg of the target compound with a yield of 51.9%.

[0456] 1 HNMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 9.1 Hz, 1H), 7.60-7.50 (m, 3H), 7.42 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 3.87 (m, 1H), 2.93 (dd, J = 13.7, 5.1 Hz, 1H), 2.68 (dd, J = 13.7, 9.6 Hz, 1H).

[0457] Step B: (R)-3-(4-(5-formylfuran-2-yl)phenyl)-2-(phenylsulfonamido)propanoic acid

[0458] To a reaction flask was added (R)-3-(4-bromophenyl)-2-(phenylsulfonamido)propanoic acid (500 mg, 1.301 mmol), 1,4-dioxane (20 mL), water (5 mL), 5-formyl-2-furanboronic acid (182 mg, 1.275 mmol), potassium phosphate (1104 mg, 5.205 mmol), Pd(PPh3)2Cl2(50 mg, 0.070 mmol), the reaction was stirred at room temperature for 10 min, then the reaction was heated to 80 °C and stirred for 4 h. The reaction was cooled to room temperature, diluted with water (20 mL) and 2 M HCl (20 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel: 12 g column; 12 g cartridge; redistilled hexanes; 10% ethyl acetate in hexanes) to afford 120 mg of the title compound in 23.1% yield.

[0459] LC-MS (m / z) [M-1]- = 398.

[0460] Step C: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(phenylsulfonamido)propanoic acid

[0461] To a reaction flask was added (R)-3-(4-(5-formylfuran-2-yl)phenyl)-2- (phenylsulfonamido)propanoic acid (120 mg, 0.300 mmol), 3-benzyl-2- thioxotetrahydrothiazol-4-one (67 mg, 0.30 mmol), ammonium acetate (47 mg, 0.601 mmol), acetic acid (4 mL), the reaction was stirred at room temperature for 10 min, then the reaction was heated to 100 °C and stirred for 2 h. The reaction was cooled to room temperature, diluted with water (20 mL) and 2 M HCl (20 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to afford 45 mg of the title compound in 23.8% yield.

[0462] LC-MS (m / z) [M-1]- = 603.

[0463] 1 HNMR (400 MHz, DMSO-d6): δ 12.85 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.44-7.23 (m, 11H), 5.27 (s, 2H), 3.94 (d, J = 7.3 Hz, 1H), 3.02 (dd, J = 13.8, 5.2 Hz, 1H), 2.78 (dd, J = 13.8, 9.5 Hz, 1H).

[0464] Example 26: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(phenylsulfonamido)propanoic acid

[0465] Referring to Example 25, (R)-2-amino-3-(4-bromophenyl)propanoic acid is replaced by (S)-2-amino-3-(4-bromophenyl)propanoic acid to obtain the target product 75.1 mg.

[0466] 1 HNMR (400 MHz, DMSO-d6): δ 12.84 (s, 1H), 8.33 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.68-7.62 (m, 2H), 7.59-7.55 (m, 2H), 7.49-7.44 (m, 1H), 7.44-7.37 (m, 3H), 7.35 (d, J = 6.4 Hz, 4H), 7.32-7.26 (m, 4H), 5.27 (s, 2H), 3.95 (q, J = 8.8, 7.8 Hz, 1H), 3.02 (dd, J = 13.8, 5.2 Hz, 1H), 2.77 (dd, J = 13.7, 9.5 Hz, 1H).

[0467] Example 27: (S,Z)-2-(4-(4-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidopropanoic acid

[0468] Step A: (S)-2-(4-hydroxyphenyl)-2-pivalamidopropanoic acid methyl ester

[0469] Into a reaction bottle, (S)-2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride (1 g, 4.59 mmol), DCM (20 mL), TEA (1.9 g, 18.38 mmol) were added, replaced with nitrogen for three times, cooled to 0 °C, dropwise added pivaloyl chloride (582 mg, 4.82 mmol), controlled the temperature of dropwise addition not more than 0 °C, after dropwise addition was completed, reacted at 0 °C for half an hour, monitored by LCMS, the raw material was completely reacted. The reaction liquid was concentrated and purified by column chromatography to obtain the target compound 1.0 g, with a yield of 82.0%.

[0470] 1HNMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 7.87 (d, J = 6.9 Hz, 1H), 7.27-7.07 (m, 2H), 6.90-6.57 (m, 2H), 5.26 (d, J = 6.9 Hz, 1H), 3.60 (s, 3H), 1.12 (s, 9H).

[0471] Step B: (S)-2-tert-butylamido-2-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetic acid methyl ester

[0472] Into a reaction flask was added (S)-2-(4-hydroxyphenyl)-2-neopentylamidoacetic acid methyl ester (1 g, 3.77 mmol), DCM (20 mL), TEA (1.14 g, 11.3 mmol), replaced with nitrogen for three times, cooled to -60 °C, added Tf20 (1.59 g, 5.65 mmol) dropwise, controlled the temperature of dropwise addition not more than -50 °C, after the completion of dropwise addition, reacted for half an hour at -60 °C, monitored by LCMS, the raw material reacted completely. The reaction system was diluted with DCM, washed with water and brine respectively, dried over anhydrous sodium sulfate and concentrated to obtain 1.35 grams of the target compound, with a crude yield of 90.1%.

[0473] LC-MS (m / z) [M+1]+= 398.0.

[0474] Step C: (S)-2-(4-(5-formylfuran-2-yl)phenyl)-2-tert-butylamidoacetic acid methyl ester

[0475] Into a reaction flask was added (S)-2-tert-butylamido-2-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetic acid methyl ester (1.35 g, 3.39 mmol), toluene (50 mL), water (5.0 mL), (5-formylfuran-2-yl)boronic acid (952 mg, 6.79 mmol), K3PO4 (2.87 g, 13.58 mmol), SPhos (228 mg, 0.34 mmol), Pd(OAc)2 (77 mg, 0.34 mmol), the reaction system was replaced with nitrogen for three times after the completion of feeding, reacted at 80 °C for 2 h, sampled, monitored by LCMS, the raw material reacted completely. The reaction system was diluted with EA, washed with water and brine respectively, dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to obtain 1.0 grams of the target compound, with a yield of 85.7%.

[0476] 1HNMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.21 (d, J = 7.3 Hz, 1H), 7.93-7.80 (m, 2H), 7.66 (d, J = 3.8 Hz, 1H), 7.57-7.50 (m, 2H), 7.31 (d, J = 3.7 Hz, 1H), 5.53 (d, J = 7.2 Hz, 1H), 3.65 (s, 3H), 1.14 (s, 9H).

[0477] Step D: (S)-2-(4-(5-formylfuran-2-yl)phenyl)-2-tert-butoxycarbonylaminoacetic acid

[0478] To the reaction flask was added (S)-2-(4-(5-formylfuran-2-yl)phenyl)-2-tert- butyloxycarbonylaminoacetic acid methyl ester (550 mg, 1.60 mmol, 1 eq), THF / H20 (11 mL), LiOH-H20 (101 mg, 2.40 mol, 1.5 eq), and the reaction was stirred at room temperature for half an hour, sampled, and LCMS was used to monitor the reaction completion. The reaction was concentrated to remove THF, and the pH was adjusted to 2 with 1 N HCl. The reaction was extracted with EA, and the organic phase was washed with water and brine, respectively. After drying, the reaction was concentrated to give the target compound (470 mg, 89.1% yield).

[0479] LC-MS (m / z) [M+1]+= 330.1.

[0480] Step E: (S,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl))phenyl)-2-tert-butoxycarbonylaminoacetic acid

[0481] To the reaction flask was added (S)-2-(4-(5-formylfuran-2-yl)phenyl)-2-tert- butyloxycarbonylaminoacetic acid methyl ester (550 mg, 1.60 mmol, 1 eq), THF / H20 (11 mL), LiOH-H20 (101 mg, 2.40 mol, 1.5 eq), and the reaction was stirred at room temperature for half an hour, sampled, and LCMS was used to monitor the reaction completion. The reaction was concentrated to remove THF, and the pH was adjusted to 2 with 1 N HCl. The reaction was extracted with EA, and the organic phase was washed with water and brine, respectively. After drying, the reaction was concentrated to give the target compound (470 mg, 89.1% yield).

[0482] LC-MS (m / z) [M+1]+= 535.0.

[0483] 1HNMR (400 MHz, DMSO-d6): δ 7.98 (d, J = 7.5 Hz, 1H), 7.89-7.78 (m, 2H), 7.73 (s, 1H), 7.62-7.56 (m, 2H), 7.40 (d, J = 3.8 Hz, 1H), 7.38-7.25 (m, 6H), 5.44 (d, J = 7.5 Hz, 1H), 5.25 (s, 2H), 1.15 (s, 9H).

[0484] Example 28: (S,Z)-2-acetylamino-3-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)propanoic acid

[0485] Step A: (S)-2-amino-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid hydrochloride

[0486] In a 250 mL single neck flask was added compound 3 ((S)-2-((tert- butoxycarbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid (4.3 g, 11.97 mmol, 1.0 eq; from example 1), dissolved in hydrochloric acid dioxane solution (50.0 mL, 200.0 mmol, 16.72 eq), stirred at room temperature for 1 hour, LCMS checked reaction complete. Concentrated under reduced pressure to get 3.5 g of crude target compound.

[0487] LC-MS (m / z) [M+H]+ = 260.

[0488] Step B: (S)-2-acetylamino-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid

[0489] Under nitrogen protection, in a reaction flask was added (S)-2-amino-3-(4-(5- formylfuran-2-yl)phenyl)propanoic acid hydrochloride (500.0 mg, 1.69 mmol), DMF (10.0 mL), then triethylamine (0.71 mL, 5.07 mmol) was added, stirred in ice bath for 10 minutes; acetyl chloride (0.14 mL, 2.03 mmol) was added dropwise, after dropwise addition, the reaction was carried out at room temperature for 2 hours. LCMS checked the reaction was substantially complete, the reaction was stopped, water (0.5 mL) was added, stirred for 10 minutes, concentrated under reduced pressure, preparative purification to get 120 mg of target compound, yield 23.6%.

[0490] 1HNMR (400 MHz, CDC13): δ 9.64 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 3.7 Hz, 1H), 7.27 (s, 1H), 6.84 (d, J = 3.7 Hz, 1H), 6.10 (d, J = 7.4 Hz, 1H), 4.96-4.87 (m, 1H), 3.34-3.15 (m, 2H), 2.04 (s, 3H).

[0491] Step C: (S,Z)-2-acetylamino-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)propanoic acid

[0492] Into a reaction vial was placed (S)-2-acetylamido-3-(4-(5-formylfuran-2- yl)phenyl)propanoic acid (120.0 mg, 0.40 mmol), 3-benzyl-2-thioxothiazolidin-4-one (106.7 mg, 0.48 mmol), ammonium acetate (61.4 mg, 0.80 mmol), acetic acid (5.0 mL), stirred at 100 °C for 2 hours. LCMS showed the reaction was complete. The reaction was quenched, cooled to room temperature, water (10 mL) was added, stirred for 10 minutes, filtered, washed with water (10 mL), washed with acetonitrile (5 mL), washed with petroleum ether (5 mL), dried in vacuum to give 105.0 mg of the target product in 52.0% yield.

[0493] 1 HNMR (400 MHz, CDC13): δ 9.64 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 3.7 Hz, 1H), 7.27 (s, 1H), 6.84 (d, J = 3.7 Hz, 1H), 6.10 (d, J = 7.4 Hz, 1H), 4.96-4.87 (m, 1H), 3.34-3.15 (m, 2H), 2.04 (s, 3H).

[0494] Example 29: (R,Z)-2-(4-(5-((3-(4-fluorobenzyl)-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl-2-pivalamidoacetic acid

[0495] Step A: 3-(4-Fluorobenzyl)-2-thioxothiazolidin-4-one

[0496] To a reaction flask was added (4-fluorophenyl)methanamine (5.0 g, 0.040 mmol), ether (40 mL), and a solution of CS2(3.04 g, 0.040 mmol) in 10 mL of ether was added dropwise at 0 °C. The temperature was maintained for 1 h with stirring, a large amount of solid precipitated, which was filtered, dried, dissolved in 50 mL of ethanol, and bromoacetic acid (2.78 g, 0.020 mmol) was added. The temperature was raised to 85 °C and the reaction was allowed to proceed for 16 h. The reaction was cooled to room temperature and poured into 50 mL of water. The reaction was extracted with 30 mL of ethyl acetate three times and concentrated. The residue was purified by column chromatography to give 3.9 g of the desired product as a light yellow solid in 40% yield.

[0497] 1 HNMR (400 MHz, DMSO-d6): δ 7.44 (dd, J = 8.6, 5.4 Hz, 2H), 6.98 (t, J = 8.7 Hz, 2H), 5.13 (s, 2H), 3.96 (s, 2H).

[0498] Step B: (R,Z)-2-(4-(5-((3-(4-fluorobenzyl)-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0499] To a reaction flask was added 3-(4-fluorobenzyl)-2-thioxotetrahydrothiazol-4-one (100 mg, 0.41 mmol), AcOH (2 mL), (R)-2-(4-(5-formylfuran-2-yl)phenyl)-2- pivalamidoacetic acid (135 mg, 0.41 mmol; from Example 4), and NH4OAc (48 mg, 0.62 mmol). The reaction was heated to 110 °C for 1 h under N2. After the reaction was completed, the reaction was cooled to room temperature, 10 mL of water was added, and the reaction was filtered, washed with 10 mL of methanol, and dried to give the desired product as a red solid (83 mg).

[0500] 1 HNMR (400 MHz, DMSO-d6): δ 12.96 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.45-7.29 (m, 4H), 7.17 (t, J = 8.9 Hz, 2H), 5.44 (d, J = 7.4 Hz, 1H), 5.23 (s, 2H), 1.15 (s, 9H).

[0501] Example 30: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(2,2,2-trifluoroacetamido)propanoic acid

[0502] The target product 151.34 mg, yield 38.4% was obtained by referring to Example 28, replacing acetyl chloride with trifluoroacetic anhydride.

[0503] LC-MS (m / z): [M+H]+= 561.

[0504] 1 HNMR (400MHz, DMSO-d6): δ 9.82 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 3.7 Hz, 1H), 7.38-7.23 (m, 6H), 5.26 (s, 2H), 4.63-4.53 (m, 1H), 3.28-3.26 (m, 1H), 3.09-3.02 (m, 1H).

[0505] Example 31: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(2,2,2-trifluoroacetamido)propanoic acid

[0506] The target product 105 mg was obtained by referring to Example 28.

[0507] 1 HNMR (400MHz, DMSO-d6): δ 9.82 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 3.7 Hz, 1H), 7.38-7.23 (m, 6H), 5.26 (s, 2H), 4.63-4.53 (m, 1H), 3.28-3.26 (m, 1H), 3.09-3.02 (m, 1H).

[0508] Example 32: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-isobutyramidopropanoic acid

[0509] Referring to example 28, acetyl chloride was replaced by 2-methylpropanoic anhydride to give the target product 86.89 mg, yield: 26.76%.

[0510] LC-MS (m / z): [M+H]+= 535.

[0511] 1 HNMR (400MHz, DMSO-d6): δ 12.71 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.49-7.23 (m, 9H), 5.26 (s, 2H), 4.51-4.41 (m, 1H), 3.14 (dd, J = 13.7, 4.8 Hz, 1H), 2.99-2.88 (m, 1H), 2.44-2.31 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H).

[0512] Example 33: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-isobutyrylamidopropanoic acid

[0513] Referring to example 32, the target product 98 mg, yield 71.9% was obtained.

[0514] 1 HNMR (400MHz, DMSO-d6): δ 7.96 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.46-7.38 (m, 3H), 7.38-7.25 (m, 6H), 5.26 (s, 2H), 4.46-4.38 (m, 1H), 3.16-2.89 (m, 2H), 2.41-2.32 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).

[0515] Example 34: (R,Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)propionic acid isopropyl ester hydrochloride

[0516] Step A: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5-yl)methyl)furan- 2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid isopropyl ester

[0517] A reaction vial was charged with (R)-isopropyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)propanoate (200.0 mg, 0.50 mmol; from Example 19), 3-benzyl-2- thioxothiohydantoin, ammonium acetate (76.8 mg, 1.0 mmol), and dioxane (6.0 mL), acetic acid (0.3 mL), and stirred at 100 °C for 2 h. The reaction was checked by LCMS. The reaction was complete. The reaction was quenched, reduced to room temperature, and concentrated under reduced pressure. The product was purified by preparative HPLC to give 150.0 mg of the target compound in 49.6% yield.

[0518] 1 HNMR (400 MHz, DMSO-d6): δ 7.79 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 3.8 Hz, 1H), 7.39-7.26 (m, 7H), 5.26 (s, 2H), 4.93-4.84 (m, 1H), 4.20-4.10 (m, 1H), 3.07-2.89 (m, 2H), 1.34 (s, 9H), 1.19 (d, J = 6.3 Hz, 3H), 1.11 (d, J = 6.2 Hz, 3H).

[0519] Step B: (R,Z)-isopropyl 2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)propanoate hydrochloride

[0520] A reaction vial was charged with (R,Z)-isopropyl 3-(4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (130.0 mg, 0.21 mmol), 4 M HC1-dioxane solution (5.0 mL), and stirred at room temperature for 2 h. The reaction was checked by TLC. The reaction was complete. The reaction was quenched, concentrated under reduced pressure, washed with EA, and dried under vacuum to give 105.0 mg of the target product in 90.2% yield.

[0521] 1HNMR (400 MHz, DMSO-d6): δ 8.56 (s, 3H), 7.85 (d, J = 8.1 Hz, 2H), 7.75 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 3.8 Hz, 1H), 7.40-7.27 (m, 6H), 5.26 (s, 2H), 4.98-4.87 (m, 1H), 4.30 (t, J = 7.1 Hz, 1H), 3.27-3.07 (m, 2H), 1.18 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H).

[0522] Example 35: (R,Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)propanoic acid ethyl ester hydrochloride

[0523] The target product was obtained by replacing (R)-isopropyl 2-amino-3-(4- bromophenyl)propanoate hydrochloride with (R)-ethyl 2-amino-3-(4-bromophenyl)propanoate hydrochloride in reference to Example 34. Yield: 258 mg, 72.4%.

[0524] 1 HNMR (400 MHz, DMSO-d6): δ 8.54 (s, 3H), 7.85 (d, J = 8.2 Hz, 2H), 7.75 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 3.8 Hz, 1H), 7.39-7.27 (m, 6H), 5.26 (s, 2H), 4.36 (t, J = 6.8 Hz, 1H), 4.15 (m, J = 7.1, 4.9 Hz, 2H), 3.21 (d, J = 6.2 Hz, 1H), 3.14 (dd, J = 14.1, 7.4 Hz, 1H), 1.13 (t, J = 7.1 Hz, 3H).

[0525] Example 36: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan- 2-yl)phenyl)-2-(methylsulfonamido)propanoic acid

[0526] Step A: (R)-3-(4-(5-formylfuran-2-yl)phenyl)-2-(methylsulfonamido)propanoic acid

[0527] To the reaction flask was added (R)-2-amino-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid (50 mg, 1.0 eq.), DMF (1.0 mL), aqueous potassium hydroxide (44 mg, 4.0 eq.) was added under ice bath, MsCl (26 mg, 1.2 eq.) was added under ice bath, the reaction was monitored by LCMS for 2 h, water (5 mL) was added to quench the reaction, the mixture was extracted by ethyl acetate (5 mL*3), the organic phase was combined, washed by saturated brine twice, dried by anhydrous sodium sulfate, the organic phase was concentrated, the target compound was obtained by column purification (20 mg).

[0528] 1 HNMR (400 MHz, DMSO-d6): δ 12.22 (s, 1H), 9.60 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 9.1 Hz, 1H), 7.66 (d, J = 3.7 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 3.7 Hz, 1H), 4.11 (td, J = 9.1, 5.2 Hz, 1H), 3.11 (dd, J = 13.7, 5.2 Hz, 1H), 2.89-2.82 (m, 1H), 2.63 (s, 3H).

[0529] Step B: (R,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(methylsulfonamido)propanoic acid

[0530] To the reaction flask was added (R)-3-(4-(5-formylfuran-2-yl)phenyl)-2- (methylsulfonamido)propanoic acid (20 mg, 1.0 eq.), 1,4-dioxane (0.7 mL), 3-benzyl-2-thioxotetrahydrothiazol-4-one (13 mg, 0.98 eq.), ammonium acetate (5 mg, 1.0 eq.), acetic acid (0.07 mL), the reaction was monitored by LCMS for 2 h at 100 °C. The solvent was concentrated, the crude product was purified to obtain 15 mg of the target product.

[0531] 1HNMR (400 MHz, DMSO-d6): δ 12.96 (s, 1H), 9.81 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 3.9 Hz, 1H), 7.39-7.25 (m, 6H), 5.26 (s, 2H), 4.57 (q, J = 7.4, 4.0 Hz, 1H), 3.27 (d, J = 4.6 Hz, 1H), 3.10-3.02 (m, 1H), 2.61 (s, 3H).

[0532] Example 37: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(methylsulfonamido)propanoic acid

[0533] Referring to example 36, (R)-2-amino-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid was replaced by (S)-2-amino-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid to afford the target compound 60.15 mg, yield: 46.74%.

[0534] 1 HNMR (400 MHz, DMSO-d6): δ 12.96 (s, 1H), 9.81 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 3.9 Hz, 1H), 7.39-7.25 (m, 6H), 5.26 (s, 2H), 4.57 (q, J = 7.4, 4.0 Hz, 1H), 3.27 (d, J = 4.6 Hz, 1H), 3.10-3.02 (m, 1H), 2.61 (s, 3H).

[0535] Example 38: (S,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(methylsulfonamido)acetic acid

[0536] Referring to example 36, (R)-2-amino-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid was replaced by (S)-2-amino-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid to afford the target compound 60.15 mg, yield: 46.74%.

[0537] 1H NMR (400 MHz, DMSO-d6): δ 8.16 (d, J = 8.5 Hz, 1 H), 7.92-7.84 (m, 2 H), 7.74 (s, 1 H), 7.68-7.59 (m, 2 H), 7.41 (d, J = 3.8 Hz, 1 H), 7.39-7.24 (m, 6 H), 5.26 (s, 2 H), 5.11 (d, J = 8.3 Hz, 1 H), 2.85 (s, 3 H).

[0538] Example 39: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(methylsulfonamido)acetic acid

[0539] The title compound was prepared according to the procedures described in Reference Example 36 by replacing (R)-2-amino-3-(4-(5-formylfuran-2-yl)phenyl)propionic acid with (R)-2-amino-4-(5-formylfuran-2-yl)phenyl)acetic acid. The target compound was obtained as 85 mg.

[0540] 1 H NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 8.2 Hz, 2 H), 7.75 (s, 1 H), 7.63 (d, J = 8.2 Hz, 2 H), 7.42 (d, J = 3.8 Hz, 1 H), 7.38 (d, J = 3.7 Hz, 1 H), 7.37-7.26 (m, 5 H), 5.26 (s, 2 H), 5.10 (d, J = 8.4 Hz, 1 H), 2.85 (s, 3 H).

[0541] Example 40: (S,Z)-2-(4-(5-((3-(4-fluorobenzyl)-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0542] The target product was obtained according to the procedures described in Reference Example 27. The yield was 123.0 mg, 47%.

[0543] 1 H NMR (400 MHz, DMSO-d6): δ 7.95 (d, J = 7.5 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 2 H), 7.72 (s, 1 H), 7.53 (d, J = 8.3 Hz, 2 H), 7.40-7.26 (m, 4 H), 7.18 (t, J = 8.9 Hz, 2 H), 5.48 (d, J = 7.4 Hz, 1 H), 5.22 (s, 2 H), 1.16 (s, 9 H).

[0544] Example 41: (R,Z)-2-acetylamino-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)acetic acid

[0545] Referring to Example 39, replace MsCl with acetic anhydride to obtain the target product 70.0 mg, yield 68%.

[0546] 1 HNMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 8.69 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.74 (s, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 3.8 Hz, 1H), 7.39-7.26 (m, 6H), 5.40 (d, J = 7.5 Hz, 1H), 5.27 (s, 2H), 1.92 (d, J = 3.8 Hz, 3H).

[0547] Example 42: (S,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(2,2,2-trifluoroacetylamino)acetic acid

[0548] Referring to Example 38, replace MsCl with trifluoroacetic anhydride to obtain the target product 81 mg, yield 37.5%.

[0549] 1 HNMR (400 MHz, DMSO-d6): δ 13.44 (s, 1H), 10.25 (d, J = 7.3 Hz, 1H), 7.94-7.85 (m, 2H), 7.74 (s, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 3.7 Hz, 1H), 7.40-7.26 (m, 6H), 5.54 (d, J = 6.8 Hz, 1H), 5.26 (s, 2H).

[0550] Example 43: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(2,2,2-trifluoroacetylamino)acetic acid

[0551] Referring to Example 39, replace MsCl with trifluoroacetic anhydride, and obtain 101 mg of the target product by preparative purification, yield 43.5%.

[0552] 1HNMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.3 Hz, 2H), 7.70 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.38-7.33 (m, 2H), 7.33-7.25 (m, 5H), 5.28 (s, 1H), 5.24 (s, 2H).

[0553] Example 44: (S,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-isobutyrylaminoacetic acid

[0554] Referring to Example 38, replace MsCl with isobutyric anhydride to obtain the target product 140 mg.

[0555] 1 HNMR (400 MHz, DMSO-d6): δ 8.47 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 3.7 Hz, 1H), 7.39-7.24 (m, 5H), 5.34 (d, J = 7.6 Hz, 1H), 5.26 (s, 2H), 3.57 (s, 1H), 2.63-2.55 (m, 1H), 1.02 (dd, J = 18.4, 6.8 Hz, 6H).

[0556] Example 45: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-isobutyrylaminoacetic acid

[0557] Referring to Example 39, replace MsCl with isobutyric anhydride to obtain the target product 48.0 mg, yield 41% by preparative purification.

