Heterofused ring compound as well as intermediate and application thereof

Abstract

The invention discloses a fused heterocycle compound as well as an intermediate and application thereof. The hetero-fused ring compound is a compound as shown in a formula I or pharmaceutically acceptable salt of the hetero-fused ring compound. The compound provided by the invention has a good PTDSS1 inhibition effect and a good medicinal prospect.

Description

Technical Field

[0001] This invention relates to a heterocyclic compound, its intermediate, and its applications. Background Technology

[0002] Lipid metabolism disorders are one of the hallmark features of cancer. Tumor cells promote and maintain rapid growth, metastasis, and immune evasion through multiple pathways, including altering fatty acid synthesis, desaturation, uptake, metabolism of lipids in the microenvironment and dietary diet, and lipid molecule-regulated signaling pathways. Targeting lipid metabolism pathways is a promising direction for cancer treatment, with research and development of anti-tumor drugs targeting phospholipid metabolism regulation pathways showing rapid progress.

[0003] Phospholipids are essential components of biological membranes, including phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidyllenthanalamine (PE), and phosphatidylinosine (PI). Their composition plays a crucial role in the stability of membrane components and in the signaling pathways regulated by phospholipid molecules. PS accounts for approximately 2-15% of cellular phospholipids. Despite its relatively low content, it occupies a central position in phospholipid metabolism. This project aims to develop cancer therapeutic strategies targeting PS.

[0004] In human cells, PS is synthesized by two isoenzymes: PS synthase 1 (PTDSS1, also known as PSS1) and PS synthase 2 (PTDSS2, also known as PSS2). PSS1 catalyzes the enzymatic reaction that synthesizes PS using PC or PE as substrates and is highly expressed in various tumor cells. PSS2 catalyzes the enzymatic reaction that synthesizes PS using PE as substrates, and PSS2 is deficient in some cancer types. Based on the protein functions of PSS1 and PSS2 and literature reports, they are a pair of promising synthetic lethal genes. Targeting and inhibiting PSS1 can kill PSS2-deficient tumor cells, making them potential targets for cancer therapy.

[0005] Targeting and inhibiting PSS1 reduces the content of newly generated PS in cells and may also exert cell-killing effects through various means such as regulating tumor immunity, inhibiting angiogenesis, and reducing PI3K / AKT pathway signaling activation. It can be used alone or in combination with other targeted drugs, antibody drugs, and immunotherapies to achieve the effect of tumor treatment. Its potential indications may not be limited to PSS2-deficient tumors, and it has significant market value. Summary of the Invention

[0006] To overcome the limitation of the limited types of PTDSS1 inhibitors in the prior art, this invention provides a heterocyclic compound, its intermediate, and its applications. The heterocyclic compound of this invention exhibits excellent inhibitory effects on PTDSS1.

[0007] This invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Among them, X 1 X 2 X 3 X 4 X 5 and X 6 Independently CH, CR RR Or N;

[0010] R 1 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 replace;

[0011] Each R 1-1 Independently, H, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein C 3-6 The cycloalkyl group, the 3-6 membered heterocycloalkyl group, the phenyl group, and the 5-6 membered heteroaryl group may independently and optionally be surrounded by 1, 2, or 3 R groups. RR replace;

[0012] L 1 and L 2 Independently, it can be a connecting key or -(CH2). m -, m is 1, 2, 3, 4 or 5, -(CH2) m Any one or two -CH2- can be optionally replaced by -O-, -S-, -S(=O)2-, or -NR. 3 -、-CR 4 R 5 One or two substitutions in - and -C(=O)-;

[0013] R 3 R 4 and R 5 Independently H, deuterium, halogen or C 1-6 Alkyl, and R4 and R 5 Not both H or R 4 and R 5 Together with the C connected to it, they form C 3-6 cycloalkanes; the C 1-6 Alkyl groups and the C 3-6 Cycloalkanes can be optionally surrounded by 1, 2, or 3 R groups. RR replace;

[0014] Ring A is C 6-10 Aromatic rings, benzene rings, and fused carbon rings 3-6 Cycloalkanes, 5-6 membered heterocycles of benzene rings, 5-6 membered heteroene rings of benzene rings, 5-10 membered heteroaromatic rings, C 3-10 Cycloalkanes or 5-10 membered heterocycles;

