Preparation and medical application of double-spiro compound

Abstract

The invention belongs to the technical field of medicines, and discloses a double-spiro compound IDO inhibitor as well as a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention discloses a compound shown in a general formula (I) and pharmaceutically acceptable salts thereof, a preparation process of the compound, a pharmaceutical composition containing the compound shown in the general formula (I), and application of the compound and the pharmaceutical composition in the anti-tumor direction.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, and relates to a kind of double spiro compound and its pharmaceutically acceptable salt, and anti-tumor preparation containing above-mentioned compound and its pharmaceutically acceptable salt. BACKGROUND

[0002] Cancer immunotherapy is an important tumor treatment method after surgical resection, radiotherapy and chemotherapy, and has received extensive attention in the past decade. In recent years, significant progress has been made in monoclonal antibodies targeting programmed death receptor 1 (PD-1), its ligand PD-L1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, some patients do not respond well to immune checkpoint blockade therapy, which suggests that there may be other tumor immunosuppression and tolerance pathways. Studies have shown that the tryptophan-kynurenine (Trp-Kyn) metabolic pathway is associated with local immunosuppression in the tumor microenvironment (TME). Enhancing the activity of the Trp-Kyn metabolic pathway leads to tryptophan depletion and accumulation of metabolites such as kynurenine, which in turn promotes the immune escape of cancer cells. Specifically, local degradation of tryptophan inhibits the mTORC1 signaling pathway and activates GCN2, leading to T lymphocyte cycle arrest and induction of T cell autophagy. In addition, Kyn and its metabolites can act as effective agonists of the aryl hydrocarbon receptor (AhR), further activating regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and inducing immune regulation. Therefore, targeting the Trp-Kyn metabolic pathway with small molecules may be a potential solution for cancer treatment.

[0003] IDO1 and TDO catalyze the catabolism of tryptophan, which can maintain the amplitude and duration of the body's normal immune response and prevent the uncontrolled immune activation of healthy cells. However, in malignant tumors, the expression of IDO1 and TDO is upregulated, leading to tryptophan depletion and accumulation of downstream products, creating an immunosuppressive microenvironment that allows tumor cells to escape effective immune responses. This involves the following three pathways: (1) depletion of tryptophan activates GCN-2 kinase, leading to phosphorylation and attenuation of its downstream target eIF-2, resulting in proliferation arrest of effector T cells (Teff) in the G1 phase. (2) Depletion of tryptophan inhibits the molecular stress response mediated by mTOR, inducing autophagy of Teff cells. (3) Binding of the catabolite kynurenine to the endogenous aryl hydrocarbon receptor (AhR) leads to selective differentiation and proliferation of Treg cells; at the same time, it prevents the maturation of helper T cells 17 (Th17), thereby inhibiting the infiltration of DC cells and the immune response of cytotoxic T cells

[0004] Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the initial and rate-limiting step of tryptophan oxidative catabolism along the kynurenine pathway, resulting in the production of bioactive metabolites such as kynurenine, kynurenic acid, excitotoxic quinolinic acid and nicotinamide adenine dinucleotide (NADt). The depletion of tryptophan and the production of metabolites result in apoptosis of effector T cells and promotion of Treg differentiation, both of which are causes of local immunosuppression. Many studies have shown that the expression of IDO1 and TDO is up-regulated in malignant tumors, leading to tryptophan depletion and accumulation of downstream products, creating an immunosuppressive microenvironment that enables tumor cells to escape effective immune responses. There are mainly three pathways: (1) the depletion of tryptophan activates GCN-2 kinase, resulting in phosphorylation and attenuation of its downstream target eIF-2, leading to proliferation arrest of effector T cells (Teff) in the G1 cycle. (2) The depletion of tryptophan inhibits the mTOR-mediated molecular stress response, inducing autophagy of Teff cells. (3) The binding of kynurenine, a catabolic metabolite of tryptophan, to the endogenous aromatic hydrocarbon receptor (AhR) leads to selective differentiation and proliferation of Treg cells; at the same time, it prevents the maturation of helper T cells 17 (Th17), and further inhibits the infiltration of DC cells and the immune response of cytotoxic T cells. Therefore, IDO1 is considered an attractive target for cancer immunotherapy

[0005] Since 4-phenylimidazole was discovered as a weak IDO inhibitor, academic and pharmaceutical companies have been developing small molecule IDO inhibitors. So far, several IDO1 inhibitors including indoximod, epacadostat, BMS-986205 and PF-06840003, navoximod have been tested in clinical trials.

[0006] Exiguamine A is isolated from Neopetrosia exigua sponges and found to be an effective IDO1 inhibitor. It is a racemate with a rare hexacyclic skeleton, also containing a spiro system. Its unique structure and IDO1 inhibitory activity make Exiguamine A an attractive lead structure for the development of new IDO1 inhibitors. Preliminary structure-activity relationship studies have shown that the charged quaternary ammonium ion and the closed pyran ring have no effect on its biological activity, while the function of the quinone is crucial to its activity. Our group has completed the total synthesis of Exiguamine A and carried out preliminary structure-activity relationship studies. The content involved in this patent is to retain its active groups while modifying its skeleton to prepare a class of double spiro compounds with IDO1 inhibitory activity. SUMMARY

[0007] A first technical problem to be solved by the present application is to provide a kind of compound with general formula (I) and pharmaceutically acceptable salt thereof;

[0008] A second technical problem to be solved by the present application is to provide a preparation method of the compound and pharmaceutically acceptable salt thereof;

[0009] Another technical problem to be solved by the present application is to provide a pharmaceutical composition containing the compound with general formula (I) and pharmaceutically acceptable salt thereof;

[0010] Still another technical problem to be solved by the present application is to provide the use of the compound with general formula (I) and pharmaceutically acceptable salt thereof in the preparation of an antitumor drug.

[0011] To solve the above technical problems, the present application adopts the following technical solutions:

[0012]

[0013] The present application is a compound with general formula (I) and pharmaceutically acceptable salt thereof, which retains the quinone structure and hydantoin ring structure in natural products, but simplifies the structure of natural products, removes unnecessary quaternary ammonium ions, effectively simplifies the synthesis difficulty; At the same time, the compound skeleton is changed to double spiro ring, which has great innovation. By introducing aryl, substituted aryl and alkyl at R1, introducing different groups at R2 and R3, and improving the efficacy and side effects of the compound by changing the substituent group.

[0014] The compound with general formula (I) involved in the present application contains multiple asymmetric carbon atoms, therefore, the compound can exist in the form of enantiomer or diastereomer.

[0015] Among them,

[0016] A and B are carbon atoms, and the configuration is independently selected from R configuration or S configuration;

[0017] X is selected from C, NBoc; when X is selected from C, n is 2, and when X is selected from NBoc, n is 1;

[0018] R1is selected from the group consisting of H, C1-C16 straight chain or branched alkyl, C3-C8 cycloalkyl, C6-C16 aryl, C4-C16 heteroaryl, aryl-substituted C1-C16 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, biphenyl; the heteroaryl groups are selected from the group consisting of furanyl, thienyl, imidazolyl, pyrrolyl, thiazolyl, quinolyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl; these aryl and heteroaryl groups can have one or more substituents, independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy C1-C16 alkyl;

[0019] R2is selected from the group consisting of H, C1-C16 straight chain or branched alkyl, C6-C16 aryl, C4-C16 heteroaryl, aryl-substituted C1-C16 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, biphenyl; the heteroaryl groups are selected from the group consisting of furanyl, thienyl, imidazolyl, pyrrolyl, thiazolyl, quinolyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl; these aryl and heteroaryl groups can have one or more substituents, independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight chain or branched alkyl;

[0020] R3is selected from the group consisting of H, halogen, C1-C16 straight chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy C1-C16 alkyl;

[0021] Preferably A, B are carbon atoms, independently of each other in the R or S configuration;

[0022] X is selected from the group consisting of C, NBoc; n is 2 when X is C, n is 1 when X is NBoc;

[0023] R1is selected from the group consisting of H, C1-C8 straight chain or branched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C8 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; these aryl groups can have one or more substituents, independently selected from the group consisting of H, halogen, NO2, CN, CF3, OCF3, C1-C8 straight chain or branched alkyl, C1-C8 alkoxy, C1-C8 alkoxy C1-C8 alkyl;

[0024] R2is selected from the group consisting of H, C1-C8 straight chain or branched alkyl, C6-C10 aryl, aryl substituted C1-C8 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can have one or more substituents, the substituents being independently selected from the group consisting of H, halogen, NO2, CN, CF3, OCF3, C1-C8 straight chain or branched alkyl, C1-C8 alkoxy, C1-C8 alkoxy C1-C8 alkyl;

[0025] R3is selected from the group consisting of H, halogen, C1-C8 straight chain or branched alkyl, C1-C8 alkoxy;

[0026] More preferred A, B are carbon atoms, the configuration being independently selected from the group consisting of R configuration or S configuration;

[0027] X is selected from the group consisting of C, NBoc; n is 2 when X is C, n is 1 when X is NBoc;

[0028] R1is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl, the aryl groups being selected from the group consisting of phenyl, naphthyl; the aryl groups can have one or more substituents, the substituents being independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0029] R2is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can have one or more substituents, the substituents being independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0030] R3is selected from the group consisting of H, halogen, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy;

[0031] Preferred compounds of the application are selected from the group consisting of:

[0032] A, B are carbon atoms, the configuration being independently selected from the group consisting of R configuration or S configuration;

[0033] X is selected from the group consisting of C, N; n is 2 when X is C, n is 1, 2 when X is N;

[0034] R1is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, benzyl, phenethyl, phenyl, naphthyl, furanyl, thienyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl;

[0035] the substituents of these aryl, heteroaryl groups are independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chained or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy-C1-C16 alkyl; the substituents of these aryl, heteroaryl groups are preferably selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, F, Cl, Br, NO2, CN, CF3, OCF3, C1-C8 straight-chained or branched alkyl, C1-C8 alkoxy, C1-C8 alkoxy-C1-C8 alkyl; the substituents of these aryl, heteroaryl groups are more preferably selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, F, Cl, Br, NO2, CN, CF3, OCF3, C1-C4 straight-chained or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl;

[0036] R2is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, phenyl, benzyl;

[0037] R3is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, halogen;

[0038] Preferred compounds of general formula (I) include, but are not limited to, compounds of formula (IA) and pharmaceutically acceptable salts thereof

[0039]

[0040] R4is selected from the group consisting of H, C1-C4 straight-chained or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can have one or more substituents, independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chained or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkyl;

[0041] R5is selected from the group consisting of H, C1-C4 straight or branched alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl; the aryl group can further have one or more substituents, the substituents being independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0042] R6is selected from the group consisting of H, halogen, C1-C4 straight or branched alkyl, C1-C4 alkoxy;

[0043] Preferred compounds of formula IA include, but are not limited to, compounds of formula IA1 and pharmaceutically acceptable salts thereof

[0044]

[0045] R 41 selected from the group consisting of H, C1-C4 straight or branched alkyl, C3-C6 cycloalkyl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0046] R 51 selected from the group consisting of H, C1-C4 straight or branched alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0047] R 61 selected from the group consisting of H, halogen, C1-C4 straight or branched alkyl, C1-C4 alkoxy;

[0048] Preferred compounds of formula IA include, but are not limited to, compounds of formula IA2 and pharmaceutically acceptable salts thereof

[0049]

[0050] R 52 selected from the group consisting of H, C1-C4 straight or branched alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0051] R 62 selected from the group consisting of H, halogen, C1-C4 straight or branched alkyl, C1-C4 alkoxy;

[0052] R 72H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0053] Preferred compounds of formula (I) include, but are not limited to, compounds of formula (IA) and pharmaceutically acceptable salts thereof

[0054]

[0055] R 53 H, C1-C4 straight-chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl;

[0056] R 63 H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0057] R 83 H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0058] Preferred compounds of formula (I) include, but are not limited to, compounds of formula (IB) and pharmaceutically acceptable salts thereof

[0059]

[0060] R9is selected from the group consisting of H, C1-C4 straight-chain or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can further have one or more substituents, independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0061] R 10selected from the group consisting of H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0062] R 11 selected from the group consisting of H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0063] Preferred compounds of formula IB include, but are not limited to, compounds of formula IB1 and pharmaceutically acceptable salts thereof

[0064]

[0065] R 91 selected from the group consisting of H, C1-C4 straight-chain or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0066] R 101 selected from the group consisting of H, C1-C4 straight-chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0067] R 111 selected from the group consisting of H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0068] Preferred compounds of formula IB include, but are not limited to, compounds of formula IB2 and pharmaceutically acceptable salts thereof

[0069]

[0070] R 102 selected from the group consisting of H, C1-C4 straight-chain or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0071] R 112 selected from the group consisting of H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0072] R 122H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0073] Preferred compounds of formula IB include, but are not limited to, compounds of formula IB3 and pharmaceutically acceptable salts thereof

[0074]

[0075] R 103 H, C1-C4 straight-chain or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl group is selected from phenyl, naphthyl;

[0076] R 113 H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0077] R 133 H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0078] Preferred compounds of formula (I) include, but are not limited to, compounds of formula IC and pharmaceutically acceptable salts thereof

[0079]

[0080] R 14 H, C1-C4 straight-chain or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl group is selected from phenyl, naphthyl; the aryl group can also have one or more substituents, independently selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0081] R 15selected from the group consisting of H, halogen, C1-C4 straight or branched chain alkyl, C1-C4 alkoxy;

[0082] R 16 selected from the group consisting of H, halogen, C1-C4 straight or branched chain alkyl, C1-C4 alkoxy;

[0083] Preferred compounds of formula IC include, but are not limited to, compounds of formula IC1 and pharmaceutically acceptable salts thereof

[0084]

[0085] R 141 selected from the group consisting of H, C1-C4 straight or branched chain alkyl, C3-C6 cycloalkyl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0086] R 151 selected from the group consisting of H, C1-C4 straight or branched chain alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0087] R 161 selected from the group consisting of H, halogen, C1-C4 straight or branched chain alkyl, C1-C4 alkoxy;

[0088] Preferred compounds of formula IC include, but are not limited to, compounds of formula IC2 and pharmaceutically acceptable salts thereof

[0089]

[0090] R 152 selected from the group consisting of H, C1-C4 straight or branched chain alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0091] R 162 selected from the group consisting of H, halogen, C1-C4 straight or branched chain alkyl, C1-C4 alkoxy;

[0092] R 172H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0093] Preferred compounds of formula IC include, but are not limited to, compounds of formula IC3 and pharmaceutically acceptable salts thereof

[0094]

[0095] R 153 H, C1-C4 straight-chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0096] R 163 H, halogen, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy;

[0097] R 183 H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0098] Preferred compounds of formula (I) include, but are not limited to, compounds of formula ID and pharmaceutically acceptable salts thereof

[0099]

[0100] R 19 H, C1-C4 straight-chain or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl; the aryl group can further have one or more substituents, which are independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0101] R 20selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy;

[0102] R 21 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy;

[0103] Preferred compounds of formula ID include, but are not limited to, compounds of formula ID1 and pharmaceutically acceptable salts thereof

[0104]

[0105] R 191 selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0106] R 201 selected from the group consisting of H, C1-C4 linear or branched alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0107] R 211 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy;

[0108] Preferred compounds of formula ID include, but are not limited to, compounds of formula ID2 and pharmaceutically acceptable salts thereof

[0109]

[0110] R 202 selected from the group consisting of H, C1-C4 linear or branched alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0111] R 212 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy;

[0112] R 222selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0113] Preferred compounds of formula ID include, but are not limited to, compounds of formula ID3 and pharmaceutically acceptable salts thereof

[0114]

[0115] R 203 selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl group is selected from the group consisting of phenyl, naphthyl;

[0116] R 213 selected from the group consisting of H, halogen, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy;

[0117] R 233 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl;

[0118] The above preferred compounds form pharmaceutically acceptable salts with acids also form part of the present application. The basic nitrogen atom in the molecule of the compound in the present application can form a salt with an acid, as long as the salt can be formed with a base and is a pharmaceutically acceptable acid, which is not particularly limited. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and other inorganic acids, oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and other organic acids can be listed.