[0558] 1 HNMR (400 MHz, DMSO-d6): δ 12.95 (s, 1H), 8.58 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.74 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 3.8 Hz, 1H), 7.39-7.25 (m, 6H), 5.42 (d, J = 7.6 Hz, 1H), 5.26 (s, 2H), 2.64-2.56 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H).

[0559] Example 46: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(piperazin-l-yl)propanoic acid

[0560] Step A: 4-(3-(4-bromophenyl)-l-methoxy-l-oxopropan-2-yl)piperazine-l- carboxylic acid tert-butyl ester

[0561] To a reaction flask was added 3-(4-bromophenyl)-l-methoxy-l-oxopropan-2-yl- trifluoromethanesulfonate (800 mg, 2.045 mmol), anhydrous dichloromethane (20 mL), piperazine- 1-carboxylic acid tert-butyl ester (1.17 g, 6.136 mmol) dissolved in dichloromethane and added dropwise to the reaction. The reaction was sampled after three hours and TLC indicated the reaction was complete. The reaction was concentrated to dryness and purified by pre-TLC to give 600 mg of the desired compound in 68.6% yield.

[0562] LC-MS (m / z) [M+l]+= 428.

[0563] 1 HNMR (400 MHz, CDC13): δ 7.40 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 3.63 (s, 3H), 3.43 (m, 5H), 3.07-2.86 (m, 2H), 2.67 (m, 2H), 2.52 (m, 2H), 1.47 (s, 9H).

[0564] Step B: 4-(3-(4-(5-formylfuran-2-yl)phenyl)-l-methoxy-l-oxopropan-2-yl)piperazine- 1-carboxylic acid tert-butyl ester

[0565] To a reaction flask was added tert-butyl 4-(3-(4-bromophenyl)-1-methoxy-1- oxopropan-2-yl)piperazine-1-carboxylate (800 mg, 1.685 mmol), 5-formyl-2- furancarboxylic acid (360.78 mg, 2.527 mmol), dioxane (40 mL), potassium acetate (668.08 mg, 6.74 mmol), water (10 mL), Pd(PPh3)2Cl2(20 mg, 0.028 mmol), the reaction system was replaced with nitrogen for three times, the temperature was raised to 100 °C for four hours, TLC was used to monitor the reaction (PE:EA = 5:1), the reaction was complete. The temperature was returned to room temperature, water was added to wash twice, ethyl acetate was added to extract three times, all the organic phases were combined, dried and concentrated to dryness, pre-TLC was used to purify to obtain 600 mg of the target compound, with a yield of 80.5%.

[0566] LC-MS (m / z) [M+1]+ = 443.

[0567] 1 HNMR (400 MHz, CDCl3): δ 9.66 (s, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 3.7 Hz, 1H), 7.30 (s, 2H), 6.83 (d, J = 3.7 Hz, 1H), 3.64 (s, 3H), 3.54-3.34 (m, 5H), 3.12 (m, 1H), 3.00 (m, 1H), 2.70 (m, 2H), 2.55 (m, 2H), 1.47 (s, 9H).

[0568] Step C: 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(4-(5-formylfuran-2- yl)phenyl)propanoic acid

[0569] To a reaction flask was added tert-butyl 4-(3-(4-bromophenyl)-1-methoxy-1- oxopropan-2-yl)piperazine-1-carboxylate (800 mg, 1.685 mmol), 5-formyl-2- furancarboxylic acid (360.78 mg, 2.527 mmol), dioxane (40 mL), potassium acetate (668.08 mg, 6.74 mmol), water (10 mL), Pd(PPh3)2Cl2(20 mg, 0.028 mmol), the reaction system was replaced with nitrogen for three times, the temperature was raised to 100 °C for four hours, TLC was used to monitor the reaction (PE:EA = 5:1), the reaction was complete. The temperature was returned to room temperature, water was added to wash twice, ethyl acetate was added to extract three times, all the organic phases were combined, dried and concentrated to dryness, pre-TLC was used to purify to obtain 600 mg of the target compound, with a yield of 80.5%.

[0570] LC-MS (m / z) [M-1]- = 427.

[0571] 1HNMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 3.7 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 3.8 Hz, 1H), 3.29-3.23 (m, 5H), 3.03-2.87 (m, 2H), 2.66 (m, 2H), 2.46 (m, 2H), 1.39 (s, 9H).

[0572] Step D: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(4-(tert-butoxycarbonyl)piperazin-1- yl)propanoic acid

[0573] To the reaction flask was added (Z)-3-(4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-yl)methyl)furan-2-yl)phenyl)-2-(4-(tert- butoxycarbonyl)piperazin-1-yl)propanoic acid (100 mg, 0.142 mmol), hydrochloric acid dioxane solution (5 mL, 20.0 mmol), and the reaction was allowed to stir at room temperature for 2 hours. The reaction mixture first became clear and then gradually precipitated an orange solid. The reaction mixture was concentrated to dryness to give 30 mg of the compound, in 36.4% yield.

[0574] LC-MS (m / z) [M-1]"= 632.

[0575] Step E: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(piperazin-1-yl)propanoic acid

[0576] To the reaction flask was added (Z)-3-(4-(5-((3-benzyl-4-oxo-2- thioxothiazolidin-5-yl)methyl)furan-2-yl)phenyl)-2-(4-(tert- butoxycarbonyl)piperazin-1-yl)propanoic acid (100 mg, 0.142 mmol), hydrochloric acid dioxane solution (5 mL, 20.0 mmol), and the reaction was allowed to stir at room temperature for 2 hours. The reaction mixture first became clear and then gradually precipitated an orange solid. The reaction mixture was concentrated to dryness to give 30 mg of the compound, in 36.4% yield.

[0577] LC-MS (m / z) [M+1]+ = 534.

[0578] 1 H NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 8.93 (s, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 3.8 Hz, 1H), 7.39-7.26 (m, 6H), 5.26 (s, 2H), 3.70-3.61 (m, 1H), 3.14-2.94 (m, 8H), 2.93-2.80 (m, 2H).

[0579] Example 47: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(4-methylpiperazin-1-yl)propanoic acid

[0580] Referring to Example 46, replace piperazine-1-carboxylic acid tert-butyl ester with 1- methylpiperazine to obtain the target product 150 mg, yield 67.0%.

[0581] LC-MS (m / z) [M+1]+ = 548.

[0582] 1 H NMR (400 MHz, DMSO-d6): δ 7.87-7.67 (m, 3H), 7.58-7.21 (m, 9H), 5.26 (s, 2H), 3.74 (t, J = 7.7 Hz, 1H), 3.34 (d, J = 65.2 Hz, 3H), 3.17-2.83 (m, 6H), 2.79 (s, 4H).

[0583] Example 48: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(dimethylamino)propanoic acid

[0584] Referring to Example 46, replace piperazine-1-carboxylic acid tert-butyl ester with N,N- dimethylamine to obtain the target product 121 mg, yield: 28.42%.

[0585] LCMS: [M+H]+= 493

[0586] 1HNMR (400 MHz, DMSO-d6): δ 7.85 (d, J = 8.3 Hz, 2H), 7.75 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.45-7.25 (m, 7H), 5.26 (s, 2H), 4.42 (dd, J = 9.8, 4.8 Hz, 1H), 3.45 (dd, J = 14.0, 4.8 Hz, 1H), 3.25-3.09 (m, 1H), 2.92 (s, 6H).

[0587] Example 49: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-morpholinopropanoic acid

[0588] Referring to Example 46, replace piperazine-1-carboxylic acid tert-butyl ester with morpholine ring to obtain the target product 41.89 mg of target product, yield: 23.89%.

[0589] LC-MS: [M+H]+=535.

[0590] 1 HNMR (400 MHz, DMSO-d6 + CF3COOD): δ 7.86 (d, J = 8.1 Hz, 2H), 7.76 (s, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 3.7 Hz, 1H), 7.40-7.25 (m, 6H), 5.26 (s, 2H), 4.47-4.26 (m, 1H), 3.88 (s, 4H), 3.63-3.24 (m, 5H), 3.16-2.98 (m, 1H).

[0591] Example 50: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(1,1-dioxo-4-thiomorpholinyl)propanoic acid

[0592] Step A: 3-(4-bromophenyl)-2-((methylsulfonyl)oxy)methyl)benzoic acid methyl ester

[0593] Into a 100 mL single necked flask was placed 3-(4-bromophenyl)-2-(((trifluoromethyl)sulfonyl)oxy)propanoic acid methyl ester (1.48 g, 3.78 mmol) dissolved in anhydrous dichloromethane (15.0 mL) and then added thiomorpholine (0.98 g, 9.46 mmol). After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC and was complete. The reaction mixture was concentrated under reduced pressure and the dichloromethane was removed by rotary evaporation. The residue was purified by column chromatography to give the target compound 0.70 g, yield 53.74%.

[0594] LC-MS (m / z) [M+H]+= 344.34.

[0595] Step B: 3-(4-bromophenyl)-2-(l,l-dioxido-4-thiomorpholinyl)propanoic acid methyl ester

[0596] In 100 mL single neck flask was taken 3-(4-bromophenyl)-2-thiomorpholinepropanoic acid methyl ester (779 mg, 2.26 mmol) dissolved in methanol (8.0 mL) and THF (8.0 mL) and sodium tungstate dihydrate (149.27 mg, 0.45 mmol, 0.2 eq) was added dropwise 30% hydrogen peroxide in water (5.1 mL, 45.26 mmol) was added dropwise, after completion of addition, stirred for 2 min at room temperature (TLC showed reaction complete, should be processed promptly, reaction time too long, will cause most of the product converted to impurities), TLC (PE:EA = 2: 1) showed new spot generation, TLC and LCMS tested reaction complete, LCMS detected target molecular weight. Washed with aqueous solution, extracted with EA (100 mL) twice, the organic phase was washed with aqueous sodium sulfite solution, dried over sodium sulfate, concentrated under reduced pressure, purified by column chromatography to obtain 500 mg of the target compound, yield 58.73%.

[0597] LC-MS [M+H]+= 378 / 376.

[0598] Step C: 2-(l,l-dioxido-4-thiomorpholinyl)-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid methyl ester

[0599] In 50 mL Schlenk tube was taken 3-(4-bromophenyl)-2-(l,l-dioxido-4- thiomorpholinyl)propanoic acid methyl ester (500 mg, 1.329 mmol) dissolved in dioxane (10 mL) and water (2.5 mL) and 5-formyl-2-furanboronic acid (223.09 mg, 1.60 mmol) was added, DIPEA (858.78 mg, 6.64 mmol), Pd(PPh3)2Cl2(139.91 mg, 0.20 mmol) was added, after completion of addition, nitrogen was purged three times, stirred at 80 °C for 2 h, LCMS tested reaction complete. Cooled to room temperature, washed with aqueous solution, extracted with EA (100 mL) three times, dried over sodium sulfate, concentrated under reduced pressure, purified by column chromatography to obtain 400 mg of the target compound, yield 76.9%.

[0600] LC-MS (m / z) [M+H]+= 392.

[0601] Step D: 2-(l,l-dioxo-4-thiomorpholinyl)-3-(4-(5-formylfuran-2-yl)phenyl)propanoic acid

[0602] In a 100 mL single-necked flask, 2-(l,l-dioxo-4-thiomorpholinyl)-3-(4-(5- formylfuran-2-yl)phenyl)propanoic acid methyl ester (230 mg, 0.59 mmol) was dissolved in THF (6.0 mL) and ethanol (3.0 mL), lithium hydroxide monohydrate (98.62 mg, 2.35 mmol) was dissolved in water (3.0 mL), and the aqueous lithium hydroxide solution was added dropwise to the reaction solution under ice-bath cooling. After the addition was completed, the ice bath was removed, and the solution was stirred at room temperature for 20 min. The reaction was confirmed to be complete by LCMS. The solution was warmed to room temperature, washed with an aqueous solution, adjusted to pH 5 with a 2 mol / L hydrochloric acid solution, extracted with EA (100 mL) three times, dried over sodium sulfate, and concentrated under reduced pressure. The resulting product was purified by column chromatography to obtain 180 mg of the target compound at a yield of 81.17%.

[0603] LC-MS (m / z) [M-H]"= 376.

[0604] Step E: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(l,l-dioxo-4-thiomorpholinyl)propanoic acid

[0605] In a 100 mL single-necked flask, 2-(l,l-dioxo-4-thiomorpholinyl)-3-(4-(5- formylfuran-2-yl)phenyl)propanoic acid (180 mg, 0.48 mmol) was dissolved in 1,4- dioxane (8.0 mL) and acetic acid (0.4 mL), and 3-benzyl-2-thioxotetrahydrothiazol-4- one (106.50 mg, 0.48 mmol) was added. Ammonium acetate (73.52 mg, 0.95 mmol) was further added, and the solution was stirred under nitrogen for 3 times. The solution was stirred at 100°C for 2 hours, and the reaction was confirmed to be complete by LCMS. The solution was cooled to room temperature and concentrated under reduced pressure. The resulting product was prepared to obtain 53.19 mg of the target compound at a yield of 19.14%.

[0606] LC-MS (m / z) [M-H]"= 581.

[0607] 1HNMR (400 MHz, DMSO-d6): δ 12.74 (s, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.74 (s, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 3.7 Hz, 1H), 7.39-7.26 (m, 6H), 5.26 (s, 2H), 3.75-3.67 (m, 1H), 3.24-3.14 (m, 2H), 3.10-2.88 (m, 8H).

[0608] Example 51: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)pyrrolidine-2-carboxylic acid

[0609] Step A: 2-benzyl-l-(tert-butyl)pyrrolidine-l,2-dicarboxylate

[0610] In a 250 mL three-necked flask, tert-butyloxycarbonyl-proline (5.0 g, 23.229 mmol) was dissolved in acetonitrile (50.0 mL), then benzyl bromide (7.95 g, 46.46 mmol), potassium carbonate (6.42 g, 46.46 mmol), potassium iodide (0.39 g, 2.32 mmol) were added, and the reaction was stirred at room temperature for 3 hours. The reaction was detected by LCMS to be complete, washed with water solution, extracted with EA (200 mL) three times, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 6.38 g of the target compound, with a yield of 89.9%.

[0611] 1 HNMR (400 MHz, CDC13): δ 7.47-7.29 (m, 5H), 5.37-5.04 (m, 2H), 4.34 (dd, J = 8.6 Hz, 3.6 Hz, 1H), 3.66-3.35 (m, 2H), 2.35-2.11 (m, 1H), 2.07-1.75 (m, 3H), 1.42 (d, J = 46.2 Hz, 9H).

[0612] Step B: 2-benzyl-l-(tert-butyl)2-(4-bromobenzyl)pyrrolidine-l,2-dicarboxylate

[0613] In a 250 mL three-necked flask, 2-benzyl-l-(tert-butyl)pyrrolidine-l,2-dicarboxylate (5.88 g, 19.26 mmol) was dissolved in THF (60.0 mL) and stirred to dissolve. After three times of nitrogen replacement, the solution was cooled to -78 °C, and LiHMDS (1.0 M, 28.88 mL) was added dropwise. After the addition was completed, the mixture was stirred at -78 °C for 1 h. Then, p-bromobenzyl bromide (7.22 g, 28.88 mmol) was added dropwise (pre-dissolved in THF). After the reaction was completed at -78 °C for 1 h, the mixture was warmed to room temperature and stirred for 2 h. After the reaction was completed, the mixture was washed with water, extracted with EA (200 mL) three times, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7.0 g of the target compound, with a yield of 76.6%.

[0614] 1 HNMR (400 MHz, CDC13): δ 7.48-7.31 (m, 7H), 7.13-6.97 (m, 2H), 5.37-5.04 (m, 2H), 3.8-3.36 (m, 2H), 3.14-2.84 (m, 2H), 2.15-1.97 (m, 2H), 1.73-1.58 (m, 2H), 1.48 (d, J = 13.6 Hz, 9H).

[0615] Step C: 2-benzyl-l-(tert-butyl)2-(4-(5-formylfuran-2-yl)benzyl)pyrrolidine-l,2-dicarboxylate

[0616] In a 50 mL Schlenk tube, 2-benzyl-l-(tert-butyl)2-(4-bromobenzyl)pyrrolidine-l,2-dicarboxylate (2.0 g, 4.22 mmol) was dissolved in dioxane (16.0 mL) and water (4.0 mL). Then, 5-formyl-2-furanboronic acid (0.71 g, 5.06 mmol), DIPEA (2.72 g, 21.08 mmol), and Pd(PPh3)2Cl2(0.44 g, 0.63 mmol) were added. After three times of nitrogen replacement, the mixture was stirred at 80 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, washed with water, extracted with EA (200 mL) three times, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 1.2 g of the target compound, with a yield of 58.14%.

[0617] 1HNMR (400 MHz, CDC13): δ 9.66 (d, J = 3.8 Hz, 1H), 7.77 (dd, J = 8.3, 2.3 Hz, 2H), 7.46-7.31 (m, 6H), 7.30-7.21 (m, 2H), 6.84 (dd, J = 3.8, 1.5 Hz, 1H), 5.41-5.03 (m, 2H), 3.78 (dd, J = 94.9, 13.8 Hz, 1H), 3.59-3.35 (m, 1H), 3.15 (dd, J = 13.8, 2.6 Hz, 1H), 3.09-2.86 (m, 1H), 2.08 (q, J = 7.5 Hz, 2H), 1.77-1.57 (m, 2H), 1.50 (d, J = 14.4 Hz, 9H).

[0618] Step D: 1-(tert-Butoxycarbonyl)-2-(4-(5-formylfuran-2-yl)benzyl)pyrrolidine-2- carboxylic acid

[0619] In 100 mL single neck flask, 2-benzyl-1-(tert-butyl) 2-(4-(5-formylfuran-2-yl)benzyl) pyrrolidine-1,2-dicarboxylate (1.2 g, 2.45 mmol) was dissolved in ethanol (38.0 mL), lithium hydroxide monohydrate (0.41 g, 9.81 mmol) was dissolved in water (9.5 mL), under ice bath, the aqueous solution of lithium hydroxide was added dropwise into the reaction solution, after the addition was completed, it was stirred at 50 °C overnight. After cooling to room temperature, it was washed with aqueous solution, the pH was adjusted to 5 with 2 mol / L hydrochloric acid solution, extracted with EA (200 mL) for three times, dried with sodium sulfate, concentrated under reduced pressure, and purified by reversed phase column to obtain 480 mg of the target compound with a yield of 49.03%.

[0620] LCMS: [M-H]"=398.

[0621] Step E: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5-ylidene)methyl)furan-2- yl)benzyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid

[0622] In a 100 mL single neck flask, 1-(tert-butoxycarbonyl)-2-(4-(5-formylfuran-2- yl)benzyl)pyrrolidine-2-carboxylic acid (250 mg, 0.63 mmol) was dissolved in 1,4- dioxane (8.0 mL) and acetic acid (0.4 mL), then 3-benzyl-2-thioxothiazetidin-4-one (139.7 mg, 0.63 mmol) was added, then ammonium acetate (96.49 mg, 1.25 mmol) was added, after the addition was completed, it was replaced with nitrogen three times, stirred at 100 °C for 2 hours, LCMS test showed that the reaction was completed. Concentration under reduced pressure obtained 150 mg of the target compound, yield 39.6%.

[0623] 1 HNMR (400 MHz, DMSO-d6): δ 7.92-7.76 (m, 2H), 7.73 (d, J = 1.1 Hz, 1H), 7.49-7.24 (m, 9H), 5.26 (s, 2H), 3.63 (d, J = 13.5 Hz, 1H), 3.10-2.97 (m, 1H), 2.88-2.73 (m, 1H), 2.20-1.89 (m, 3H), 1.63-1.36 (m, 10H), 0.99-0.82 (m, 1H).

[0624] Step F: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)pyrrolidine-2-carboxylic acid

[0625] (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-yl)methyl)furan-2- yl)benzyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) was dissolved in hydrochloric acid / dioxane solution (0.85 mL, 3.4 mmol) and stirred at room temperature for 1 hour, LCMS test showed that the reaction was completed. Concentration under reduced pressure, twice with dichloromethane, obtained 49 mg of the target product, yield 58.7%.

[0626] LCMS: [M+H]+=505.

[0627] 1HNMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 9.18 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 3.8 Hz, 1H), 7.39-7.26 (m, 5H), 5.26 (s, 2H), 2.68 (s, 1H), 2.47-2.38 (m, 2H), 2.33 (s, 1H), 2.07 (dd, J = 15.7, 9.8 Hz, 2H), 1.96-1.73 (m, 2H).

[0628] Example 52: (S,Z)-2-(2-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-tert-butylamidoacetic acid

[0629] Step A: (S)-2-(2-bromophenyl)-2-(((S)-1-(4-methoxyphenyl)ethyl)amino)acetonitrile

[0630] Into a reaction flask was placed (S)-1-(4-methoxyphenyl)ethan-1-amine (2.45 g, 0.016 mol), TMSCN (1.69 g, 0.017 mol), TBAF (1 M / L, 17 mL), 2-bromobenzaldehyde (3.0 g, 0.016 mol), methanol (30 mL), after addition was complete, the reaction was allowed to stir at 25 °C for 16 h. 100 mL of water was added, a white solid precipitated, which was filtered and the filter cake was dried. The crude product (2.8 g) was used directly in the next step.

[0631] Step B: (S)-2-amino-2-(2-bromophenyl)acetic acid

[0632] Into a reaction flask was placed (S)-2-(2-bromophenyl)-2-(((S)-1-(4-methoxyphenyl)ethyl)amino)acetonitrile (2.8 g crude, 8.40 mmol), 6 M HC1 (40 mL), the reaction was allowed to stir at 95 °C for 16 h, a sample was taken and the reaction was monitored by LCMS. 40 mL of methyl tert-butyl ether was added, the layers were separated, the aqueous layer was extracted with another 40 mL of methyl tert-butyl ether, the aqueous layer was concentrated to give 2.2 g of crude product, which was used directly in the next step.

[0633] Step C: (S)-2-amino-2-(2-bromophenyl)acetic acid methyl ester

[0634] Into a reaction flask was placed (S)-2-amino-2-(2-bromophenyl)acetic acid (2.2 g crude, 9.13 mmol), methanol (20 mL), and SOCl2(6.5 g, 54.8 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction system was reacted at 70 °C for 6 h. The reaction was monitored by LCMS, and the system was concentrated to give 2.2 g of a crude product, which was used directly in the next step.

[0635] LC-MS (m / z) [M+1]+= 244.1.

[0636] Step D: (S)-2-(2-bromophenyl)-2-tetrahydropyranoylaminoacetic acid methyl ester

[0637] Into a reaction flask was placed (S)-2-amino-2-(2-bromophenyl)acetic acid methyl ester (2.2 g, 9.13 mmol), TEA (2.8 g, 27.4 mol), dichloromethane (30 mL), and tetrahydropyranoyl chloride (1.6 g, 13.7 mol) was added dropwise at 0 °C. After the addition was complete, the reaction system was reacted at 25 °C for 1 h. The reaction was monitored by LCMS, and 40 mL of water was added. The aqueous phase was extracted with 30 mL of dichloromethane, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated. The product was purified by column chromatography to give 1.7 g of the target compound.

[0638] LC-MS (m / z) [M+1]+= 328.1.

[0639] Step E: (S)-2-(2-(5-formylfuran-2-yl)phenyl)-2-tetrahydropyranoylaminoacetic acid methyl ester

[0640] Into a reaction flask was placed (S)-2-(2-bromophenyl)-2-tetrahydropyranoylaminoacetic acid methyl ester (1.0 g, 3.05 mmol), dioxane (20 mL), water (4 mL), (5-formylfuran-2-yl)boronic acid (854 mg, 6.10 mmol), K3PO4(1.94 g, 9.15 mmol), SPhos (208 mg, 0.31 mmol), Pd(OAc)2(70.1 mg, 0.31 mmol), and the reaction system was purged with nitrogen three times. After the addition was complete, the reaction system was reacted at 80 °C for 2 h. The reaction was monitored by LCMS, and the system was diluted with EA, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The product was purified by column chromatography to give 900 mg of the target compound.

[0641] LC-MS (m / z) [M+1]+= 344.3.

[0642] Step F: (S)-2-(2-(5-formylfuran-2-yl)phenyl)-2-tetrahydropyranoylaminoacetic acid methyl ester

[0643] To the reaction flask was added (S)-methyl 2-(2-(5-formylfuran-2-yl)phenyl)-2- tiglyamidoacetate (900 mg, 2.63 mmol), THF / H2O (6 mL / 6 mL), LiOH H2O (170 mg, 3.94 mol), and the reaction was allowed to stir at room temperature for half an hour. A sample was taken and the reaction was monitored by LCMS to be complete. The reaction was concentrated to remove the THF and the reaction was acidified to pH = 2 with 1 N HC1. The reaction was extracted with EA and the organic phase was washed with water and brine, dried, and concentrated to give the target compound (600 mg).

[0644] LC-MS (m / z) [M+1]+= 330.2.

[0645] Step G: (S,Z)-2-(2-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-tiglyamidoacetic acid

[0646] To the reaction flask was added (S)-methyl 2-(2-(5-formylfuran-2-yl)phenyl)-2- tiglyamidoacetate (300 mg, 0.91 mmol), AcOH (10 mL), 3-benzyl-2- thioxotetrahydrothiazol-4-one (204 mg, 0.91 mmol), ammonium acetate (106 mg, 1.36 mmol), and the reaction was allowed to stir at 100 °C for 1 hour. A sample was taken and the reaction was monitored by LCMS to be complete. The reaction was cooled and partitioned between ethyl acetate and water. The aqueous phase was extracted twice more with ethyl acetate, the organic phases were combined, dried over sodium sulfate, concentrated, and slurried in methanol. The solid was collected by filtration and dried to give the target compound (142 mg).

[0647] LC-MS (m / z) [M+1]+= 535.0.

[0648] 1 HNMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 8.09 (d, J = 7.1 Hz, 1H), 7.85-7.71 (m, 2H), 7.63-7.46 (m, 3H), 7.42 (d, J = 3.6 Hz, 1H), 7.39-7.26 (m, 5H), 7.04 (s, 1H), 5.84 (d, J = 7.0 Hz, 1H), 5.26 (s, 2H), 1.11 (s, 9H).