[0015] n is 0, 1, 2, 3 or 4;

[0016] Each R 2 Independently, it can be deuterium, halogen, cyano, oxo, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, -C(=O)OC 1-6 Alkyl, trifluoromethoxy, -NR 2-1 R 2-2 , -C(=O)NR 2-3 R 2-4 C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; the C 1-6 Alkyl group, the aforementioned C 1-6 Alkoxy, the aforementioned C 6-10 Aryl, the 5-10 membered heteroaryl, the C 3-10 The cycloalkyl group and the 3-10 membered heterocyclic alkyl group may optionally be associated with 1, 2 or 3 R groups. RR replace;

[0017] R 2-1 R 2-2 R 2-3 and R 2-4 Independent of H, deuterium, and C 1-6 Alkyl or C 3-6 cycloalkyl, or R 2-1 and R 2-2 Together with the atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups;

[0018] Each R RR Independently deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 cycloalkyl or C 6-10 Aryl, the C 6-10 The aryl group may optionally be substituted by one or more of the following groups: halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy;

[0019] The heteroatoms in the 3-6 membered heterocyclic alkyl group, the 5-6 membered heteroaryl group, the benzo[a] 5-6 membered heterocyclic ring, the benzo[a] 5-6 membered heteroene ring, the 5-10 membered heteroaryl group, and the 5-10 membered heterocyclic ring are independently one or more of P, N, S, and O, and the number is 1, 2, or 3.

[0020] In some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0021] Among them, X 1 X 2 X 3 X 4 X 5 and X 6 Independently CH, CR RR Or N;

[0022] R 1 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 Replace (when R) 1 C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, R 1-1 C 3-6 When R is cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, 1-1 The number of them can be 1.

[0023] Each R 1-1 Independently, H, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein C 3-6 The cycloalkyl group, the 3-6 membered heterocycloalkyl group, the phenyl group, and the 5-6 membered heteroaryl group may independently and optionally be surrounded by 1, 2, or 3 R groups. RR replace;

[0024] L 1and L 2 Independently, it can be a connecting key or -(CH2). m -, m is 1, 2, 3, 4 or 5, -(CH2) m Any one or two -CH2- can be optionally replaced by -O-, -S-, -S(=O)2-, or -NR. 3 -、-CR 4 R 5 One or two substitutions in - and -C(=O)-;

[0025] R 3 R 4 and R 5 Independently H, deuterium, halogen or C 1-6 Alkyl, and R 4 and R 5 Not both H or R 4 and R 5 Together with the C connected to it, they form C 3-6 cycloalkanes; the C 1-6 Alkyl groups and the C 3-6 Cycloalkanes can be optionally surrounded by 1, 2, or 3 R groups. RR replace;

[0026] Ring A is C 6-10 Aromatic rings, benzene rings, and fused carbon rings 3-6 Cycloalkanes, 5-6 membered heterocycles of benzene rings, 5-6 membered heteroene rings of benzene rings, 5-10 membered heteroaromatic rings, C 3-10 Cycloalkanes or 5-10 membered heterocycles;

[0027] n is 0, 1, 2, 3 or 4;

[0028] Each R 2 Independently, it can be deuterium, halogen, cyano, oxo, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, -C(=O)OC 1-6 Alkyl, trifluoromethoxy, -NR 2-1 R 2-2 , -C(=O)NR 2-3 R 2-4 C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; the C 1-6 Alkyl group, the aforementioned C 1-6 Alkoxy, the aforementioned C 6-10 Aryl, the 5-10 membered heteroaryl, the C 3-10The cycloalkyl group and the 3-10 membered heterocyclic alkyl group may optionally be associated with 1, 2 or 3 R groups. RR replace;

[0029] R 2-1 R 2-2 R 2-3 and R 2-4 Independent of H, deuterium, and C 1-6 Alkyl or C 3-6 cycloalkyl, or R 2-1 and R 2-2 Together with the atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups;

[0030] Each R RR Independently deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0031] The heteroatoms in the 3-6 membered heterocyclic alkyl group, the 5-6 membered heteroaryl group, the benzo[a] 5-6 membered heterocyclic ring, the benzo[a] 5-6 membered heteroene ring, the 5-10 membered heteroaryl group, and the 5-10 membered heterocyclic ring are independently one or more of P, N, S, and O, and the number is 1, 2, or 3.