[0119] The second aspect of the present application discloses a preparation method of the compound with general formula (I) and pharmaceutically acceptable salts thereof, and the specific preparation route is as follows:

[0120]

[0121] wherein, A and B are carbon atoms, and the configuration is independently selected from R configuration or S configuration;

[0122] X is selected from C, NBoc; when X is C, n is 2, and when X is NBoc, n is 1;

[0123] R1is selected from the group consisting of H, C1-C16 straight-chain or branched alkyl, C3-C8 cycloalkyl, C6-C16 aryl, C4-C16 heteroaryl, aryl-substituted C1-C16 alkyl; the aryl is selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, biphenyl; the heteroaryl is selected from the group consisting of furanyl, thienyl, imidazolyl, pyrrolyl, thiazolyl, quinolinyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl; the aryl and heteroaryl can have one or more substituents, which are independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy C1-C16 alkyl;

[0124] R2is selected from the group consisting of H, C1-C16 straight-chain or branched alkyl, C6-C16 aryl, C4-C16 heteroaryl, aryl-substituted C1-C16 alkyl; the aryl is selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, biphenyl; the heteroaryl is selected from the group consisting of furanyl, thienyl, imidazolyl, pyrrolyl, thiazolyl, quinolinyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl; the aryl and heteroaryl can have one or more substituents, which are independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl;

[0125] R3is selected from the group consisting of H, halogen, C1-C16 straight-chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy C1-C16 alkyl;

[0126] Step 1: using N-substituted amino acid ethyl ester A1 as starting material, add to substituted isocyanate, then perform intramolecular ester exchange to obtain intermediate B1;

[0127] Step 2: intermediate B1 is condensed with different substituted o-bromobenzaldehyde to obtain intermediate C1;

[0128] Step 3: intermediate C1 is prepared by Suzuki-Miyaura coupling reaction to obtain intermediate D1;

[0129] Step 4: intermediate D1 is catalytically hydrogenated by 10% palladium on carbon to obtain intermediate E1;

[0130] Step 5: intermediate E1 is oxidized to p-quinone to obtain intermediate F1;

[0131] Step 6: intermediate F1 is prepared by intramolecular Michael addition to obtain the target product shown in general formula (I).

[0132] The third aspect of the present application also relates to pharmaceutical compositions comprising the compounds of the present application as an active ingredient. The pharmaceutical compositions can be prepared according to methods known in the art. The compounds of the present application can be combined with one or more solid or liquid excipient and / or adjuvant, and prepared into any dosage form suitable for human or animal use. The content of the compounds of the present application in the pharmaceutical compositions thereof is usually 0.1-95% by weight.

[0133] The compounds of the present application or the pharmaceutical compositions containing them can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, buccal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, etc.

[0134] The dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid dosage form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), eye drops, nose drops, lotion and liniment, etc.; the solid dosage form can be a tablet (including ordinary tablet, enteric tablet, chewing tablet, dispersible tablet, effervescent tablet, oral disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric capsule), a granule, a powder, a micro-pellet, a dripping pellet, a suppository, a film, a patch, an aerosol (powder) mist, a spray, etc.; the semi-solid dosage form can be an ointment, a gel, a paste, etc.

[0135] The compounds of the present application can be prepared into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various micro-particle drug delivery systems.

[0136] In order to prepare the compounds of the present application into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrating agents, lubricants, glidants. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agents can be water, ethanol, isopropyl alcohol, etc.; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, acacia paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrating agents can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further prepared into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0137] To make the administration unit into a capsule, the effective component, the compound of the present application, can be mixed with a diluent, a glidant, and the mixture can be directly put into a hard capsule or a soft capsule. The effective component, the compound of the present application, can also be mixed with a diluent, a binder, a disintegrant, to make granules or pellets, and then put into a hard capsule or a soft capsule. The various diluents, binders, wetting agents, disintegrants, and glidants used for making tablets of the compound of the present application can also be used for making capsules of the compound of the present application.

[0138] To make the compound of the present application into an injection, water, ethanol, isopropyl alcohol, propylene glycol, or a mixture thereof can be used as a solvent, and an appropriate amount of a solubilizer, a co-solvent, a pH adjuster, an osmotic pressure adjuster commonly used in the art can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjuster can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If a lyophilized powder injection is prepared, mannitol, glucose, etc. can also be added as a supporting agent.

[0139] In addition, if necessary, a coloring agent, a preservative, a flavoring agent, a taste-correcting agent, or other additives can also be added to the pharmaceutical preparation.

[0140] To achieve the purpose of medication and enhance the therapeutic effect, the pharmaceutical or pharmaceutical composition of the present application can be administered by any known administration method.

[0141] The compounds of the present application can be used in combination with other anticancer drugs, which are also part of the present application, such as taxol, paclitaxel, taxotere, docetaxel, vincristine, vinblastine, 5-fluorouracil, cytarabine, gemcitabine, pentostatin, methotrexane, cyclophosphamide, ifosphamide, adriamycin, doxorubicin, pharmorubicin, epirubicin, etoposide, tamoxifen, flutamide, leuprorelin, goserelin, cyrotone, octreotide, herceptin, cis-platin, carboplatin, oxaplatin, dexamethasone, etc. The compounds of the present application can also be used in combination with compounds belonging to the following classes of antitumor drugs, which are also part of the present application, such as taxols, podophyllotoxins, vinca alkaloids, nitrogen mustards, anthracenes, estrogens, antiestrogens, androgens, antiandrogens, antibody derivatives, platinums, matrix protease inhibitors, etc.

[0142] The compounds of the present application can also be used in combination with compounds belonging to the following classes of antitumor drugs, which are also part of the present application, such as microtubulin modulators, antimetabolites, alkylating agents, antitumor drugs targeting DNA, antitumor drugs targeting topoisomerases, hormones and hormone agonists or antagonists, drugs targeting intracellular signaling in cancer cells, gene therapy or antisense therapy drugs, antibody therapy drugs, active compounds of marine origin, hormone analogs, antiinflammatory drugs or antiemetic drugs.

[0143] The compounds of the present application can be used alone or as pharmaceutically active ingredients for the treatment of patients suffering from leukemia, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermoid cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, etc.

[0144] The dosage of the pharmaceutical composition of the present application varies depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. Generally, the suitable dosage of the compound of the present application per day ranges from 0.001 to 150 mg / Kg of body weight, preferably from 0.1 to 100 mg / Kg of body weight, more preferably from 1 to 60 mg / Kg of body weight, and most preferably from 2 to 30 mg / Kg of body weight. The above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the administration schedule including the use of other therapeutic agents.

[0145] The compound or composition of the present application can be used alone or in combination with other therapeutic agents or symptomatic agents. When the compound of the present application has a synergistic effect with other therapeutic agents, the dosage thereof should be adjusted according to the actual situation DETAILED DESCRIPTION

[0146] The present application is further illustrated by the following examples, but the present application is not limited to these examples.

[0147] I. Preparation of compounds 1-66

[0148] 1. Preparation of compounds 1-66

[0149] Example 1, Preparation of compound 1 and compound 2:

[0150]

[0151] a) Preparation of intermediate B1: Dissolve sarcosine ethyl ester hydrochloride (1.53 g, 10 mmol) in CH2Cl2(30 mL), dropwise add Et3N (1.8 mL, 13 mmol), then add p-tolyl isocyanate (1.33 g, 10.0 mmol), stir at room temperature for 24 h, extract with CH2Cl2(15 mL x 3), wash with saturated aqueous sodium chloride solution, dry over anhydrous Na2SO4and concentrate under reduced pressure. Purify the residue by column chromatography (petroleum ether / EtOAc = 1:1) to obtain intermediate B1 (1.97 g, 88%) as a white solid. 1 H NMR (500 MHz, Chloroform-d) δ 7.26 (s, 4H), 4.03 (s, 2H), 3.08 (s, 3H), 2.37 (s, 3H); 13 CNMR (125 MHz, Chloroform-d) δ 168.9, 156.0, 138.3, 129.8 (2C), 129.2, 126.1 (2C), 51.7, 30.0, 21.3; HRMS calcd for C 11 H13 N2O2[M+H] + 205.0972, found 205.0960.

[0152] b) Preparation of Intermediate CI: Intermediate Bl (2.04 g, 10 mmol) was dissolved in acetic acid (30 mL), n-butylamine (1.97 mL, 2.0 mmol) was added dropwise, followed by o-bromobenzaldehyde (1.85 g, 10 mmol), and the reaction was refluxed for 18 h. The reaction mixture was concentrated in vacuo, quenched with a saturated solution of NaHC03and extracted with CH2Cl2(50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / CH2Cl2= 1 : 1) to give Intermediate CI (3.19 g, 86%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.94 (dd, J = 7.8, 1.8 Hz, 1H), 7.60 (dd, J = 8.0, 1.4 Hz, 1H), 7.31 - 7.23 (m, 5H), 7.18 (td, J = 7.8, 1.8 Hz, 1H), 6.48 (s, 1H), 3.33 (s, 3H), 2.36 (s, 3H). 13 C NMR (100 MHz, CHLOROFORM-D) δ 160.6, 152.8, 138.4, 132.5, 132.4, 132.0, 130.3, 129.8 (2C), 129.8, 128.7, 126.9, 126.1 (2C), 124.8, 115.2, 26.8, 21.3. HRMS calcd for C 18 H 16 BrN2O2[M+H] + 371.0390, found 371.0381.

[0153] c) Preparation of Intermediate D1: Intermediate C1 (1.11 g, 3.0 mmol), Pd(PPh3)4 (346 mg, 0.3 mmod), Na2CO3 (954 mg, 9 mmol), 2-(1,4-dimethoxynaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.03 g, 3.3 mmol) were dissolved in ethylene glycol dimethyl ether (25 mL) and water (5 mL), purged with nitrogen and replaced three times, and the reaction was refluxed for 8 h. The mixture was filtered through celite, extracted with EtOAc (20 mL x 3), washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 10:1) to give Intermediate D1 (1.20 g, 83%) as a white solid.

[0154] The exocyclic double bond is a mixture of Z / E configurations, with an isomer ratio of about 5:1. 1 H NMR (400 MHz, CDC13) δ 7.99 (s, 0.2H), 7.93 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 0.2H), 7.35 (d, J = 8.0 Hz, 1.2H), 7.21 (dt, J = 7.2, 1.2 Hz, 1.2H), 7.14 (dt, J = 8.0, 1.2 Hz, 1.2H), 5.50 (d, J = 6.8 Hz, 0.2H), 5.44 (q, J = 6.8 Hz, 1H), 4.30 (dd, J = 11.2, 5.2 Hz, 0.2H), 4.15 (dd, J = 11.2, 5.2 Hz, 1H), 3.33 (dd, J = 15.2, 5.2 Hz, 1.2H), 2.71 (ddd, J = 15.2, 11.2, 1.6 Hz, 0.2H), 2.69 (ddd, J = 15.2, 11.2, 1.6 Hz, 1H), 2.58 (s, 0.6H), 2.50 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.57 (d, J = 6.8 Hz, 0.6H); HRMS calcd for C 17 H 17 N2O3[M+H] + 297.1234, found 297.1222.

[0155] d) Preparation of Intermediate El: To a solution of Intermediate Dl (956 mg, 2 mmol) in MeOH (10 mL) and THF (5 mL) was added Pd / C (50 mg), then the mixture was hydrogenated for 10 h. The reaction mixture was filtered through celite, extracted with CH2Cl2(20 mL x 3), washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / EtOAc = 3: 1) to give Intermediate El (870 mg, 90%) as a white solid (isomer ratio = 5:3). 1 H NMR (500 MHz, Chloroform-d) δ 8.29 (d, J = 8.5 Hz, 1.6 H), 8.13 (t, J = 8.0 Hz, 1.6 H), 7.59 (t, J = 7.5 Hz, 1.6 H), 7.53 (t, J = 7.5 Hz, 1.6 H), 7.50 - 7.46 (m, 1 H), 7.44 - 7.30 (m, 5.4 H), 7.17 (dd, J = 8.5, 3.5 Hz, 3.2 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1.6 H), 6.66 (s, 1 H), 6.65 (s, 0.6 H), 4.01 (t, J = 4.5 Hz, 1 H), 4.00 (s, 3 H), 3.97 (s, 1.8 H), 3.93 (t, J = 6.5 Hz, 0.6 H), 3.52 (s, 1.8 H), 3.50 (d, J = 14.5, 4.5 Hz, 1 H), 3.43 (s, 3 H), 3.33 (dd, J = 14.5, 6.5 Hz, 0.6 H), 3.24 (dd, J = 14.5, 4.5 Hz, 1 H), 3.13 (dd, J = 14.5, 6.5 Hz, 0.6 H), 2.49 (s, 1.8 H), 2.33 (s, 4.8 H), 2.10 (s, 3 H). 13C NMR (125 MHz, Chloroform-d) δ 171.7, 171.6, 155.7, 155.7, 152.1, 152.0, 146.3, 145.6, 140.0, 139.3, 138.2, 138.0, 134.9, 133.5, 131.5, 130.8 (2C), 130.2, 129.7 (3C), 129.6, 129.4, 129.2, 129.1, 128.9, 128.8, 128.6, 127.9, 127.7, 127.5, 127.3, 127.2, 127.1, 126.3, 126.3 (2C), 126.1, 126.0 (3C), 125.9, 122.5, 122.5, 122.3, 122.2, 107.1, 106.4, 62.5, 61.8, 61.6, 61.5, 56.0, 55.9, 34.3, 32.8, 28.5, 28.2, 21.3, 21.3. HRMS calcd for C 30 H 29 N2O4[M+H] + 481.2122, found 481.2111.

[0156] e) Preparation of Intermediate Fl: To a solution of Intermediate El (960 mg, 2 mmol) in CH3CN (10 mL) and H2O (5 mL) was added a solution of CAN (2.74 g, 5 mmol) in CH3CN (5 mL) dropwise at 0 °C, then stirred at room temperature for 2 h. The reaction was quenched with aqueous NaHC03solution, extracted with CH2Cl2(20 mL x 3), washed with saturated aqueous NaCl solution, dried over anhydrous Na2S04and concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether / EtOAc = 3: 1) to give Intermediate Fl (720 mg, 80%) as a yellow solid. 1 H NMR (500 MHz, Chloroform-d) δ 8.16 - 8.11 (m, 2H), 7.81 - 7.77 (m, 2H), 7.45 - 7.35 (B m, 3H), 7.23 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.01 - 6.95 (m, 3H), 4.15 (t, J = 5.5 Hz, 1H), 3.37 - 2.96 (m, 2H), 2.84 (s, 3H), 2.33 (s, 3H). 13C NMR (125 MHz, Chloroform-d) δ 184.9, 170.9, 155.9, 149.7, 138.3, 137.9 (2C), 134.5, 134.2, 134.2, 133.8, 132.2, 132.2, 130.5, 130.1, 129.7 (3C), 129.0, 127.6, 127.3, 126.4, 126.0 (2C), 62.0, 33.7, 29.3, 21.3. HRMS calcd for C 28 H 23 N2O4[M+H] + 451.1652, found 451.1640.

[0157] f) Preparation of compound 1 and compound 2: Intermediate Fl (450 mg, 1.0 mmol) was dissolved in CH2Cl2(5 mL) and MeOH (5 mL), placed at -20 °C, and a methanol solution of NaOH (1.0 M, 0.2 mL) was added dropwise, and the reaction was allowed to proceed for 2 h. The mixture was quenched with 1 N HC1 solution, extracted with CH2Cl2(20 mL x 3), washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc = 5: 1) to give compound 10 (261 mg, 58%) as a yellow-white solid and compound 11 (158 mg, 35%) as a white solid.

[0158] Compound 1: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.6 Hz, 1H), 7.98 (dd, J = 7.6, 1.6 Hz, 1H), 7.78 (td, J = 7.6, 1.6 Hz, 1H), 7.72 (td, J = 7.6, 1.6 Hz, 1H), 7.47 - 7.34 (m, 4H), 7.06 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 8.0 Hz, 2H), 3.89 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 18.8 Hz, 1H), 3.22 (d, J = 16.8 Hz, 1H), 3.01 (d, J = 18.8 Hz, 1H), 2.53 (s, 3H), 2.30 (s, 3H). 13C NMR (100 MHz, CHLOROFORM-D) δ 195.1, 190.9, 171.4, 154.3, 140.7, 138.2, 137.9, 136.3, 135.3, 135.1, 134.7, 129.4, 129.3 (2C), 128.5, 128.3, 127.2, 127.1, 125.8, 125.3 (2C), 124.5, 73.4, 67.5, 46.3, 39.9, 27.2, 21.2. HRMS calcd for C 28 H 23 N2O4[M+H] + 451.1652, found 451.1644.