[0649] Example 53: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0650] To the reaction flask was added (R)-2-(4-(5-formylfuran-2-yl)phenyl)-2- pivalamidoacetic acid (240 mg, 0.73 mol; from Example 4), AcOH (25 mL), 3-benzyl-2- thioxotetrahydrothiazol-4-one (163 mg, 0.73 mol), ammonium acetate (85 mg, 1.15 mmol), the reaction was purged with nitrogen three times after the addition was complete, and the reaction was heated at 120 °C for 2 hours. The reaction was monitored by LCMS sampling, and the reaction was complete. The reaction was cooled and diluted with a mixture of ethyl acetate and water. The mixture was stirred and filtered, and the filter cake was washed with EA and water, then slurried with methanol, filtered, and dried to give the target product (300 mg, 77% yield).

[0651] LC-MS (m / z) [M+1] + = 535.0.

[0652] 1 HNMR (400 MHz, DMSO-d6): δ 7.98 (d, J = 7.5 Hz, 1H), 7.91-7.79 (m, 2H), 7.73 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 3.8 Hz, 1H), 7.38-7.25 (m, 6H), 5.45 (d, J = 7.4 Hz, 1H), 5.25 (s, 2H), 1.15 (s, 9H).

[0653] Example 54: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)pyrrolidine-2-carboxylic acid

[0654] Step A: (3R,7aS)-3-(trichloromethyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazole-1-one

[0655] To a solution of L-proline (5.0 g, 0.043 mol) in chloroform (50 mL) was added chloral hydrate (12.8 g, 0.087 mol) at room temperature. The reaction was heated to 60 °C for 24 hours and the water was collected using a Dean-Stark trap. The solvent was removed under reduced pressure and the residue was slurried with ethanol, filtered, and dried to give the target compound (2.1 g, 20% yield).

[0656] 1HNMR (400 MHz, DMSO-d6): δ 5.84 (s, 1H), 4.10 (dd, J = 9.2, 4.4 Hz, 1H), 3.37-3.26 (m, 1H), 3.19-3.13 (m, 1H), 2.16-2.10 (m, 1H), 2.02-1.87 (m, 1H), 1.85-1.70 (m, 1H), 1.68-1.49 (m, 1H).

[0657] Step B: (3R,7aR)-7a-(4-bromobenzyl)-3-(trichloromethyl)tetrahydro-lH,3H- pyrrolo[l,2-c]oxazole-l-one

[0658] To a solution of diisopropylamine (1.62 mL, 11.2 mmol) in THF (10 mL) was added dropwise n-BuLi (4.43 mL, 11.1 mmol; 2.5 M in cyclohexane) at -78 °C under nitrogen protection. After the addition was completed, the system was warmed to -20 °C and stirred for 1 h. The system was cooled to -78 °C again, and (3R,7aS)-3-(trichloromethyl)tetrahydro-lH,3H-pyrrolo[l,2-c]oxazole-l-one (1.8 g, 7.41 mmol) in THF (10 mL) was added. Then 1-bromo-4-(bromomethyl)benzene (2.4 g, 9.6 mmol) was added dropwise and the reaction was stirred for 1 h. The reaction was quenched with ice water (100 mL) and extracted with MBTE (50 mL*2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the target compound (1.7 g, 58% yield).

[0659] LC-MS: (ES+): m / z 412.0 [M+l]+.

[0660] Step C: (R)-2-(4-bromobenzyl)pyrrolidine-2-carboxylic acid methyl ester

[0661] To a solution of (3R,7aR)-7a-(4-bromobenzyl)-3-(trichloromethyl)tetrahydro-lH,3H- pyrrolo[l,2-c]oxazole-l-one in MeOH (15 mL) was added SOCl2(3.0 g, 25.3 mmol) under ice bath. The system was heated to 70 °C and stirred for 16 h. The solvent was removed under reduced pressure to give the crude product (1.4 g), which was used directly in the next step.

[0662] LC-MS: (ES+): m / z 300.0 [M+l]+.

[0663] Step D: l-(tert-butyl)-2-methyl (R)-2-(4-bromobenzyl)pyrrolidine-l,2-dicarboxylate

[0664] To a solution of methyl (R)-2-(4-bromobenzyl)pyrrolidine-2-carboxylate (1.4 g, crude, 4.71 mmol) in DCM (20 mL) was added Et3N (1.44 g, 14.1 mmol) dropwise under nitrogen atmosphere and ice bath. The reaction was stirred for 10 min under ice bath, then Boc anhydride (1.54 g, 7.07 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The stirring was stopped and water (50 mL) was added. The organic phase was extracted with DCM (3 x 30 mL), combined and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give the target compound (1.0 g, 53% yield).

[0665] LC-MS: (ES+): m / z 300.1 [M+1-100]+.

[0666] Step E: 1-(tert-butyl)-2-methyl (R)-2-(4-(5-formylfuran-2-yl)benzyl)pyrrolidine-1,2- dicarboxylate

[0667] To a solution of 1-(tert-butyl) 2-methyl (R)-2-(4-bromobenzyl)pyrrolidine-1,2-dicarboxylate (1.0 g, 2.51 mmol) in dioxane / H2O (10 mL / 2 mL) was added DIEA (0.97 g, 7.53 mmol), 5-formyl-2-furanboronic acid (458 mg, 3.27 mmol) at room temperature. The reaction was purged with nitrogen for 3 times, Pd(PPh3)2Cl2 (88 mg, 0.13 mmol) was added; the final reaction was stirred at 80 °C for 2 h. The reaction was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give the target compound (800 mg, 77% yield).

[0668] Step F: (R)-1-(tert-butoxycarbonyl)-2-(4-(5-formylfuran-2-yl)benzyl)pyrrolidine-2- carboxylic acid

[0669] To a solution of 1-(tert-butyl) 2-methyl (R)-2-(4-(5-formylfuran-2-yl)benzyl)pyrrolidine-1,2- dicarboxylate (400 mg, 0.97 mmol) in MeOH / THF / H2O (2 mL / 2 mL / 1 mL) was added LiOH (406 mg, 9.68 mmol) and the reaction was stirred at 60 °C for 4 h. The reaction was poured into 20 mL water and adjusted to pH 4 with 1M hydrochloric acid. The aqueous phase was extracted with EA (30 mL*3) and the organic phase was washed with saturated brine. The concentrated gave the crude product (270 mg) which was used directly in the next step.

[0670] LC-MS: (ES-): m / z 398.1 [M-1]-

[0671] Step G: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)benzyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid

[0672] To a solution of (R)-1-(tert-butoxycarbonyl)-2-(4-(5-formylfuran-2- yl)benzyl)pyrrolidine-2-carboxylic acid (270 mg, 0.676 mmol) in dioxane / acetic acid (10 mL / 2 mL) was added NH4OAc (78 mg, 1.02 mmol), 3-benzyl-2- thioxotetrahydrothiazol-4-one (151 mg, 0.676 mmol) at room temperature. The reaction was heated to 100 °C and stirred for 1 h. The reaction was complete, water (50 mL) was added and the organic phase was extracted with EA (30 mL*3) and washed with saturated brine (30 mL). The solvent was removed by reduced pressure concentration, and the residue was purified by Pre-TLC to give the target product (160 mg, 39% yield).

[0673] 1 HNMR (400 MHz, DMSO-d6): d 7.81 (dd, J = 8.0, 4.4 Hz, 2H), 7.73 (s, 1H), 7.40 (d, J = 3.6 Hz, 1H), 7.39-7.14 (m, 8H), 5.26 (s, 2H), 3.63 (d, J = 13.6 Hz, 1H), 3.47 (d, J = 13.6 Hz, 1H), 3.32-3.22 (m, 1H), 3.07-2.96 (m, 1H), 2.83 (d, J = 5.6 Hz, 1H), 2.15-1.98 (m, 2H), 1.61-1.52 (m, 1H), 1.46 (d, J = 13.6 Hz, 9H).

[0674] Step H: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)benzyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid

[0675] To a solution of (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)benzyl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (160 mg, 0.265 mmol) in dioxane (1 mL) was added 4 M hydrochloric acid in dioxane (4 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure. DCM (10 mL) was added and the precipitate was collected by filtration. The filter cake was rinsed with DCM and PE to give the target product (87 mg, 65% yield).

[0676] LC-MS: (ES+): m / z 505.1 [M+1]+.

[0677] 1 HNMR (400 MHz, DMSO-d6): δ 14.34 (s, 1H), 10.19 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.39-7.25 (m, 6H), 5.26 (s, 2H), 3.71-3.43 (m, 3H), 3.19 (s, 1H), 2.47-2.37 (m, 1H), 2.11 (dd, J = 18.0, 6.4 Hz, 2H), 1.96-1.76 (m, 1H).

[0678] Example 55: (S,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)benzyl)pyrrolidine-2-carboxylic acid

[0679] The target product was obtained by replacing L-proline with D-proline according to the procedure described in Example 54 (36.6 mg, 79% yield).

[0680] LC-MS: (ES+): m / z 505.1 [M+1]+.

[0681] 1HNMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.37 (d, J = 3.6 Hz, 1H), 7.33-7.29 (m, 5H), 5.26 (s, 2H), 3.75-3.41 (m, 3H), 3.20 (s, 1H), 2.48-2.36 (m, 1H), 2.10 (dd, J = 18.0, 6.4 Hz, 2H), 1.85 (s, 1H).

[0682] Example 56: (R,Z)-2-(4-(5-((4-oxo-3-((phenyl-4-d) methyl-d2)-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalaminoacetic acid

[0683] Step A: Benzoic acid-4-d

[0684] Benzoic aldehyde-4-d (2.7 g, 25.2 mmol; from Example 4) was dissolved in THF / H20 (27 mL / 14 mL), and an aqueous solution of sulfamic acid (2.9 g, 30.2 mmol, 14 mL) was added dropwise while maintaining the temperature at 0-5 °C, and then stirred at 0-5 °C for 30 min. An aqueous solution of NaCl02(2.7 g, 30.2 mmol) was added dropwise while maintaining the temperature at 0-5 °C, and then stirred at 0-5 °C for 2 h. TLC monitoring showed that the reaction was complete, water (10 mL) was added, 1 N HC1 was added to adjust the pH to 2-3, and EA (40 mL x 3) was added for extraction, anhydrous sodium sulfate was added for drying, and the concentrate was used directly in the next step.

[0685] Step B: Benzoic amide-4-d

[0686] Benzoic acid-4-d (2 g, 16.2 mmol), NH4CI (4.4 g, 81.2 mmol), HATU (9.2 g, 24.3 mmol), and DIPEA (6.3 g, 49.6 mmol) were dissolved in DMF (40 mL), and then reacted at 25 °C for 10 h. TLC monitoring showed that the reaction was complete, water was added to quench (100 mL), EA (100 mL x 2) was added for extraction, and saturated brine was added once (100 mL) for washing, anhydrous sodium sulfate was added for drying, and the concentrate was purified by column chromatography to obtain the target compound (1.2 g, yield 61%).

[0687] 1H NMR (400 MHz, Methanol-d4): δ 7.87 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H).

[0688] Step C: (phenyl-4-d)methane-d2-amine

[0689] LiAlD4(416 mg, 12.28 mmol) was dissolved in THF (20 mL), and a THF (5 mL) solution of benzamide-4-d (500 mg, 4.09 mmol) was added dropwise at 0-5 °C, and then the reaction was allowed to proceed at 70 °C for 2 h. The reaction was monitored by LCMS. After the reaction was completed, the reaction was diluted with THF (10 mL) at 0 °C, and water (0.5 mL), 1 M aqueous NaOH (0.5 mL), and water (1.5 mL) were added slowly. The mixture was stirred at room temperature for 0.5 h, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give the crude product (300 mg), which was used directly in the next step.

[0690] Step D: 3-((phenyl-4-d)methyl-d2)-2-thioxothiazolidin-4-one

[0691] (phenyl-4-d)methane-d2-amine (300 mg, 2.7 mmol), (biscarbomethyl)trithiocarbonate (1.2 g, 5.4 mmol), and TEA (545 mg, 5.4 mmol) were dissolved in DME (10 mL), and the reaction was allowed to proceed at 90 °C for 20 min. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated to dryness, and the residue was purified by column chromatography to give the target compound (210 mg, 34% yield).

[0692] 1 H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 3.96 (s, 2H).

[0693] Step E: (R,Z)-2-(4-(5-((4-oxo-3-((phenyl-4-d)methyl-d2)-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)-2-pivalamide

[0694] To a reaction flask was added 3-((phenyl-4-d) methyl-d2)-2- thioxotetrahydrothiazol-4-one (210 mg, 0.93 mmol), (R)-2-(4-(5- formylfuran-2-yl)phenyl)-2-pivalamidoacetic acid (306 mg, 0.93 mmol; from Example 4), ammonium acetate (109 mg, 1.40 mmol), AcOH (6 mL), the reaction was purged with nitrogen three times after the addition was completed, 120 °C for 2 h. The reaction was monitored by LCMS, after the reaction was cooled, it was added to water / methanol (20 mL / 4 mL), stirred, suction filtered; the filter cake was slurried with methanol (10 mL), the solid was dried to give the target compound (182.2 mg, 39% yield).

[0695] 1 HNMR (400 MHz, CDC13): δ 12.96 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.87-7.85 (m, 2H), 7.73 (s, 1H), 7.61-7.59 (m, 2H), 7.41-7.40 (m, 1H), 7.35-7.34 (m, 5H), 7.46-7.44 (m, 1H), 1.16 (s, 9H).

[0696] Example 57: (R,Z)-2-(4-(5-((3-((4-fluorophenyl)methyl-d2)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2- pivalamidoacetic acid

[0697] Step A: (4-fluorophenyl)methane-d2-amine

[0698] LiAlD4(188 mg, 4.31 mmol) was added to THF (3 mL) under N2protection, a solution of 4-fluorobenzamide (200 mg, 1.43 mmol) in 3 mL THF was added dropwise at 0 °C. After the dropwise addition was completed, the reaction was warmed to 70 °C for 2 h. LCMS showed the reaction was complete, the reaction was cooled to 0 °C, 0.2 mL water, 0.2 mL 15% NaOH solution, 0.6 mL water were added in sequence. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed by rotary evaporation to give the target compound (120 mg) which was used directly in the next step.

[0699] Step B: 3-((4-fluorophenyl)methyl-d2)-2-thioxotetrahydrothiazol-4-one

[0700] Into a microwave tube was placed (4-fluorophenyl)methane-d2-amine (80 mg, 0.63 mmol), bis(carboxymethyl)trithiocarbonate (142 mg, 0.63 mmol), TEA (127 mg, 1.26 mmol), DME (2.0 mL) under nitrogen. The reaction was heated at 90 °C for 10 min in the microwave. TLC showed the reaction was complete. The solvent was evaporated and the product was scraped off the plate (60 mg).

[0701] 1 HNMR (400 MHz, CDC13): δ 7.56-7.36 (m, 2H), 6.99 (t, J = 8.6 Hz, 2H), 3.98 (s, 2H).

[0702] Step C: (R,Z)-2-(4-(5-((3-((4-fluorophenyl)methyl-d2)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-tert- butylaminoacetic acid

[0703] Into a reaction vial was placed 3-((4-fluorophenyl)methyl-d2)-2- thioxotetrahydrothiazol-4-one (100 mg, 0.41 mmol), AcOH (2 mL), (R)-2-(4-(5- formylfuran-2-yl)phenyl)-2-tert-butylaminoacetic acid (135 mg, 0.41 mmol; from Example 4), NH4OAc (48 mg, 0.62 mmol) under N2protection. The reaction was heated to 110 °C for 1 h. TLC showed the reaction was complete. The reaction was cooled to room temperature, 10 mL water was added to the reaction, filtered, slurried with 10 mL methanol, and oven dried to give the red solid target product (83 mg).

[0704] 1 HNMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.37 (dd, J = 20.5, 5.4 Hz, 4H), 7.17 (t, J = 8.8 Hz, 2H), 5.41 (d, J = 6.9 Hz, 1H), 1.15 (s, 9H).

[0705] Example 58: (S,Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2- methylpropanoic acid

[0706] Step A: (2S,4R)-3-Benzoyl-4-methyl-2-phenyloxazol-5-one

[0707] To a reaction flask was added compound (R)-alanine (8.4 g, 0.094 mol), NaOH (3.78 g, 0.095 mol) H20 (94 mL), EtOH (30 mL). After the addition was complete, the temperature was raised to 100 °C for 1 h. The temperature was lowered to room temperature and the crude product was concentrated. The crude product was dissolved in 100 mL of n-pentane, benzaldehyde (15 g, 0.140 mol) was added and the system was heated to 60 °C for 8 h with a water trap. The temperature was lowered to room temperature and the crude product was concentrated. The crude product was dissolved in 100 mL of dichloromethane and a solution of benzoyl chloride (13.3 g, 0.094 mol) in dichloromethane was added dropwise at 0 °C. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 16 h. The reaction was sampled and LCMS was used to monitor the completion of the reaction. The reaction was washed sequentially with water, 5% NaHC03 aqueous solution, 5% NaHS03 aqueous solution, and water. The organic phase was concentrated and purified by column chromatography to give 1.2 g of the target compound in 4.6% yield.

[0708] LC-MS: (ES+): m / z 282.1 [M+l]+.

[0709] Step B: (2S,4R)-3-Benzoyl-4-(4-bromobenzyl)-4-methyl-2-phenyloxazol-5-one

[0710] (2S,4R)-3-Benzoyl-4-methyl-2-phenyloxazol-5-one (1.2 g, 4.27 mmol) was dissolved in THF (12 mL) under nitrogen protection. LiHMDS (6.4 mL, 6.4 mmol) was added dropwise at -78 °C. The dropwise addition was continued for 2 h. A solution of l-bromo-4-(bromomethyl)benzene (1.38 g, 5.55 mmol) in THF (5 mL) was added dropwise. The temperature was raised to room temperature and the reaction was allowed to proceed for 1 h. The reaction was sampled and LCMS was used to monitor the completion of the reaction. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to give 1.0 g of the target compound in 52% yield.

[0711] Step C: (R)-2-Amino-3-(4-bromophenyl)-2-methylpropionic acid methyl ester

[0712] To a reaction flask was added (2S,4R)-3-benzoyl-4-(4-bromobenzyl)-4-methyl-2- phenyloxazol-5-one (1.0 g, 2.23 mmol), concentrated hydrochloric acid (18 mL), and the reaction mixture was heated to 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature and a solid precipitated. The solid was filtered and the filtrate was concentrated. The residue was dissolved in methanol (12 mL) and sulfurous anhydride (796 mg, 6.69 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h and concentrated. The residue was triturated with petroleum ether to give 500 mg of the title compound in 82% yield.

[0713] LC-MS: (ES+): m / z 272.1 [M+1]+.

[0714] Step D: (R)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid methyl ester

[0715] To a reaction flask was added (R)-2-amino-3-(4-bromophenyl)-2-methylpropionic acid methyl ester (500 mg, 1.84 mmol), Et3N (563 mg, 5.52 mmol), Boc anhydride (601 mg, 2.76 mmol), and DCM (20 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were concentrated to give 645 mg of the title compound which was used directly in the next step.

[0716] Step E: (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)-2- methylpropionic acid methyl ester

[0717] To a reaction flask was added (R)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)-2- methylpropionic acid methyl ester (645 mg, 1.74 mmol), DIEA (674 mg, 5.22 mmol), 5- formyl-2-furanboronic acid (316 mg, 2.25 mmol), and Pd(PPh3)Cl2 (122 mg, 0.17 mmol) in dioxane / H2O (10 mL / 2 mL). The reaction mixture was purged with nitrogen three times and heated to 80 °C for 3 h. The reaction mixture was allowed to cool to room temperature and the solvent was concentrated. The residue was purified by column chromatography to give 380 mg of the title compound in 59% yield.

[0718] Step F: (R)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-formylfuran-2-yl)phenyl)-2- methylpropionic acid

[0719] To a reaction flask was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)-2-methylpropanoate (400 mg, 1.03 mmol), LiOH (183 mg, 4.13 mmol), THF / H2O (6 mL / 2 mL), after addition was complete, the reaction was stirred at 25 °C for 2 h. LCMS monitoring showed the starting material was consumed. The reaction was concentrated to remove the solvent, the aqueous phase was adjusted to pH 4 with 1M aqueous HC1, extracted with ethyl acetate for 3 times, combined the organic phase, concentrated to give 400 mg of the target compound which was used directly in the next step.

[0720] Step G: (S,Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid

[0721] To a reaction flask was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)-2-methylpropanoate (400 mg, 1.03 mmol), LiOH (183 mg, 4.13 mmol), THF / H2O (6 mL / 2 mL), after addition was complete, the reaction was stirred at 25 °C for 2 h. LCMS monitoring showed the starting material was consumed. The reaction was concentrated to remove the solvent, the aqueous phase was adjusted to pH 4 with 1M aqueous HC1, extracted with ethyl acetate for 3 times, combined the organic phase, concentrated to give 400 mg of the target compound which was used directly in the next step.

[0722] LC-MS: (ES+): m / z 579.1 [M+l]+.

[0723] Step H: (S,Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-methylpropanoic acid

[0724] To a reaction flask was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5- formylfuran-2-yl)phenyl)-2-methylpropanoate (400 mg, 1.03 mmol), LiOH (183 mg, 4.13 mmol), THF / H2O (6 mL / 2 mL), after addition was complete, the reaction was stirred at 25 °C for 2 h. LCMS monitoring showed the starting material was consumed. The reaction was concentrated to remove the solvent, the aqueous phase was adjusted to pH 4 with 1M aqueous HC1, extracted with ethyl acetate for 3 times, combined the organic phase, concentrated to give 400 mg of the target compound which was used directly in the next step.

[0725] LC-MS: (ES+): m / z 479.0 [M+1]+.

[0726] 1 HNMR (400 MHz, DMSO-d6): δ 14.12 (s, 1H), 8.45 (s, 3H), 7.85 (d, J = 8.1 Hz, 2H), 7.75 (s, 1H), 7.48 - 7.28 (m, 9H), 5.26 (s, 2H), 3.23 - 3.15 (m, 2H), 1.52 (s, 3H).

[0727] Example 59: (R,Z)-2-amino-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-methylpropanoic acid

[0728] The title compound can be prepared according to the procedures described in Example 58.

[0729] LC-MS: (ES+): m / z 479.0 [M+1]+.

[0730] Example 60: (S,Z)-2-(4-(5-((3-((4-fluorophenyl)methyl-d2)-4-oxo-2-thioxotetrahydrothiazol- 5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0731] The title compound can be synthesized according to the procedures described in Example 57. 82 mg was obtained.

[0732] 1 HNMR (400 MHz, DMSO-d6): δ 7.93 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.31 (dd, J = 20.5, 5.4 Hz, 4H), 7.17 (t, J = 8.8 Hz, 2H), 5.38 (d, J = 6.9 Hz, 1H), 1.12 (s, 9H).

[0733] Example 61: (S,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5-ylidene)methyl)furan- 2-yl)phenyl)-2-(2-fluoro-2-methylpropanamido)acetic acid

[0734] The title compound can be synthesized according to the procedures described in Example 27. 56 mg was obtained.

[0735] LC-MS: (ES-): m / z 539.06 [M+1]+.

[0736] Example 62: (R,Z)-2-(4-(5-((4-oxo-3-((phenyl-d5)methyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0737] Step A: 2-((phenyl-d5)methyl)isoindoline-1,3-dione

[0738] Into a reaction bottle, was placed 1-(bromomethyl)phenyl-2,3,4,5,6-d5 (0.95 g, 5.397 mmol), potassium phthalimide (1.1 g, 5.937 mol), acetonitrile (10 mL), after the addition was complete, the reaction system was protected by nitrogen, and was reacted at 60 °C for 8 hours. Sampling, TLC monitoring reaction completion. The reaction system was filtered, and the filtrate was concentrated to obtain white solid compound 1.1 g.

[0739] 1 HNMR (400 MHz, DMSO-d6): δ 7.88 (d, J = 10.5 Hz, 4H), 4.78 (s, 2H).

[0740] Step B: (phenyl-d5)methanamine

[0741] Into a reaction bottle, was placed 2-((phenyl-d5)methyl)isoindoline-1,3-dione (1.1 g, 4.54 mmol), hydrazine hydrate (1.13 g, 22.73 mmol), dioxane (20 mL), after the addition was complete, the reaction system was replaced with nitrogen for three times, and was reacted at 100 °C for 2 hours. Sampling, LCMS monitoring reaction completion. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated. Water (20 mL) was added, and the mixture was extracted with DCM (20 mL). The organic phase was concentrated to obtain yellow oil (400 mg) which was directly used in the next reaction.

[0742] LC-MS (m / z) [M+1]+= 113.2.

[0743] Step C: 3-((phenyl-d5)methyl)-2-thioxotetrahydrothiazol-4-one

[0744] To a microwave tube was added (phenyl-d5)methylamine (350 mg, 3.125 mmol), (biscarbomethoxy)trithiocarbonate (1.41 g, 6.250 mmol), TEA (631 mg, 6.250 mmol), DME (10 mL). The system was microwaved at 90 °C for 15 minutes, LCMS monitored the completion of the reaction. The reaction system was cooled to room temperature, concentrated, purified by column chromatography to get yellow solid 290 mg.

[0745] LC-MS (m / z) [M-1]" = 227.0.

[0746] Step D: (R,Z)-2-(4-(5-((4-oxo-3-((phenyl-d5)methyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2- pivalamidoacetic acid

[0747] To a reaction flask was added 3-((phenyl-d5)methyl)-2- thioxotetrahydrothiazol-4-one (100 mg, 0.438 mmol), NH4OAc (50 mg, 0.657 mmol) and (R)-2-(4-(5-formylfuran-2-yl)phenyl)-2- pivalamidoacetic acid (144 mg, 0.438 mmol; from Example 4), acetic acid (3 mL), after the addition, warmed to 120 °C for 1 hour, LCMS monitored the completion of the reaction. The reaction system was cooled to room temperature, added water (20 mL), MeOH (5 mL), filtered, the filter cake was washed with MeOH (5 mL), dried to get red-brown solid 119.9 mg.