[0032] In some embodiments, the compound represented by formula I is a compound represented by formula I-1a, I-2a, I-3a, I-1b, I-2b, or I-3b:

[0033]

[0034] The definitions of each group are the same as those described in any one of the present invention.

[0035] In some embodiments, the compound represented by formula I is a compound represented by any of the general formulas Ia to Io:

[0036]

[0037] In formulas Ia to Io, "*" marks the carbon atom as either an S-configuration chiral carbon atom or an R-configuration chiral carbon atom, and the definitions of the other groups are the same as those described above.

[0038] Preferably, in formulas Ia to Io, ring A is a benzene ring, a naphthyl ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, an oxazole ring, a cyclobutane ring, a cyclohexane ring, an oxacyclobutane ring, a tetrahydrofuran ring, a pyrrole ring, a 1,4-dioxane ring, a benzocyclopentane ring, a benzopyrrolene ring, or a benzo3,6-dihydro-2H-pyran.

[0039] Preferably, in formulas Ia to Io, for

[0040] Preferably, in formulas Ia to Io, X 4 X 5 and X 6 For CH.

[0041] Preferably, in formulas Ia to Io, R 1 C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one, two or three halogens.

[0042] In some schemes, R 1 Each R 2 R 3 R 4 R 5 Each R 1-1 R 2-1 R 2-2 R 2-3 R 2-4 and each R RR In the context, C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, n-propyl, isopropyl, or tert-butyl.

[0043] In some schemes, R 1 Each R 2 Each R 1-1 and each R RR In the context, C 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyl or tert-butoxy, such as methoxy.

[0044] In some schemes, R 1 Each R 1-1 R 2-1 R 2-2 R 2-3 R 2-4 and each R RR In the context, C 3-6 Cycloalkyl groups are monocyclic C 3-6 C of cycloalkyl, bispiro, or bibridged rings 5-6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl or spiro[2.3]hexyl.

[0045] In some schemes, R 1 and each R 1-1In this context, the 3-6 membered heterocyclic alkyl group is a monocyclic 3-6 membered heterocyclic alkyl group, with heteroatoms being N and / or O, and the number being 1 or 2, which can be tetrahydrofuranyl, oxobutyranyl or azirheptabutyranyl.

[0046] In some schemes, each R 2 R 3 R 4 R 5 Each R 1-1 and each R RR In this context, the halogen is F, Cl, Br, or I, for example, F.

[0047] In some schemes, when R 4 and R 5 Together with the C connected to it, they form C 3-6 In the case of cycloalkanes, the C 3-6 Cycloalkanes are cyclopropane, cyclobutane, cyclopentane, or cyclohexane, such as cyclopropane.

[0048] In some schemes, in ring A, the aforementioned C 6-10 The aromatic ring is a benzene ring or a naphthalene ring.

[0049] In some schemes, in ring A, the benzene ring is fused to C. 3-6 C in cycloalkanes 3-6 Cycloalkanes can be monocyclic C164 ... 3-6 Cycloalkanes, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane, and again, cyclopentane.

[0050] In some schemes, in ring A, the 5-6 membered heterocyclic ring of the 5-6 cyclic phenyl ring has N and / or O heteroatoms, and the number is 1 or 2, which may be pyrrolidine.

[0051] In some schemes, ring A and each R 2 In the above, the 5-6 membered heteroene ring in the 5-6 membered heteroene ring is a 5-6 membered monocyclic heteroene ring, the heteroatom is N and / or O, the number is 1 or 2, and it can be 3,6-dihydro-2H-pyran.

[0052] In some schemes, the 5-10 membered heteroaromatic ring in ring A is a 5-6 membered monocyclic heteroaromatic ring, with heteroatoms being N and / or O, and the number being 1 or 2, which can be a pyridine ring, pyrimidine ring, pyrazine ring or oxazole ring.

[0053] In some schemes, in ring A, the aforementioned C 3-10 Cycloalkanes are C16-365 ... 3-6 Monocyclic cycloalkanes can be cyclopropyl, cyclobutane, cyclopentane, or cyclohexane, such as cyclobutane or cyclohexane.