[0159] Compound 2: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.15 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 3.86 (d, J = 16.4 Hz, 1H), 3.75 (d, J = 15.6 Hz, 1H), 3.17 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 2.72 (s, 3H), 2.30 (s, 3H). 13 C NMR (101 MHz, CDC13) δ 193.7, 193.2, 170.5, 154.7, 140.3, 139.9, 138.2, 135.6, 135.3, 134.2, 134.0, 129.6, 129.5 (2C), 128.6, 128.4, 128.4, 126.0, 125.3 (2C), 124.4, 123.2, 76.7, 68.5, 44.2, 39.8, 28.1, 21.2. HRMS calcd for C 28 H 23 N2O4[M+H] + 451.1652, found 451.1648.

[0160] Example 2, Preparation of Compound 3 and Compound 4:

[0161]

[0162] Compound 3 was prepared according to the procedure of Example 1, substituting tert-butyl isocyanate for p-tolyl isocyanate.

[0163] Compound 3: 1 H NMR (500 MHz, Chloroform-d) δ 8.20 (dd, J = 7.5, 1.5 Hz, 1H), 8.00 (dd, J = 7.5, 1.5 Hz, 1H), 7.85 (td, J = 7.5, 1.5 Hz, 1H), 7.80 (td, J = 7.5, 1.5 Hz, 1H), 7.47 - 7.34 (m, 4H), 3.79 (d, J = 16.5 Hz, 1H), 3.69 (d, J = 18.5 Hz, 1H), 3.09 (d, J = 16.5 Hz, 1H), 3.01 (d, J = 18.5 Hz, 1H), 2.45 (s, 3H), 1.18 (s, 9H). 13 C NMR (100 MHz, CHLOROFORM-D) δ 195.2, 191.3, 172.8, 155.9, 141.2, 138.2, 136.4, 135.5, 135.0, 134.6, 129.2, 128.3, 127.4, 127.1, 125.6, 124.4, 77.5, 77.2, 76.8, 72.8, 67.2, 58.2, 46.5, 40.1, 28.3 (3C), 26.8. HRMS calcd for C 25 H 25 N2O4[M+H] + 417.1809, found 417.1798.

[0164] Compound 4: 1 H NMR (500 MHz, Chloroform-d) δ 8.09 (dd, J = 7.5, 1.5 Hz, 1H), 8.02 (dd, J = 7.5, 1.5 Hz, 1H), 7.78 (td, J = 7.5, 1.5 Hz, 1H), 7.73 (td, J = 7.5, 1.5 Hz, 1H), 7.40 - 7.35 (m, 3H), 7.11 (dd, J = 7.0, 2.0 Hz, 1H), 3.72 (d, J = 16.5 Hz, 1H), 3.67 (d, J = 16.0 Hz, 1H), 3.03 (d, J = 16.0 Hz, 1H), 2.99 (d, J = 16.5 Hz, 1H), 2.58 (s, 3H), 1.19 (s, 9H). 13C NMR (100 MHz, CHLOROFORM-D) δ 193.7, 193.5, 171.8, 156.2, 140.5, 140.3, 135.9, 135.1, 134.5, 133.9, 129.5, 128.5, 128.3, 126.1, 124.3, 123.1, 77.5, 77.2, 76.8, 76.4, 67.9, 58.4, 44.0, 40.1, 27.9 (3C), 27.6. HRMS calcd for C 25 H 25 N2O4[M+H] + 417.1809, found 417.1800.

[0165] Example 3, Preparation of compound 5 and compound 6:

[0166]

[0167] The procedure of Example 1 was followed for the preparation of compound 5 and compound 6, with benzyl isocyanate in place of p-tolyl isocyanate.

[0168] Compound 5: 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (dd, J = 7.6, 1.2 Hz, 1H), 7.84 (dd, J = 7.6, 1.2 Hz, 1H), 7.66 (td, J = 7.6, 1.2 Hz, 1H), 7.57 (td, J = 7.6, 1.2 Hz, 1H), 7.42 - 7.34 (m, 3H), 7.33 - 7.28 (m, 1H), 7.25 - 7.20 (m, 3H), 7.18 - 7.13 (m, 2H), 4.04 (d, J = 14.0 Hz, 1H), 3.93 (d, J = 14.0 Hz, 1H), 3.75 (d, J = 16.8 Hz, 1H), 3.64 (d, J = 18.4 Hz, 1H), 3.05 (d, J = 16.8 Hz, 1H), 2.95 (d, J = 18.4 Hz, 1H), 2.44 (s, 3H). 13C NMR (100 MHz, CHLOROFORM-D) δ 195.0, 191.1, 172.2, 155.0, 140.6, 137.9, 136.0, 135.3, 135.1, 134.8, 134.6, 129.3, 129.1 (2C), 128.7 (2C), 128.4, 128.0, 126.7, 126.6, 125.8, 124.5, 77.5, 77.2, 76.8, 73.7, 67.2, 46.1, 42.6, 39.5, 26.9. HRMS calcd for C 28 H 23 N2O4[M+H] + 451.1652, found 451.1641.

[0169] Compound 6: 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (dd, J = 7.6, 1.2 Hz, 1H), 7.69 (td, J = 7.6, 1.2 Hz, 1H), 7.60 (dd, J = 7.6, 1.2 Hz, 1H), 7.54 (td, J = 7.6, 1.2 Hz, 1H), 7.44 - 7.32 (m, 3H), 7.29 - 7.21 (m, 3H), 7.16 - 7.08 (m, 3H), 4.26 (d, J = 14.4 Hz, 1H), 4.21 (d, J = 14.4 Hz, 1H), 3.74 (d, J = 16.4 Hz, 1H), 3.61 (d, J = 16.0 Hz, 1H), 3.03 (d, J = 16.4 Hz, 1H), 3.03 (d, J = 16.0 Hz, 1H), 2.63 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 193.2, 193.2, 171.3, 155.6, 140.4, 139.9, 135.3, 135.1, 134.9, 134.0, 133.9, 129.5, 129.1 (2C), 128.7 (2C), 128.4, 128.1, 127.9, 125.9, 124.4, 123.1, 77.4, 77.2, 76.9, 76.9, 67.8, 43.9, 42.8, 39.9, 28.0. HRMS calcd for C 28 H 23 N2O4[M+H] + 451.1652, found 451.1644.

[0170] Example 4, Preparation of Compound 7 and Compound 8:

[0171]

[0172] Compound 7 was prepared according to the procedure of Example 1, substituting p-trifluoromethyl isocyanate for p-tolyl isocyanate.

[0173] Compound 7: 1 H NMR (400 MHz, Chloroform-d) δ 8.05 - 7.96 (m, 2H), 7.78 (td, J = 7.6, 1.2 Hz, 1H), 7.69 (td, J = 7.6, 1.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.48 - 7.35 (m, 4H), 7.00 (d, J = 8.0 Hz, 2H), 3.92 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 18.4 Hz, 1H), 3.25 (d, J = 16.8 Hz, 1H), 3.05 (d, J = 18.4 Hz, 1H), 2.56 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 194.8, 190.9, 171.1, 153.4, 140.4, 137.6, 136.2, 135.2, 135.2, 134.8, 134.1, 129.9 (q, J = 32.5 Hz, 1C), 129.5, 128.7, 127.2, 127.1, 125.9 (q, J = 4.0 Hz, 2C), 125.8, 125.2 (2C), 124.6, 123.7 (q, J = 272.5 Hz, 1C) 73.5, 67.7, 46.3, 39.8, 27.3. HRMS calcd for C 28 H 20 F3N2O4[M+H] + 505.1370, found 505.1359.

[0174] Compound 8: 1 H NMR (400 MHz, Chloroform-d) δ 8.05 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.73 (td, J = 7.6, 1.2 Hz, 1H), 7.63 (td, J = 7.6, 1.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.47 - 7.37 (m, 3H), 7.20 - 7.12 (m, 3H), 3.87 (d, J = 16.4 Hz, 1H), 3.78 (d, J = 16.0 Hz, 1H), 3.20 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 16.0 Hz, 1H), 2.75 (s, 3H).13 C NMR (125 MHz, CDC13) δ 193.7, 193.0, 170.3, 153.8, 139.9, 139.6, 135.5, 135.5, 134.4, 134.2 (2C), 129.9 (q, J = 35.0 Hz, 1C), 129.8, 128.6, 128.5, 126.0 (q, J = 4.0 Hz, 2C), 126.0, 125.3 (2C), 124.5, 123.8 (q, J = 272.5 Hz, 1C), 123.2, 76.7, 68.8, 44.4, 39.6, 28.2. HRMS calcd for C 28 H 20 F3N2O4[M+H] + 505.1370, found 505.1362.

[0175] Example 5, Preparation of Compound 9 and Compound 10:

[0176]

[0177] The procedure for the preparation of Compound 9 and Compound 10 was the same as Example 1, with phenethyl isocyanate instead of p-tolyl isocyanate.

[0178] Compound 9: 1 H NMR (400 MHz, Chloroform-d) δ 8.17 - 8.08 (m, 1H), 7.93 - 7.85 (m, 1H), 7.78 - 7.69 (m, 2H), 7.46 - 7.30 (m, 4H), 7.29 - 7.17 (m, 3H), 7.11 - 7.04 (m, 2H), 3.72 (d, J = 16.8 Hz, 1H), 3.64 (d, J = 18.4 Hz, 1H), 3.24 - 3.05 (m, 2H), 2.99 (d, J = 16.8 Hz, 1H), 2.96 (d, J = 18.4 Hz, 1H), 2.44 (s, 3H), 2.39 - 2.20 (m, 2H). 13 C NMR (100 MHz, CHLOROFORM-D) δ 195.0, 191.0, 172.2, 154.9, 140.7, 137.9, 137.5, 136.3, 135.4, 135.0, 134.6, 129.3, 128.9 (2C), 128.6 (2C), 128.5, 127.1, 126.8 (2C), 125.7, 124.5, 73.5, 67.2, 46.2, 39.9, 39.4, 33.6, 26.8. HRMS calcd for C 29 H 25N2O4[M+H] + 465.1809, found 465.1800.

[0179] Compound 10: 1 H NMR (400 MHz, Chloroform-d) δ 8.21 - 8.03 (m, 1H), 8.00 - 7.93 (m, 1H), 7.79 (td, J = 7.6, 1.2 Hz, 1H), 7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.43 - 7.33 (m, 3H), 7.26 - 7.15 (m, 3H), 7.14 - 7.03 (m, 3H), 3.72 (d, J = 16.8 Hz, 1H), 3.64 (d, J = 16.0 Hz, 1H), 3.41 (ddd, J = 13.2, 10.8, 5.6 Hz, 1H), 3.31 (ddd, J = 13.2, 10.8, 5.6 Hz, 1H), 3.01 (d, J = 16.0 Hz, 1H), 2.98 (d, J = 16.8 Hz, 1H), 2.68 (ddd, J = 13.2, 10.8, 5.6 Hz, 1H), 2.62 (s, 3H), 2.40 (ddd, J = 13.2, 10.8, 5.6 Hz, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 193.7, 193.1, 171.3, 155.4, 140.4, 140.0, 137.7, 135.6, 135.3, 134.4, 134.1, 129.6, 128.9 (2C), 128.6 (2C), 128.4 (2C), 126.7, 125.9, 124.5, 123.1, 76.8, 67.8, 44.0, 40.2, 39.7, 33.2, 27.8. HRMS calcd for C 29 H 25 N2O4[M+H] + 465.1809, found 465.1798.

[0180] Example 6, Preparation of Compound 11 and Compound 12:

[0181]

[0182] The preparation of Compound 11 and Compound 12 was carried out as in Example 1, using m-tolyl isocyanate instead of p-tolyl isocyanate.

[0183] Compound 11: 1H NMR (500 MHz, Chloroform-d) δ 8.05 (dd, J = 7.5, 1.5 Hz, 1H), 8.00 (dd, J = 7.5, 1.5 Hz, 1H), 7.81 (td, J = 7.5, 1.5 Hz, 1H), 7.73 (td, J = 7.5, 1.5 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.43 - 7.35 (m, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 3.91 (d, J = 16.5 Hz, 1H), 3.71 (d, J = 18.5 Hz, 1H), 3.23 (d, J = 16.5 Hz, 1H), 3.01 (d, J = 18.5 Hz, 1H), 2.54 (s, 3H), 2.27 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 195.0, 190.9, 171.3, 154.2, 140.7, 138.7, 137.8, 136.3, 135.3, 135.1, 134.7, 130.7, 129.4, 129.1, 128.6, 128.5, 127.3, 127.2, 126.2, 125.8, 124.6, 122.7, 73.4, 67.6, 46.3, 39.9, 27.2, 21.4. HRMS calcd for C 28 H 23 N2O4[M+H] + 451.1652, found 451.1646.

[0184] Compound 12: 1 H NMR (500 MHz, Chloroform-d) δ 8.05 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.47 - 7.35 (m, 3H), 7.21 - 7.10 (m, 2H), 7.05 (d, J = 7.5 Hz, 1H), 6.82 - 6.71 (m, 1H), 6.66 (s, 1H), 3.84 (d, J = 16.5 Hz, 1H), 3.75 (d, J = 15.5 Hz, 1H), 3.17 (d, J = 16.5 Hz, 1H), 3.14 (d, J = 15.5 Hz, 1H), 2.73 (s, 3H), 2.27 (s, 3H). 13CNMR (125 MHz, Chloroform-d) δ 193.7, 193.2, 170.6, 154.6, 140.2, 139.9, 138.8, 135.7, 135.3, 134.2, 134.0, 131.1, 129.7, 129.1, 128.8, 128.5 (2C), 126.1, 126.1, 124.5, 123.2, 122.6, 76.7, 68.6, 44.3, 39.9, 28.1, 21.4. HRMS calcd for C 28 H 23 N2O4[M+H] + 451.1652, found 451.1642.

[0185] Example 7, Preparation of compound 13 and compound 14:

[0186]

[0187] The preparation of compound 13 and compound 14 was carried out as in example 1, using isopropyl isocyanate instead of p-tolyl isocyanate.

[0188] Compound 13: 1 H NMR (400 MHz, Chloroform-d) δ 8.17 - 8.08 (m, 1H), 7.97 - 7.89 (m, 1H), 7.82 - 7.68 (m, 2H), 7.45 - 7.30 (m, 4H), 3.98 - 3.84 (m, 1H), 3.77 (d, J = 16.4 Hz, 1H), 3.68 (d, J = 18.4 Hz, 1H), 3.07 (d, J = 16.4 Hz, 1H), 2.97 (d, J = 18.4 Hz, 1H), 2.44 (s, 3H), 0.90 (d, J = 5.2 Hz, 3H), 0.88 (d, J = 5.2 Hz, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 195.1, 191.1, 172.1, 155.1, 141.2, 137.9, 136.2, 135.4, 135.0, 134.7, 129.2, 128.4, 127.3, 127.1, 125.6, 124.5, 72.9, 67.0, 46.4, 44.0, 40.0, 26.9, 19.3, 19.0. HRMS calcd for C 24 H 23 N2O4[M+H] + 403.1652, found403.1640.

[0189] Compound 14: 1 H NMR (400 MHz, Chloroform-d) δ 8.09 (dd, J = 7.6, 1.2 Hz, 1H), 7.96 (dd, J = 7.6, 1.2 Hz, 1H), 7.77 (td, J = 7.6, 1.2 Hz, 1H), 7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.43 - 7.35 (m, 3H), 7.15 - 7.08 (m, 1H), 4.01 - 3.91 (m, 1H), 3.73 (d, J = 16.4 Hz, 1H), 3.68 (d, J = 16.0 Hz, 1H), 3.04 (d, J = 16.0 Hz, 1H), 3.01 (d, J = 16.4 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 193.8, 193.3, 171.1, 155.4, 140.5, 140.1, 135.8, 135.2, 134.4, 133.9, 129.5, 128.4, 128.3, 126.0, 124.4, 123.0, 76.4, 67.6, 44.4, 43.9, 40.0, 27.8, 19.0, 18.8. HRMS calcd for C 24 H 23 N2O4[M+H] + 403.1652, found 403.1641.