[0748] 1 HNMR (400 MHz, DMSO-d6): δ 7.99 (d, J = 7.5 Hz, 1H), 7.90-7.82 (m, 2H), 7.73 (s, 1H), 7.65-7.57 (m, 2H), 7.41 (d, J = 3.8 Hz, 1H), 7.35 (d, J = 3.7 Hz, 1H), 5.45 (d, J = 7.4 Hz, 1H), 5.26 (s, 2H), 1.16 (s, 9H).

[0749] Example 63: (R,Z)-2-(3-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2- pivalamidoacetic acid

[0750] Step A: (R)-2-(3-bromophenyl)-2-(((R)-1-(4-methoxyphenyl)ethyl)amino)acetonitrile

[0751] To a reaction flask was added ((R)-1-(4-methoxyphenyl)ethan-1-amine) (2.45 g, 0.016 mol), TMSCN (1.69 g, 0.017 mol), TBAF (1 M / L, 17 mL), 3-bromobenzaldehyde (3.0 g, 0.016 mol), methanol (30 mL), and the reaction was stirred at room temperature for 16 hours. 100 mL of water was added and the reaction was extracted with 40 mL of dichloromethane three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product (6 g) was used directly in the next step.

[0752] Step B: (R)-2-amino-2-(3-bromophenyl)acetic acid

[0753] To a reaction flask was added (R)-2-(3-bromophenyl)-2-(((R)-1-(4- methoxyphenyl)ethyl)amino)acetonitrile (6 g crude, 0.017 mol), 6 M HCl (100 mL), and the reaction was stirred at 95 °C for 16 hours. The reaction was sampled and LCMS was used to monitor the completion of the reaction. 40 mL of methyl tert-butyl ether was added and the layers were separated. The aqueous layer was extracted with an additional 40 mL of methyl tert-butyl ether. The aqueous layer was concentrated to give 2.2 g of crude product, which was used directly in the next step.

[0754] LC-MS (m / z) [M+2]+ = 230.1.

[0755] Step C: (R)-2-amino-2-(3-bromophenyl)acetic acid methyl ester

[0756] To a reaction flask was added (R)-2-amino-2-(3-bromophenyl)acetic acid (2.2 g crude, 9.13 mmol), methanol (20 mL), and SOCl2 (6.5 g, 54.8 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was stirred at 70 °C for 6 hours. The reaction was sampled and LCMS was used to monitor the completion of the reaction. The reaction was concentrated to dryness to give 2.2 g of crude product, which was used directly in the next step.

[0757] Step D: (R)-2-(3-bromophenyl)-2-pivalamidomethyl acetate

[0758] To a reaction flask was added (R)-2-amino-2-(3-bromophenyl)acetic acid methyl ester (2.2 g crude, 9.13 mmol), TEA (2.8 g, 27.4 mmol), dichloromethane (30 mL), and pivaloyl chloride (1.6 g, 13.7 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was stirred at 25 °C for 1 hour. The reaction was sampled and LCMS was used to monitor the completion of the reaction. 40 mL of water was added and the layers were separated. The aqueous layer was extracted with an additional 30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The product was purified by column chromatography to give 1.7 g of the target compound.

[0759] LC-MS (m / z) [M+1]+= 328.1.

[0760] Step E: (R)-2-(3-(5-formylfuran-2-yl)phenyl)-2-tert-butylamino)acetic acid methyl ester

[0761] To the reaction flask was added (R)-2-(3-bromophenyl)-2-tert-butylamino)acetic acid methyl ester (1.0 g, 3.05 mmol), dioxane (20 mL), water (4 mL), (5-formylfuran-2-yl)boronic acid (854 mg, 6.10 mmol), K3PO4(1.94 g, 9.15 mmol), SPhos (208 mg, 0.31 mmol), Pd(OAc)2(70.1 mg, 0.31 mmol), the system was replaced with nitrogen for 3 times, 80 °C for 2 h, LCMS monitoring of raw materials to complete the reaction. The system was diluted with EA, washed with water and brine respectively, dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to obtain the target compound (450 mg).

[0762] LC-MS (m / z) [M+1]+= 344.2.

[0763] Step F: (R)-2-(3-(5-formylfuran-2-yl)phenyl)-2-tert-butylamino)acetic acid

[0764] To the reaction flask was added (R)-2-(3-(5-formylfuran-2-yl)phenyl)-2-tert-butylamino)acetic acid methyl ester (450 mg, 131 mmol), THF / H2O (6 mL / 6 mL), LiOH H2O (85 mg, 1.97 mol), room temperature for half an hour, sampling, LCMS monitoring of the reaction to complete. The reaction system was concentrated to remove THF, acidified to PH to 2 with 1N HCl, extracted with EA, the organic phase was washed with water and brine respectively, dried and concentrated to obtain the target compound (380 mg).

[0765] LC-MS (m / z) [M+1]+= 330.2.

[0766] Step G: (R,Z)-2-(3-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5-ylidene)methyl)furan-2- yl)phenyl)-2-tert-butylamino)acetic acid

[0767] To a reaction flask was added (R)-2-(3-(5-formylfuran-2-yl)phenyl)-2-tert- butylaminoacetic acid (380 mg, 1.15 mmol), AcOH (10 mL), 3-benzyl-2-thioxothio- rane-4-one (257 mg, 1.15 mmol), ammonium acetate (134 mg, 1.73 mmol), the reaction system was replaced with nitrogen three times, 100 °C for 1 h, sample LCMS monitoring reaction complete. The reaction was cooled and added to a mixture of ethyl acetate and water, separated, the aqueous phase was extracted with ethyl acetate twice, the organic phase was combined, concentrated, and purified by Pre-HPLC to obtain the target product (117 mg).

[0768] LC-MS (m / z) [M+1]+= 535.1.

[0769] 1 HNMR (400MHz, DMSO-d6): δ 8.00 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 3.6 Hz, 1H), 7.39-7.19 (m, 6H), 5.43 (d, J = 7.1 Hz, 1H), 5.26 (s, 2H), 1.17 (s, 9H).

[0770] Example 64: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)-2-fluorophenyl)-2-tert-butylaminoacetic acid

[0771] Step A: (R)-N-(4-bromo-2-fluorobenzyl)oxaziridine-2-methylpropane-2- sulfonimidate

[0772] To a reaction flask was added 4-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol), THF (130 mL), R-tert-butylsulfinamide (6 g, 49.3 mmol), titanium(IV) isopropoxide (28 g, 98.5 mmol) sequentially, warmed to 70 °C, reacted for 2 h, TLC monitoring of raw materials until the reaction was complete. The reaction was cooled to room temperature, 100 mL of water and 50 mL of THF were added, stirred well, then filtered, the filter cake was washed with THF, the filtrate was extracted twice with EA, the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (7.2 g, yield 95.4%)

[0773] LC-MS (m / z) [M+H]+= 306.0.

[0774] 1 HNMR (400 MHz, CDC13): δ 8.83 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.47-7.31 (m, 2H), 1.27 (s, 9H).

[0775] Step B: (R)-N-((R)-l-(4-bromo-2-fluorophenyl)-2,2,2-tris(methylthio)ethyl)-2- methylpropane-2-sulfmamide

[0776] Into a reaction flask was added tris(methylthio)methane (1.5 g, 9.8 mmol), THF (20 mL), nitrogen was replaced for three times, cooling to -60 °C, dropwise added LDA (6.5 mL, 13.0 mmol), keep the reaction at -60 °C for 0.5 h, then added (R)-N-(4-bromo-2-fluorobenzyl)-2-methylpropane-2-sulfmamide (2.0 g, 6.5 mmol), continue to react at -60 °C for 2 h, TLC monitoring the reaction of raw materials is complete. To the reaction solution was added 50 mL saturated ammonium chloride solution to quench, diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, purified by column chromatography to obtain the target compound (2.7 g, yield 90.0%)

[0777] LC-MS (m / z) [M+H]+ = 459.9.

[0778] 1 HNMR (400 MHz, CDC13): δ 7.61 (s, 1H), 7.27-7.32 (m, 1H), 7.25 -7.20 (m, 1H), 4.87 (d, J = 10.2 Hz, 1H), 4.49 (d, J = 10.4 Hz, 1H), 2.08 (s, 9H), 1.26 (s, 9H).

[0779] Step C: (R)-2-(4-bromo-2-fluorophenyl)-2-(((R)-tert-butylsulfonyl)amino)ethyl acetate

[0780] Into a reaction flask was added (R)-N-((R)-l-(4-bromo-2-fluorophenyl)-2,2,2- tris(methylthio)ethyl)-2-methylpropane-2-sulfmamide (2.7 g, 5.9 mmol), MeOH (300 mL), AgN03(6 g, 35.2 mmol) was added, the reaction system was replaced with nitrogen for two times, and the reaction was carried out at room temperature for 2 h. LCMS monitoring the reaction of raw materials is complete, the reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain the crude product 2.4 g.

[0781] LC-MS (m / z) [M+H]+= 366.0.

[0782] Step D: (R)-methyl 2-amino-2-(4-bromo-2-fluorophenyl)acetate

[0783] To the reaction flask was added (R)-methyl 2-(4-bromo-2-fluorophenyl)-2-(((R)- tert-butylsulfonyl)amino)acetate (2.4 g, 5.9 mmol), HCl (4 M solution in dioxane, 24 mL), stirred at room temperature for 0.5 h, LCMS monitored the reaction was complete. The reaction system was directly concentrated to dryness, diluted with water, acidified with 1 M HCl to pH ~ 2, extracted with EA twice, the aqueous phase was adjusted to pH = 9-10 with 5% sodium carbonate solution, EA was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product (600 mg) which was directly used in the next step reaction.

[0784] LC-MS (m / z) [M+H] + = 264.0.

[0785] Step E: (R)-methyl 2-(4-bromo-2-fluorophenyl)-2-pivalamidacetate

[0786] To the reaction flask was added (R)-methyl 2-amino-2-(4-bromo-2-fluorophenyl)acetate (600 mg, 2.28 mmol), THF (6 mL), potassium carbonate (508 mg, 3.7 mmol), cooled to 0 °C, added pivaloyl chloride (304 mg, 2.5 mmol), stirred at room temperature for 0.5 h, LCMS monitored, the starting material was completely reacted. Extracted with EA twice, the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated, purified by column chromatography to give the target compound (500 mg, yield 63.1%).

[0787] 1 HNMR (400 MHz, CDC13): δ 7.32-7.26 (m, 2H), 7.26-7.21 (m, 1H), 6.76 (d, J = 6.7 Hz, 1H), 5.68 (d, J = 6.8 Hz, 1H), 3.74 (s, 3H), 1.20 (s, 9H).

[0788] Step F: (R)-methyl 2-(2-fluoro-4-(5-formylfuran-2-yl)phenyl)-2-pivalamidacetate

[0789] To a reaction vial was added (R)-2-(4-bromo-2-fluorophenyl)-2-tert- butylaminoacetic acid methyl ester (500 mg, 1.4 mmol), dioxane (10 mL), water (2 mL), (5-formylfuran-2-yl)boronic acid (304 mg, 2.2 mmol), K3PO4(0.912 g, 4.3 mmol), SPhos (67.2 mg, 0.10 mmol), Pd(OAc)2(22.6 mg, 0.10 mmol), the reaction system was replaced with nitrogen for 3 times, and 80 °C was reacted for 2 h. The sample was subjected to LCMS monitoring to ensure that the reaction was complete. The reaction system was diluted with EA, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography yielded the target compound (460 mg, yield 88.1%).

[0790] 1 HNMR (400 MHz, CDCl3): δ 9.67 (s, 1H), 7.62-7.50 (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 3.8 Hz, 1H), 6.86 (d, J = 3.8 Hz, 1H), 6.81 (d, J = 6.9 Hz, 1H), 5.74 (d, J = 6.8 Hz, 1H), 3.76 (s, 3H), 1.22 (s, 9H).

[0791] Step G: (R)-2-(2-fluoro-4-(5-formylfuran-2-yl)phenyl)-2-tert- butylaminoacetic acid methyl ester

[0792] To a reaction vial was added (R)-2-(2-fluoro-4-(5-formylfuran-2-yl)phenyl)-2- tert-butylaminoacetic acid methyl ester (400 mg, 1.1 mmol), THF (4 mL), H2O (4 mL), LiOH H2O (70 mg, 1.7 mmol), the reaction system was reacted at room temperature for half an hour, and TLC was used to monitor the sample to ensure that the reaction was complete. The reaction liquid was acidified to pH ≈ 2 with 1M HCl solution, extracted with EA three times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude target compound (350 mg, yield 90.9%).

[0793] LC-MS (m / z) [M+1]+ = 348.1.

[0794] Step H: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)-2-fluorophenyl)-2-tert-butylaminoacetic acid methyl ester

[0795] To a reaction flask was added (R)-2-(2-fluoro-4-(5-formylfuran-2-yl)phenyl)-2- tert-butylaminoacetic acid (300 mg, 0.86 mmol), AcOH (7.5 mL), 3-benzyl-2- thioxothiohydantoin (193 mg, 0.86 mmol), ammonium acetate (169 mg, 2.16 mmol), the reaction was purged with nitrogen for 3 times after the addition was completed, the reaction was heated at 120 °C for 2 hours, the reaction was monitored by LCMS. After the reaction was cooled, a mixture of ethyl acetate and water was added, stirred uniformly, filtered, the filter cake was washed with EA and water respectively, then was slurried with methanol, suction filtered, the solid was dried to give the target product (120 mg, yield 26.5%).

[0796] LC-MS (m / z) [M+1]+= 553.1.

[0797] 1 HNMR (400MHz, DMSO-d6): δ 8.12 (d, J = 7.7 Hz, 1H), 7.73 (s, 1H), 7.71-7.60 (m, 3H), 7.45-7.38 (m, 2H), 7.38-7.24 (m, 5H), 5.72 (d, J = 7.6 Hz, 1H), 5.25 (s, 2H), 1.15 (s, 9H).

[0798] Example 65: (R,Z)-2-(2-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-tert-butylaminoacetic acid

[0799] The target compound was synthesized according to the method described in Example 63, 82 mg was obtained.

[0800] 1 HNMR (400MHz, DMSO-d6): δ 8.12 (d, J = 7.7 Hz, 1H), 7.73 (s, 1H), 7.71-7.60 (m, 3H), 7.45-7.38 (m, 2H), 7.38-7.24 (m, 5H), 5.72 (d, J = 7.6 Hz, 1H), 5.25 (s, 2H), 1.15 (s, 9H).

[0801] Example 66: (R,Z)-N-(2-amino-1-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-oxoethyl)tert-butylaminoacetate

[0802] The title compound 226 mg was synthesized according to the procedures of Reference Example 27.

[0803] 1 HNMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 10.6 Hz, 2H), 7.62 (t, J = 9.1 Hz, 3H), 7.40 (d, J = 3.8 Hz, 1H), 7.38 - 7.25 (m, 7H), 5.43 (d, J = 7.7 Hz, 1H), 5.26 (s, 2H), 1.15 (d, J = 4.2 Hz, 9H).

[0804] Example 67: (R,Z)-2-(2-amino-2-methylpropanamido)-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)acetic acid

[0805] The title compound 123 mg was synthesized according to the procedures of Reference Example 18.

[0806] 1 HNMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 10.6 Hz, 2H), 7.62 (t, J = 9.1 Hz, 3H), 7.40 (d, J = 3.8 Hz, 1H), 7.38 - 7.25 (m, 7H), 5.43 (d, J = 7.7 Hz, 1H), 5.26 (s, 2H), 1.15 (d, J = 4.2 Hz, 9H).

[0807] Example 68: (R,Z)-2-(4-(5-((3-(carboxymethyl)-4-oxo-2-thioxotetrahydrothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidopropanoic acid

[0808] (R)-2-(4-(5-formylfuran-2-yl)phenyl)-2-pivalamidopropanoic acid (200 mg, 0.60 mmol, from Example 53) was added to acetic acid (5 mL), 2-(4-oxo-2- thioxotetrahydrothiazol-3-yl)acetic acid (115 mg, 0.6 mmol; commercially available) and NH4OAc (70 mg, 0.90 mmol) were added at room temperature, the reaction was raised to 100 °C and stirred for 2 hours. Then 10 ml water was added, filtered, slurry with 20 mL methanol, oven dried to give red solid 158 mg.

[0809] LC-MS (m / z) [M+1]+ = 503.0.

[0810] 1 HNMR (400 MHz, DMSO-d6): δ 7.87 (d, J = 6.9 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.66 (s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 3.8 Hz, 1H), 7.31 (d, J = 3.7 Hz, 1H), 5.26 (d, J = 6.9 Hz, 1H), 4.56 (d, J = 2.9 Hz, 2H), 1.15 (s, 9H).

[0811] Example 76: (R,Z)-2-acetylamino-3-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)propanoic acid

[0812] Referring to Example 28, the (S)-2-amino-3-(4-(5-formylfuran-2- yl)phenyl)propanoic acid hydrochloride was replaced by (R)-2-amino-3-(4-(5- formylfuran-2-yl)phenyl)propanoic acid hydrochloride to give the target product 18.0 mg, yield 35.7%.

[0813] 1 HNMR (400 MHz, DMSO-d6): δ 7.85 (d, J = 7.7 Hz, 1H), 7.80-7.69 (m, 3H), 7.44-7.35 (m, 4H), 7.35-7.24 (m, 5H), 5.26 (s, 2H), 4.34-4.26 (m, 1H), 3.14-2.87 (m, 2H), 1.79 (s, 3H).

[0814] Example 77: (R,Z)-2-(4-(5-((3-(3-fluorobenzyl)-4-oxo-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2- neopentanoylaminoacetic acid

[0815] Referring to Example 4, the target product was obtained 60 mg.

[0816] LC-MS: m / z = 553.10 [M+H] + .

[0817] Example 78: (S,Z)-2-acetylamino-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)acetic acid

[0818] Referring to example 38, replace MsCl with acetic anhydride to obtain the target product 60 mg.

[0819] 1 HNMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 3.8 Hz, 1H), 7.32 (m, J = 10.7, 7.2 Hz, 6H), 5.43-5.34 (m, 1H), 5.26 (s, 2H), 1.93 (s, 3H).

[0820] Example 79: (R,Z)-2-(4-(5-((3-(2-fluorobenzyl)-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamide

[0821] Referring to example 4, the target compound 98 mg can be synthesized.

[0822] LC-MS: m / z = 553.10 [M+H] + .

[0823] Example 80: (R,Z)-2-(4-(5-((3-(4-chloro-3-fluorobenzyl)-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamide

[0824] Referring to example 4, the target compound 45 mg can be synthesized.

[0825] LC-MS: m / z = 588.10 [M+H] + .

[0826] Example 81: (R,Z)-2-(4-(5-((4-oxo-3-(prop-2-yn-1-yl)-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-neopentanamide

[0827] Step A: 3-(prop-2-yn-1-yl)-2-thioxotetrahydrothiazolidin-4-one

[0828] Prop-2-yn-l-amine (200 mg, 3.57 mmol) was added to DME (5 mL), bis(carboxymethyl) trithiocarbonate (807 mg, 3.57 mmol), TEA (360 mg, 3.57 mmol) and reacted under microwave conditions at 90 °C for 10 minutes under nitrogen. The solvent was evaporated and the product was scraped off the plate to give the target product 153 mg.

[0829] 1 HNMR (400 MHz, CDC13): δ 4.75-4.74 (d, J = 2.4 Hz, 2H), 4.03 (s, 2H), 2.22 (s, 1H).

[0830] Step B: (R,Z)-2-(4-(5-((4-oxo-3-(prop-2-yn-l-yl)-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)-2-pivalamide acetic acid

[0831] (R)-2-(4-(5-Formylfuran-2-yl)phenyl)-2-pivalamidoacetic acid (290 mg, 0.88 mmol; from Example 53) was added to acetic acid (5 mL) and 3-(prop-2-yn-l-yl)-2- thioxothiazolidin-4-one (150 mg, 0.88 mmol) and NH4OAc (101 mg, 1.31 mmol) were added at room temperature. The reaction was stirred at 100 °C for 2 hours. Then 10 mL of water was added, filtered, slurried with 20 mL of methanol and oven dried to give the target compound as a red solid (191 mg).

[0832] LC-MS (m / z) [M+l]+ = 483.0.

[0833] 1 HNMR (400 MHz, DMSO-d6): δ 12.99 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.76 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 3.7 Hz, 2H), 5.44 (d, J = 7.5 Hz, 1H), 4.79 (d, J = 2.0 Hz, 2H), 1.15 (s, 9H).

[0834] Example 82: (R,Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- ylidene)methyl)furan-2-yl)phenyl)-2-(2-fluoro-2-methylpropanamido)acetic acid

[0835] The target product was synthesized according to the procedure described in Reference Example 61 to give 96 mg of the target product in 63% yield.

[0836] LC-MS: m / z = 539.10 [M+H] + .

[0837] Example 83: (S,Z)-2-(4-(5-((4-oxo-3-((phenyl-4-d)methyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2- isopentanoylaminoacetic acid

[0838] The target product was synthesized according to the procedure described in Reference Example 4 to give 68 mg of the target product in 57% yield.

[0839] LC-MS: m / z = 536.10 [M+H] + .

[0840] Example 84: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-isopentanoylaminoacetic acid

[0841] Step A: 2-(4-hydroxyphenyl)-2-isopentanoylaminoacetic acid methyl ester

[0842] Into a reaction flask was added 2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester (0.42 g, 1.93 mmol), tetrahydrofuran / water (15 mL / 10 mL), K2CO3(0.48 g, 3.65 mmol), replaced with nitrogen for three times, cooled to 0 °C, added isopentanoyl chloride (0.30 g, 2.52 mmol) dropwise, after the addition was completed, reacted for half an hour at room temperature, monitored by LCMS, the raw material was completely reacted, the reaction liquid was added to 30 mL of water, extracted with 30 mL of ethyl acetate for three times, the organic phase was combined, washed with 80 mL of brine, dried with anhydrous sodium sulfate and concentrated to give the target compound 0.52 g in 100% yield.

[0843] LC-MS (m / z) [M+1]+= 266.1.

[0844] Step B: 2-isopentanoylamino-2-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetic acid methyl ester

[0845] Into a reaction flask was placed 2-(4-hydroxyphenyl)-2-tert- butylacetamide methyl acetate (0.50 g, 1.90 mmol), DCM (50 mL), pyridine (0.15 g, 5.70 mmol), nitrogen was replaced for three times, triflic anhydride (0.80 g, 2.85 mmol) was added dropwise at 0 °C, after the addition was completed, the reaction was carried out at room temperature for half an hour. LCMS monitoring of the reaction was complete, the reaction system was diluted with DCM, washed with water and brine respectively, dried over anhydrous sodium sulfate and concentrated to give the target compound 0.52 g, yield 72%.

[0846] LC-MS (m / z) [M+1]+= 398.1.

[0847] Step C: 2-(4-(5-formylfuran-2-yl)phenyl)-2-tert-butylacetamide methyl acetate

[0848] Into a reaction flask was placed 2-tert-butylacetamide-2-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)methyl acetate (270 mg, 0.69 mmol), dioxane (25 mL), water (5.0 mL), 5-formylfuran-2-boronic acid (141 mg, 1.01 mmol), DIEA (0.268 g, 2.07 mmol), Pd(PPh3)2Cl2(48.4 mg, 0.069 mmol), the reaction system was replaced with nitrogen for three times, and reacted at 80 °C for 2.5 h. LCMS monitoring of the sample showed that the reaction was complete, the reaction system was diluted with EA, washed with water and brine respectively, dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to give the target product 180 mg, yield 78%.

[0849] LC-MS (m / z) [M+1]+= 344.1.

[0850] Step D: 2-(4-(5-formylfuran-2-yl)phenyl)-2-tert-butylacetamide methyl acetate

[0851] Into a reaction flask was placed 2-(4-(5-formylfuran-2-yl)phenyl)-2-tert- butylacetamide methyl acetate (300 mg, 1 eq), THF / H2O (30 mL / 15 mL), LiOH H2O (59 mg, 1.5 eq), the reaction was carried out at room temperature for half an hour, sampling, LCMS monitoring showed that the reaction was complete, the reaction system was concentrated, acidified with 1N HCl to PH≈2, extracted with EA, the organic phase was washed with water and brine respectively, dried and concentrated to give the compound 286 mg, yield 99%.

[0852] LC-MS (m / z) [M+1]+= 330.1.

[0853] 1 HNMR (400 MHz, DMSO-d6): δ 12.93 (br s, 1H), 9.61 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 4.0 Hz, 1H), 5.44 (d, J = 7.5 Hz, 1H), 1.15 (s, 9H).

[0854] Step E: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0855] To a reaction flask was added 2-(4-(5-formylfuran-2-yl)phenyl)-2- pivalamidoacetic acid (280 mg, 0.859 mmol), NH4OAc (99.2 mg, 1.26 mmol) and 3-benzyl-2-thioxotetrahydrothiazol-4-one (187.6 mg, 0.859 mmol), acetic acid (15 mL), after the addition, the temperature was raised to 120 °C for 1 hour. LCMS was used to monitor the reaction. When the starting material was consumed, the system was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL) three times. The organic phase was combined and concentrated. The resulting crude product was slurried with methanol (35 mL), the filter cake was concentrated and dried to give 149 mg of the target product in 33% yield.

[0856] 1 H NMR (400 MHz, DMSO): δ 12.72 (s, 1H), 7.99 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 3.8 Hz, 1H), 7.39 - 7.32 (m, 6H), 5.45 (d, J = 7.2 Hz, 1H), 5.25 (s, 2H), 1.23 (s, 9H).

[0857] Example 85: (Z)-3-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamidopropanoic acid

[0858] The target compound was synthesized according to the procedure described in Example 84 to give 92 mg.

[0859] LC-MS (m / z) [M+1]+= 549.18.