[0054] In some schemes, the 3-10 membered heterocycle in ring A is a 5-6 membered monocyclic heterocycle, with heteroatoms being N and / or O, and the number being 1 or 2, which can be an oxocyclic butane ring, a tetrahydrofuran ring, a pyrrole ring, or a 1,4-dioxane ring.

[0055] In some schemes, each R 2 In the context, C 2-6 The alkenyl group is vinyl.

[0056] In some schemes, each R 2 In this context, the 5-10 member heteroaryl group refers to a 5-6 member monocyclic heteroaryl group.

[0057] In some schemes, each R 2 In the context, C 3-10 Cycloalkyl group is C 3-6 The monocyclic cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, such as cyclopropyl.

[0058] In some schemes, each R 2 In this context, the 3-10 membered heterocyclic alkyl group is a 5-6 membered monocyclic heterocyclic alkyl group, with heteroatoms being N and / or O, and the number being 1 or 2, which may be oxocyclic butyl.

[0059] In some schemes, each R RR In the context, C 6-10 The aromatic ring is a benzene ring or a naphthalene ring.

[0060] In some schemes, for

[0061] In some schemes, X 4 X 5 and X 6 For CH.

[0062] In some schemes, R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 Replace; each R 1-1 Independently, it is H, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl group and the aforementioned 3-6 membered heterocycloalkyl group may independently and optionally be surrounded by 1, 2, or 3 R groups. RR replace;

[0063] R 1 It can also be C1-6 Alkyl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 Replace; each R 1-1 Halogens are independent of each other.

[0064] In some schemes, R 1 It is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or spiron[2.3]hexyl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 Replace; each R 1-1 Independently, F, methyl, ethyl,

[0065] In some schemes, R 1 It is n-propyl, R 1 It can be optionally replaced by 1, 2 or 3 Fs.

[0066] In some schemes, R 1 for It can also be used for

[0067] In some schemes, L 1 and L 2 Independently, it can be a connecting key or -(CH2). m -, m can be 1, 2, or 3, -(CH2) m -Any one of -CH2- can be optionally replaced by -O- or -NR 3 -or-CR 4 R 5 - Replace, or any two -CH2- can optionally be replaced by "-NR 3 -and-C(=O)-” or "-O-and-CR 4 R 5 -"Replace; R 3 H, halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be surrounded by 1, 2, or 3 R groups. RR Replace, R 4 and R 5 Together with the C connected to it, they form C 3-6 Cycloalkanes.

[0068] In some schemes, L 1 and L 2 Independently for connection keys, For example

[0069] In some schemes, ring A is a benzene ring, naphthyl ring, pyridine ring, pyrimidine ring, pyrazine ring, oxazole ring, cyclobutane ring, cyclohexane ring, oxetane ring, tetrahydrofuran ring, pyrrole ring, 1,4-dioxane ring, benzocyclopentane ring, benzopyrrole, or benzo3,6-dihydro-2H-pyran.

[0070] In some schemes, It can be any of the following structures:

[0071]

[0072]

[0073] In some schemes, each R 2 Independently, it can be a halogen, cyano group, oxo group (=O), or C group. 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)OC 1-6 Alkyl, -NR 2-1 R 2-2 -C(=O)NR 2-3 R 2-4 C 6-10 Aryl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein the C 1-6 alkyl groups and the C 1-6 The alkoxy group can be optionally replaced by one, two or three halogens.

[0074] In some schemes, each R 2 Independently, it can be F, Cl, Br, cyano, amino, oxo (=O), methyl, isopropyl, tert-butyl, -CF3. -OCH3, -OCF3, Or -P(=O)(CH3)2.

[0075] In some embodiments, the compound represented by Formula I is any of the following compounds:

[0076]

[0077]

[0078]

[0079] Its stereoisomers or mixtures of the two in any proportion.

[0080] Enantiomer In the following separation conditions, It can be a compound that elutes first (preferably a compound that elutes at 1.628 min) or a compound that elutes later (preferably a compound that elutes at 2.610 min);

[0081] Separation conditions: Column: ChiralPak IG (e.g., 250×30mm ID); Mobile phase: Mobile phase A is CO2, mobile phase B is MeOH (0.1% 7M NH3 in MeOH solution); Elution: 45% mobile phase B.