[0190] Example 8, Preparation of Compound 15 and Compound 16:

[0191]

[0192] The preparation of Compound 15 and Compound 16 was carried out according to the procedure of Example 1, using cyclohexyl isocyanate instead of p-tolyl isocyanate.

[0193] Compound 15: 1H NMR (500 MHz, Chloroform-d) δ 8.13 (dd, J = 7.0, 2.0 Hz, 1H), 7.92 (dd, J = 7.0, 2.0 Hz, 1H), 7.82 - 7.65 (m, 2H), 7.48 - 7.31 (m, 4H), 3.77 (d, J = 16.5 Hz, 1H), 3.68 (d, J = 18.5 Hz, 1H), 3.53 - 3.45 (m, 1H), 3.06 (d, J = 16.5 Hz, 1H), 2.96 (d, J = 18.5 Hz, 1H), 2.44 (s, 3H), 1.86 - 1.41 (m, 5H), 1.15 - 1.01 (m, 3H), 0.86 (t, J = 13.3 Hz, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 195.1, 191.2, 172.2, 155.3, 141.2, 138.0, 136.3, 135.4, 135.0, 134.5, 129.2, 128.4, 127.3, 127.1, 125.6, 124.5, 72.9, 67.0, 51.8, 46.4, 40.0, 28.9, 28.5, 27.0, 25.7, 25.6, 24.8. HRMS calcd for C 27 H 27 N2O4[M+H] + 443.1965, found 443.1955.

[0194] Compound 16: 1 H NMR (500 MHz, Chloroform-d) δ 8.12 (dd, J = 7.5, 1.5 Hz, 1H), 7.99 (dd, J = 7.5, 1.5 Hz, 1H), 7.81 (td, J = 7.5, 1.5 Hz, 1H), 7.74 (td, J = 7.5, 1.5 Hz, 1H), 7.45 - 7.39 (m, 3H), 7.17 - 7.12 (m, 1H), 3.76 (d, J = 16.5 Hz, 1H), 3.71 (d, J = 16.0 Hz, 1H), 3.60 (tt, J = 12.0, 4.0 Hz, 1H), 3.07 (d, J = 16.0 Hz, 1H), 3.04 (d, J = 16.5 Hz, 1H), 1.95 - 1.51 (m, 5H), 1.44 - 1.33 (m, 2H), 1.21 - 0.82 (m, 3H). 13C NMR (125 MHz, Chloroform-d) δ 193.8, 193.3, 171.2, 155.5, 140.6, 140.1, 135.8, 135.2, 134.4, 133.8, 129.5, 128.4, 128.3, 126.1, 124.4, 123.0, 76.4, 67.5, 52.1, 43.9, 40.1, 28.6, 28.3, 27.9, 25.7, 25.6, 24.9. HRMS calcd for C 27 H 27 N2O4[M+H] + 443.1965, found 443.1952.

[0195] Example 9, Preparation of Compound 17 and Compound 18:

[0196]

[0197] The procedure for the preparation of Compound 17 and Compound 18 was the same as Example 1, with p-fluorophenyl isocyanate instead of p-tolyl isocyanate.

[0198] Compound 17: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.99 (dd, J = 7.6, 1.2 Hz, 1H), 7.79 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.47 - 7.35 (m, 4H), 6.99 - 6.91 (m, 2H), 6.77 - 6.70 (m, 2H), 3.90 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 18.4 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 3.03 (d, J = 18.4 Hz, 1H), 2.55 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 194.9, 190.9, 171.3, 162.9, 160.9, 153.9, 140.5, 137.8, 136.3, 135.3, 135.1, 134.8, 129.5, 128.6, 127.3, 127.2, 127.2, 127.2, 126.9, 126.8, 125.8, 124.6, 115.9, 115.7, 73.5, 67.6, 46.3, 39.8, 27.2. HRMS calcd for C 27 H 20 FN2O4[M+H] +455.1402, found 455.1392.

[0199] Compound 18: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.92 (dd, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.63 (td, J = 7.6, 1.2 Hz, 1H), 7.48 - 7.35 (m, 3H), 7.20 - 7.09 (m, 1H), 7.07 - 6.93 (m, 4H), 3.85 (d, J = 16.4 Hz, 1H), 3.77 (d, J = 15.6 Hz, 1H), 3.18 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 2.73 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 193.8, 193.1, 170.4, 162.9, 161.0, 154.3, 140.1, 139.8, 135.5, 135.4, 134.2, 134.1, 129.7, 128.6, 128.4, 127.3, 127.2, 127.2, 127.1, 125.9, 124.5, 123.2, 116.0, 115.8, 76.7, 68.6, 44.3, 39.7, 28.1. HRMS calcd for C 27 H 20 FN2O4[M+H] + 455.1402, found 455.1393.

[0200] Example 10, Preparation of Compound 19 and Compound 20:

[0201]

[0202] Compound 19 and Compound 20 were prepared according to the procedure of Example 1, using m-chlorophenyl isocyanate instead of p-tolyl isocyanate.

[0203] Compound 19: 1H NMR (400 MHz, Chloroform-d) δ 8.08 - 8.02 (m, 1H), 8.01 - 7.96 (m, 1H), 7.82 (td, J = 7.6, 1.2 Hz, 1H), 7.74 (td, J = 7.6, 1.2 Hz, 1H), 7.47 - 7.37 (m, 4H), 7.25 - 7.17 (m, 2H), 6.77 (dt, J = 6.8, 2.0 Hz, 1H), 6.65 - 6.60 (m, 1H), 3.92 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.8 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 3.02 (d, J = 18.8 Hz, 1H), 2.55 (s, 3H). 13 C NMR (100 MHz, CHLOROFORM-D) δ 194.9, 190.8, 171.0, 153.5, 140.5, 137.7, 136.3, 135.3, 135.2, 134.9, 134.3, 131.9, 129.7, 129.5, 128.6, 128.4, 127.2 (2C), 125.8, 125.6, 124.6, 123.6, 73.5, 67.7, 46.3, 39.8, 27.2. HRMS calcd for C 27 H 20 ClN2O4[M+H] + 471.1106, found 471.1094.

[0204] Compound 20: 1 H NMR (500 MHz, Chloroform-d) δ 8.06 (dd, J = 7.5, 1.5 Hz, 1H), 7.95 (dd, J = 7.5, 1.5 Hz, 1H), 7.75 (td, J = 7.5, 1.5 Hz, 1H), 7.68 (td, J = 7.5, 1.5 Hz, 1H), 7.47 - 7.39 (m, 3H), 7.24 - 7.21 (m, 2H), 7.17 - 7.12 (m, 1H), 6.96 (ddd, J = 6.0, 3.5, 2.0 Hz, 1H), 6.85 - 6.81 (m, 1H), 3.84 (d, J = 16.5 Hz, 1H), 3.77 (d, J = 15.5 Hz, 1H), 3.18 (d, J = 16.5 Hz, 1H), 3.13 (d, J = 15.5 Hz, 1H), 2.74 (s, 3H). 13C NMR (125 MHz, Chloroform-d) δ 193.6, 193.1, 170.3, 153.9, 140.0, 139.7, 135.6, 135.5, 134.4, 134.3, 134.1, 132.3, 129.9, 129.7, 128.6, 128.5, 128.3, 126.1, 125.5, 124.5, 123.5, 123.3, 76.6, 68.9, 44.4, 39.7, 28.2. HRMS calcd for C 27 H 20 ClN2O4 [M+H] + 471.1106, found 471.1092.

[0205] Example 11, Preparation of compound 21 and compound 22:

[0206]

[0207] The preparation of compound 21 and compound 22 was carried out according to the procedure of Example 1, using p-chlorophenyl isocyanate instead of p-tolyl isocyanate.

[0208] Compound 21: 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (dd, J = 7.6, 1.2 Hz, 1H), 7.98 (dd, J = 7.6, 1.2 Hz, 1H), 7.78 (td, J = 7.6, 1.2 Hz, 1H), 7.71 (td, J = 7.6, 1.2 Hz, 1H), 7.50 - 7.33 (m, 4H), 7.26 - 7.20 (m, 2H), 6.87 - 6.61 (m, 2H), 3.90 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.8 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 3.03 (d, J = 18.8 Hz, 1H), 2.55 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 194.9, 190.9, 171.1, 153.7, 140.5, 137.7, 136.3, 135.3, 135.1, 134.8, 133.9, 129.5, 128.9 (2C), 128.6, 127.2, 127.1, 126.5 (2C), 125.8, 124.6, 73.5, 67.7, 46.3, 39.8, 27.2. HRMS calcd for C 27 H 20 ClN2O4 [M+H] +471.1106, found 471.1095.

[0209] Compound 22: 1 H NMR (500 MHz, Chloroform-d) δ 8.04 (dd, J = 7.5, 1.5 Hz, 1H), 7.90 (dd, J = 7.5, 1.5 Hz, 1H), 7.72 (td, J = 7.5, 1.5 Hz, 1H), 7.64 (td, J = 7.5, 1.5 Hz, 1H), 7.47 - 7.37 (m, 3H), 7.29 - 7.26 (m, 2H), 7.14 (d, J = 7.0 Hz, 1H), 6.98 - 6.93 (m, 2H), 3.85 (d, J = 16.5 Hz, 1H), 3.77 (d, J = 15.5 Hz, 1H), 3.18 (d, J = 16.5 Hz, 1H), 3.13 (d, J = 15.5 Hz, 1H), 2.73 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 193.8, 193.1, 170.3, 154.1, 140.0, 139.7, 135.5, 135.4, 134.1, 134.1, 133.9, 129.8, 129.7, 129.1 (2C), 128.6, 128.4, 126.5 (2C), 125.9, 124.5, 123.2, 76.7, 68.7, 44.3, 39.6, 28.1. HRMS calcd for C 27 H 20 ClN2O4[M+H] + 471.1106, found 471.1093.

[0210] Example 12, Preparation of Compound 23 and Compound 24:

[0211]

[0212] Compound 23 and Compound 24 were prepared according to the procedure of Example 1, using 2-bromo-4-methoxybenzaldehyde instead of o-bromobenzaldehyde.

[0213] Compound 23: 1H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.99 (dd, J = 7.6, 1.2 Hz, 1H), 7.79 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.09 - 7.02 (m, 2H), 6.99 - 6.90 (m, 2H), 6.60 - 6.53 (m, 2H), 3.86 (s, 3H), 3.82 (d, J = 16.4 Hz, 1H), 3.71 (d, J = 18.8 Hz, 1H), 3.15 (d, J = 16.4 Hz, 1H), 3.02 (d, J = 18.8 Hz, 1H), 2.57 (s, 3H), 2.30 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 195.1, 190.9, 171.3, 160.0, 154.3, 142.1, 138.2, 136.3, 135.3, 135.1, 134.7, 129.5, 129.4 (2C), 128.2, 127.2, 127.1, 125.4 (2C), 125.2, 115.9, 110.6, 73.8, 67.6, 55.7, 46.2, 39.2, 27.2, 21.2. HRMS calcd for C 29 H 25 N2O5[M+H] + 481.1758, found 481.1745.

[0214] Compound 24: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.2 Hz, 1H), 7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.63 (td, J = 7.6, 1.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 6.86 - 6.79 (m, 2H), 6.66 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 3.77 (d, J = 16.4 Hz, 1H), 3.70 (d, J = 15.6 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 3.10 (d, J = 16.4 Hz, 1H), 2.74 (s, 3H). 13C NMR (125 MHz, Chloroform-d) δ 193.7, 193.1, 170.4, 160.1, 154.7, 141.6, 138.2, 135.6, 135.3, 134.2, 134.0, 131.7, 129.6 (2C), 128.6, 128.4, 126.0, 125.3 (2C), 125.1, 115.2, 108.9, 77.1, 68.5, 55.6, 44.2, 39.1, 28.1, 21.2. HRMS calcd for C 29 H 25 N2O5[M+H] + 481.1758, found 481.1747.

[0215] Example 13, Preparation of compound 25 and compound 26:

[0216]

[0217] The procedure of Example 1 was followed for the preparation of compound 25 and compound 26, using 2-bromo-5-methoxybenzaldehyde instead of o-bromobenzaldehyde.

[0218] Compound 25: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.98 (dd, J = 7.6, 1.2 Hz, 1H), 7.78 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.98 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.62 - 6.46 (m, 2H), 3.87 (s, 3H), 3.86 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.8 Hz, 1H), 3.16 (d, J = 16.8 Hz, 1H), 2.98 (d, J = 18.8 Hz, 1H), 2.57 (s, 3H), 2.30 (s, 3H). 13C NMR (125 MHz, Chloroform-d) δ 195.4, 191.1, 171.3, 160.7, 154.3, 139.4, 138.2, 136.4, 135.3, 135.0, 134.6, 132.7, 129.4 (2C), 128.2, 127.1, 127.1, 126.5, 125.3 (2C), 114.6, 109.6, 73.6, 66.9, 55.7, 46.5, 39.9, 27.2, 21.2. HRMS calcd for C 29 H 25 N2O5[M+H] + 481.1758, found 481.1745.

[0219] Compound 26: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 7.95 (ddd, J = 7.6, 1.6, 0.8 Hz, 1H), 7.70 (td, J = 7.6, 1.6 Hz, 1H), 7.63 (td, J = 7.6, 1.6 Hz, 1H), 7.12 - 7.06 (m, 2H), 7.04 (d, J = 9.2 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.85 - 6.79 (m, 2H), 3.86 (s, 3H), 3.82 (d, J = 16.6 Hz, 1H), 3.69 (d, J = 15.6 Hz, 1H), 3.12 (d, J = 15.6 Hz, 1H), 3.11 (d, J = 16.6 Hz, 1H), 2.75 (s, 3H), 2.29 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 193.8, 193.6, 170.4, 160.9, 154.6, 141.3, 138.1, 135.6, 135.2, 134.2, 133.9, 132.2, 129.5 (2C), 128.5, 128.3, 125.9, 125.3 (2C), 124.0, 114.3, 109.7, 76.8, 67.9, 55.6, 44.4, 39.7, 28.0, 21.2. HRMS calcd for C 29 H 25 N2O5[M+H] + 481.1758, found 481.1745.

[0220] Example 14, Preparation of Compound 27 and Compound 28:

[0221]

[0222] Compound 27 and compound 28 were prepared according to the procedure of Example 1, using 2-bromo-5-methylbenzaldehyde in place of o-bromobenzaldehyde.

[0223] Compound 27: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.98 (dd, J = 7.6, 1.2 Hz, 1H), 7.78 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.18 (s, 1H), 7.09 - 7.03 (m, 2H), 6.63 - 6.42 (m, 2H), 3.85 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.8 Hz, 1H), 3.17 (d, J = 16.8 Hz, 1H), 2.99 (d, J = 18.8 Hz, 1H), 2.55 (s, 3H), 2.43 (s, 3H), 2.30 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 195.3, 191.1, 171.4, 154.3, 139.4, 138.2, 138.0, 137.8, 136.4, 135.3, 135.0, 134.6, 129.4, 129.4 (2C), 128.2, 127.1, 127.1, 125.4, 125.3 (2C), 125.1, 73.5, 67.3, 46.4, 39.8, 27.2, 21.6, 21.2. HRMS calcd for C 29 H 25 N2O4[M+H] + 465.1809, found 465.1800.

[0224] Compound 28: 1H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.2 Hz, 1H), 7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.63 (td, J = 7.6, 1.2 Hz, 1H), 7.24 - 7.17 (m, 2H), 7.10 - 7.06 (m, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.86 - 6.79 (m, 2H), 3.81 (d, J = 16.8 Hz, 1H), 3.72 (d, J = 15.6 Hz, 1H), 3.12 (d, J = 15.6 Hz, 1H), 3.12 (d, J = 16.8 Hz, 1H), 2.73 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 193.9, 193.4, 170.5, 154.7, 139.9, 139.7, 138.2, 137.4, 135.7, 135.3, 134.2, 133.9, 129.6 (2C), 129.3, 128.6, 128.4, 126.0, 125.3 (2C), 125.1, 122.9, 76.8, 68.3, 44.3, 39.7, 28.1, 21.6, 21.2. HRMS calcd for C 29 H 25 N2O4[M+H] + 465.1809, found 465.1798.