[0860] Example 86: (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-l-yl)but-2-yn-l-yl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0861] Step A: l-tert-Butoxycarbonyl-4-(4-(l,3-phthalazin-2-yl)but-2-yn-l-yl)piperazine

[0862] To 2-(4-chlorobut-2-yn-l-yl)phthalazin-l-ium (5 g, 0.02 mol) in ACN (50 mL) was added potassium carbonate (89.4 mg, 0.7 mmol), tert-butyl piperazine-l- carboxylate (4.8 g, 0.025 mol), and the reaction was protected with nitrogen. The reaction was stirred at 100 °C for 4 h. LCMS showed the reaction was complete. The reaction was filtered, the solvent was evaporated, and the crude product was purified by column to give a yellow solid (4.8 g).

[0863] LC-MS (m / z) 384.2 [M+l] +

[0864] Step B: l-tert-Butoxycarbonyl-4-(4-aminobut-2-yn-l-yl)piperazine

[0865] To l-tert-butoxycarbonyl-4-(4-(l,3-phthalazin-2-yl)but-2-yn-l-yl)piperazine (1 g, 2.6 mmol) in EtOH (30 mL) was added hydrazine hydrate (2 mL), and the reaction was protected with nitrogen. The reaction was stirred at 80 °C for 2 h. LCMS showed the reaction was complete. The reaction was filtered, the filtrate was concentrated, 10 mL of DCM was added, the insoluble was filtered, and the filtrate was concentrated to give a yellow liquid (600 mg).

[0866] LC-MS (m / z) 254.3 [M+l] +

[0867] Step C: l-tert-Butoxycarbonyl-4-(4-(4-oxo-2-thioxotetrahydrothiazol-3-yl)but-2-yn-l- yl)piperazine

[0868] Step B: 2-(4-(5-((3-(4-(4-(tert-butoxycarbonyl)piperazin-l-yl)butyl-2- ynyl-l -yl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2- isobutyrylaminoacetic acid

[0869] LC-MS (m / z) 370.1 [M + 1] +

[0870] Step D: (Z)-2-(4-(5-((3-(4-(4-(tert-butoxycarbonyl)piperazin-l-yl)butyl-2- ynyl-l -yl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2- isobutyrylaminoacetic acid

[0871] Compound 1-tert-butoxycarbonyl-4-(4-(4-oxo-2-thioxothiazolidin-3-yl)butyl-2- ynyl-l -yl)piperazine (336 mg, 0.91 mmol), 2-(4-(5-formylfuran-2-yl)phenyl)-2- isobutyrylaminoacetic acid (300 mg, 0.91 mmol), NH4OAc (106 mg, 1.37 mmol) were dissolved in 1.4-dioxane / acetic acid (10 mL / 0.5 mL) and reacted at 120 °C for 2 hours. The reaction was cooled and concentrated to dryness. The residue was slurried in methanol / water (10 mL / 10 mL) for 30 minutes, filtered, and the filter cake was slurried in methanol (10 mL). The solid was dried to give the compound as a red solid (260 mg, 41.9% yield).

[0872] LC-MS (m / z) [M + 1 - 100] + = 581.2.

[0873] Step E: (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-l-yl)but-2-yn-l-yl)-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-isobutyrylaminoacetic acid

[0874] (Z)-2-(4-(5-((3-(4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)butyl-2-yn-1-yl)-4-oxo-2-thiotetrahydrothiazo-5-ylidene)methyl)furan-2-yl)phenyl)-2-tertivalamidoacetic acid (260 mg, 0.38 mmol), TMSOTf (253 mg, 1.14 mmol), and TEA (115 mg, 1.14 mmol) were dissolved in DCM (10 mL), and the mixture was heated to 50 °C and reacted for 15 h. The reaction was monitored by LCMS until complete. After cooling, the reaction solution was concentrated to dryness, and the mixture was stirred with methanol / water (10 mL / 5 mL) for 30 min. The mixture was then filtered, and the filter cake was stirred with methanol (5 mL), filtered again, and the solid was dried to give a red solid compound (150 mg, yield 67.9%).

[0875] 1 H NMR (400MHz, DMSO-d6): δ8.84(s,1H),8.00(d,J=7.5Hz,1H),7.86(d,J=8.3Hz,2H),7.76(s,1H),7.58(dd,J=22.6,8.1Hz,2H),7.4 3(d,J=3.7Hz,1H),7.36(d,J=3.7Hz,1H),5.46(d,J=7.4Hz,1H),4.88(s,2H),3.77(s,2H),3.23(s,4H),2.96(s,4H),1.16(s,9H).

[0876] Example 87: Sodium (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thiotetrahydrothiazolyl-5-ylidene)methyl)furan-2-yl)phenyl)-2-pentanoylaminopropionate

[0877] Step A: 5-(4-bromophenyl)-5-methylimidazol-2,4-dione

[0878] Add 1-(4-bromophenyl)ethane-1-one (3 g, 15 mmol) to EtOH (30 mL), then add (NH4)2CO3 (8.7 g, 90 mmol), TMSCN (3.0 g, 30 mmol), K2CO3 (4.2 g, 30 mmol), and NH3. . H2O (15 mL), stirred at 70℃ for 18 h. LC-MS showed that the reaction was complete. The solvent was evaporated, diluted with 20 mL H2O, stirred at room temperature for 0.5 h, filtered, and the filter cake was dried to give a white solid (3.81 g).

[0879] 1H NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 7.62-7.56 (m, 2H), 7.46-7.40 (m, 2H), 1.62 (s, 3H).

[0880] Step B: 2-Amino-2-(4-bromophenyl)propanoic acid

[0881] Compound 5-(4-bromophenyl)-5-methylimidazole-2,4-dione (2.0 g, 7.4 mmol) was added into H2O (25 mL), then NaOH (1.2 g, 29.7 mmol) was added, stirred at 140 °C for 16 h. LC-MS showed the reaction was completed. The reaction solution was cooled to 0 °C, 2N HCl was added dropwise to adjust the pH value to 6, filtered, washed with 20 mL H2O, and the filter cake was dried to obtain a white solid (2.4 g).

[0882] 1 H NMR (400 MHz, DMSO-d6): δ 7.53-7.49 (m, 2H), 7.49-7.43 (m, 2H), 1.58 (s, 3H).

[0883] Step C: 2-(4-bromophenyl)-2-pivalamidopropanoic acid

[0884] Compound 2-amino-2-(4-bromophenyl)propanoic acid (1.0 g, 4.10 mmol) was added into THF / H2O (10 mL / 5 mL), then K2CO3 (0.85 g, 6.16 mmol) was added, cooled to 0 °C, pivaloyl chloride (0.52 g, 4.3 mmol) was added dropwise, after addition, the temperature was raised to room temperature and stirred for 4 h. The reaction was completed, 1N HCl was added dropwise to adjust the pH value to 2-3, extracted with EA three times (20 mL*3), dried over anhydrous sodium sulfate, filtered, the solvent was rotary evaporated, and the crude product was purified by column chromatography to obtain a white solid (320 mg).

[0885] 1 H NMR (400 MHz, CDCl3): δ 7.52-7.47 (m, 2H), 7.47-7.42 (m, 2H), 1.34 (s, 9H), 1.23 (s, 3H).

[0886] Step D: 2-(4-(5-formylfuran-2-yl)phenyl)-2-pivalamidopropanoic acid

[0887] Compound 2-(4-bromophenyl)-2-tetrahydropyranylaminopropanoic acid (200 mg, 0.61 mmol) was added to dioxane / H2O (5 mL / 1 mL), then compound (5-formylfuran-2-yl)boronic acid (111 mg, 0.79 mmol), DIEA (236 mg, 1.83 mmol), Pd(PPh3)Cl2(43 mg, 0.06 mmol) were added, the reaction was replaced by N2, and stirred at 80 °C for 4 h. LC-MS showed that the reaction was completed. 10 mL of water was added to the reaction solution, and extracted with EA for 3 times (20 mL*3), the organic phase was combined and washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The crude product was purified by large plate to obtain a yellow solid (70 mg).

[0888] LC-MS (m / z) 344.1 [M+1] +

[0889] Step E: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5-ylidene)methyl)furan-2- yl)phenyl)-2-tetrahydropyranylamino propanoic acid

[0890] Compound 2-(4-(5-formylfuran-2-yl)phenyl)-2-tetrahydropyranylamino propanoic acid (35 mg, 0.10 mmol) was added to AcOH (2 mL), then 3-benzyl-2-thioxotetrahydrothiazol-4-one (22 mg, 0.10 mmol), NH4OAc (11.7 mg, 0.15 mmol) were added, and stirred at 120 °C for 2 h. LCMS showed that the reaction was completed, 6 mL of water was added to the reaction solution, stirred for 1 h, filtered, the filter cake was stirred with 5 mL of methanol and 1 mL of EA for 1 h, filtered, and the filter cake was dried to obtain a red solid (34 mg).

[0891] 1 H NMR (400 MHz, DMSO-d6): δ 7.86-7.81 (m, 2H), 7.73 (s, 1H), 7.71-7.68 (m, 1H), 7.65-7.60 (m, 2H), 7.42-7.39 (m, 1H), 7.36-7.28 (m, 6H), 5.26 (s, 2H), 1.83 (s, 3H), 1.16 (s, 9H).

[0892] Step F: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5-ylidene)methyl)furan-2- yl)phenyl)-2-tetrahydropyranylamino propanoic acid sodium

[0893] (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(N-methylpentanoylamino)propanoic acid (34 mg, 0.06 mmol) was added to 1 mL of 0.05 M aqueous NaOH and stirred at room temperature for 1 h and lyophilized to give a red solid (35.6 mg).

[0894] LC-MS (m / z) 549.1 [M+1] +

[0895] 1 H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H), 7.74-7.67 (m, 3H), 7.47-7.43 (m, 2H), 7.40-7.38 (m, 1H), 7.36-7.32 (m, 4H), 7.31-7.27 (m, 1H), 7.27-7.23 (m, 1H), 5.26 (s, 2H), 1.77 (s, 3H), 1.13 (s, 9H).

[0896] Example 88: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(N-methylpentanoylamino)propanoic acid

[0897] Step A: 2-(4-bromophenyl)ethyl acetate

[0898] Into a reaction bottle was added 2-(4-bromophenyl)acetic acid (2 g, 9.302 mmol), O-tert-butyl-N,N'-diisopropyl isourea (9.3 g, 46.5 mmol), DCM (20 mL), after the addition was completed, the temperature was raised to 40 °C and reacted overnight. LCMS monitoring of the complete reaction of the raw material, the system was concentrated, and column chromatography was purified to obtain 2.29 g of the target compound with a yield of 90.8%.

[0899] Step B: 2-bromo-2-(4-bromophenyl)ethyl acetate

[0900] Into a reaction bottle was added 2-(4-bromophenyl)ethyl acetate (2.29 g, 8.45 mmol), NBS (1.8 g, 10.11 mmol), BPO (327.2 mg, 1.35 mmol), CCl4(23 mL), after the addition was completed, the reaction system was replaced with nitrogen three times, the temperature was raised to 80 °C and reacted for 4 h, sampling, TLC monitoring, complete reaction of the raw material. The reaction system was cooled to room temperature and concentrated to dryness, and column chromatography was purified to obtain 2.8 g of the target compound with a yield of 95.2%.

[0901] 1 H NMR (400 MHz, DMSO-d6): δ 7.64-7.59 (m, 2H), 7.53-7.48 (m, 2H), 5.79 (s, 1H), 1.41 (s, 9H).

[0902] Step C: tert-Butyl 2-(4-bromophenyl)-2-(methylamino)acetate

[0903] To the reaction bottle was added tert-butyl 2-(4-bromophenyl)-2-(methylamino)acetate (2 g, 5.74 mmol), methylamine hydrochloride (770.1 mg, 11.49 mmol), K2CO3(1.59 g, 11.49 mmol), ACN (20 mL), the reaction system was replaced with nitrogen three times, and then the temperature was increased to 55 °C for reaction for 10 h. Sampling, LCMS monitoring, the raw material was completely reacted. The reaction system was detected by LCMS to obtain the target compound, and the reaction system was concentrated to dryness at room temperature. Purification by column chromatography gave 876 mg of the target compound in a yield of 51.0%.

[0904] 1 H NMR (400 MHz, DMSO-d6): δ 7.57-7.52 (m, 2H), 7.35-7.29 (m, 2H), 4.11 (s, 1H), 2.21 (s, 3H), 1.35 (s, 9H).

[0905] Step D: tert-Butyl 2-(4-bromophenyl)-2-(N-methylpivalamido)acetate

[0906] At 0 °C, tert-butyl 2-(4-bromophenyl)-2-(methylamino)acetate (1.1 g, 3.70 mmol), K2CO3(765.9 g, 5.55 mmol) in THF / H2O (10 mL / 5 mL) was added dropwise pivaloyl chloride (488.4 mg, 4.07 mmol), and stirred at room temperature for 4 h. Sampling, LCMS monitoring, the raw material was completely reacted. The reaction system was detected by LCMS to obtain the target compound, and the reaction system was concentrated to dryness. Water (150 mL) was added, and the organic phase was extracted with ethyl acetate three times. The combined organic phase was concentrated and dried, and then purified by column chromatography to give 1.39 g of the target compound in a yield of 97.8%.

[0907] 1 H NMR (400 MHz, DMSO-d6): δ 7.59 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 5.64 (s, 1H), 2.87 (s, 3H), 1.42 (s, 9H), 1.24 (s, 9H).

[0908] Step E: tert-Butyl 2-(4-(5-formylfuran-2-yl)phenyl)-2-(N- methylpivalamido)acetate

[0909] To the reaction flask was added tert-butyl 2-(4-(5-formylfuran-2-yl)phenyl)-2-(N- methylpivalamido)acetate (300 mg, 0.75 mmol), 3-benzyl-2-thioxothiazetidin-4-one (175.2 mg, 0.79 mmol), NH4OAc (88 mg, 1.13 mmol), Dioxane / AcOH (4 mL / 0.2 mL), the reaction flask was purged with nitrogen for three times, then the reaction was heated to 120 °C for 4 h. The reaction was cooled to room temperature, then 10 mL H2O:MeOH = 3:1 was added, the mixture was stirred for 30 min, then filtered, the filter cake was dried to give the crude product, then the crude product was stirred in 10 mL MeOH for 30 min, then filtered, the filter cake was dried to give 360 mg of the desired product in 79.1% yield.

[0910] Step F: tert-Butyl (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(N-methylpivalamido)acetate

[0911] To the reaction flask was added tert-butyl 2-(4-(5-formylfuran-2-yl)phenyl)-2-(N- methylpivalamido)acetate (300 mg, 0.75 mmol), 3-benzyl-2-thioxothiazetidin-4-one (175.2 mg, 0.79 mmol), NH4OAc (88 mg, 1.13 mmol), Dioxane / AcOH (4 mL / 0.2 mL), the reaction flask was purged with nitrogen for three times, then the reaction was heated to 120 °C for 4 h. The reaction was cooled to room temperature, then 10 mL H2O:MeOH = 3:1 was added, the mixture was stirred for 30 min, then filtered, the filter cake was dried to give the crude product, then the crude product was stirred in 10 mL MeOH for 30 min, then filtered, the filter cake was dried to give 360 mg of the desired product in 79.1% yield.

[0912] 1 H NMR (400 MHz, DMSO-d6): δ 7.89 (d, J = 8.1 Hz, 2H), 7.73 (s, 1H), 7.45-7.40 (m, 3H), 7.38-7.28 (m, 6H), 5.77 (s, 1H), 5.25 (s, 2H), 2.89 (s, 3H), 1.44 (s, 9H), 1.26 (s, 9H).

[0913] Step G: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-yl)methyl)furan-2- yl)phenyl)-2-(N-methylpivalamido)acetic acid

[0914] To the reaction flask was added compound (Z)-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-(N- methylpivalamido)acetic acid tert-butyl ester (100 mg, 0.17 mmol), TEA (29 mg, 0.287 mmol), DCM (4 mL) stirred at room temperature for 30 min, then TMSOTf (59.8 mg, 0.27 mmol) was added dropwise, the reaction was heated to 70 °C for 2 h, the reaction was cooled to room temperature and the solvent was concentrated, the residue was purified by flash column to give 130 mg of the target product, yield 95.6%.

[0915] 1 H NMR (400 MHz, Methanol-d4): δ 7.82 (d, J = 7.5 Hz, 2H), 7.56 (s, 1H), 7.48 (s, 2H), 7.40 (d, J = 7.4 Hz, 2H), 7.29-7.24 (m, 3H), 7.10 (dd, J = 26.2, 3.8 Hz, 2H), 5.30 (s, 2H), 3.35 (s, 3H), 1.36 (s, 9H).

[0916] Example 89: (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-1-ylsulfonyl)benzyl)-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0917] Step A: 1-tert-Butoxycarbonyl-4-((4-cyanophenyl)sulfonyl)piperazine

[0918] To the reaction flask was added compound 4-cyanophenylsulfonyl chloride (2.0 g, 0.99 mmol) in DCM (30 mL), then TEA (3.0 g, 2.97 mmol), 1-tert-butoxycarbonylpiperazine (2.2 g, 1.19 mmol) was added, stirred at room temperature for 2 h. LCMS showed that the reaction was complete, the reaction was quenched by adding 20 mL of water, extracted with DCM three times (60 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated, the crude product was purified by column to give white solid compound (1.8 g).

[0919] 1 H NMR (400 MHz, DMSO-d6): δ 8.13 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 3.44-3.36 (m, 4H), 3.00-2.86 (m, 4H), 1.34 (s, 9H).

[0920] Step B: l-tert-butoxycarbonyl-4-((4-(aminomethyl)phenyl)sulfonyl)piperazine

[0921] To l-tert-butoxycarbonyl-4-((4-cyanophenyl)sulfonyl)piperazine (A19-91-1, 1.8 g, 5.12 mmol) was added MeOH (30 mL), then Ni (2.0 g), replaced H2, stirred at room temperature for 2 h. LCMS showed the reaction was completed. Filtered with celite, rinsed with MeOH (20 mL), concentrated, purified by reverse phase column to give compound (1.31 g) as a white solid.

[0922] 1 H NMR (400 MHz, DMSO-d6): δ 7.66 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 3.81 (s, 2H), 3.42-3.35 (m, 4H), 2.85-2.79 (m, 4H), 1.33 (s, 9H).

[0923] Step C: l-tert-butoxycarbonyl-4-((4-((4-oxo-2-thioxotetrahydrothiazol-3- yl)methyl)phenyl)sulfonyl)piperazine

[0924] To compound l-tert-butoxycarbonyl-4-((4-(aminomethyl)phenyl)sulfonyl)piperazine (500 mg, 1.4 mmol) was added DME, then 2,2'-(thiocarbonylbis(sulfonimidoyl di-))diacetic acid (477 mg, 2.11 mmol), TEA (424 mg, 4.2 mmol), DME (7 mL), replaced N2, microwave reacted for 30 min. LCMS showed the reaction was completed, the reaction solution was rotary evaporated, the crude product was purified by column to give compound (598 mg) as a white solid.

[0925] 1 H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 5.16 (s, 2H), 4.36 (s, 2H), 3.41-3.35 (m, 4H), 2.88-2.78 (m, 4H), 1.34 (s, 9H).

[0926] Step D: (Z)-2-(4-(5-((3-(4-((4-(tert-butoxycarbonyl)piperazin-l-yl)sulfonyl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0927] Compound 1 -tert-butoxycarbonyl-4-((4-((4-oxo-2-thioxotetrahydrothiazol-3- yl)methyl)phenyl)sulfonyl)piperazine (150 mg, 0.32 mmol) was added to Dioxane / AcOH (4 mL / 0.2 mL), then 2-(4-(5-formylfuran-2-yl)phenyl)-2-tert- butylacetamidoacetic acid (105 mg, 0.38 mmol), NH4OAc (36. mg, 0.48 mmol) was added, stirred at 120 °C for 2 h. LCMS showed the reaction was completed. The reaction was rotary evaporated, the crude was purified by column to give red solid compound (230 mg).

[0928] 1 H NMR (400 MHz, DMSO-d6): δ 7.76-7.68 (m, 6H), 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.42-7.24 (m, 2H), 5.34 (s, 2H), 4.62 (d, J = 4.0 Hz, 1H), 3.39-3.26 (m, 4H), 2.80-2.75 (m, 4H), 1.36 (s, 9H), 1.15 (s, 9H).

[0929] Step E: (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-1-ylsulfonyl)benzyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-tert- butylacetamidoacetic acid

[0930] Compound (Z)-2-(4-(5-((3-(4-((4-(tert-butoxycarbonyl)piperazin-1- yl)sulfonyl)benzyl)-4-oxo-2-thioxotetrahydrothiazol-5-ylidene)methyl)furan-2- yl)phenyl)-2-tert-butylacetamidoacetic acid (200 mg, 0.25 mmol) was added to DCM (10 mL), then TMSOTf (170 mg, 0.76 mmol), TEA (50 mg, 0.51 mmol) was added, stirred at 45 °C for 4 h. LCMS showed the reaction was completed. The reaction was rotary evaporated, 3 mL ACN, 9 mL H2O was added to slurry, dried to give red solid compound (140 mg).

[0931] LC-MS (m / z) 683.2 [M+1] +

[0932] 1H NMR (400 MHz, DMSO-d6): δ 7.85 - 7.62 (m, 6H), 7.58 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 4.0 Hz, 1H), 5.36 (s, 2H), 5.07 (d, J = 4.0 Hz, 1H), 2.86 - 2.79 (m, 8H), 1.15 (s, 9H).

[0933] Example 90: (Z)-4-((5-((5-(4-(carboxy(pivalamidomethyl)phenyl)furan-2-yl)methenyl)-4- oxo-2-thioxothi azolidin-3-yl)methyl)benzoic acid

[0934] Step A: tert-Butyl 4-((4-oxo-2-thioxothiazolidin-3-yl)methyl)benzoate

[0935] tert-Butyl 4-(aminomethyl)benzoate (200 mg, 0.965 mmol) was added to DME (8 mL), followed by bis(carboxymethyl)trithiocarbonate (327 mg, 1.45 mmol), TEA (292 mg, 2.89 mmol), nitrogen protection, 100 °C sealed tube reaction for 16 h. The solvent was removed by concentration, and Pre-TLC purification gave the compound (220 mg, yield 70%) as yellow oil.

[0936] 1 H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 5.21 (s, 2H), 4.00 (s, 2H), 1.57 (s, 9H).

[0937] Step B: 4-((4-Oxo-2-thioxothiazolidin-3-yl)methyl)benzoic acid

[0938] tert-Butyl 4-((4-oxo-2-thioxothiazolidin-3-yl)methyl)benzoate (220 mg, 0.68 mmol) was added to DCM / TFA (5 mL / 5 mL), and the reaction was stirred at 25 °C for 2 h, and TLC monitoring showed that the raw material disappeared. The solvent was removed by concentration, and was directly used in the next step (300 mg of crude product, light yellow solid).

[0939] Step C: (Z)-4-((5-((5-(4-(carboxy(pivalamidomethyl)phenyl)furan-2-yl)methenyl)-4- oxo-2-thioxothiazolidin-3-yl)methyl)benzoic acid

[0940] Compound 4-((4-oxo-2-thioxotetrahydrothiazol-3-yl)methyl)benzoic acid (300 mg, 0.681 mmol) was added to dioxane / acetic acid (5 mL / 0.3 mL), 2-(4-(5-formylfuran-2-yl)phenyl)-2- neopentanoylaminoacetic acid (224 mg, 0.681 mmol; from Example 84) and NH4OAc (78 mg, 1.02 mmol) were added at room temperature, the reaction was stirred at 120 °C for 2 hours, LCMS showed the reaction was complete. Then 30 mL water was added, filtered, slurry with 30 mL methanol, oven dried to give red solid (53 mg).

[0941] 1 H NMR (400 MHz, DMSO-d6): δ 13.04 (br, 2H), 7.91 (d, J = 8.0 Hz, 3H), 7.82 (d, J = 8.1 Hz, 2H), 7.73 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.6 Hz, 3H), 7.32 (d, J = 3.7 Hz, 1H), 5.31 (s, 2H), 5.23 (d, J = 6.0 Hz, 1H), 1.15 (s, 9H).

[0942] Example 91: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-tert-butylaminoacetic acid

[0943] Step A: 2-(4-bromophenyl)-2-tert-butylaminoacetic acid tert-butyl ester

[0944] Referring to the procedure of Example 88, Step C, replace methylamine with tert-butylamine to give the target compound 1.1 g.

[0945] Step B: 2-tert-butylamino-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid tert-butyl ester

[0946] Step B: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-tert-butylaminoacetic acid tert-butyl ester

[0947] LC-MS (m / z) 358.2 [M+1] +

[0948] Step C: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-tert-butylaminoacetic acid tert-butyl ester

[0949] Step C: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-tert-butylaminoacetic acid tert-butyl ester

[0950] LC-MS (m / z) 564.2 [M+1] +

[0951] Step D: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-tert-butylaminoacetic acid

[0952] The compound (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-tert-butylaminoacetic acid tert-butyl ester (140 mg, 0.25 mmol) was added to DCM (2 mL), HCl / Dioxane (2 mL) was added at room temperature, after the addition was completed, the reaction liquid was stirred at 25 °C for 2 h, LCMS detection showed that the reaction was completed, filtration to obtain the yellow solid target product (100 mg).

[0953] LC-MS (m / z) 507.1 [M+1] +

[0954] 1 H NMR (400 MHz, DMSO-d6): δ 9.30 (br, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.43 (s, 2H), 7.39-7.25 (m, 5H), 5.29-5.26 (m, 3H), 1.29 (s, 9H).

[0955] Example 92: (Z)-2-(4-(5-((3-(4-((4-methylpiperazin-1-yl)sulfonyl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[0956] The compound (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-1-ylsulfonyl)benzyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid (50 mg, 0.07 mmol) was added to MeOH / DMF (5 mL / 1 mL), then formaldehyde aqueous solution (50 mg) was added, stirred at room temperature for 2 h; NaBH(OAc)3 (74 mg, 0.35 mmol) was added, stirred at room temperature for another 2 h. LCMS showed that the reaction was completed, the reaction liquid was quenched with 20 mL of water, extracted with EA three times (60 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was rotary evaporated to obtain a crude product, which was prepared to obtain a red solid compound (23.6 mg).

[0957] LC-MS (m / z) 697.1 [M+1] + .