[0082] Enantiomer In the following separation conditions, The compound can be either the first to elute (preferably the compound that elutes at 1.363 min) or the last to elute (preferably the compound that elutes at 1.881 min);

[0083] Separation conditions: Column: ChiralCel OD (e.g., 250×30mm ID); Mobile phase: Mobile phase A is CO2, mobile phase B is MeOH (0.1% 7M NH3 in MeOH solution); Elution: 50% mobile phase B.

[0084] The present invention also provides a method for preparing the above-described compound as shown in Formula I or a pharmaceutically acceptable salt thereof, comprising the following steps: subjecting compound II and compound III to a cyclization reaction (e.g., in acetic acid) to obtain the compound as shown in Formula I.

[0085]

[0086] The definitions of each group are the same as those described above.

[0087] The present invention also provides a compound as shown in Formula II:

[0088]

[0089] Among them, X 1 X 2 X 3 X 4 X 5 X 6 L 1 L 2 n, ring A, R 1 and R 2 The definitions are as described above.

[0090] The compound shown in Formula II is preferably...

[0091]

[0092]

[0093] The present invention also provides a pharmaceutical composition comprising the above-described compound as shown in Formula I or a pharmaceutically acceptable salt thereof (therapeutic amount) and pharmaceutical excipients.

[0094] The present invention also provides the use of the above-described compound as shown in Formula I or a pharmaceutically acceptable salt thereof in the preparation of a PTDSS1 inhibitor.

[0095] The present invention also provides a kit for detecting PTDSS1, comprising the compound shown in Formula I above or a pharmaceutically acceptable salt thereof.

[0096] The present invention also provides the use of the above-described compound as shown in Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of diseases related to PTDSS1.

[0097] The PTDSS1-related diseases mentioned above can be tumors associated with PTDSS2 deficiency. These tumors may include those with PTDSS2 mutations, loss of heterozygosity, low expression, or no expression of PTDSS2.

[0098] The PTDSS2 deficiency can be a mutation, heterozygous deletion, low expression, or no expression of PTDSS2.

[0099] The tumors mentioned may be testicular germ cell tumors, ovarian cancer, bladder cancer, lung cancer, breast cancer, esophageal cancer, colon cancer, prostate cancer, stomach cancer, cervical cancer, endometrial cancer, uterine body cancer, kidney cancer, thyroid cancer, squamous cell carcinoma, osteosarcoma, melanoma, glioblastoma, neuroblastoma, head and neck cancer, testicular cancer, colorectal cancer, hematologic malignancies, retinoblastoma, or pancreatic cancer.

[0100] In structural fragments This refers to the structural segment being connected to the rest of the molecule through this site. For example, It is a difluoro-substituted cyclohexyl group.

[0101] The "-" at the end of a group indicates that the group is attached to the rest of the molecule through that site. For example, -CF3 refers to trifluoromethyl.

[0102] The term "pharmaceuticalally acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, and methanesulfonate salts. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0103] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0104] The term "oxo" refers to the =O group, where an oxygen atom replaces two hydrogen atoms on the same carbon atom; that is, a carbonyl group replaces a methylene group.

[0105] The term "alkyl" refers to a saturated monovalent hydrocarbon group that has a specified number of carbon atoms (e.g., C1 to C6), is straight-chain or branched. Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0106] The term "alkoxy" refers to the group R. X -O-,R X The definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0107] The term "alkenyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2 to C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bond. Alkenyl groups include, but are not limited to: vinyl groups, wait.

[0108] The term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3 to C6), which can be monocyclic or polycyclic (e.g., bicyclic bridged or spirocyclic). Cycloalkyl groups include, but are not limited to: wait.

[0109] The term "cycloalkane" is defined in the same way as the term "cycloalkyl" if it meets any of the following conditions: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0110] The term "heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3 to 10 membered monocyclic or bicyclic), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of P, N, O, and S). Heterocyclic alkyl groups are attached to the remainder of the molecule via carbon atoms or heteroatoms. Heterocyclic alkyl groups include, but are not limited to:

[0111] wait.