[0225] Example 15, Preparation of compound 29 and compound 30:

[0226]

[0227] The preparation of compound 29 and compound 30 was carried out according to the procedure of Example 1, using 2-bromo-5-chlorobenzaldehyde instead of o-bromobenzaldehyde.

[0228] Compound 29: 1H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.47 - 7.31 (m, 3H), 7.06 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 8.4 Hz, 2H), 3.86 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.4 Hz, 1H), 3.20 (d, J = 16.8 Hz, 1H), 2.98 (d, J = 18.4 Hz, 1H), 2.55 (s, 3H), 2.30 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 194.7, 190.6, 170.9, 154.2, 139.8, 139.2, 138.4, 136.1, 135.3 (2C), 135.2, 134.9, 129.4 (2C), 128.9, 128.1, 127.3, 127.2, 127.0, 125.3 (2C), 124.8, 73.4, 67.0, 46.1, 39.5, 27.2, 21.2. HRMS calcd for C 28 H 22 ClN2O4[M+H] + 485.1263, found 485.1250.

[0229] Compound 30: 1 H NMR (400 MHz, Chloroform-d) δ 8.03 (dd, J = 7.6, 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.2 Hz, 1H), 7.71 (td, J = 7.6, 1.2 Hz, 1H), 7.65 (td, J = 7.6, 1.2 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.12 - 7.05 (m, 3H), 6.85 - 6.75 (m, 2H), 3.82 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 15.6 Hz, 1H), 3.15 (d, J = 16.8 Hz, 1H), 3.13 (d, J = 15.6 Hz, 1H), 2.75 (s, 3H), 2.30 (s, 3H). 13CNMR (125 MHz, Chloroform-d) δ 193.3, 192.9, 170.1, 154.6, 141.7, 138.8, 138.4, 135.5, 135.4 (2C), 134.2, 134.1, 129.6 (2C), 128.8, 128.4 (2C), 126.1, 125.3 (2C), 124.8, 124.4, 76.7, 68.0, 44.1, 39.4, 28.2, 21.3. HRMS calcd for C 28 H 22 ClN2O4[M+H] + 485.1263, found 485.1252.

[0230] Example 16, Preparation of Compound 31 and Compound 32:

[0231]

[0232] The procedure for the preparation of Compound 31 and Compound 32 was the same as Example 1, with 2-bromo-4-methyl-6-fluorobenzaldehyde instead of o-bromobenzaldehyde.

[0233] Compound 31: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.99 (dd, J = 7.6, 1.2 Hz, 1H), 7.80 (td, J = 7.6, 1.2 Hz, 1H), 7.74 (td, J = 7.6, 1.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.00 (s, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 3.76 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 18.4 Hz, 1H), 3.30 (d, J = 16.8 Hz, 1H), 3.02 (d, J = 18.4 Hz, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H). 13C NMR (125 MHz, CHLOROFORM-d) δ 193.3, 192.8, 170.1, 158.4 (d, J = 248.8 Hz), 154.6, 143.3 (d, J = 5.8 Hz), 141.3 (d, J = 6.8 Hz), 138.3, 135.4, 135.4, 134.2 (2C), 129.6 (2C), 128.5, 128.4, 126.0, 125.3 (2C), 123.3 (d, J = 18.8 Hz), 119.6 (d, J = 2.6 Hz), 116.9 (d, J = 19.7 Hz), 76.8, 68.6, 44.2, 35.6, 28.0, 21.7, 21.2. HRMS calcd for C 29 H 24 FN2O4[M+H] + 483.1715, found 483.1705.

[0234] Compound 32: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.95 (dd, J = 7.6, 1.2 Hz, 1H), 7.71 (td, J = 7.6, 1.2 Hz, 1H), 7.64 (td, J = 7.6, 1.2 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.95 (d, J = 9.6 Hz, 1H), 6.85 - 6.78 (m, 2H), 6.75 (s, 1H), 3.72 (d, J = 16.8 Hz, 1H), 3.71 (d, J = 15.6 Hz, 1H), 3.25 (d, J = 16.8 Hz, 1H), 3.13 (d, J = 15.6 Hz, 1H), 2.76 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 193.3, 192.8, 170.1, 158.4 (d, J = 248.8 Hz), 154.6, 143.3 (d, J = 5.8 Hz), 141.3 (d, J = 6.8 Hz), 138.3, 135.4, 135.4, 134.2 (2C), 129.6 (2C), 128.5, 128.4, 126.0, 125.3 (2C), 123.3 (d, J = 18.8 Hz), 119.6 (d, J = 2.6 Hz), 116.9 (d, J = 19.7 Hz), 76.8, 68.6, 44.2, 35.6, 28.0, 21.7, 21.2. HRMS calcd for C 29 H24 FN2O4[M+H] + 483.1715, found 483.1702.

[0235] Example 17, Preparation of compound 33 and compound 34:

[0236]

[0237] The procedure for the preparation of compound 33 and compound 34 was the same as example 1, with 2-bromo-4-fluorobenzaldehyde instead of o-bromobenzaldehyde.

[0238] Compound 33: 1 H NMR (400 MHz, Chloroform-d) δ 8.05 (dd, J = 7.6, 1.6 Hz, 1H), 7.99 (dd, J = 7.6, 1.6 Hz, 1H), 7.80 (td, J = 7.6, 1.6 Hz, 1H), 7.74 (td, J = 7.6, 1.6 Hz, 1H), 7.33 (dd, J = 9.2, 5.2 Hz, 1H), 7.17 - 7.09 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.0 Hz, 2H), 3.84 (d, J = 16.8 Hz, 1H), 3.71 (d, J = 18.4 Hz, 1H), 3.19 (d, J = 16.8 Hz, 1H), 2.99 (d, J = 18.4 Hz, 1H), 2.56 (s, 3H), 2.30 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 194.6, 190.5, 170.9, 162.9 (d, J = 246.7 Hz), 154.2, 142.7 (d, J = 8.2 Hz), 138.3, 136.0, 135.3, 135.2, 134.9, 133.3 (d, J = 2.5 Hz), 129.4 (2C), 128.1, 127.2, 127.2, 125.8 (d, J = 8.8 Hz), 125.3 (2C), 116.7 (d, J = 22.7 Hz), 113.1 (d, J = 23.5 Hz), 73.8, 67.4, 45.9, 39.1, 27.2, 21.2. HRMS calcd for C 28 H 22 FN2O4[M+H] + 469.1558, found 469.1546.

[0239] Compound 34: 1H NMR (400 MHz, Chloroform-d) δ 8.06 - 8.01 (m, 1H), 8.00 - 7.88 (m, 1H), 7.72 (td, J = 7.6, 1.6 Hz, 1H), 7.65 (td, J = 7.6, 1.6 Hz, 1H), 7.37 (dd, J = 8.4, 5.2 Hz, 1H), 7.17 - 7.06 (m, 3H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H), 6.84 - 6.79 (m, 2H), 3.79 (d, J = 16.4 Hz, 1H), 3.67 (d, J = 15.6 Hz, 1H), 3.15 (d, J = 15.6 Hz, 1H), 3.14 (d, J = 16.4 Hz, 1H), 2.75 (s, 3H), 2.30 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 193.2, 192.8, 170.1, 163.11 (d, J = 246.8 Hz), 154.6, 142.31 (d, J = 7.7 Hz), 138.3, 135.4 (2C), 135.3 (d, J = 2.5 Hz), 134.2, 134.1, 129.6 (2C), 128.5, 128.4, 126.1, 125.70 (d, J = 8.7 Hz), 125.3 (2C), 116.81 (d, J = 22.6 Hz), 110.78 (d, J = 23.4 Hz), 77.0, 68.4, 44.1, 39.1, 28.1, 21.3. HRMS calcd for C 28 H 22 FN2O4[M+H] + 469.1558, found 469.1548.

[0240] Example 18, Preparation of compound 35 and compound 36:

[0241]

[0242] a) Preparation of intermediate II: To a solution of intermediate HI (938 mg, 2 mmol) in THF (15 mL) was added DMAP (97.6 mg, 0.8 mmol) and stirred, followed by dropwise addition of (Boc)20 (0.92 mL, 4 mmol) and reaction at room temperature for 3 h. The reaction mixture was quenched by dropwise addition of hydrochloric acid, extracted with CH2Cl2(20 mL x 3), washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / EtOAc = 5: 1) to give intermediate II (978 mg, 86%) as a white solid (isomer ratio = 5:3). 1H NMR (500 MHz, Chloroform-d) δ 7.52 - 7.47 (m, 1.6H), 7.46 - 7.40 (m, 1H), 7.40 - 7.36 (m, 0.6H), 7.36 - 7.27 (m, 4.4H), 7.18 (t, J = 9.0 Hz, 3H), 7.14 (d, J = 8.0 Hz, 1.6H), 6.91 (d, J = 8.0 Hz, 2H), 6.73 - 6.69 (m, 1.6H), 6.53 (s, 1.6H), 4.03 (t, J = 5.0 Hz, 1H), 3.94 (t, J = 6.5 Hz, 0.6H), 3.91 (s, 3H), 3.89 (s, 1.6H), 3.52 (dd, J = 14.5, 5.0 Hz, 1H), 3.38 (dd, J = 14.5, 6.5 Hz, 0.6H), 3.37 (s, 1.6H), 3.29 (s, 3H), 3.23 (dd, J = 14.5, 5.0 Hz, 1H), 3.09 (dd, J = 14.6, 6.5 Hz, 0.6H), 2.53 (s, 1.6H), 2.33 (s, 4.6H), 2.21 (s, 3H), 1.64 (s, 9H), 1.63 (s, 5H). 13 C NMR (125 MHz, CDC13) δ 171.8, 171.7, 155.7, 155.7, 149.2 (2C), 149.1, 149.0, 140.4, 139.6, 139.5, 139.1, 138.2, 138.0, 135.1, 133.8, 131.4, 131.2, 131.2, 131.0, 130.8, 130.3, 129.7 (2C), 129.7 (2C), 129.3, 129.2, 128.8, 128.6, 127.7, 127.7, 127.5, 127.4, 127.3, 127.1, 126.3 (2C), 126.0 (2C), 123.6, 123.4, 107.0, 106.3, 104.3, 104.2, 83.9, 83.8, 62.5, 61.6, 61.2, 61.1, 55.9 (2C), 34.6, 33.1, 28.5, 28.2, 28.1 (6C), 21.3 (2C). HRMS calcd for C 33 H 36 N3O6[M+H] + 570.2599, found 570.2589.

[0243] b) Preparation of Intermediate Jl: To a solution of Intermediate II (1.14 g, 2 mmol) in CH3CN (15 mL) and H2O (735 mL) was added dropwise a solution of B(PIFA) (2.15 g, 5 mmol) in CH3CN (20 mL), after the addition was completed, it was allowed to react at room temperature for 3 h. NaHCO3solution was added to quench, extracted with CH2Cl2(20 mL x 3), washed with saturated aqueous NaCl, dried over anhydrous Na2SO4and concentrated under reduced pressure. Then the residue was dissolved in CH2Cl2(15 mL), trifluoroacetic acid (0.2 mL) was added dropwise at 0 °C, reacted for 1 h. Then NaHCO3solution was added to quench, extracted with CH2Cl2(20 mL x 3), washed with saturated aqueous NaCl, dried over anhydrous Na2SO4and concentrated under reduced pressure, the residue was purified by column chromatography (petroleum ether / EtOAc = 2: 1) to give Intermediate Jl (570 mg, 65%) as a yellow solid.

[0244] 1 H NMR (400 MHz, Chloroform-d) δ 10.14 (s, 1H), 7.43 - 7.27 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.07 - 6.93 (m, 2H), 6.93 - 6.86 (m, 1H), 6.66 - 6.61 (m, 1H), 6.57 (s, 1H), 4.20 (t, J = 5.2 Hz, 1H), 3.51 - 2.90 (m, 2H), 2.78 (s, 3H), 2.32 (s, 3H). 13 CNMR (125 MHz, Chloroform-d) δ 183.1, 176.6, 171.3, 156.0, 147.1, 138.5, 137.1 (2C), 134.2, 133.8, 130.9, 130.7, 130.3, 129.8 (2C), 129.5, 128.9, 127.5, 126.1 (2C), 126.0, 108.3, 62.1, 33.5, 29.3, 21.3. HRMS calcd for C 26 H 22 N3O4[M+H] + 440.1605, found 440.1597.

[0245] c) Preparation of compound 35 and compound 36: Intermediate J1 (440 mg, 1.0 mmol) was dissolved in CH2Cl2(5 mL) and MeOH (5 mL), placed at -20 °C, and a methanolic solution of NaOH (1.0 M, 0.2 mL) was added dropwise, and the reaction was allowed to proceed for 2 h. The mixture was quenched with 1 N HC1 solution, extracted with CH2Cl2(20 mL x 3), washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was dissolved in THF (10 mL), DMAP (49 mg, 0.4 mmol) was added, stirred, followed by dropwise addition of (Boc)20 (0.46 mL, 2 mmol), and the reaction was allowed to proceed at room temperature for 3 h. The reaction mixture was quenched with hydrochloric acid dropwise, extracted with CH2Cl2(20 mL x 3), washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / EtOAc = 5:1) to give compound 35 (286 mg, 53%) as a white solid and compound 36 (156 mg, 29%) as a white solid.

[0246] Compound 35: 1 H NMR (400 MHz, Chloroform-d) δ 7.52 (d, J = 3.2 Hz, 1H), 7.46 - 7.33 (m, 4H), 7.14 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 3.2 Hz, 1H), 3.89 (d, J = 16.8 Hz, 1H), 3.56 (d, J = 18.4 Hz, 1H), 3.20 (d, J = 16.8 Hz, 1H), 2.88 (d, J = 18.4 Hz, 1H), 2.58 (s, 3H), 2.33 (s, 3H), 1.61 (s, 9H). 13 C NMR (100 MHz, CHLOROFORM-D) δ 188.2, 183.9, 171.5, 154.0, 146.9, 140.4, 138.2, 137.8, 135.4, 133.8, 130.3, 129.6 (2C), 129.2, 128.7, 128.3, 126.1, 125.5 (2C), 124.5, 108.0, 87.3, 73.6, 68.6, 48.5, 39.8, 27.8 (3C), 27.6, 21.2. HRMS calcd for C 31 H 30 N3O6[M+H] + 540.2129, found 540.2117.

[0247] Compound 36: 1H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J = 3.2 Hz, 1H), 7.40 - 7.27 (m, 4H), 7.15 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 3.2 Hz, 1H), 3.77 (d, J = 16.4 Hz, 1H), 3.53 (d, J = 16.4 Hz, 1H), 3.18 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.68 (s, 3H), 2.32 (s, 3H), 1.47 (s, 9H). 13 C NMR (100 MHz, CHLOROFORM-D) δ 189.7, 183.4, 170.0, 151.3, 146.5, 142.1, 136.9, 137.1, 136.2, 131.8, 131.3, 128.6, 128.1 (2C), 127.2, 127.0, 125.8, 124.5 (2C), 124.4, 109.1, 88.4, 73.4, 67.8, 47.9, 38.4, 27.7 (3C), 24.2, 20.3. HRMS calcd for C 31 H 30 N3O6[M+H] + 540.2129, found 540.2120.

[0248] Example 19, Preparation of compound 37 and compound 38:

[0249]

[0250] The preparation of compound 37 and compound 38 was carried out according to the procedure of example 18, using p-chlorophenyl isocyanate instead of p-tolyl isocyanate.

[0251] Compound 37: 1 H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J = 3.2 Hz, 1H), 7.40 - 7.27 (m, 4H), 7.15 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 3.2 Hz, 1H), 3.77 (d, J = 16.4 Hz, 1H), 3.53 (d, J = 16.4 Hz, 1H), 3.18 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.68 (s, 3H), 2.32 (s, 3H), 1.47 (s, 9H). 13C NMR (125 MHz, Chloroform-d) δ 188.2, 183.8, 171.3, 153.5, 146.7, 140.2, 137.7, 135.2, 133.8, 130.4, 129.9, 129.6, 129.3 (2C), 129.1, 128.4, 126.6 (2C), 126.1, 124.6, 107.9, 87.5, 73.6, 68.7, 48.5, 39.9, 27.9 (3C), 27.6. HRMS calcd for C 30 H 27 ClN3O6[M+H] + 560.1583, found 560.1571.