[0958] 1H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.78 (s, 1H), 7.76 (d, J = 2.8 Hz, 2H), 7.64 - 7.58 (m, 4H), 7.43 (d, J = 4.0 Hz, 1H), 7.37 (d, J = 4.0 Hz, 1H), 5.46 (d, J = 7.6 Hz, 1H), 5.37 (s, 2H), 3.35 (s, 8H), 2.72 (s, 3H), 1.15 (s, 9H).

[0959] Example 93: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(3-fluoro-2,2-dimethylpropanamido)acetic acid

[0960] Step A: 3-Fluoro-2,2-dimethylpropanoic acid-N-succinimidyl ester

[0961] 3-Fluoro-2,2-dimethylpropanoic acid (200 mg, 1.7 mmol), N-hydroxysuccinimide (196 mg, 1.7 mmol), DCC (350 mg, 1.7 mmol) and DMAP (21 mg, 0.17 mmol) were dissolved in DCM (6 mL) and then kept at 25 °C for 4 h. LCMS detection of the main product, the reaction was directly concentrated to dryness, and purified by column to obtain the compound (145 mg, yield 37.7%).

[0962] 1 H NMR (400 MHz, DMSO-d6): δ 4.60 (s, 1H), 4.48 (s, 1H), 2.82 (s, 4H), 1.33 (d, J = 12 Hz, 6H).

[0963] Step B: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(3-fluoro-2,2-dimethylpropanamido)acetic acid

[0964] (Z)-2-amino-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)acetic acid (100 mg, 0.22 mmol, from example 5), 3- fluoro-2,2-dimethylpropanoic acid-N-succinimidyl ester (76 mg, 0.33 mmol), NaHC03(55 mg, 0.66 mmol) were dissolved in THF / H20 (5 mL / 5 mL) and stirred at 25 °C for 10 h. LC-MS indicated the reaction was complete, the reaction was concentrated to dryness, slurried in methanol / H20 (5 mL / 5 mL) for 30 min, filtered to give the crude product, and then slurried in methanol (5 mL) for 30 min, filtered and dried to give the product (35.1 mg, yield 28.5%).

[0965] 1 H NMR (400 MHz, DMSO-d6): δ 8.16 (d, J = 7.1 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.74 (s, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.41 - 7.25 (m, 7H), 5.42 (d, J = 7.2 Hz, 1H), 5.26 (s, 2H), 4.50 (dd, J = 17.1, 8.8 Hz, 1H), 4.39 (dd, J = 17.1, 8.8 Hz, 1H), 1.18 (d, J = 4.3 Hz, 6H).

[0966] Example 94: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(3,3,3-trifluoro-2,2-dimethylpropanamido)acetic acid

[0967] Step A: 2-(4-bromophenyl)-2-(3,3,3-trifluoro-2,2-dimethylpropanamido)acetic acid

[0968] Into DCM / DMF (10 mL / 1 mL) was placed 3,3,3-fluoro-2,2-dimethylpropanoic acid (400 mg, 2.56 mmol) and oxalyl chloride (357.6 mg, 0.28 mmol) was added at 0 °C under nitrogen protection. The reaction was stirred at 25 °C for 2 h. TEA (784 mg, 7.68 mmol) was added at 0 °C, followed by 2-amino-2-(4-bromophenyl)acetic acid (680 mg, 2.56 mmol) under nitrogen protection. The reaction was stirred at 25 °C for 2 h. LCMS showed the reaction was completed. The reaction was adjusted to pH = 2-3 with 1M dilute hydrochloric acid and extracted with ethyl acetate for 3 times (60 mL). The organic phase was washed with 30 mL of brine and dried over sodium sulfate. The solvent was removed by rotary evaporation and purified by flash to give a white solid (210 mg).

[0969] LC-MS (m / z) 370.0 [M+1] +

[0970] Step B: 2-(4-(5-formylfuran-2-yl)phenyl)-2-(3,3,3-trifluoro-2,2-dimethylpropanamido)acetic acid

[0971] Into dioxane / H2O (5 mL / 1 mL) was placed 2-(4-bromophenyl)-2-(3,3,3-trifluoro-2,2-dimethylpropanamido)acetic acid (210 mg, 0.57 mmol) and (5-formylfuran-2-yl)boronic acid (159 mg, 1.14 mmol), DIEA (220 mg, 1.71 mmol) and Pd(PPh3)Cl2 (40 mg, 0.057 mmol) was added under nitrogen protection. The reaction was stirred at 80 °C for 4 h. LCMS showed the reaction was completed. The reaction was added with 10 mL of water and extracted with ethyl acetate for 3 times (60 mL). The organic phase was washed with 30 mL of brine and dried over sodium sulfate. The solvent was removed by rotary evaporation and purified by flash to give a yellow solid (150 mg).

[0972] LC-MS (m / z) 384.1 [M+1] +

[0973] Step C: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-(3,3,3-trifluoro-2,2-dimethylpropanamido)acetic acid

[0974] To a reaction flask was added 2-(4-(5-formylfuran-2-yl)phenyl)-2-(3,3,3- trifluoro-2,2-dimethylpropanamido)acetic acid (30 mg, 0.078 mmol) in MeOH (5 mL), 3-benzyl-2-thioxothiazetidin-4-one (17.5 mg, 0.078 mmol) and piperidine hydrochloride (9.5 mg, 0.078 mmol), TEA (15.8 mg, 0.156 mmol) was added at room temperature, the reaction was heated to 80 °C and stirred for 4 h, LCMS showed the reaction was completed. Then 10 mL water was added, filtered, slurry with 5 mL methanol, dried to get yellow solid (29.2 mg).

[0975] 1 H NMR (400 MHz, DMSO-d6): δ 13.29-12.90 (m, 1H), 8.40 (d, J = 6.6 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 6.4 Hz, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 3.7 Hz, 1H), 7.37-7.23 (m, 6H), 5.34 (s, 1H), 5.26 (s, 2H), 1.41 (d, J = 6.5 Hz, 6H).

[0976] Example 95: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(3,3-difluoro-2,2-dimethylpropanamido)acetic acid

[0977] Step A: 3-hydroxy-2,2-dimethylpropanoic acid benzyl ester

[0978] To a reaction flask was added compound 3-hydroxy-2,2-dimethylpropanoic acid (3.0 g, 0.025 mol), K2CO3(3.9 g, 0.027 mol), DMF (30 mL), then benzyl bromide (4.34 g, 0.025 mol) was added dropwise, the system was reacted at 20 °C for 2 h. TLC showed that the reaction was completed, the reaction was diluted with water (30 mL), extracted with EA (50 mL), the organic phase was concentrated, and purified by column chromatography to obtain colorless oil (3.2 g).

[0979] 1 H NMR (400 MHz, DMSO-d6): δ 7.44-7.26 (m, 5H), 5.09 (s, 2H), 4.89 (t, J = 5.4 Hz, 1H), 3.45 (d, J = 5.4 Hz, 2H), 1.11 (s, 6H).

[0980] Step B: 2,2-dimethyl-3-oxopropanoic acid benzyl ester

[0981] Oxalyl chloride (2.18 g, 0.017 mol) was added dropwise to a solution of DMSO (2.65 g, 0.034 mol) in DCM (50 mL) at -70 °C and stirred for 15 min. A solution of 3-hydroxy-2,2-dimethylpropanoic acid benzyl ester (3.0 g, 0.014 mol) in DCM (10 mL) was added and the system was stirred at -70 °C for 1 h and then TEA (5.65 g, 0.056 mol) was added and the reaction was continued at 20 °C for 1 h. TLC showed the completion of the reaction. The reaction was quenched with water (50 mL) and extracted with DCM (50 mL). The organic phase was concentrated and purified by column chromatography to get a colorless oil (2.4 g).

[0982] 1 H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 7.43-7.31 (m, 5H), 5.18 (s, 2H), 1.30 (s, 6H).

[0983] Step C: 3,3-difluoro-2,2-dimethylpropanoic acid benzyl ester

[0984] Benzyl 2,2-dimethyl-3-oxopropanoate (1.0 g, 4.86 mmol) was dissolved in DCM (10 mL) and DAST (1.5 mL) was added dropwise. The system was allowed to react at 25 °C for 16 h. TLC showed the completion of the reaction. The reaction was quenched with water (30 mL) and extracted with DCM (50 mL). The organic phase was concentrated and purified by column chromatography to get a yellow oil (1.0 g).

[0985] 1 H NMR (400 MHz, DMSO-d6): δ 7.45-7.28 (m, 5H), 6.23 (t, J = 55.9 Hz, 1H), 5.19 (s, 2H), 1.24 (s, 6H).

[0986] Step D: 3,3-difluoro-2,2-dimethylpropanoic acid

[0987] Benzyl 3,3-difluoro-2,2-dimethylpropanoate (1.0 g, 4.385 mmol) was dissolved in EtOH (20 mL) and Pd / C (10%, 0.5 g) was added. The system was allowed to react under H2atmosphere at 25 °C for 16 h. LC-MS showed the completion of the reaction. The reaction was filtered and concentrated to get a colorless oil (450 mg).

[0988] LC-MS: (ES +): m / z 137.1 [M-1] + .

[0989] Step E: 3,3-Difluoro-2,2-dimethylpropanoic acid-N-succinimidyl ester

[0990] 3,3-Difluoro-2,2-dimethylpropanoic acid (450 mg, 3.26 mmol), N-hydroxysuccinimide (450 mg, 3.91 mmol), EDCI (747 mg, 3.91 mmol) were dissolved in DCM (10 mL) and the system was reacted at 20 °C for 16 hours. TLC showed that the reaction was complete, the reaction solution was concentrated and purified by column chromatography to obtain a white solid (500 mg).

[0991] LC-MS: (ES + ): m / z 236.2 [M+1] + .

[0992] Step F: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(3,3-difluoro-2,2-dimethylpropanamido)acetic acid

[0993] (Z)-2-Amino-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)acetic acid (100 mg, 0.22 mmol, from Example 5), 3,3-difluoro-2,2-dimethylpropanoic acid-N-succinimidyl ester (78 mg, 0.333 mmol), NaHCO3(56 mg, 0.666 mmol) were dissolved in THF (5 mL) and H2O (5 mL) and the system was reacted at 25 °C for 16 hours. The reaction was filtered, the filtrate was concentrated and purified by prep-HPLC to obtain a yellow solid (11.0 mg).

[0994] LC-MS: (ES + ): m / z 571.1 [M+1] + .

[0995] 1H NMR (400MHz, DMSO-d6): δ8.36(d,J=7.3Hz,1H),7.87(d,J=8.2Hz,2H),7.73(s,1H),7.59(d,J=8.3Hz,2H),7.41(d, J=3.7Hz,1H),7.36-7.29(m,5H),6.24(t,J=56.4Hz,1H),5.48(d,J=7.3Hz,1H),5.26(s,2H),1.23(d,J=5.1Hz,6H).

[0996] Example 96: (Z)-2-(4-(5-((3-(3-morpholinyl)-4-oxo-2-thiotetrahydrothiazolyl-5-ylidene)methyl)furan-2-yl)phenyl)-2-pentanamide acetic acid

[0997] Step A: 3-Morphyrin phenyl cyanide

[0998] Weigh 20 g (0.165 mol) of m-fluorobenzonitrile and 28.8 g (0.303 mol) of morpholine into a 500 mL three-necked flask, and add 200 mL of DMSO and 45.6 g (0.30 mol) of potassium carbonate. Heat the system to 120 °C and maintain this temperature overnight. Cool the reaction solution to room temperature and slowly add it to 1000 mL of ice water. With vigorous stirring, a white solid precipitates. Filter and dry to obtain 5 g of white solid.

[0999] LC-MS (m / z) 189.10 [M+1] +

[1000] Step B: (3-morpholinophenyl)-methylamine

[1001] Weigh 4.9 g (26.0 mmol) of 3-morpholine phenyl cyanide into a 250 mL three-necked flask, add 80 mL of THF, and cool the system to 0 °C. While maintaining 0 °C, add LiAlH4 (2.96 g, 78.0 mmol) in portions; bubbles emerge and the temperature rises significantly. After the addition is complete, allow the system to warm freely to room temperature, then transfer it to an oil bath at 60 °C and incubate overnight. Slowly add the reaction solution dropwise to 400 mL of ice water, extract with ethyl acetate (80 mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a solid product (3.0 g).

[1002] LC-MS (m / z) 193.3 [M+1] +

[1003] Step C: 3-(3-morpholinyl)-2-thiotetrahydrothiazo-4-one

[1004] A solution of (3-morpholinophenyl)methanamine (2 g, 10.4 mmol), 2,2'-(thiocarbonylbis(sulfonyl di))diacetic acid (3.54 g, 15.6 mmol), and TEA (3.16 g, 31.2 mmol) in DME (30 mL) was prepared in a microwave vial. The reaction was heated at 100 °C in a microwave reactor for 20 min, and the solution color changed from yellow to red-brown. LCMS confirmed the reaction was complete. The reaction was cooled to room temperature and concentrated. The residue was purified by silica gel column to give a yellow solid (1.8 g).

[1005] LC-MS (m / z) 309.1 [M+1] +

[1006] Step D: (Z)-2-(4-(5-((3-(3-morpholinobenzyl)-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamide

[1007] A solution of 3-(3-morpholinobenzyl)-2-thioxotetrahydrothiazol-4-one (200 mg, 0.61 mmol), 2-(4-(5-formylfuran-2-yl)phenyl)-2-pivalamide (199.8 mg, 0.61 mmol; from Example 84), piperidine hydrochloride (81.0 mg, 0.61 mmol), and triethylamine (61.3 mg, 0.61 mmol) was prepared in methanol (5 mL). The reaction was heated to 80 °C for 3 h. TLC confirmed the complete conversion of the starting material. The reaction was cooled to room temperature, and 10 mL of water was added. The solid was filtered, slurried with 10 mL of methanol, and dried to give a red solid (140 mg).

[1008] LC-MS (m / z) 620.2 [M+1] +

[1009] 1 H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.36 (dd, J = 22.1, 3.7 Hz, 2H), 7.18 (t, J = 7.9 Hz, 1H), 6.93 (s, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 7.5 Hz, 1H), 5.44 (d, J = 7.4 Hz, 1H), 5.19 (s, 2H), 3.71 (dd, J = 17.0, 12.2 Hz, 4H), 3.11 - 2.96 (m, 4H), 1.16 (s, 9H).

[1010] Example 97: (Z)-2-(4-(5-((3-(but-2-yn-1-yl)-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)-2-methoxyphenyl)-2-pivalamidoacetic acid

[1011] Step A: 2-(4-bromo-2-methoxyphenyl)-2-pivalamidoacetic acid

[1012] Into a reaction flask was added a solution of 2-amino-2-(4-bromo-2- methoxyphenyl)acetic acid (2.4 g, 9.22 mmol) in THF (24 mL) and a solution of K2CO3 (1.91 g, 13.82 mmol) in water (12 mL). The mixture was cooled to 0 °C, and pivaloyl chloride (1.34 g, 11.11 mmol) was added slowly. The mixture was stirred at room temperature for 4 h. The reaction was diluted with ethyl acetate (20 mL), and the pH was adjusted to 5 with 2N HCl. The mixture was extracted with ethyl acetate (20 mL x 2), and the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to give a white solid. The white solid was slurried in ethyl acetate (30 mL) for 30 min, and the target compound (2.1 g) was collected by filtration.

[1013] LC-MS (m / z) 344.0, 346.0 [M+1] +

[1014] Step B: 2-(4-(5-formylfuran-2-yl)-2-methoxyphenyl)-2-pivalamidoacetic acid

[1015] Into a 50 mL single-necked reaction flask was added 2-(4-bromo-2-methoxyphenyl)-2- pivalamidoacetic acid (1 g, 2.91 mmol), dioxane / H2O (5:1, 18 mL), (5-formylfuran-2- yl)boronic acid (812.89 mg, 5.82 mmol), and Pd(dppf)Cl2(213 mg, 0.29 mmol). After the addition was complete, the reaction system was purged with nitrogen three times, and the temperature was increased to 100 °C for 3 h. The reaction was monitored by LC-MS. After the reaction was complete, the system was cooled to room temperature, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL x 3), and the aqueous phase was adjusted to pH = 3-4 with 4N HCl. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous Na2SO4, and concentrated to give the target compound (1 g).

[1016] LC-MS (m / z) 360.1 [M+1] +

[1017] Step C: (Z)-2-(4-(5-((3-(but-2-yn-1-yl)-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)-2-methoxyphenyl)-2-pivalamidoacetic acid

[1018] To 2-(4-(5-formylfuran-2-yl)-2-methoxyphenyl)-2-pivalamidoacetic acid (250 mg, 0.70 mmol), 3-(but-2-yn-1-yl)-2-thioxotetrahydrothiazol-4-one (129.0 mg, 0.70 mmol), piperidine hydrochloride (85.0 mg, 0.70 mmol) and triethylamine (70.0 mg, 0.70 mmol) were added to methanol (5 mL). The reaction was stirred at 80 °C for 3 hours. After TLC confirmed the complete conversion of the starting material, it was cooled to room temperature, 10 mL of water was added, filtered, the solid was slurried with 10 mL of methanol and oven dried to give a red solid (200 mg).

[1019] 1 H NMR (400 MHz, DMSO-d6): δ 7.83-7.52 (m, 2H), 7.54-7.42 (m, 5H), 5.75 (s, 1H), 4.77 (s, 2H), 3.98 (s, 3H), 1.82 (s, 3H), 1.16 (s, 9H).

[1020] Example 98: (Z)-2-(4-(5-((3-(4-morpholinobut-2-yn-1-yl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1021] To compound 2-(4-(5-formylfuran-2-yl)phenyl)-2-pivalamidoacetic acid (50 mg, 0.15 mmol; from Example 84) was added to Dioxane / AcOH (5 mL / 0.5 mL), 3-(4- morpholinobut-2-yn-1-yl)-2-thioxotetrahydrothiazol-4-one (41 mg, 0.15 mmol) and ammonium acetate (17.5 mg, 0.23 mmol) were added at room temperature, the reaction was stirred at 120 °C for 2 hours, LCMS showed the reaction was complete. The reaction was then concentrated to give a solid, 5 mL of methanol, 10 mL of water were added, slurried, filtered, the filter cake was reslurried with 5 mL of methanol, oven dried to give a yellow solid (60 mg).

[1022] LC-MS (m / z) 582.2 [M+1] +

[1023] 1H NMR (400 MHz, DMSO-d6): δ 12.99 (s, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.76 (s, 1H), 7.59 (d, J = 11.6 Hz, 2H), 7.41 (d, J = 3.8 Hz, 1H), 7.34 (d, J = 3.7 Hz, 1H), 5.43 (d, J = 7.4 Hz, 1H), 4.83 (s, 2H), 3.62 - 3.50 (m, 4H), 3.27 (s, 1H), 3.17 (s, 1H), 2.43 - 2.36 (m, 4H), 1.15 (s, 9H).

[1024] Example 99: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(tert-butyl(methyl)amino)acetic acid

[1025] Step A: tert-Butyl 2-(4-bromophenyl)-2-(tert-butyl(methyl)amino)acetate

[1026] Into the reaction bottle, tert-butyl 2-bromo-2-(4-bromophenyl)acetate (200 mg, 0.571 mmol), N-methyl-tert-butylamine (99 mg, 1.142 mmol), K2CO3 (157 mg, 1.142 mmol), ACN (4 mL) were added, after the addition was completed, the reaction system was replaced with nitrogen for three times, and then the temperature was increased to 55 °C for reaction for 4 h. LCMS was used to monitor the complete reaction of the raw material. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated. Purification was performed by column chromatography (PE:EA = 5: 1) to obtain a yellow oil (140 mg).

[1027] LC-MS: (ES + ): m / z 358.1 [M+1] + .

[1028] Step B: tert-Butyl 2-(tert-butyl(methyl)amino)-2-(4-(5-formylfuran-2-yl)phenyl)acetate

[1029] To a reaction flask was added tert-butyl 2-(4-bromophenyl)-2-(tert- butyl(methyl)amino)acetate (140 mg, 0.39 mmol), (5-formylfuran-2-yl)boronic acid (71 mg, 0.51 mmol), DIEA (152 mg, 1.179 mmol) and Pd(PPh3)2Cl2 (27 mg, 0.039 mmol), Dioxane / H2O (5 mL / 1 mL) was added, the reaction system was replaced with nitrogen for three times, and then the temperature was raised to 80 °C for reaction for 2 h. LC-MS monitoring showed that the raw material was completely reacted, the system was concentrated to dryness, and column chromatography (PE:EA = 5:1) was used for purification to obtain a yellow oil (90 mg).

[1030] LC-MS:(ES + ): m / z 372.2 [M+1] + .

[1031] Step C: tert-butyl (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(tert-butyl(methyl)amino)acetate

[1032] To a reaction flask was added tert-butyl 2-(tert-butyl(methyl)amino)-2-(4-(5- formylfuran-2-yl)phenyl)acetate (90 mg, 0.24 mmol), 3-benzyl-2-thioxotetrahydrothiazol-4- one (54 mg, 0.24 mmol), piperidine hydrochloride (29 mg, 0.24 mmol), TEA (49 mg, 0.48 mmol), MeOH (6 mL), and the system was reacted at 80 °C for 4 h. LC-MS showed that the reaction was complete, water (6 mL) was added to the reaction solution, and the system was stirred and filtered. The filter cake was dried to obtain a yellow solid (80 mg).

[1033] LC-MS:(ES + ): m / z 577.2 [M+1] +， Rt = 5.074 min.

[1034] Step D: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5-yl)methyl)furan-2- yl)phenyl)-2-(tert-butyl(methyl)amino)acetic acid

[1035] To a reaction flask was added (Z)-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-(tert- butyl(methyl)amino)acetate tert-butyl ester (80 mg, 0.165 mmol), TEA (42 mg, 0.42 mmol), TMSOTf (92 mg, 0.42 mmol), DCM (10 mL), the system reacted at 55 °C for 16 h. LCMS showed that the reaction was complete, the reaction liquid was concentrated, purified by prep-HPLC to obtain a yellow solid (41.0 mg).

[1036] LC-MS: (ES + ): m / z 521.1 [M+1] + .

[1037] 1 H NMR (400 MHz, DMSO-d6): δ 7.96 (d, J = 8.2 Hz, 2H), 7.75 (s, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.43 (s, 2H), 7.37 - 7.27 (m, 5H), 5.33 (s, 1H), 5.26 (s, 2H), 2.50 (s, 3H), 1.15 (s, 9H).

[1038] Example 100: (Z)-2-(4-(5-((3-(4-morpholinobenzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-tert- butylamino)acetic acid

[1039] Step A: 4-morpholinobenzonitrile

[1040] Compound 4-fluorobenzonitrile (2.3 g, 19 mmol) and K2CO3(5.3 g, 38 mmol) were dissolved in DMSO (30 mL), under nitrogen protection, dropwise added morpholine (2.5 g, 28.5 mmol), and stirred at 100 °C for 6 h. LC-MS detected that the reaction was complete, the reaction liquid was added to 100 mL water, extracted with EA (100 mL) twice, the combined organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous sodium sulfate, rotary evaporation to get the crude product, column chromatography to obtain the target compound (1.6 g, yield 44.8%).

[1041] LC-MS (m / z) [M+1] + = 189.2

[1042] Step B: (4-morpholinophenyl)methanamine

[1043] To a solution of 4-morpholinobenzonitrile (1.6 g, 8.5 mmol) in THF (100 mL) was added LiAlH4(3.2 g, 85 mmol) portionwise at 0 °C, then the mixture was stirred at 60 °C for 6 h. LC-MS showed the reaction was complete. The reaction mixture was quenched with water (50 mL) slowly at 0 °C, then filtered to remove the white insoluble substance. The filtrate was extracted with EA (100 mL) twice, washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give the target compound (810 mg, yield 49.7%).

[1044] LC-MS (m / z) [M+1] + = 193.2

[1045] Step C: 3-(4-morpholinobenzyl)-2-thioxothiohydantoin

[1046] To a solution of (4-morpholinophenyl)methanamine (0.81 g, 4.2 mmol), 2,2'-(thiocarbonylbis(sulfinyldi))diacetic acid (1.4 g, 6.3 mmol), TEA (1.3 g, 12.6 mmol) in DME (20 mL) was heated at 100 °C for 10 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated to dryness directly after cooling, and purified by column chromatography to give a yellow solid (660 mg, yield 50.8%).

[1047] LC-MS (m / z) [M-1] + = 309.1, Rt = 3.57 min

[1048] Step D: (Z)-2-(4-(5-((3-(4-morpholinobenzyl)-4-oxo-2-thioxothiohydantoin-5- ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1049] To a solution of 3-(4-morpholinobenzyl)-2-thioxothiohydantoin (A19-30-3, 100 mg, 0.3 mmol), 2-(4-(5-formylfuran-2-yl)phenyl)-2-pivalamidoacetic acid (93 mg, 0.3 mmol; from Example 84), NH4OAc (35 mg, 0.45 mmol) in 1.4-dioxane / acetic acid (4 mL / 0.4 mL) was heated at 120 °C for 2 h. The reaction mixture was concentrated to dryness directly after cooling, and slurried in methanol / water (10 mL / 10 mL) for 30 min before filtration. The filter cake was further slurried in methanol (10 mL) and suction filtered. The solid was dried to give the red solid compound (127.5 mg, yield 67.6%).

[1050] 1 H NMR (400 MHz, DMSO-d6): δ 7.97 (d, J = 5.3 Hz, 1H), 7.84 (d, J = 6.0 Hz, 2H), 7.71 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 6.0 Hz, 2H), 7.39 (s, 1H), 7.33 (s, 1H), 7.24 (d, J = 6.4 Hz, 2H), 6.90 (d, J = 6.5 Hz, 2H), 5.41 (d, J = 4.6 Hz, 1H), 5.15 (s, 2H), 3.71 (s, 4H), 3.07 (s, 4H), 1.16 (s, 9H).