[0112] The term “heterocyclic” is defined in the same way as the term “(monocyclic)heterocyclic alkyl” if it meets any of the following conditions: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0113] The term "aromatic ring" is defined as follows, with the rest being the same as the term "aryl": 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0114] The term "heterene ring" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of ring atoms (e.g., 5- to 10-membered monocyclic or bicyclic), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom type (one or more of N, O, and S), having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 A double bond is non-aromatic. It satisfies any of the following conditions: 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0115] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6 to C5). 10 Aryl groups are cyclic, unsaturated monovalent hydrocarbon groups, which can be monocyclic or polycyclic (e.g., two or three). When polycyclic, the monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0116] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5 to 10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with the monocyclic rings sharing two atoms and one bond, and (at least one ring / each ring) is aromatic. Heteroaryl groups are attached to the rest of the molecule via carbon atoms or heteroatoms; they can be attached to the rest of the molecule via a ring with or without heteroatoms; or they can be attached to the rest of the molecule via an aromatic ring or a non-aromatic ring. Heteroaryl groups include, but are not limited to: wait.

[0117] The term “heteroaryl ring” meets any of the following conditions, and the rest of the definition is the same as that of the term “heteroaryl group”: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0118] The term "therapeutic effective dose" refers to the amount given to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0119] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the *Pharmacopoeia of the People's Republic of China (2020 Edition)* and *Handbook of Pharmaceutical Excipients* (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0120] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0121] The reagents and raw materials used in this invention are all commercially available.

[0122] The positive and progressive effect of this invention is that the compound of this invention has a good inhibitory effect on PTDSS1. Detailed Implementation

[0123] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0124] All compounds of this invention can be synthesized by those skilled in the art of organic chemistry using various methods. General synthetic schemes for preparing the compounds of this invention are described below. These schemes are general but do not imply limitation on possible techniques for preparing the compounds disclosed herein. Different methods for preparing the compounds of this invention will be apparent to those skilled in the art. Furthermore, the various steps in the synthesis can be performed alternately and sequentially to obtain one or more desired compounds. The preparation and examples sections below provide examples of preparing the compounds of this invention using the methods described in the general scheme. The preparation of compounds containing chiral centers in the embodiments can be performed using techniques mastered by those skilled in the art. For example, chiral compounds can be prepared by chiral resolution of racemic products using HPLC or SFC; or, example compounds can be prepared using known methods to obtain chiral compounds.

[0125] The chemical reactions and synthetic techniques described herein are carried out using the reagents and corresponding solvents described herein, and the corresponding reaction yields will also be affected by the reagents and solvents used. Furthermore, it should be understood that all reaction conditions mentioned in the synthetic methods described below, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and reaction reaction order, should be considered as standard operating conditions for the reaction, which should be readily identifiable by those skilled in the art. This is also understandable to those skilled in the art of organic synthesis. The functional groups present on each part of the molecule must be compatible with the reagents used and the reaction itself. Such limitations where some functional groups on each part of the molecule are incompatible with the reaction conditions must be addressed by alternative methods, which will be obvious to those skilled in the art. It is obvious that it is necessary to determine and adjust the order of synthetic steps, or to select a specific synthetic process scheme, to obtain the compounds required by this invention. This is understandable and readily identifiable to those skilled in the art of organic synthesis. It should also be recognized that another major consideration in designing any synthetic route in this field is the rational selection of protecting groups to protect the tolerance of reactive functional groups present in the compounds described herein. For details, please refer to the book by Greene et al. in the field of chemistry (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

[0126] Example

[0127] The preparation of compounds and intermediates used in compound preparation can be carried out using the procedures shown in the following examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not intended to be limiting, but rather to illustrate how the relevant compounds can be prepared. The starting materials and reagents used in these examples, when not prepared using the procedures described herein, are generally commercially available, or reported in relevant chemical literature, or can be prepared using the procedures described in the chemical literature.

[0128] In the examples given in this article, the terms "drying" and "concentration" generally refer to the addition of anhydrous sodium sulfate or magnesium sulfate to an organic solvent for drying, followed by filtration and removal of the solvent from the filtrate (usually under reduced pressure and at a temperature suitable for the stability of the compound being prepared). Column chromatography typically uses conventional or rapid column chromatography for column separation and purification, or a medium-pressure chromatograph (Biotage Isola One) pre-packed with a silica gel column, eluting in a specified solvent or solvent mixture. In some cases, the final product is rapidly purified by preparative thin-layer chromatography using 20 cm x 20 cm x 0.5 mm or 20 cm x 20 cm x 1 mm silica gel plates in a suitable solvent system. Preparative high-performance liquid chromatography (HPLC) is performed using a reversed-phase column (Waters Sunfire C18, Waters Xbridge C18, or similar) with dimensions suitable for the amount of the compound being separated. Elution is typically performed using a gradient of methanol or acetonitrile concentrations in an aqueous phase, with the eluent containing 0.05% or 0.1% formic acid, trifluoroacetic acid, or 10 mM ammonium acetate. The elution rate is matched to the size of the reversed-phase column used and the resolution of the compound being prepared.