[0252] Compound 38: 1 H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J = 3.2 Hz, 1H), 7.40 - 7.36 (m, 3H), 7.37 - 7.29 (m, 2H), 7.17 - 7.14 (m, 1H), 7.13 - 7.06 (m, 2H), 6.51 (d, J = 3.2 Hz, 1H), 3.79 (d, J = 16.4 Hz, 1H), 3.57 (d, J = 16.4 Hz, 1H), 3.19 (d, J = 16.4 Hz, 1H), 2.99 (d, J = 16.4 Hz, 1H), 2.69 (s, 3H), 1.51 (s, 9H). 13 C NMR (100 MHz, Chloroform-d) δ 188.5, 181.5, 169.2, 153.3, 146.1, 138.9, 138.5, 133.6, 133.2, 131.7, 129.3, 129.2, 128.8, 128.4 (2C), 127.6, 126.3 (2C), 123.8, 123.1, 106.3, 86.6, 76.7, 70.6, 46.5, 39.7, 29.0, 28.3 (3C). HRMS calcd for C 30 H 27 ClN3O6[M+H] + 560.1583, found 560.1571.

[0253] Example 20, Preparation of Compound 39 and Compound 40:

[0254]

[0255] The preparation of Compound 39 and Compound 40 was carried out according to the procedure of Example 18, using phenethyl isocyanate instead of p-tolyl isocyanate.

[0256] Compound 39: 1 H NMR (500 MHz, Chloroform-d) δ 7.50 (d, J = 3.2 Hz, 1H), 7.42 - 7.27 (m, 6H), 7.22 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.4 Hz, 2H), 6.65 (d, J = 3.2 Hz, 1H), 3.75 (d, J = 16.8 Hz, 1H), 3.51 (d, J = 18.4 Hz, 1H), 3.47 - 3.38 (m, 2H), 2.99 (d, J = 16.8 Hz, 1H), 2.83 (d, J = 18.4 Hz, 1H), 2.50 - 2.42 (m, 4H), 2.30 (ddd, J = 12.4, 11.6, 5.6 Hz, 1H), 1.61 (s, 9H). 13 CNMR (125 MHz, Chloroform-d) δ 188.4, 183.9, 172.3, 154.8, 146.9, 140.5, 137.8, 137.6, 135.5, 133.8, 130.3, 129.2, 128.9 (2C), 128.7 (2C), 128.3, 126.9, 126.0, 124.6, 107.8, 87.3, 73.8, 68.3, 48.5, 40.1, 39.5, 34.1, 27.9 (3C), 27.4. HRMS calcd for C 32 H 32 N3O6[M+H] + 554.2286, found 554.2275.

[0257] Compound 40: 1H NMR (500 MHz, Chloroform-d) δ 7.50 (d, J = 3.0 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.27 - 7.23 (m, 2H), 7.21 - 7.14 (m, 3H), 7.09 (d, J = 7.0 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H), 3.72 (d, J = 16.5 Hz, 1H), 3.57 (ddd, J = 13.5, 10.5, 6.0 Hz, 1H), 3.49 (ddd, J = 13.5, 10.5, 6.0 Hz, 1H), 3.41 (d, J = 16.5 Hz, 1H), 2.98 (d, J = 16.5 Hz, 1H), 2.85 (d, J = 16.5 Hz, 1H), 2.76 (td, J = 13.0, 11.0, 6.0 Hz, 1H), 2.62 (td, J = 13.0, 11.0, 6.0 Hz, 1H), 2.55 (s, 3H), 1.59 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 190.3, 183.1, 171.5, 155.6, 147.4, 140.5, 139.9, 137.9 (2C), 132.5, 130.1, 129.4, 129.0 (2C), 128.6 (2C), 128.2, 126.7, 124.5, 123.4, 106.8, 86.6, 77.6, 69.2, 45.2, 40.2, 39.4, 33.5, 27.8, 27.7 (3C). HRMS calcd for C 32 H 32 N3O6[M+H] + 554.2286, found 554.2273.

[0258] Example 21, Preparation of compound 41 and compound 42:

[0259]

[0260] Compound 41 and compound 42 were prepared according to the procedure of Example 18, using tert-butyl isocyanate instead of p-tolyl isocyanate.

[0261] Compound 41: 1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 3.2 Hz, 1H), 7.39 - 7.29 (m, 4H), 6.69 (d, J = 3.2 Hz, 1H), 3.77 (d, J = 16.8 Hz, 1H), 3.47 (d, J = 18.4 Hz, 1H), 3.01 (d, J = 16.8 Hz, 1H), 2.80 (d, J = 18.4 Hz, 1H), 2.42 (s, 3H), 1.60 (s, 9H), 1.29 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 188.6, 184.1, 172.6, 155.5, 147.1, 140.8, 138.1, 135.7, 134.0, 130.4, 129.0, 128.2, 125.8, 124.5, 107.9, 87.2, 73.0, 68.4, 58.1, 48.7, 39.7, 28.4 (3C), 27.8 (3C), 27.1. HRMS calcd for C 28 H 32 N3O6[M+H] + 506.2286, found 506.2274.

[0262] Compound 42: 1 H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 3.2 Hz, 1H), 7.41 - 7.29 (m, 3H), 7.14 - 7.06 (m, 1H), 6.59 (d, J = 3.2 Hz, 1H), 3.69 (d, J = 16.4 Hz, 1H), 3.50 (d, J = 16.4 Hz, 1H), 2.97 (d, J = 16.4 Hz, 1H), 2.88 (d, J = 16.4 Hz, 1H), 2.52 (s, 3H), 1.58 (s, 9H), 1.32 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 190.3, 184.0, 172.2, 156.3, 147.4, 140.1, 140.1, 135.0, 132.5, 129.7, 129.4, 128.1, 124.3, 123.7, 107.0, 86.4, 76.5, 69.9, 58.2, 45.6, 39.7, 28.1 (3C), 27.6 (3C), 27.5. HRMS calcd for C 28 H 32 N3O6[M+H] + 506.2286, found506.2276.

[0263] Example 22, Preparation of compound 43 and compound 44:

[0264]

[0265] The procedure for the preparation of compound 43 and compound 44 was the same as example 18, with isocyanate instead of p-toluenesulfonyl isocyanate.

[0266] Compound 43: 1 H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J = 3.2 Hz, 1H), 7.41 - 7.29 (m, 4H), 6.65 (d, J = 3.2 Hz, 1H), 3.77 (d, J = 16.8 Hz, 1H), 3.67 (tt, J = 13.2, 4.0 Hz, 1H), 3.51 (d, J = 18.4 Hz, 1H), 3.03 (d, J = 16.8 Hz, 1H), 2.80 (d, J = 18.4 Hz, 1H), 2.45 (s, 3H), 1.95 - 1.82 (m, 1H), 1.81 - 1.62 (m, 3H), 1.60 (s, 9H), 1.24 - 1.01 (m, 6H). 13 C NMR (125 MHz, Chloroform-d) δ 188.5, 184.0, 172.3, 154.9, 147.0, 140.8, 137.9, 135.6, 133.7, 130.2, 129.0, 128.2, 125.8, 124.5, 107.9, 87.2, 73.0, 68.1, 51.5, 48.6, 39.8, 29.2, 28.7, 27.8 (3C), 27.3, 25.8, 25.7, 24.9. HRMS calcd for C 30 H 34 N3O6[M+H] + 532.2442, found 532.2430.

[0267] Compound 44: 1H NMR (400 MHz, Chloroform-d) δ 7.49 (d, J = 3.2 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.14 - 7.07 (m, 1H), 6.54 (d, J = 3.2 Hz, 1H), 3.68 (d, J = 16.4 Hz, 1H), 3.66 (tt, J = 12.4, 4.0 Hz, 1H), 3.48 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.89 (d, J = 16.4 Hz, 1H), 2.54 (s, 3H), 1.96 (qd, J = 12.4, 3.6 Hz, 1H), 1.73 (dd, J = 20.4, 12.0 Hz, 3H), 1.59 (s, 9H), 1.64 - 1.53 (m, 2H), 1.51 - 1.35 (m, 2H), 1.27 - 1.06 (m, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 190.2, 183.5, 171.5, 155.7, 147.4, 140.3, 140.0, 134.8, 132.4, 129.8, 129.3, 128.1, 124.4, 123.5, 106.8, 86.4, 76.4, 69.5, 51.9, 45.4, 39.6, 28.9, 28.8, 27.8, 27.7 (3C), 25.8, 25.8, 25.0. HRMS calcd for C 30 H 34 N3O6[M+H] + 532.2442, found 532.2431.

[0268] Example 23, Preparation of compound 45 and compound 46:

[0269]

[0270] The preparation of compound 45 and compound 46 was carried out according to the procedure of Example 18, using p-chloro m-trifluoromethyl isocyanate instead of p-tolyl isocyanate.

[0271] Compound 45: 1H NMR (400 MHz, Chloroform-d) δ 7.49 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 7.43 - 7.34 (m, 4H), 7.32 - 7.26 (m, 2H), 6.54 (d, J = 3.2 Hz, 1H), 3.90 (d, J = 16.8 Hz, 1H), 3.51 (d, J = 18.4 Hz, 1H), 3.21 (d, J = 16.8 Hz, 1H), 2.89 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 1.61 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 188.0, 183.6, 171.1, 152.9, 146.5, 139.9, 137.5, 135.1, 133.8, 132.1, 131.7, 130.3, 130.1, 129.6, 129.4, 129.0 (q, J = 31.1 Hz), 128.5, 126.2, 124.6, 124.6 (q, J = 5.3 Hz), 122.35 (q, J = 273.8 Hz), 107.9, 87.6, 73.8, 68.8, 48.5, 39.7, 27.8 (3C), 27.6. HRMS calcd for C 31 H 26 ClF3N3O6[M+H] + 628.1457, found 628.1446.

[0272] Compound 46: 1 H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.40 - 7.35 (m, 4H), 7.17 - 7.11 (m, 1H), 6.50 (d, J = 3.2 Hz, 1H), 3.78 (d, J = 16.4 Hz, 1H), 3.57 (d, J = 16.4 Hz, 1H), 3.20 (d, J = 16.4 Hz, 1H), 2.98 (d, J = 16.4 Hz, 1H), 2.71 (s, 3H), 1.50 (s, 9H). 13C NMR (125 MHz, Chloroform-d) δ 190.1, 183.0, 170.6, 153.9, 147.0, 139.6, 139.3, 134.4, 132.5, 132.1, 131.8, 130.3, 130.3, 129.8, 129.7, 129.1 (q, J = 32.0 Hz), 128.4, 124.9 (q, J = 5.3 Hz), 124.6, 123.8, 122.4 (q, J = 273.4 Hz), 106.8, 86.9, 76.6, 70.8, 46.3, 39.0, 28.3, 27.5 (3C). HRMS calcd for C 31 H 26 ClF3N3O6[M + H] + 628.1457, found 628.1445.

[0273] Example 24, Preparation of Compound 47 and Compound 48:

[0274]

[0275] The procedure for the preparation of Compound 47 and Compound 48 was the same as Example 18, with isocyanate instead of p-toluenesulfonyl isocyanate.

[0276] Compound 47: 1 H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 3.2 Hz, 1H), 7.46 - 7.33 (m, 4H), 7.08 - 6.94 (m, 4H), 6.62 (d, J = 3.2 Hz, 1H), 3.89 (d, J = 17.2 Hz, 1H), 3.56 (d, J = 18.4 Hz, 1H), 3.20 (d, J = 17.2 Hz, 1H), 2.89 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 1.61 (s, 9H). 13 C NMR (100 MHz, CHLOROFORM-D) δ 188.2, 183.8, 171.5, 161.8 (d, J = 248.2 Hz), 153.7, 146.8, 140.2, 137.7, 135.3, 133.8, 130.3, 129.3, 128.4, 127.4 (d, J = 8.6 Hz, 2C), 127.3 (d, J = 3.1 Hz), 126.1, 124.6, 115.95 (d, J = 22.7 Hz, 2C), 107.9, 87.5, 73.6, 68.7, 48.5, 39.8, 27.8 (3C), 27.6. HRMS calcd for C 30 H27 FN3O6[M+H] + 544.1878, found 544.1869.

[0277] Compound 48: 1 H NMR (400 MHz, Chloroform-d) δ 7.42 (d, J = 3.2 Hz, 1H), 7.41 - 7.35 (m, 3H), 7.19 - 6.99 (m, 5H), 6.52 (d, J = 3.2 Hz, 1H), 3.79 (d, J = 16.4 Hz, 1H), 3.57 (d, J = 16.4 Hz, 1H), 3.19 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.69 (s, 3H), 1.50 (s, 9H). 13 CNMR (125 MHz, Chloroform-d) δ 190.3, 183.1, 170.8, 162.1 (d, J = 248.1 Hz), 154.7, 147.2, 139.8, 139.5, 134.5, 132.5, 130.1, 129.5, 128.3, 127.8 (d, J = 8.8 Hz, 2C), 127.4 (d, J = 3.1 Hz), 124.5, 123.8, 116.0 (d, J = 22.8 Hz, 2C), 106.7, 86.7, 76.7, 70.4, 46.0, 39.1, 28.2, 27.5 (3C). HRMS calcd for C 30 H 27 FN3O6[M+H] + 544.1878, found 544.1866.

[0278] Example 25, Preparation of Compound 49 and Compound 50:

[0279]

[0280] Compound 49 and Compound 50 were prepared according to the procedure of Example 18, using 2-bromo-5-methylbenzaldehyde instead of o-bromobenzaldehyde.

[0281] Compound 49: 1H NMR (500 MHz, Chloroform-d) δ 7.51 (d, J = 3.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 3.5 Hz, 1H), 3.84 (d, J = 16.5 Hz, 1H), 3.54 (d, J = 18.5 Hz, 1H), 3.14 (d, J = 16.5 Hz, 1H), 2.85 (d, J = 18.5 Hz, 1H), 2.59 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 1.60 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 188.4, 184.1, 171.6, 154.1, 146.9, 139.2, 138.1, 137.9, 137.5, 135.3, 133.8, 130.3, 129.6 (2C), 129.2, 128.7, 125.7, 125.5 (2C), 125.1, 108.0, 87.3, 73.7, 68.4, 48.6, 39.8, 27.9 (3C), 27.6, 21.5, 21.2. HRMS calcd for C 32 H 32 N3O6[M+H] + 554.2286, found 554.2277.

[0282] Compound 50: 1 H NMR (500 MHz, Chloroform-d) δ 7.43 (d, J = 3.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 3H), 7.15 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 3.0 Hz, 1H), 3.74 (d, J = 16.5 Hz, 1H), 3.51 (d, J = 16.5 Hz, 1H), 3.14 (d, J = 16.5 Hz, 1H), 2.99 (d, J = 16.5 Hz, 1H), 2.70 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 1.48 (s, 9H). 13C NMR (125 MHz, Chloroform-d) δ 190.3, 183.6, 170.9, 155.1, 147.4, 139.7, 139.5, 138.3, 137.1, 134.6, 132.6, 129.9, 129.7 (2C), 129.1, 128.9, 125.9 (2C), 125.1, 123.5, 106.8, 86.5, 76.7, 70.2, 46.2, 39.1, 28.3, 27.5 (3C), 21.6, 21.3. HRMS calcd for C 32 H 32 N3O6[M+H] + 554.2286, found 554.2274.

[0283] Example 26, Preparation of compound 51 and compound 52:

[0284]

[0285] The preparation of compound 51 and compound 52 was carried out according to the procedure of Example 18, using 2-bromo-4-methylbenzaldehyde instead of o-bromobenzaldehyde.

[0286] Compound 51: 1 H NMR (500 MHz, Chloroform-d) δ 7.51 (d, J = 3.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 3.0 Hz, 1H), 3.83 (d, J = 16.5 Hz, 1H), 3.54 (d, J = 18.5 Hz, 1H), 3.15 (d, J = 16.5 Hz, 1H), 2.87 (d, J = 18.5 Hz, 1H), 2.59 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H), 1.61 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 188.3, 184.1, 171.6, 154.1, 146.9, 140.5, 138.1, 138.1, 135.4, 134.8, 133.8, 130.3, 130.1, 129.6 (2C), 128.7, 126.6, 125.5 (2C), 124.2, 107.9, 87.3, 73.8, 68.5, 48.6, 39.6, 27.9 (3C), 27.6, 21.7, 21.3. HRMS calcd for C 32H 32 N3O6[M+H] + 554.2286, found 554.2274.