[1051] Example 101: (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-l-yl)benzyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid hydrochloride

[1052] Step A: l-tert-Butoxycarbonyl-4-(4-cyanophenyl)piperazine

[1053] Into a reaction flask was added compound 4-fluorobenzonitrile (3 g, 2.47 mmol), DMSO (30 mL), l-tert-butoxycarbonylpiperazine (6.9 g, 3.71 mmol), K2CO3(6.8 g, 4.95 mmol), replaced with nitrogen, warmed to 100 °C for 2 h, LCMS monitored until the starting material was consumed. Added EA, water, extracted, dried over anhydrous sodium sulfate, concentrated. Purified by column chromatography to obtain the target compound (3.3 g, 46.4%).

[1054] 1 H NMR (400 MHz, DMSO-d6): δ 7.58 (d, J = 4.8 Hz, 2H), 7.02 (d, J = 4.8 Hz, 2H), 3.45 (s, 4H), 3.36-3.32 (d, J = 4.8 Hz, 4H), 1.42 (s, 9H).

[1055] Step B: l-tert-Butoxycarbonyl-4-(4-(aminomethyl)phenyl)piperazine

[1056] Into a reaction flask was added l-tert-butoxycarbonyl-4-(4-cyanophenyl)piperazine (3 g, 10.45 mmol), MeOH (120 mL), Raney Ni, after the addition was completed, the reaction system was replaced with hydrogen three times, and reacted at 25 °C for 16 h. LCMS was used to monitor until the starting material was consumed. The reaction solution was concentrated after being sucked out with a dropper, and purified by column chromatography to obtain the compound (900 mg, 29.6%).

[1057] LC-MS (m / z) [M+1] 408.1. + = 292.2.

[1058] Step C: 1-tert-Butoxycarbonyl-4-(4-((4-oxo-2-thioxotetrahydrothiazol-3- yl)methyl)phenyl)piperazine

[1059] To the reaction flask was added 1-tert-butoxycarbonyl-4-(4-(aminomethyl)phenyl)piperazine (900 mg, 3.09 mmol), 2,2'-(thiocarbonylbis(sulfonyl di))diacetic acid (1.05 g, 4.63 mmol) and TEA (937 mg, 9.27 mmol), DME (20 mL), 100 °C for 16 h, LCMS monitored the reaction was complete. The reaction was concentrated and purified by column chromatography to give the compound (600 mg, 47.6%).

[1060] LC-MS (m / z) [M+1] 408.1. + = 292.2.

[1061] Step D: (Z)-2-(4-(5-((3-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-tert-pentylaminoacetic acid

[1062] To the reaction flask was added 1-tert-butoxycarbonyl-4-(4-(aminomethyl)phenyl)piperazine (900 mg, 3.09 mmol), 2,2'-(thiocarbonylbis(sulfonyl di))diacetic acid (1.05 g, 4.63 mmol) and TEA (937 mg, 9.27 mmol), DME (20 mL), 100 °C for 16 h, LCMS monitored the reaction was complete. The reaction was concentrated and purified by column chromatography to give the compound (600 mg, 47.6%).

[1063] 1H NMR (400 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.76 (d, J = 7.7 Hz, 2H), 7.67 (s, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 3.7 Hz, 1H), 7.26 (d, J = 3.7 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.19-5.09 (m, 3H), 3.42 (t, J = 5.4 Hz, 4H), 3.06 (t, J = 5.3 Hz, 4H), 1.41 (s, 9H), 1.16 (s, 9H).

[1064] Step E: (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-l-yl)benzyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid hydrochloride

[1065] To the reaction bottle was added (Z)-2-(4-(5-((3-(4-(4-(tert- butoxycarbonyl)piperazin-l-yl)benzyl)-4-oxo-2-thioxotetrahydrothiazol-5- ylidenemethyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid (200 mg, 0.27 mmol), DCM (2 mL) and HCl (4 M in dioxane, 2 mL) successively, and the mixture was reacted at 25 °C for 1 h. TLC monitoring showed that the starting material was completely reacted. EA was added to the reaction solution to slurry, and the slurry was filtered and freeze-dried to obtain the target product (130 mg, 71.4%).

[1066] 1 H NMR (400 MHz, DMSO-d6): δ 8.98 (br, 2H), 7.99 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.41 (s, 1H), 7.35 (s, 1H), 7.26 (d, J = 8.3 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 5.45 (d, J = 7.5 Hz, 1H), 5.16 (s, 2H), 3.32 (d, J = 5.3 Hz, 4H), 3.19 (t, J = 2.4 Hz, 4H), 1.15 (s, 9H).

[1067] Example 102: (Z)-2-(4-(5-((3-(4-(4-methylpiperazin-l-yl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid hydrochloride

[1068] Step A: 4-(4-methylpiperazin-1-yl)benzonitrile

[1069] Into a reaction flask was added 4-fluorobenzonitrile (3 g, 24.8 mmol), DMSO (30 mL), 1-methylpiperazine (3.7 g, 37.2 mmol), K2CO3(6.84 g, 74.4 mmol), replaced with nitrogen, and warmed to 100 °C for 2 h. LC-MS was used to monitor the reaction. The reaction solution was added to 50 mL of water and extracted with EA (30 mL*3) three times. The organic phase was combined and washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The crude product was purified by column chromatography to obtain a yellow solid (1.2 g).

[1070] LC-MS (m / z) [M+1] + = 202.2

[1071] Step B: (4-(4-methylpiperazin-1-yl)phenyl)methanamine

[1072] Into a reaction flask was added 4-(4-methylpiperazin-1-yl)benzonitrile (2.5 g, 12.4 mmol), THF (100 mL), and LiAlH4(4.71 g, 124 mmol) was added portionwise under ice bath. After the addition was completed, the reaction system was replaced with nitrogen three times, and warmed to 60 °C for 16 h. LC-MS was used to monitor the reaction. The reaction system was slowly quenched with water under ice bath, and filtered under suction. The residue was washed with MeOH (100 mL) three times, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (1.5 g).

[1073] LC-MS (m / z) [M+1] + = 206.2

[1074] Step C: 3-(4-(4-methylpiperazin-1-yl)phenyl)-2-thioxothiohydantoin

[1075] Into a reaction flask was added (4-(4-methylpiperazin-1-yl)phenyl)methanamine (1.5 g, 7.31 mmol), DME (35 mL), and 2,2'-(thiocarbonylbis(sulfinyldi))diacetic acid (2.48 g, 10.97 mmol), TEA (2.22 g, 21.95 mmol), and the mixture was reacted at 100 °C for 16 h. LC-MS was used to monitor the reaction. The reaction solution was concentrated, and the crude product was purified by column chromatography to obtain a white solid (1.6 g).

[1076] LC-MS (m / z) [M+1] + = 322.1.

[1077] Step D: (Z)-2-(4-(5-((3-(4-(4-methylpiperazin-l-yl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid hydrochloride

[1078] Into a reaction bottle was added 3-(4-(4-methylpiperazin-l-yl)phenyl)-2- thioxotetrahydrothiazol-4-one (200 mg, 0.62 mmol), 2-(4-(5-formylfuran-2-yl)phenyl)- 2-pivalamidoacetic acid (205 mg, 0.62 mmol), piperidine hydrochloride (76 mg, 0.62 mmol), TEA (126 mg, 1.24 mmol), methanol (20 mL), after the addition was completed, the temperature was raised to 80 °C for 4 hours, LC-MS monitored the completion of the reaction. The system was reduced to room temperature, concentrated and purified by Flash (hydrochloric acid water system), freeze-dried to obtain a yellow solid (49 mg).

[1079] LC-MS (m / z) 633.2 [M+l] +

[1080] 1 H NMR (400 MHz, DMSO-d6): δ 10.83 (br, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.71 (s, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.43 - 7.14 (m, 4H), 6.96 (d, J = 8.6 Hz, 2H), 5.45 (d, J = 7.4 Hz, 1H), 5.16 (s, 2H), 3.79 (d, J = 10.2 Hz, 2H), 3.45 (d, J = 9.3 Hz, 2H), 3.20 - 2.98 (m, 4H), 2.78 (d, J = 4.1 Hz, 3H), 1.15 (s, 9H).

[1081] Example 103: (Z)-2-(4-(5-((3-(4-(morpholinosulfonyl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1082] Step A: 4-(morpholinosulfonyl)benzonitrile

[1083] Compound 4-cyanobenzenesulfonyl chloride (3.0 g, 14.98 mmol) was added to DCM (30 mL), then TEA (4.5 g, 44.94 mmol), morpholine (1.55 g, 17.98 mmol) was added, stirred at room temperature for 2 h. LCMS showed the reaction was completed. The reaction solution was added to 20 mL water to quench the reaction, extracted with DCM three times (60 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The crude product was purified by column to obtain a white solid compound (2.1 g).

[1084] 1 H NMR (400 MHz, DMSO-d6): δ 8.15 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 3.64-3.61 (m, 4H), 2.95-2.90 (m, 4H).

[1085] Step B: (4-(Morpholine sulfonyl)phenyl)methanamine

[1086] Compound 4-(morpholine sulfonyl)benzonitrile (2.0 g, 7.93 mmol) was added to MeOH (30 mL), then Ni (2.0 g) was added, replaced with H2, stirred at room temperature for 2 h. LCMS showed the reaction was completed, filtered with diatomite, eluted with MeOH (20 mL), concentrated, and purified by reverse phase column to obtain a white solid compound (720 mg).

[1087] 1 H NMR (400 MHz, DMSO-d6): δ 8.28 (br, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 4.18 (s, 2H), 3.65-3.61 (m, 4H), 2.89-2.83 (m, 4H).

[1088] Step C: 3-(4-(Morpholine sulfonyl)benzyl)-2-thioxothiohydantoin

[1089] Compound (4-(morpholine sulfonyl)phenyl)methanamine (300 mg, 1.17 mmol) was added, then 2,2'-(thiocarbonylbis(sulfonyl di))diacetic acid (397 mg, 1.75 mmol), TEA (355 mg, 3.51 mmol), DME (10 mL) was added, replaced with N2, and reacted in a microwave for 30 min. LCMS showed the reaction was completed. The reaction solution was evaporated, and the crude product was purified by column to obtain a white solid compound (223 mg).

[1090] 1H NMR (400 MHz, DMSO-d6): δ 7.70 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 5.17 (s, 2H), 4.37 (s, 2H), 3.65-3.59 (m, 4H), 2.88-2.81 (m, 4H).

[1091] Step D: (Z)-2-(4-(5-((3-(4-(morpholine-4-sulfonyl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1092] Compound 3-(4-(morpholine-4-sulfonyl)benzyl)-2-thioxotetrahydrothiazol-4-one (100 mg, 0.27 mmol) was added to Dioxane / AcOH (4 mL / 0.2 mL), then 2-(4-(5- formylfuran-2-yl)phenyl)-2-pivalamidoacetic acid (88 mg, 0.27 mmol; from Example 84), NH4OAc (31 mg, 0.40 mmol) were added, stirred at 120 °C for 2 h. LCMS showed the reaction was completed. The reaction was rotary evaporated, MeOH / H2O (3 mL / 9 mL) was added, stirred for 1 h, filtered, the filter cake was stirred with MeOH / DCM (4 mL / 0.2 mL) for 1 h, filtered, the filter cake was dried to give the compound (121 mg) as a yellow solid.

[1093] 1 H NMR (400 MHz, DMSO-d6): δ 7.97 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 7.8 Hz, 4H), 7.42 (d, J = 3.6 Hz, 1H), 7.35 (d, J = 3.6 Hz, 1H), 5.39 (d, J = 7.2 Hz, 1H), 5.36 (s, 2H), 3.63-3.59 (m, 4H), 2.86-2.82 (m, 4H), 1.15 (s, 9H).

[1094] Example 104: (Z)-2-(4-(5-((4-oxo-3-(2-(piperazin-l-ylmethyl)benzyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1095] Step A: l-tert-Butoxycarbonyl-4-(2-cyanobenzyl)piperazine

[1096] Step A: 1 -tert-butoxycarbonyl-4-(2-(bromomethyl)benzyl)piperazine Into DMF (10 mL) was placed 2-(bromomethyl)benzonitrile (5 g, 25.5 mmol), NaH (1.32 g, 33.1 mmol) was added portionwise under ice bath, the reaction was stirred at room temperature for 30 min before piperazine-1-tert-butoxycarbonyl (5.69 g, 30.6 mmol) was added, the reaction was stirred at 25 °C for 4 h. LC-MS showed the reaction was complete, the reaction was diluted with 50 mL water, extracted with EA (80 mL*3), the organic phase was combined and washed with 30 mL saturated brine, dried over Na2SO4, filtered and concentrated to give a yellow solid (4 g).

[1097] LC-MS (m / z) 302.2 [M+1] +

[1098] Step B: 1 -tert-butoxycarbonyl-4-(2-(aminomethyl)benzyl)piperazine

[1099] Into MeOH / NH3-H2O (10 mL / 0.5 mL) was placed 1 -tert-butoxycarbonyl-4-(2- cyanobenzyl)piperazine (500 mg, 1.66 mmol), Raney nickel (1 g) was added, the hydrogen was replaced for 3 times, the reaction was stirred at 20 °C under hydrogen atmosphere for 12 h. LC-MS showed the reaction was complete, the reaction was filtered, concentrated to give a white solid (500 mg).

[1100] LC-MS (m / z) 306.3 [M+1] + .

[1101] Step C: 1 -tert-butoxycarbonyl-4-(2-((4-oxo-2-thioxothiazolidin-3-yl)methyl)benzyl)piperazine

[1102] Into DME (15 mL) was placed 1 -tert-butoxycarbonyl-4-(2-(aminomethyl)benzyl)piperazine (500 mg, 2.6 mmol), TEA (495 mg, 3.9 mmol) and 2,2'-(thiocarbonylbis(sulfinyldi))diacetic acid (881 mg, 3.9 mmol). The reaction was heated to 100 °C and stirred overnight. LC-MS showed the reaction was complete, the reaction was concentrated, the crude was purified by silica gel column to give a white solid (600 mg).

[1103] LC-MS (m / z) 422.1 [M+1] +

[1104] Step D: (Z)-2-(4-(5-((3-(2-((4-(tert-butoxycarbonyl)piperazin-l- yl)methyl)benzyl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2- yl)phenyl)-2-pivalamidoacetic acid

[1105] Step D: (Z)-2-(4-(5-((3-(2-((4-(tert-butoxycarbonyl)piperazin-l- yl)methyl)benzyl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2- yl)phenyl)-2-pivalamidoacetic acid

[1106] LC-MS (m / z) 733.3 [M+l] +

[1107] Step D: (Z)-2-(4-(5-((3-(2-((4-(tert-butoxycarbonyl)piperazin-l- yl)methyl)benzyl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2- yl)phenyl)-2-pivalamidoacetic acid

[1108] Step D: (Z)-2-(4-(5-((3-(2-((4-(tert-butoxycarbonyl)piperazin-l- yl)methyl)benzyl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2- yl)phenyl)-2-pivalamidoacetic acid

[1109] LC-MS (m / z) 633.2 [M+l] +

[1110] 1H NMR (400 MHz, DMSO-d6): δ 8.68 (br, 2H), 8.01 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.76 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 3.8 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.26 (dd, J = 5.5, 3.4 Hz, 2H), 6.96 - 6.89 (m, 1H), 5.49 (s, 1H), 5.46 (d, J = 7.6 Hz, 2H), 3.80 (s, 2H), 3.18 - 3.05 (m, 4H), 2.70 - 2.53 (m, 4H), 1.16 (s, 9H).

[1111] Example 105: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(1-fluorocyclopropane-1-carboxamido)acetic acid

[1112] Step A: 1-Fluorocyclopropane-1-carboxylic acid N-succinimidyl ester

[1113] 1-Fluorocyclopropane-1-carboxylic acid (1 g, 9.6 mmol), N-hydroxysuccinimide (1.1 g, 9.6 mmol), DCC (2.0 g, 9.6 mmol) and DMAP (116 mg, 0.96 mmol) were dissolved in DCM (15 mL) and reacted at 25 °C for 4 h. The reaction was detected to be complete by LC-MS, and the reaction solution was directly concentrated to dryness and purified by column to obtain the target compound (540 mg, yield 28.0%).

[1114] LC-MS (m / z) [M+1] + = 202.1.

[1115] Step B: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(1-fluorocyclopropane-1-carboxamido)acetic acid

[1116] (Z)-2-amino-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)acetic acid (100 mg, 0.22 mmol; from example 5), 1- fluorocyclopropane-1 -carboxylic acid- N -succinimidyl ester (66 mg, 0.33 mmol), NaHC03(55 mg, 0.66 mmol) were dissolved in THF / H20 (5 mL / 5 mL) and stirred at 25 °C for 10 h. The reaction was checked by HPLC and was complete. The reaction was concentrated to dryness and slurried in methanol / water (5 mL / 5 mL) for 30 min and filtered to give the crude product. The crude product was slurried in methanol (5 mL) for 30 min and filtered to dryness to give the target product (30.2 mg, 25.4% yield).

[1117] 1 H NMR (400 MHz, DMSO-d6): δ 8.67 (d, J = 6.5 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 3.7 Hz, 1H), 7.37-7.25 (m, 6H), 5.26 (s, 3H), 1.38-1.09 (m, 4H).

[1118] Example 106: (Z)-2-(4-(5-((3-(but-2-yn-1-yl)-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1119] To a reaction flask was added 2-(4-(5-formylfuran-2-yl)phenyl)-2- pivalamidopropanoic acid (270 mg, 0.78 mmol; from example 87), 3-(but-2-yn-1-yl)- 2-thioxotetrahydrothiazol-4-one (144 mg, 0.78 mmol), ammonium acetate (92 mg, 1.17 mmol), AcOH (5 mL). After the addition was complete, the reaction was purged with nitrogen three times and heated to 120 °C for 2 h. The reaction was cooled and added to water / methanol (20 mL / 4 mL). The mixture was stirred and filtered. The filter cake was slurried in methanol (10 mL) and filtered. The solid was dried and purified by preparative HPLC to give the target compound (63.7 mg, 16% yield).

[1120] LC-MS (m / z) [M+1] + = 511.1.

[1121] 1H NMR (400 MHz, DMSO-d6): δ 7.83 (d, J = 8.4 Hz, 2H), 7.74-7.73 (m, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 4.0 Hz, 1H), 4.75 (d, J = 2.4 Hz, 2H), 1.83 (s, 3H), 1.78 (s, 3H), 1.61 (s, 9H).

[1122] Example 107: (Z)-2-(4-(5-((3-(4-(morpholine methyl)benzyl)-4-oxo-2- thioxotetrahydrothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-tert- butylaminoacetic acid

[1123] Step A: 4-(4-cyanobenzyl)morpholine

[1124] Into a reaction flask was placed 4-(bromomethyl)benzonitrile (3.0 g, 0.015 mol), K2CO3(4.14 g, 0.03 mol), DMSO (30 mL), and morpholine (1.99 g, 0.022 mol) was added dropwise. The system was reacted at 20 °C for 20 min, TLC showed that the reaction was completed, the reaction liquid was diluted with water (30 mL), extracted with EA (50 mL), the organic phase was concentrated, and purified by column chromatography to obtain a white solid (2.8 g).

[1125] LC-MS: (ES + ): m / z 203.1 [M+1] + .

[1126] Step B: (4-(morpholine methyl)phenyl)methanamine

[1127] Into a reaction flask was placed 4-(4-cyanobenzyl)morpholine (1.2 g, 5.94 mmol), THF (50 mL), then LiAlH4(1.12 g, 29.70 mmol) was slowly added, and the system was reacted at 25 °C for 0.5 h. TLC showed that the reaction was completed, the reaction liquid was slowly added dropwise with H2O (4.4 mL), and NaOH (10%, 1.1 mL) was added to quench the reaction, filtered, and the filtrate was concentrated to obtain a yellow solid (860 mg).

[1128] LC-MS: (ES + ): m / z 207.2 [M+1] + .

[1129] Step C: 3-(4-(morpholine methyl)benzyl)-2-thioxotetrahydrothiazol-4-one

[1130] To a reaction flask was added (4-(morpholinomethyl)phenyl)methanamine (500 mg, 2.415 mmol), 2,2'-(thiocarbonylbis(sulfonyl di))diacetic acid (818 mg, 3.62 mmol), TEA (731 mg, 7.25 mmol) in DME (10 mL) and microwaved at 90 °C for 15 minutes. TLC showed the reaction was complete and the reaction was concentrated and purified by column chromatography to give a yellow oil (560 mg).

[1131] LC-MS: (ES + ): m / z 323.1 [M+1] + .

[1132] Step D: (Z)-2-(4-(5-((3-(4-(morpholinomethyl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1133] To a reaction flask was added 3-(4-(morpholinomethyl)benzyl)-2- thioxotetrahydrothiazol-4-one (100 mg, 0.31 mmol), NH4OAc (36 mg, 0.47 mmol), 2-(4-(5-formylfuran-2-yl)phenyl)-2-pivalamidoacetic acid (102 mg, 0.31 mmol; from Example 84), dioxane (6 mL), acetic acid (0.3 mL), and the reaction was heated to 120 °C for 4 hours. LC-MS monitoring showed the starting material was consumed and the reaction was concentrated and purified by prep-TLC to give a yellow solid (104.1 mg).

[1134] LC-MS: (ES + ): m / z 634.2 [M+1] + .

[1135] 1 H NMR (400 MHz, DMSO-d6): δ 7.95 (d, J = 7.1 Hz, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.72 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 3.7 Hz, 1H), 7.33 (d, J = 3.7 Hz, 1H), 7.30 - 7.24 (m, 4H), 5.37 (d, J = 7.2 Hz, 1H), 5.23 (s, 2H), 3.58 - 3.52 (m, 4H), 3.43 (s, 2H), 2.43 - 2.16 (m, 4H), 1.15 (s, 9H).

[1136] Example 108: (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-l-ylmethyl)benzyl)-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1137] Step A: l-tert-Butoxycarbonyl-4-(4-cyanobenzyl)piperazine

[1138] To a solution of 4-(bromomethyl)benzonitrile (6.0 g, 49.2 mmol) in DMF (150 mL) was added l-tert-butoxycarbonylpiperazine (13.7 g, 73.8 mmol), K2CO3(13.5 g, 98.4 mmol) sequentially. The reaction was stirred at 80 °C for 6 h. LCMS showed the reaction was complete. The reaction was cooled to room temperature and 450 mL of water was added. The white solid was collected by filtration and dried (7.6 g, 51%).

[1139] 1 H NMR (400 MHz, CDC13): δ 7.61 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 3.55 (s, 2H), 3.44-3.43 (m, 4H), 2.39-2.38 (m, 4H), 1.45 (s, 9H).

[1140] Step B: l-tert-Butoxycarbonyl 4-(4-(aminomethyl)benzyl)piperazine

[1141] To a solution of l-tert-butoxycarbonyl-4-(4-cyanobenzyl)piperazine (8.8 g, 29.2 mmol) in MeOH (120 mL) was added Raney nickel (5.0 g) and ammonia (5 mL, 37%) and the reaction was purged with hydrogen three times. The reaction was stirred at room temperature for 6 h. TLC showed the reaction was complete. The reaction was filtered through celite and the filtrate was concentrated to give a light yellow liquid which was used directly in the next step.

[1142] LC-MS (m / z) [M+l] + = 306.2.

[1143] Step C: l-tert-Butoxycarbonyl-4-(4-((4-oxo-2-thioxotetrahydrothiazol-3-yl)methyl)benzyl)piperazine

[1144] DME (150 mL) and stirred at 80 °C for 10 h. The reaction was cooled and concentrated to dryness. The residue was purified by column to give the compound (8.8 g, 74%).

[1145] LC-MS (m / z) [M+1] + = 422.2.

[1146] Step D: (Z)-2-(4-(5-((3-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzyl)-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1147] To a solution of (Z)-2-(4-(5-((3-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzyl)-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid (280 mg, 0.38 mol) in DCM (10 mL) was added TFA (3 mL) and the reaction was stirred at room temperature for 1 h. The reaction was concentrated to dryness and the residue was purified by preparative column to give the product as a brownish yellow solid (196.4 mg, 81% yield).

[1148] LC-MS (m / z) [M+1] + = 733.3.

[1149] Step E: (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-1-ylmethyl)benzyl)-2- thioxothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1150] To a solution of (Z)-2-(4-(5-((3-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzyl)-4- oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid (280 mg, 0.38 mol) in DCM (10 mL) was added TFA (3 mL) and the reaction was stirred at room temperature for 1 h. The reaction was concentrated to dryness and the residue was purified by preparative column to give the product as a brownish yellow solid (196.4 mg, 81% yield).

[1151] LC-MS (m / z) [M+1] 633.2. + = 633.2.

[1152] 1 H NMR (400 MHz, DMSO-d6) : δ 8.85 (s, br., 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.42-7.35 (m, 6H), 5.45 (d, J = 7.6 Hz, 1H), 5.26 (s, 2H), 3.91 (s, 2H), 3.20 (s, br., 4H), 2.89 (s, br., 4H), 1.16 (s, 9H).

[1153] Example 109: (Z)-2-(4-(5-((3-(4-((4-methylpiperazin-l-yl)methyl)benzyl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1154] (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-l-ylmethyl)benzyl)-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid (130 mg, 0.2 mmol) was added to MeOH (20 mL), and aqueous formaldehyde (60 mg, 2.0 mmol, 37%) was added. After stirring at room temperature for 2 h, NaBH(OAc)3(212 mg, 1.0 mmol) was added to the reaction solution, which was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. Water (20 mL) was added to the reaction solution, which was filtered and dried to give a brown-yellow solid (104 mg, 80%).

[1155] LC-MS (m / z) [M+1] 647.3. + = 647.3.

[1156] 1 H NMR (400 MHz, DMSO-d6): δ 7.83-7.79 (m, 3H), 7.71 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 4.0 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.26-7.19 (m, 4H), 5.21 (s, 2H), 5.10 (d, J = 6.0 Hz, 1H), 3.38 (s, br., 6H), 2.32 (s, br., 4H), 2.30 (s, 3H), 1.15 (s, 9H).