[0287] Compound 52: 1 H NMR(400MHz,Chloroform-d)δ7.43(d,J=3.2Hz,1H),7.25–7.13(m,4H),7.01–6.89(m,3H),6.54(d,J=3.2Hz,1H),3.74(d,J=16.4H z,1H),3.53(d,J=16.4Hz,1H),3.13(d,J=16.4Hz,1H),2.99(d,J=16.4Hz,1H),2.68(s,3H),2.39(s,3H),2.33(s,3H),1.50(s,9H). 13 C NMR(125MHz,Chloroform-d)δ190.3,183.4,170.8,155.0,147.3,140.1,138.3,138.0,136.7,134.6,132.6,130.4,130.0,12 9.7(2C),128.9,125.9(2C),124.4,124.1,106.8,86.5,77.4,77.2,76.9,70.2,46.0,38.9,28.2,27.5(4C),21.7,21.3.HRMS calcd for C 32 H 32 N3O6[M+H] + 554.2286, found 554.2275.

[0288] Example 27, Preparation of Compounds 53 and 54:

[0289]

[0290] Compounds 53 and 54 were prepared in the same manner as in Example 18, except that 2-bromo-4-methoxybenzaldehyde was used instead of o-bromobenzaldehyde.

[0291] Compound 53: 1H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J = 3.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.93 (dd, J = 8.4, 2.4 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 3.81 (s, 3H), 3.71 (d, J = 16.4 Hz, 1H), 3.51 (d, J = 16.4 Hz, 1H), 3.11 (d, J = 16.4 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.70 (s, 3H), 2.33 (s, 3H), 1.50 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 188.3, 183.9, 171.5, 159.8, 154.1, 146.9, 141.8, 138.2, 135.4, 133.8, 130.3, 129.6 (2C), 129.5, 128.7, 125.6 (2C), 125.2, 115.8, 110.9, 108.0, 87.4, 74.0, 68.6, 55.7, 48.5, 39.2, 27.9 (3C), 27.6, 21.3. HRMS calcd for C 32 H 32 N3O7[M+H] + 570.2235, found 570.2226.

[0292] Compound 54: 1 H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 3.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.97 - 6.90 (m, 2H), 6.86 - 6.79 (m, 2H), 6.62 (d, J = 3.2 Hz, 1H), 3.85 (s, 3H), 3.81 (d, J = 16.4 Hz, 1H), 3.56 (d, J = 18.4 Hz, 1H), 3.12 (d, J = 16.4 Hz, 1H), 2.88 (d, J = 18.4 Hz, 1H), 2.61 (s, 3H), 2.32 (s, 3H), 1.61 (s, 9H). 13C NMR (125 MHz, Chloroform-d) δ 190.1, 183.1, 170.7, 159.9, 155.0, 147.3, 141.4, 138.3, 134.5, 132.6, 131.5, 130.0, 129.7 (2C), 128.9, 125.9 (2C), 125.1, 115.2, 109.5, 106.8, 86.6, 76.9, 70.4, 55.6, 46.0, 38.5, 28.2, 27.6 (3C), 21.3. HRMS calcd for C 32 H 32 N3O7[M+H] + 570.2235, found 570.2224.

[0293] Example 28, Preparation of compound 55 and compound 56:

[0294]

[0295] The procedure of Example 18 was followed for the preparation of compound 55 and compound 56, using 2-bromo-5-methoxybenzaldehyde in place of o-bromobenzaldehyde.

[0296] Compound 55: 1 H NMR (500 MHz, Chloroform-d) δ 7.51 (d, J = 3.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 3.5 Hz, 1H), 3.86 (s, 3H), 3.85 (d, J = 16.5 Hz, 1H), 3.54 (d, J = 18.5 Hz, 1H), 3.13 (d, J = 16.5 Hz, 1H), 2.84 (d, J = 18.5 Hz, 1H), 2.61 (s, 3H), 2.33 (s, 3H), 1.61 (s, 9H). 13C NMR (125 MHz, Chloroform-d) δ 188.5, 184.3, 171.4, 160.5, 154.1, 146.9, 139.3, 138.2, 135.3, 133.9, 132.4, 130.3, 129.6 (2C), 128.7, 126.8, 125.5 (2C), 114.3, 109.6, 108.0, 87.2, 73.8, 67.9, 55.6, 48.8, 40.0, 27.9 (3C), 27.6, 21.3. HRMS calcd for C 32 H 32 N3O7[M+H] + 570.2235, found 570.2223.

[0297] Compound 56: 1 H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J = 3.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 6.8 Hz, 1H), 6.89 (s, 1H), 6.54 (d, J = 3.2 Hz, 1H), 3.85 (s, 3H), 3.74 (d, J = 16.4 Hz, 1H), 3.48 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 16.4 Hz, 1H), 2.99 (d, J = 16.4 Hz, 1H), 2.72 (s, 3H), 2.33 (s, 3H), 1.49 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 190.3, 183.7, 170.8, 160.8, 155.0, 147.3, 141.1, 138.3, 134.6, 132.7, 132.0, 129.9, 129.7 (2C), 128.8, 125.9 (2C), 124.7, 114.1, 109.8, 106.8, 86.5, 76.8, 69.8, 55.6, 46.4, 39.2, 28.2, 27.5 (3C), 21.3. HRMS calcd for C 32 H 32 N3O7[M+H] + 570.2235, found 570.2226.

[0298] Example 29, Preparation of Compound 57 and Compound 58:

[0299]

[0300] Compound 57 was prepared according to the procedure of Example 18, using 2-bromo-5-chlorobenzaldehyde in place of o-bromobenzaldehyde.

[0301] Compound 57: 1 H NMR (400 MHz, Chloroform-d) δ 7.52 (d, J = 3.2 Hz, 1H), 7.43 - 7.29 (m, 3H), 7.17 - 7.11 (m, 2H), 6.86 - 6.80 (m, 2H), 6.62 (d, J = 3.2 Hz, 1H), 3.86 (d, J = 16.8 Hz, 1H), 3.54 (d, J = 18.4 Hz, 1H), 3.17 (d, J = 16.8 Hz, 1H), 2.83 (d, J = 18.4 Hz, 1H), 2.59 (s, 3H), 2.33 (s, 3H), 1.61 (s, 9H). 13 C NMR (125 MHz, Chloroform-d) δ 187.8, 183.5, 171.1, 153.9, 146.7, 139.8, 138.9, 138.3, 135.4, 135.1, 133.5, 130.5, 129.6 (2C), 128.7, 128.6, 127.3, 125.5 (2C), 124.8, 108.1, 87.5, 73.6, 68.1, 48.3, 39.5, 27.9 (3C), 27.6, 21.3. HRMS calcd for C 31 H 29 ClN3O6[M+H] + 574.1739, found 574.1729.

[0302] Compound 58: 1 H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J = 3.2 Hz, 1H), 7.36 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 3.2 Hz, 1H), 3.73 (d, J = 16.8 Hz, 1H), 3.47 (d, J = 16.4 Hz, 1H), 3.17 (d, J = 16.8 Hz, 1H), 2.98 (d, J = 16.4 Hz, 1H), 2.71 (s, 3H), 2.32 (s, 3H), 1.47 (s, 9H). 13C NMR (100 MHz, CHLOROFORM-D) δ 189.6, 182.9, 170.5, 154.9, 147.3, 141.5, 138.6, 138.4, 135.3, 134.2, 132.8, 130.2, 129.7 (2C), 128.8, 128.6, 125.8 (2C), 125.2, 124.8, 107.0, 86.7, 76.5, 70.0, 46.1, 38.8, 28.4, 27.5 (3C), 21.3. HRMS calcd for C 31 H 29 ClN3O6[M+H] + 574.1739, found 574.1726.

[0303] Example 30, Preparation of compound 59:

[0304]

[0305] The procedure of Example 18 was followed for the preparation of compound 59, using benzyl isocyanate instead of p-tolyl isocyanate, to give a ratio of isomers of 5:3.

[0306] Compound 59: 1 H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.30 (m, 6.4H), 7.30 - 7.25 (m, 2.2H), 7.25 - 7.17 (m, 5.8H), 7.12 - 7.07 (m, 0.6H), 7.03 (d, J=3.2 Hz, 1H), 6.23 (d, J=3.2 Hz, 0.6H), 6.20 (d, J=3.2 Hz, 1H), 4.42 - 4.39 (m, 3.2H), 3.80 (d, J=16.8 Hz, 1H), 3.71 (d, J=16.4 Hz, 0.6H), 3.48 (d, J=18.4 Hz, 1H), 3.42 (d, J=16.8 Hz, 0.6H), 3.04 (d, J=16.8 Hz, 1H), 3.03 (d, J=16.4 Hz, 0.6H), 2.91 (d, J=16.8 Hz, 0.6H), 2.77 (d, J=18.4 Hz, 1H), 2.58 (s, 1.8H), 2.47 (s, 3H), 1.61 (s, 9H), 1.58 (s, 5.2H). 13C NMR (101 MHz, CHLOROFORM-D) δ 189.7, 188.3, 183.5, 183.2, 172.0, 171.6, 155.8, 155.2, 147.3, 147.0, 140.8, 140.4, 139.7, 137.7, 135.7, 135.5, 135.4, 135.1, 130.5, 129.7, 129.3, 129.1 (2C), 129.0, 128.9 (2C), 128.7 (2C), 128.6 (2C), 128.4, 128.3, 128.3, 128.1, 127.9 (2C), 125.8, 124.5, 124.4, 123.6, 107.1, 106.7, 86.9, 86.4, 76.8, 73.9, 69.5, 68.0, 48.6, 45.3, 42.8, 42.6, 39.8, 39.6, 27.8, 27.8 (3C), 27.6 (3C), 27.5. HRMS calcd for C 31 H 30 N3O6[M+H] + 540.2129, found 540.2120.

[0307] Example 31, Preparation of compound 60:

[0308]

[0309] The procedure of Example 18 was followed for the preparation of compound 60, using ethyl isocyanate instead of p-tolyl isocyanate, to give a mixture of isomers in the ratio 10:7.

[0310] Compound 60: 1H NMR (500 MHz, Chloroform-d) δ 7.53 (d, J = 3.5 Hz, 1 H), 7.49 (d, J = 3.5 Hz, 0.7 H), 7.41 - 7.32 (m, 6.1 H), 7.12 (d, J = 6.5 Hz, 0.7 H), 6.65 (d, J = 3.5 Hz, 1 H), 6.54 (d, J = 3.5 Hz, 0.7 H), 3.79 (d, J = 17.0 Hz, 1 H), 3.71 (d, J = 16.5 Hz, 0.7 H), 3.52 (d, J = 18.5 Hz, 1 H), 3.51 (d, J = 16.5 Hz, 0.7 H), 3.43 - 3.21 (m, 3.4 H), 3.05 (d, J = 17.0 Hz, 1 H), 3.00 (d, J = 16.5 Hz, 0.7 H), 2.91 (d, J = 16.5 Hz, 0.7 H), 2.83 (d, J = 18.5 Hz, 1 H), 2.55 (s, 2.1 H), 2.47 (s, 3 H), 1.61 (s, 9 H), 1.58 (s, 6.3 H), 0.97 (t, J = 7.0 Hz, 2.1 H), 0.71 (t, J = 7.0 Hz, 3 H). 13 C NMR (126 MHz, CDC13) δ 190.1, 188.4, 183.8, 183.4, 172.2, 171.5, 155.6, 154.9, 147.3, 146.9, 140.6, 139.9, 137.8, 136.7, 135.5, 134.7, 133.7, 132.3, 130.3, 129.4, 129.1, 128.3, 128.2, 127.7, 125.9, 124.5, 124.3, 123.5, 107.8, 106.7, 87.2, 86.4, 76.9, 73.7, 69.5, 68.2, 48.5, 45.3, 39.4, 39.3, 34.1, 33.8, 27.8 (3C), 27.7, 27.6 (3C), 27.3, 13.2, 12.8. HRMS calcd for C 26 H 28 N3O6[M+H] + 478.1973, found 478.1961.

[0311] Example 32, Preparation of compound 61 and compound 62:

[0312]

[0313] The preparation of compound 61 and compound 62 was carried out according to the procedure of Example 18, using N-phenylglycine ethyl ester instead of sarcosine ethyl ester.

[0314] Compound 61: 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 3.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.11 - 6.97 (m, 6H), 6.91 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 3.2 Hz, 1H), 3.83 (d, J = 16.4 Hz, 1H), 3.57 (d, J = 18.4 Hz, 1H), 3.09 (d, J = 16.4 Hz, 1H), 2.96 (d, J = 18.4 Hz, 1H), 2.34 (s, 3H), 1.43 (s, 9H). 13 C NMR (125 MHz, CDC13) δ 188.3, 184.9, 171.7, 155.0, 147.7, 141.1, 138.3, 138.1, 135.6 (2C), 133.8, 130.8, 129.6 (2C), 129.4 (2C), 128.6, 128.5, 127.9, 127.9 (2C), 127.6, 125.6, 125.2 (2C), 124.3, 108.0, 88.1, 77.9, 70.3, 49.5, 38.4, 27.7 (3C), 21.3. HRMS calcd for C36H32N306 [M+H]+ 602.2286, found 602.2276.

[0315] Compound 62: 1 H NMR (500 MHz, Chloroform-d) δ 7.49 (d, J = 3.0 Hz, 1H), 7.25 - 7.10 (m, 12H), 6.89 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 3.0 Hz, 1H), 3.77 (d, J = 16.0 Hz, 1H), 3.52 (d, J = 16.0 Hz, 1H), 3.47 (d, J = 16.0 Hz, 1H), 3.22 (d, J = 16.0 Hz, 1H), 2.36 (s, 3H), 1.49 (s, 9H). 13CNMR (125 MHz, CDC13) δ 190.4, 183.9, 170.0, 155.3, 147.5, 140.8, 139.1, 138.3, 135.4, 135.0, 134.9, 133.1, 130.0, 129.6 (2C), 129.1 (2C), 129.0, 128.9 (2C), 128.2, 127.8, 126.2 (2C), 124.7, 122.9, 107.0, 86.8, 77.8, 70.8, 46.7, 39.9, 27.5 (3C), 21.3. HRMS calcd for C36H32N306 [M+H]+602.2286, found 602.2274.

[0316] Example 33, Preparation of Compound 63 and Compound 64:

[0317]

[0318] The procedure for the preparation of Compound 63 and Compound 64 was the same as Example 18, using N-benzylglycine ethyl ester instead of sarcosine ethyl ester.

[0319] Compound 63: 1 H NMR (500 MHz, Chloroform-d) δ 7.56 - 7.46 (m, 3H), 7.39 (td, J = 7.5, 1.5 Hz, 1H), 7.28 - 7.17 (m, 5H), 6.99 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 1H), 6.86 (d, J = 7.5 Hz, 2H), 6.65 (d, J = 3.5 Hz, 1H), 5.18 (d, J = 16.0 Hz, 1H), 3.65 (d, J = 17.0 Hz, 1H), 3.57 (d, J = 18.5 Hz, 1H), 3.49 (d, J = 16.0 Hz, 1H), 2.91 (d, J = 18.5 Hz, 1H), 2.76 (d, J = 17.0 Hz, 1H), 2.39 (s, 3H), 1.67 (s, 9H). 13C NMR (126 MHz, CDC13) δ 188.2, 184.4, 171.5, 154.5, 146.3, 140.5, 138.1, 138.0, 137.9, 135.3, 134.3, 130.2, 129.5 (2C), 128.8, 128.8, 128.4 (2C), 128.2, 128.2 (2C), 127.8, 125.9, 125.7, 125.4 (2C), 108.0, 87.2, 74.4, 69.0, 48.8, 45.0, 40.5, 28.0 (3C), 21.3. HRMS calcd for C37H34N3O6 [M+H]+616.2442, found 616.2431.

[0320] Compound 64: 1 H NMR (500 MHz, Chloroform-d) δ 7.45 - 7.36 (m, 3H), 7.25 - 7.23 (m, 1H), 7.22 (d, J = 7.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.16 - 7.11 (m, 2H), 7.04 (dd, J = 8.5 Hz, 2H), 6.87 (d, J = 7.5 Hz, 2H), 6.51 (dd, J = 3.5, 1.5 Hz, 1H), 4.92 (d, J = 15.5 Hz, 1H), 3.64 (d, J = 16.5 Hz, 1H), 3.59 (d, J = 15.5 Hz, 1H), 3.54 (d, J = 16.5 Hz, 1H), 2.98 (d, J = 16.5 Hz, 1H), 2.84 (d, J = 16.5 Hz, 1H), 2.35 (s, 3H), 1.50 (s, 9H). 13 C NMR (125 MHz, CDC13) δ 190.4, 183.3, 170.7, 155.5, 147.3, 140.3, 140.1, 138.4, 137.1, 134.5, 132.3, 130.0, 129.7 (2C), 129.3, 128.9, 128.6 (2C), 128.3, 128.3 (2C), 128.1, 125.9 (2C), 125.3, 123.5, 106.8, 86.5, 78.1, 70.6, 45.6, 45.2, 39.5, 27.6 (3C), 21.3. HRMS calcd for C37H34N3O6 [M+H]+616.2442, found 616.2430.

[0321] Example 34, Preparation of Compound 65 and Compound 66:

[0322]

[0323] Compound 65 was prepared according to the procedure of Example 1, substituting N-benzylglycine ethyl ester for sarcosine ethyl ester.

[0324] Compound 65: 1 H NMR (400 MHz, Chloroform-d) δ 8.06 - 7.99 (m, 2H), 7.81 (td, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.38 (tt, J = 8.4, 4.0 Hz, 1H), 7.23 - 7.13 (m, 3H), 7.07 (d, J = 7.2 Hz, 2H), 6.97 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 7.2 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 4.88 (d, J = 16.0 Hz, 1H), 3.66 (d, J = 18.8 Hz, 2H), 3.52 (d, J = 16.0 Hz, 1H), 2.98 (d, J = 18.8 Hz, 1H), 2.76 (d, J = 18.8 Hz, 1H), 2.30 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 195.4, 190.8, 171.2, 154.7, 141.0, 138.2, 137.9, 137.5, 136.4, 135.3, 135.2, 134.9, 129.3 (2C), 129.0, 128.5, 128.5 (2C), 128.3, 128.1 (2C), 127.9, 127.3 (2C), 125.7, 125.4, 125.2 (2C), 74.4, 68.0, 46.6, 44.7, 40.4, 21.3. HRMS calcd for C34H27N2O4 [M+H]+527.1965, found 527.1955.

[0325] Compound 66: 1H NMR (500 MHz, Chloroform-d) δ 8.02 (d, J = 7.5 Hz, 1H), 7.92 (dd, J = 7.5, 1.5 Hz, 1H), 7.68 (td, J = 7.5, 1.5 Hz, 1H), 7.61 (td, J = 7.5, 1.5 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.25 - 7.16 (m, 4H), 7.14 - 7.08 (m, 3H), 6.95 - 6.81 (m, 4H), 4.92 (d, J = 15.5 Hz, 1H), 3.70 (d, J = 16.5 Hz, 1H), 3.69 (d, J = 15.5 Hz, 2H), 3.08 (d, J = 15.5 Hz, 1H), 2.86 (d, J = 16.5 Hz, 1H), 2.31 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 193.9, 193.2, 170.3, 155.3, 140.4, 140.3, 138.2, 137.1, 135.5, 135.3, 134.1, 134.0, 129.5 (2C), 129.5, 128.6 (2C), 128.5 (2C), 128.5 (2C), 128.4, 128.2, 126.0, 125.2, 125.2 (2C), 123.0, 78.0, 68.8, 45.7, 43.6, 39.9, 21.3. HRMS calcd for C34H27N2O4 [M+H]+527.1965, found 527.1957.

[0326] Pharmacological experiments:

[0327] Experimental methods:

[0328] 2.1 Cell lines and culture

[0329] U251 cells were derived from the National Experimental Cell Resource Sharing Platform. U251 cells were cultured in Gibco Dulbecco's Modified Eagle Medium (without phenol red) containing 10% fetal bovine serum and 100 IU / mL penicillin / streptomycin. Cells were cultured at 37 °C in a humidified incubator with a 5% (v / v) CO2 atmosphere.

[0330] 2.2 MTT assay

[0331] MTT assay was used to detect the anti-proliferative effect of the compounds in vitro. U251 cells were seeded in 96-well plates at 1 x 104per well. Cells were treated with different concentrations (10, 1, 0.1 mM) of the compounds and Epacadostat (positive control) and incubated at 37 °C with 5% CO2for 48 h. MTT solution was added to each well at a final concentration of 0.5 mg / ml and incubated at 37 °C for 3 h in the dark. DMSO was added to each well and the OD value was measured at 570 nm. The inhibition of cell proliferation by the compounds was calculated as follows: Cell proliferation inhibition (%) = (OD control - OD compound) / (OD control - OD blank) x 100%. IC 50 values were calculated using GraphPad Prism 8.0 software.

[0332] 2.3 Enzymatic assay for IDOl inhibition

[0333] A 100 pL reaction system consisting of 50 mM potassium phosphate buffer (pH 6.5), 20 mM ascorbic acid (neutralized with NaOH), 10 pg / mL catalase, 10 mM methylene blue and different concentrations (20, 2, 0.2 mM) of the compounds was added to a 96-well plate. Subsequently, a final concentration of 200 mM of the substrate L-tryptophan and 10 pg / mL of rhIDOl enzyme was added to each well. The reaction was carried out at 37 °C for 45 min and stopped using 20 pL of trichloroacetic acid at a concentration of 30% (v / v). The mixture was heated at 65 °C for 15 min to convert N'-formyl-L-kynurenine to kynurenine. Finally, an equal volume (2% w / v) of p-dimethylaminobenzaldehyde acetic acid solution was added to each well and the OD value was detected at 490 nm. IC 50 values were calculated using GraphPad Prism 8.0 software.

[0334] 2.4 Cell IDOl inhibition assay

[0335] A total of 1 x 104U251 cells were seeded in 96-well plates. Different concentrations (10, 1, 0.1 mM) of the compounds were added to each well, along with a final concentration of 50 ng / mL of IFN-g and 1 mM of the substrate L-tryptophan. The plates were then incubated at 37 °C with 5% CO2for 48 h, and 80 ul of the supernatant was transferred to a new 96-well plate and mixed with 20 pL of trichloroacetic acid (30% v / v) to stop the reaction. Subsequently, the reaction mixture was heated at 65 °C for 15 min, 100 pL of p-dimethylaminobenzaldehyde acetic acid solution (2% w / v) was added and mixed thoroughly for 5 min. The OD value was measured at 490 nm and the IC 50 values were calculated using GraphPad Prism 8.0 software.

[0336] Experimental results:

[0337] Table 1. In vitro inhibitory activity of compounds on IDO1 enzyme

[0338]

[0339]

[0340] Conclusion:

[0341] The double spiro compound involved in the present application has certain inhibitory activity on IDO1, and the double spiro compound is synthesized from amino acid ethyl ester as a starting material, the starting material is simple and easy to obtain, the synthesis route is more simple and efficient, and is more suitable for industrial production. In summary, the compound involved in the present application is simple in synthesis, low in cost, and has good IDO1 inhibitory activity, and is convenient for subsequent development of IDO1 inhibitors.

Claims

1. Compounds of the general formula (I) and pharmaceutically acceptable salts thereof: ###0001### wherein A, B are carbon atoms, the configuration of which is independently of each other selected from the group consisting of R-configuration or S-configuration; X is selected from the group consisting of C, NBoc; n is 2 if X is C, n is 1 if X is NBoc; R1 is selected from the group consisting of H, C1-C16 straight chain or branched alkyl, C3-C8 cycloalkyl, C6-C16 aryl, C4-C16 heteroaryl, aryl-substituted C1-C16 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, biphenyl; the heteroaryl groups are selected from the group consisting of furanyl, thienyl, imidazolyl, pyrrolyl, thiazolyl, quinolyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl; these aryl, heteroaryl groups can have one or more substituents, the substituents being independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy C1-C16 alkyl; R2 is selected from the group consisting of H, C1-C16 straight chain or branched alkyl, C6-C16 aryl, C4-C16 heteroaryl, aryl-substituted C1-C16 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, biphenyl; the heteroaryl groups are selected from the group consisting of furanyl, thienyl, imidazolyl, pyrrolyl, thiazolyl, quinolyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl; these aryl, heteroaryl groups can have one or more substituents, the substituents being independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight chain or branched alkyl; R3 is selected from the group consisting of H, halogen, C1-C16 straight chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy C1-C16 alkyl.

2. Compounds according to claim 1 and pharmaceutically acceptable salts thereof, characterized in that A, B are carbon atoms, the configuration of which is independently of each other selected from the group consisting of R-configuration or S-configuration; X is selected from the group consisting of C, NBoc; n is 2 if X is C, n is 1 if X is NBoc; R1 is selected from the group consisting of H, C1-C8 straight chain or branched alkyl, C3-C8 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C8 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; these aryl groups can have one or more substituents, the substituents being independently of each other selected from the group consisting of H, halogen, NO2, CN, CF3, OCF3, C1-C8 straight chain or branched alkyl, C1-C8 alkoxy, C1-C8 alkoxy C1-C8 alkyl. ​ ​ ​ ​ ​ ​ ​ ​ R2is selected from the group consisting of H, C1-C8 straight chain or branched alkyl, C6-C10 aryl, aryl substituted C1-C8 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can have one or more substituents, the substituents being independently selected from the group consisting of H, halogen, NO2, CN, CF3, OCF3, C1-C8 straight chain or branched alkyl, C1-C8 alkoxy, C1-C8 alkoxy C1-C8 alkyl; R3is selected from the group consisting of H, halogen, C1-C8 straight chain or branched alkyl, C1-C8 alkoxy.

3. The compound according to claim 2, characterized in that A, B are carbon atoms, the configuration being independently selected from the group consisting of R configuration or S configuration; X is selected from the group consisting of C, NBoc; n is 2 when X is C, n is 1 when X is NBoc; R1is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl, the aryl groups being selected from the group consisting of phenyl, naphthyl; the aryl groups can have one or more substituents, the substituents being independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R2is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can have one or more substituents, the substituents being independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R3is selected from the group consisting of H, halogen, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy.

4. The compounds according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, characterized in that, the compound is represented by the formula IA R4is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can have one or more substituents, the substituents being independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R5is selected from the group consisting of H, C1-C4 linear or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can further have one or more substituents, independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R6is selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy.

5. The compound according to claim 4, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IA1 R 41 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl groups mentioned above are selected from the group consisting of phenyl, naphthyl; R 51 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups mentioned above are selected from the group consisting of phenyl, naphthyl; R 61 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy.

6. The compound according to claim 4, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IA2 R 52 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 62 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy; R 72 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl.

7. The compound according to claim 4, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IA3 R 53 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 63 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy; R 83 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl.

8. The compounds according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IB R9is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can further have one or more substituents, independently selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R 10 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl is selected from the group consisting of phenyl, naphthyl; the aryl can also have one or more substituents, the substituents being independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R 11 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy.

9. The compound according to claim 8, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IB1 R 91 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl groups mentioned above are selected from the group consisting of phenyl, naphthyl; R 101 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 111 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy.

10. The compound according to claim 8, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IB2 R 102 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl groups mentioned above are selected from the group consisting of phenyl, naphthyl; R 112 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy; R 122 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl.

11. The compound according to claim 8, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IB3 R 103 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl groups mentioned above are selected from the group consisting of phenyl, naphthyl; R 113 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy; R 133 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl.

12. The compounds according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IC R 14 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can also have one or more substituents, the substituents being independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R 15 H, C1-C4 straight-chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from phenyl, naphthyl; the aryl groups can also have one or more substituents, which are independently of one another selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R 16 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy.

13. The compound according to claim 12, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IC1 R 141 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl groups mentioned above are selected from the group consisting of phenyl, naphthyl; R 151 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 161 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy.

14. The compound according to claim 12, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IC2 R 152 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 162 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy; R 172 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl.

15. The compound according to claim 12, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula IC3 R 153 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 163 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy; R 183 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl.

16. The compounds according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula ID R 19 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; the aryl groups can also have one or more substituents, the substituents being independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R 20 H, C1-C4 straight-chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups mentioned are selected from phenyl, naphthyl; the aryl groups mentioned can also have one or more substituents, which are independently of one another selected from H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 straight-chain or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl; R 21 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy.

17. The compound according to claim 16, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula ID1 R 191 is selected from the group consisting of H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl, aryl-substituted C1-C4 alkyl; the aryl groups mentioned above are selected from the group consisting of phenyl, naphthyl; R 201 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 211 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy.

18. The compound according to claim 16, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula ID2 R 202 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 212 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy; R 222 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl.

19. The compound according to claim 16, and pharmaceutically acceptable salts thereof, characterized in that, The compound is represented by formula ID3 R 203 is selected from the group consisting of H, C1-C4 straight chain or branched alkyl, C6-C10 aryl, aryl-substituted C1-C4 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl; R 213 selected from the group consisting of H, halogen, C1-C4 linear or branched alkyl, C1-C4 alkoxy; R 233 selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C4 linear or branched alkyl, C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl.

20. The compounds according to any one of claims 1 to 19, and pharmaceutically acceptable salts thereof, characterized in that, The compound is selected from the group consisting of Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound 14 Compound 15 Compound 16 Compound 17 Compound 18 Compound 19 Compound 20 Compound 21 Compound 22 Compound 23 Compound 24 Compound 25 Compound 26 Compound 27 Compound 28 Compound 29 Compound 30 Compound 31 Compound 32 Compound 33 Compound 34 Compound 35 Compound 36 Compound 37 Compound 38 Compound 39 Compound 40 Compound 41 Compound 42 Compound 43 Compound 44 Compound 45 Compound 46 Compound 47 Compound 48 Compound 49 Compound 50 Compound 51 Compound 52 Compound 53 Compound 54 Compound 55 Compound 56 Compound 57 Compound 58 Compound 59 Compound 60 Compound 61 Compound 62 Compound 63 Compound 64 Compound 65 Compound 66 21. A pharmaceutical composition, characterized by A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one of claims 1-19, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

22. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a neoplasm.

23. A process for the preparation of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein A, B are carbon atoms, independently of each other in the R or S configuration; X is selected from the group consisting of C, NBoc; n is 2 when X is C, n is 1 when X is NBoc; R1 is selected from the group consisting of H, C1-C16 straight-chain or branched alkyl, C3-C8 cycloalkyl, C6-C16 aryl, C4-C16 heteroaryl, aryl-substituted C1-C16 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, biphenyl; the heteroaryl groups are selected from the group consisting of furanyl, thienyl, imidazolyl, pyrrolyl, thiazolyl, quinolinyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl; these aryl and heteroaryl groups can have one or more substituents, independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy C1-C16 alkyl; R2 is selected from the group consisting of H, C1-C16 straight-chain or branched alkyl, C6-C16 aryl, C4-C16 heteroaryl, aryl-substituted C1-C16 alkyl; the aryl groups are selected from the group consisting of phenyl, naphthyl, anthryl, phenanthryl, biphenyl; the heteroaryl groups are selected from the group consisting of furanyl, thienyl, imidazolyl, pyrrolyl, thiazolyl, quinolinyl, pyridyl, indolyl, biphenyl, furanyl-biphenyl, thienyl-biphenyl; these aryl and heteroaryl groups can have one or more substituents, independently of each other selected from the group consisting of H, OH, SH, COOH, NH2, aldehyde, carbamoyl, halogen, NO2, CN, CF3, OCF3, C1-C16 straight-chain or branched alkyl; R3 is selected from the group consisting of H, halogen, C1-C16 straight-chain or branched alkyl, C1-C16 alkoxy, C1-C16 alkoxy C1-C16 alkyl; Step 1: N-substituted amino acid ethyl ester A1 is used as starting material, added with substituted isocyanate, followed by intramolecular transesterification to obtain intermediate B1; Step 2: intermediate B1 is condensed with different substituted o-bromobenzaldehyde to obtain intermediate C1; Step 3: intermediate C1 is prepared by Suzuki-Miyaura coupling reaction to obtain intermediate D1; Step 4: intermediate D1 is catalytically hydrogenated by 10% palladium on carbon to obtain intermediate E1; Step 5: intermediate E1 is oxidized to p-quinone to obtain intermediate F1; Step 6: intermediate F1 is prepared by intramolecular Michael addition to obtain the target product of general formula (I).

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