[1157] Example 110: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(1-(trifluoromethyl)cyclopropane-1- carboxamido)acetic acid

[1158] Step A: 1-(trifluoromethyl)cyclopropane-1 -carboxylic acid-N-succinimidyl ester

[1159] Into a reaction flask was added 1-(trifluoromethyl)cyclopropane-1 -carboxylic acid (1.3 g, 8.69 mmol), DCM (10 mL), N-hydroxysuccinimide (1 g, 8.69 mmol), DMAP (106 mg, 0.87 mmol), DCC (1.8 g, 8.69 mmol) sequentially, after addition, the reaction was stirred at room temperature for 16 h. The reaction was filtered, the filter cake was washed with 20 mL of DCM, the mother liquor was concentrated and purified by column chromatography (PE:EA = 3:1) to give a white solid (1.5 g).

[1160] 1 H NMR (400 MHz, DMSO-d6): δ 2.84 (s, 4H), 1.84-1.76 (m, 2H), 1.74 (m, J = 8.7 Hz, 2H).

[1161] Step B: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-(1-(trifluoromethyl)cyclopropane-1- carboxamido)acetic acid

[1162] Into a reaction flask was added 1-(trifluoromethyl)cyclopropane-1 -carboxylic acid-N-succinimidyl ester (56 mg, 0.22 mmol), (Z)-2-amino-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)acetic acid (100 mg, 0.22 mmol; from Example 5), DMSO (1.5 mL), TEA (44 mg, 0.44 mmol), after addition, the reaction was stirred at room temperature for 3 h. LC-MS was used to monitor the reaction completion, the reaction was purified by Pre-HPLC to give a yellow solid (12 mg).

[1163] LC-MS (m / z) 587.0 [M+1] +

[1164] 1H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.74 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 3.8 Hz, 1H), 7.37 - 7.26 (m, 6H), 5.46 (d, J = 7.0 Hz, 1H), 5.26 (s, 2H), 1.30 (dd, J = 22.7, 19.7 Hz, 4H).

[1165] Example 111: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- ylidene)methyl)furan-2-yl)-2-methoxyphenyl)-2-pivalaminoacetic acid sodium salt

[1166] Step A: 2-(4-(5-Formylfuran-2-yl)-2-methoxyphenyl)-2-pivalaminoacetic acid methyl ester

[1167] To a reaction flask was added 2-(4-(5-formylfuran-2-yl)-2-methoxyphenyl)-2- pivalaminoacetic acid methyl ester (200 mg, 0.54 mmol), LiOH (100 mg, 4.32 mmol), THF / H2O (2.0 mL / 0.4 mL), and the reaction was stirred at 80 °C for 4 h. LCMS indicated the reaction was complete. The reaction was concentrated and the residue was dissolved in 20 mL water and 20 mL ethyl acetate. The aqueous phase was extracted with 20 mL ethyl acetate twice. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by prep-HPLC to give the title compound (180 mg, 87% yield).

[1168] LC-MS (m / z) 374.1 [M+l]+

[1169] Step B: 2-(4-(5-Formylfuran-2-yl)-2-methoxyphenyl)-2-pivalaminoacetic acid

[1170] To a reaction flask was added 2-(4-(5-formylfuran-2-yl)-2-methoxyphenyl)-2- pivalaminoacetic acid methyl ester (200 mg, 0.54 mmol), LiOH (100 mg, 4.32 mmol), THF / H2O (2.0 mL / 0.4 mL), and the reaction was stirred at 80 °C for 4 h. LCMS indicated the reaction was complete. The reaction was concentrated and the residue was dissolved in 20 mL water and 20 mL ethyl acetate. The aqueous phase was extracted with 20 mL ethyl acetate twice. The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by prep-HPLC to give the title compound (180 mg, 87% yield). .H20 (33.74 mg, 0.8 mmol), THF / H20 (2 mL / 2 mL), after the addition, the reaction system was reacted at 25 °C for 1 h. LCMS detection reaction was complete, the reaction liquid was adjusted to pH = 1-2 with 1M HC1, extracted with 20 mL of ethyl acetate twice, combined organic phase, washed with brine, dried over anhydrous sodium sulfate and concentrated to give the target compound 150 mg.

[1171] LC-MS (m / z) 360.1 [M+1] +

[1172] Step C: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)-2-methoxyphenyl)-2-pivalaminoacetic acid

[1173] To the reaction bottle was added compound 2-(4-(5-formylfuran-2-yl)-2- methoxyphenyl)-2-pivalaminoacetic acid (150 mg, 0.42 mmol), 3-benzyl-2- thioxotetrahydrothiazol-4-one (93.7 mg, 0.42 mmol), NH4OAc (48.3 mg, 0.63 mmol), AcOH (2 mL), after the addition, the reaction system was reacted at 120 °C for 1 h. LCMS detection reaction was complete, 20 mL of water was added, extracted with 20 mL of ethyl acetate twice, combined organic phase, dried over anhydrous sodium sulfate and concentrated, the crude product was washed with methanol to give the target compound (40 mg).

[1174] LC-MS (m / z) 565.1 [M+1] +

[1175] Step D: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)-2-methoxyphenyl)-2-pivalaminoacetic acid sodium

[1176] To the reaction bottle was added compound (Z)-2-(4-(5-((3-benzyl-4-oxo-2- thioxotetrahydrothiazol-5-yl)methyl)furan-2-yl)-2-methoxyphenyl)-2- pivalaminoacetic acid (40 mg, 0.07 mmol), NaOH solution (0.05 M), after the addition, the reaction system was reacted at 25 °C for 1 h, then freeze-dried to give the target product (37.7 mg).

[1177] 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.52-7.43 (m, 3H), 7.43-7.38 (m, 2H), 7.36-7.26 (m, 5H), 5.71 (d, J = 7.9 Hz, 1H), 5.26 (s, 2H), 3.93 (s, 3H), 1.13 (d, J = 3.6 Hz, 9H).

[1178] LC-MS (m / z) 565.1 [M-Na+1] + .

[1179] Example 112: (Z)-2-(4-(5-((3-(4-(4-methylpiperazin-1-yl)but-2-yn-1-yl)-4-oxo-2- thioxotetrahydrothiazol-5-ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid

[1180] (Z)-2-(4-(5-((4-oxo-3-(4-(piperazin-1-yl)but-2-yn-1-yl)-2-thioxotetrahydrothiazol-5- ylidene)methyl)furan-2-yl)phenyl)-2-pivalamidoacetic acid (60 mg, 0.1 mmol) was dissolved in DCM / DMF (5 mL / 2 mL), 37% aqueous formaldehyde (41 mg, 0.5 mmol) was added, and stirring was continued at room temperature for 2 h; then NaBH(OAc)3(106 mg, 0.5 mmol) was added, and the reaction was continued at 50 °C for 10 h. LCMS detection showed that the reaction was complete, the reaction solution was quenched with water (5 mL), extracted with EA (30 mL), and the product was in the aqueous phase. The aqueous phase was concentrated to an oil, which was slurried in methanol / water (5 mL / 3 mL) for 30 min, filtered, and the filter cake was slurried again with methanol (3 mL), suction filtered, and the solid was dried to give the red solid compound (47.3 mg, yield 76.3%).

[1181] 1 H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.77 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 3.7 Hz, 1H), 7.36 (d, J = 3.7 Hz, 1H), 5.47 (d, J = 7.5 Hz, 1H), 4.89 (s, 2H), 3.78 (s, 2H), 2.82 (s, 3H), 2.53 (d, J = 12.8 Hz, 8H), 1.16 (s, 9H).

[1182] Example 113: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazolidin-5- yl)methyl)furan-2-yl)phenyl)-2-(2-fluoro-2-methylpropanamido)acetic acid

[1183] Step A: 2-(4-bromophenyl)-2-(2-fluoro-2-methylpropanamido)acetic acid

[1184] 2-fluoro-2-methylpropanoic acid (400 mg, 3.76 mmol) was added to DCM / DMF (10 mL / 0.2 mL), oxalyl chloride (526.4 mg, 4.12 mmol) was added at 0 °C, protected by nitrogen, the reaction was stirred at 25 °C for 2 hours. TEA (1.14 g, 11.28 mmol) was added at 0 °C, 2-amino-2-(4-bromophenyl)acetic acid (1.0 g, 3.76 mmol), protected by nitrogen, the reaction was stirred at 25 °C for 2 hours, LCMS showed that the reaction was completed. 1M dilute hydrochloric acid was added to the reaction solution to adjust pH = 2-3, extracted with ethyl acetate for 3 times (50 mL). The organic phase was washed with 30 mL of saline, dried over anhydrous sodium sulfate, rotary evaporation of solvent, flash purification to obtain white solid (230 mg).

[1185] LC-MS (m / z) 320.0 [M+1] +

[1186] Step B: 2-(2-fluoro-2-methylpropanamido)-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid

[1187] 2-(4-bromophenyl)-2-(2-fluoro-2-methylpropanamido)acetic acid (230 mg, 0.72 mmol) was added to dioxane / H2O (5 mL / 1 mL), (5-formylfuran-2-yl)boronic acid (202 mg, 1.44 mmol), DIEA (279 mg, 2.17 mmol) and Pd(PPh3)Cl2(50.5 mg, 0.072 mmol) were added, protected by nitrogen. The reaction was stirred at 80 °C for 4 hours. LCMS showed that the reaction was completed, 10 mL of water was added to the reaction solution, and extracted with ethyl acetate for 3 times (30 mL). The organic phase was washed with 30 mL of saline, dried over sodium sulfate, rotary evaporation of solvent, and purified by large plate to obtain yellow solid (80 mg).

[1188] LC-MS (m / z) 334.1 [M+1] +

[1189] Step C: (Z)-2-(4-(5-((3-benzyl-4-oxo-2-thioxotetrahydrothiazol-5- yl)methyl)furan-2-yl)phenyl)-2-(2-fluoro-2-methylpropanamido)acetic acid

[1190] To 2-(2-fluoro-2-methylpropanamido)-2-(4-(5-formylfuran-2-yl)phenyl)acetic acid (80 mg, 0.24 mmol) was added to MeOH (5 mL), 3-benzyl-2-thioxotetrahydrothiazol-4-one (53.8 mg, 0.24 mmol) and piperidine hydrochloride (29.2 mg, 0.24 mmol), TEA (49 mg, 0.48 mmol) at room temperature, the reaction was stirred at 80 °C for 4 h, LCMS showed the reaction was completed. Then added 10 mL water, filtered, slurry with 5 mL methanol, dried to get yellow solid (58.9 mg).

[1191] 1 H NMR (400 MHz, DMSO-d6): δ 8.15 (br, 1H), 7.75 (d, J = 7.9 Hz, 2H), 7.71 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 3.7 Hz, 1H), 7.36 - 7.23 (m, 6H), 5.26 (s, 2H), 4.71 (s, 1H), 1.55 (d, J = 2.4 Hz, 3H), 1.45 (d, J = 2.4 Hz, 3H), 1.54 -...

Claims

1. A compound of formula (I) or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically-labeled derivatives, pharmaceutically acceptable salts thereof; wherein R1is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 3-6 cycloalkyl or C 2-6 alkynyl; R2is selected from cyano, -C(=O)OR 21 , substituted with m R B , C 2-6 alkenyl, substituted with m R B , C 2-6 alkynyl, substituted with m R B , phenyl, or, pyridyl, substituted with m R B ; R 21 Selected from hydrogen, optionally substituted with R 20 C 1-6 Alkyl, or optionally substituted with R 20 C 6-12 Aryl, of which R 20 Selected from halogens, hydroxyl groups, C 6-12 Aryl, heteroaryl containing 1-3 heteroatoms selected from N, S and O, or heterocyclic group containing 1-3 heteroatoms selected from N, S and O; R B each independently is selected from hydrogen (including protium, deuterium or tritium), halogen, cyano, hydroxyl, oxo, thioxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; m is 0, 1, 2, 3, 4, or 5; R3and R4are each independently selected from the group consisting of fluorine, hydrogen (including protium, deuterium, or tritium); R 10 selected from hydrogen, halogen or C 1-6 alkyl; R A having the structure of Formula II, wherein R represents A the position of attachment to the phenyl ring; In formula II, R5and R6are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C(=O)R 51 , -C(=O)OR 51 , and -S(=O)2R 52 , with the proviso that R5and R6are not simultaneously -C(=O)R 51 , -C(=O)OR 51 , and -S(=O)2R 52 ; or, R5and R6together with the N atom to which they are attached form a 5-8 membered N-containing heterocyclyl group optionally substituted with R 61 . R7is -OR 71 or -NR 72 R 73 ; R 11 Selected from hydrogen or C 1-6 Alkyl; or, R 11 R5, together with the atoms they are attached to, forms an optional substituted R. 61 5-8 N-containing heterocyclic groups; or, when R A is located at the para position of the *C atom of the phenyl ring to which R A is attached, R 11 and R 10 together with the C atom to which they are attached form a 5-6 membered cyclic group; x is 0 or 1; when x is 1, R8and R9are each independently selected from hydrogen or C 1-6 alkyl; or, R8and R 11 and the C atom to which they are attached together form a C 3-6 cycloalkyl; R 51 and R 52 Each is independently hydrogen, optionally substituted with R 50 C 1-6 Alkyl, or optionally substituted with R 50 C 6-12 Aryl, wherein R 50 Selected from halogens, hydroxyl groups, NH2, C 6-12 Aryl, heteroaryl containing 1-3 heteroatoms selected from N, S and O, or heterocyclic group containing 1-3 heteroatoms selected from N, S and O; R 61 is hydrogen, oxo, hydroxy, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R 71 is hydrogen or C 1-6 alkyl; R 72 and R 73 each independently is hydrogen or C 1-6 alkyl; or, R 72 and R 73 and the N atom to which they are attached together form a 5-6 membered cyclic group.

2. The compound of claim 1, wherein, R1is hydrogen or C 1-3 alkyl, for example methyl; preferably, R1is hydrogen.

3. The compound of claim 1, wherein, R2 is the following structural formula: wherein represents the position at which R2is attached to the starred C atom in Formula I; R B each independently is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; m is each independently 0 or 1.

4. The compound of claim 1, wherein, R2is wherein R B is hydrogen, halogen or C 1-3 alkoxy.

5. The compound of claim 4, wherein, R2is wherein R B is hydrogen, deuterium or F; in particular R B is deuterium; or R B is F.

6. The compound of claim 1, wherein, R3and R4are each independently selected from the group consisting of fluorine, hydrogen (including protium, deuterium, or tritium); 7. The compound of claim 1, wherein, R7is OH.

8. The compound of claim 1, wherein, R 10 is hydrogen.

9. The compound of claim 1, wherein, x is 0.

10. The compound according to any one of claims 1-9, wherein, R A Located in R A The *C atom is superscripted on the benzene ring to which it is attached; R5is hydrogen, R6is -C(=O)R 51 or -S(=O)2R 52 , wherein R 51 and R 52 are each independently hydrogen, C 50 1-6 alkyl optionally substituted with R 1-6 , or C 50 1-6 aryl optionally substituted with R 6-12 , wherein R 50 is selected from halogen, hydroxy, or C 6-12 1-6 aryl.

11. The compound of claim 10, wherein, R6is -S(=0)2R 52 , wherein R 52 is C 50 alkyl optionally substituted with R 1-6 , or C 50 aryl optionally substituted with R 6-12 , wherein R 50 is selected from halogen, hydroxy or C 6-12 aryl.

12. The compound of claim 11, wherein, R 52 is phenyl.

13. The compound of claim 10, wherein, R6is -C(=O)R 51 , wherein R 51 is C 1-6 alkyl or C 1-6 haloalkyl, for example methyl, trifluoromethyl, ethyl, isopropyl or tert-butyl.

14. The compound of claim 13, wherein, R 51 is tert-butyl.

15. The compound according to any one of claims 1-9, wherein, R A located in para position to the *C atom of the phenyl ring to which R A is attached; R5and R6together with the N atom to which they are attached form a 5-8 membered N-containing heterocyclyl group optionally substituted with R 61 ; Preferably, the heterocyclyl group has one of the following structural formulae: The above heterocyclyl is optionally substituted with one or more R 61 wherein R 61 is hydrogen, oxo, hydroxyl, halogen or C 1-6 alkyl.

16. The compound of claim 15, wherein, R5and R6together with the N atom to which they are attached form one of the following structural formulae:

17. A compound of formula (III) or stereoisomers, tautomers, solvates, hydrates, active metabolites, isotopically-labeled derivatives, pharmaceutically acceptable salts thereof; wherein R1is selected from hydrogen (including protium, deuterium or tritium), halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 3-6 cycloalkyl or C 2-6 alkynyl; R3and R4are each independently selected from the group consisting of fluorine, hydrogen (including protium, deuterium, or tritium); R 10 selected from hydrogen (including protium, deuterium or tritium), halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R D L1or L2 or In L1, R L1 is selected from hydrogen (including protium, deuterium or tritium), halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -(CR L11 R L12 ) p -R L0 ; wherein p is 0, 1, 2, or 3; R L11 and R L12 are each independently selected from the group consisting of hydrogen (including protium, deuterium or tritium), halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R L0 is C 1-6 is C 1-6 is C 1-6 is C 1-6 is C L10 is C 3-6 is C L10 is C 6-12 is C L10 is C L10 is C L13 R L14 , -OR L13 , -OC(=O)R L15 , -N(R L16 )C(=O)R L15 or -S(=O)2R L15 ; wherein R L13 and R L14 are each independently selected from hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, -(CR L11 R L12 ) s OC(=O)R L25 , -(CR L11 R L12 ) s C(=O)R L25 , or -(CR L11 R L12 ) s S(=O)2R L25 ; or, R L13 and R L14 together with the N atom to which they are attached form a 3-10 membered ring; s is 0, 1, 2, 3, or 4; R L15 Each is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, optionally substituted with R L10 C 3-6 Cycloalkyl, optionally substituted with R L10 C 6-12 Aryl, optionally substituted with R L10 It contains 1-3 heteroatoms selected from N, S, and O, with optional substitutions of R. L10 A 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, with optional substitutions including R. L10 C 3-6 cycloalkyl C 1-6 Alkyl groups, optionally substituted with R L10 C 6-12 Aryl C 1-6 Alkyl groups, optionally substituted with R L10 5-10 membered heteroaryl C containing 1-3 heteroatoms selected from N, S and O 1-6 Alkyl, or optionally substituted with R L10 C containing 1-3 heteroatoms selected from N, S, and O, consisting of 5-10 membered heterocyclic groups. 1-6 alkyl; R L16 is independently selected from hydrogen (including protium, deuterium or tritium), C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, or C 3-6 halocycloalkyl; R L10 independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 haloalkenyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 2-6 alkynyl or C 2-6 haloalkynyl; In L2, R L2 is selected from hydrogen (including protium, deuterium or tritium), halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -(CR L21 R L22 ) q -R L20 ; u is 0, 1 or 2; q is 0, 1, 2, or 3; R L20 is C 1-6 is C 1-6 is C 1-6 is C 1-6 is C L30 is C 3-6 is C L30 is C 6-12 is C L30 is C L30 is C L23 is C L24 is C L25 is C L23 is C L25 is C L25 is C R L21 and R L22 are each independently selected from the group consisting of hydrogen (including protium, deuterium or tritium), halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R L23 and R L24 are each independently selected from the group consisting of hydrogen (including protium, deuterium, or tritium), C 1-3 alkyl, C 1-3 haloalkyl, -(CR L21 R L22 ) t OC(=O)R L25 , -(CR L21 R L22 ) t C(=O)R L25 , or -(CR L21 R L22 ) t S(=O)2R L25 ; or, R L23 and R L24 together with the N atom to which they are attached form a 3-10 membered ring; t is 0, 1, 2, 3, or 4; R L25 Independently selected from hydrogen (including protium, deuterium, or tritium), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, optionally substituted with R L30 C 3-6 Cycloalkyl, optionally substituted with R L30 C 6-12 Aryl, optionally substituted with R L30 It contains 1-3 heteroatoms selected from N, S, and O, with optional substitutions of R. L30 A 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, with optional substitutions including R. L30 C 3-6 cycloalkyl C 1-6 Alkyl groups, optionally substituted with R L30 C 6-12 Aryl C 1-6 Alkyl groups, optionally substituted with R L30 5-10 membered heteroaryl C containing 1-3 heteroatoms selected from N, S and O 1-6 Alkyl, or optionally substituted with R L30 C containing 1-3 heteroatoms selected from N, S, and O, consisting of 5-10 membered heterocyclic groups. 1-6 alkyl; R L30 independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 haloalkenyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 2-6 alkynyl or C 2-6 haloalkynyl; R A having the structure of Formula II, wherein R represents A the position of attachment to the phenyl ring; In formula II, R5and R6are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C(=O)R 51 , -C(=O)OR 51 , and -S(=O)2R 52 , with the proviso that R5and R6are not simultaneously -C(=O)R 51 , -C(=O)OR 51 , and -S(=O)2R 52 ; or, R5and R6together with the N atom to which they are attached form a 5-8 membered N-containing heterocyclyl group optionally substituted with R 61 ; R7is -OR 71 or -NR 72 R 73 ; R 11 Selected from hydrogen (including protium, deuterium, or tritium) or C 1-6 Alkyl; or, R 11 R5, together with the atoms they are attached to, forms an optional substituted R. 61 5-8 N-containing heterocyclic groups; or, when R A is located at the para position of the *C atom of the phenyl ring to which R A is attached, R 11 and R 10 together with the C atom to which they are attached form a 5-6 membered cyclic group; x is 0 or 1; when x is 1, R8and R9are each independently selected from hydrogen (including protium, deuterium or tritium) or C 1-6 alkyl; or, R8and R 11 and the C atom to which they are attached together form a C 3-6 cycloalkyl; R 51 and R 52 Each is independently hydrogen (including protium, deuterium, or tritium), optionally substituted with R. 50 C 1-6 Alkyl, or optionally substituted with R 50 C 6-12 Aryl, wherein R 50 Selected from halogens, hydroxyl groups, NH2, C 6-12 Aryl, heteroaryl containing 1-3 heteroatoms selected from N, S and O, or heterocyclic group containing 1-3 heteroatoms selected from N, S and O; R 61 is hydrogen (including protium, deuterium or tritium), oxo, hydroxy, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R 71 is hydrogen or C 1-6 alkyl; R 72 and R 73 each independently is hydrogen (including protium, deuterium or tritium) or C 1-6 alkyl; or, R 72 and R 73 and the N atom to which they are attached together form a 5-6 membered cyclic group.

18. The compound of claim 17, wherein, R D For L3 wherein, R L2 is hydrogen (including protium, deuterium or tritium) or -(CH2) q -R L20 ; when R L2 is -(CH2) q -R L20 , it is located in the 3- or 4-position of the phenyl ring; R L20 R is selected from the group consisting of H, F, CI, Br, I, CN, CF2H, CF3, CH2F, CHF2, OCF3, S(0)pR L30 , NR R R R R R R R R R R R R R R R R R R L30 independently selected from halogen, C 1-3 alkyl, or C 1-3 haloalkyl; q is 0 or 1.

19. The compound of claim 18, wherein, R L2 is -(CH2)q-R L20 , R L20 is one of the following structural formulae:

20. The compound of claim 17, wherein, R L2 is hydrogen (including protium, deuterium or tritium); and / or R 10 is hydrogen (including protium, deuterium or tritium), halogen, C 1-6 alkyl or C 1-6 haloalkyl; for example, hydrogen (including protium, deuterium or tritium), F, or C 1-6 alkoxy such as C 1-3 alkoxy such as methoxy, ethoxy; and / or R 10 Located in R 10 The benzene ring to which the *C atom is attached is located at the meta or ortho position, preferably at the meta position.

21. The compound of any one of claims 17-20, wherein, R A located in the para position to the *C atom on the phenyl ring to which it is attached; A located in the para position to the *C atom on the phenyl ring to which it is attached; R5is hydrogen, R6is -C(=O)R 51 or -S(=O)2R 52 , wherein R 51 and R 52 are each independently hydrogen, C 50 alkyl optionally substituted with R 1-6 , or C 50 aryl optionally substituted with R 6-12 , wherein R 50 is selected from halogen, hydroxy, or C 6-12 aryl; R7is -OR 71 ; R 11 is hydrogen; R 71 is hydrogen or C 1-6 alkyl such as C 1-3 alkyl such as methyl, ethyl, propyl or isopropyl; x is 0.

22. The compound of claim 21, wherein, R6is -C(=O)R 51 , wherein R 51 is C 1-6 alkyl or C 1-6 haloalkyl, for example methyl, trifluoromethyl, ethyl, isopropyl or tert-butyl, in particular tert-butyl.

23. The compound of claim 21 or 22, wherein, R7is -OH.

24. The compound according to any one of claims 17-23, wherein, R3and R4are each independently selected from the group consisting of fluorine, hydrogen (including protium, deuterium, or tritium); 25. The compound according to any one of claims 1-24, wherein, The compound is selected from one of the following compounds or a pharmaceutically acceptable salt thereof:

26. A pharmaceutical composition comprising a compound of any one of claims 1-25, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically-labeled derivative, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. Use of a compound of any one of claims 1-25, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically-labeled derivative, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 26, in the manufacture of a medicament for treating a disorder associated with β2integrin activity.

28. Use of a compound of any one of claims 1-25, or a stereoisomer, tautomer, solvate, hydrate, active metabolite, isotopically-labeled derivative, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 26, for treating a disorder associated with β2integrin activity.

29. Use according to claim 27 or 28, wherein, the disorder is selected from the group consisting of allergic diseases (e.g., allergic rhinitis, food allergy, asthma, etc.), acute gout, systemic lupus erythematosus, inflammatory bowel disease (IBD), rheumatoid arthritis, Sjogren’s syndrome, chronic kidney disease (e.g., IgA nephropathy, lupus nephritis, membranous nephropathy, etc.), lupus arthritis, autoimmune liver disease (e.g., autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis); atopic dermatitis, graft-versus-host disease (GVHD), alopecia areata, psoriasis, chronic spontaneous urticaria, Behcet’s disease, hidradenitis suppurativa, neointimal thickening associated with vascular injury, peritonitis, and the like.

30. A method of treating a disorder associated with β2integrin activity, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of claims 1-25 or a pharmaceutical composition of claim 26.

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