[0129] List of abbreviations

[0130] Table 1

[0131]

[0132]

[0133] Example 1: 7-(4-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0134]

[0135] Step 1: Methyl 4-bromo-3-((2-hydroxyphenoxy)methyl)benzoate

[0136] Under nitrogen protection at room temperature, potassium carbonate (397 mg, 2.87 mmol) was added to a solution of methyl 4-bromo-3-(bromomethyl)benzoate (885 mg, 2.87 mmol) and catechol (316 mg, 2.87 mmol) in N,N-dimethylformamide (9 mL). The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-15% ethyl acetate) to give the title compound (white solid, 650 mg, yield 67.1%). LC / MS (ESI) m / z: 337 [M+H] + .

[0137] Step 2: 11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid methyl ester

[0138] Sodium hydroxide (318 mg, 5.66 mmol) was added to an anhydrous dimethyl sulfoxide (8 mL) solution of methyl 4-bromo-3-((2-hydroxyphenoxy)methyl)benzoate (477 mg, 1.41 mmol) at room temperature under nitrogen protection. The reaction mixture was stirred at room temperature for 48 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (white solid, 150 mg, yield 41.5%). LC / MS (ESI) m / z: 257 [M+H] + .

[0139] Step 3: (11H-dibenzo[b,e][1,4]dioxane-2-yl)methanol

[0140] Under nitrogen protection at 0 °C, lithium aluminum hydride (44 mg, 1.17 mmol) was added fractionally to an anhydrous tetrahydrofuran (3 mL) solution of methyl 11H-dibenzo[b,e][1,4]dioxane-2-carboxylate (150 mg, 0.586 mmol). The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-35% ethyl acetate) to give the title compound (white solid, 104 mg, yield 77.8%). LC / MS (ESI) m / z: 229 [M+H] + .

[0141] Step 4: 11H-Dibenzo[b,e][1,4]dioxane-2-carboxaldehyde

[0142] Under nitrogen protection at 0 °C, Dysmart reagent (386 mg, 0.91 mmol) was added fractionally to a solution of (11H-dibenzo[b,e][1,4]dioxane-2-yl)methanol (104 mg, 0.46 mmol) in anhydrous dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (white solid, 100 mg, 97% yield). 1 H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 8.01-7.89 (m, 2H), 7.43 (d, J = 8.3Hz, 1H) ,7.32-7.19(m,1H),7.09-6.96(m,3H),5.35(s,2H).LC / MS(ESI)m / z:227[M+H] + .

[0143] Step 5: 5-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-1-(2,2-difluoropropyl)-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)pyrrolidine-2,3-dione

[0144] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (29 mg, 0.216 mmol), triethylamine (110 mg, 1.08 mmol), and 11H-dibenzo[b,e][1,4]dioxane-2-carboxaldehyde (49 mg, 0.216 mmol) were added to acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (50 mg, 0.180 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to give the title compound (yellow solid, 20 mg, yield 20.8%). LC / MS (ESI) m / z: 535 [M+H] + .

[0145] Step 6: 7-(4-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0146] At room temperature, hydrazine hydrate (0.05 mL) was added to acetic acid (1 mL) containing 20 mg (0.037 mmol) of 5-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-1-(2,2-difluoropropyl)-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)pyrrolidine-2,3-dione. The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the mixture was filtered and purified by preparative HPLC (20-95% acetonitrile in an aqueous solution containing 0.1% FA) to give the title compound (white solid, 7 mg, yield 35.7%). 1 H NMR(400MHz, DMSO-d6)δ7.30(d,J=7.9Hz,1H),7.21(dd,J=8.5,1.6Hz,1H),7.16-7.09(m,4H),7.00(d,J=7.7Hz,1H),6.96-6.89(m,2H),6.8 7(dd,J=7.6,2.0Hz,1H),5.98(s,1H),5.13(s,2H),4.23-4.09(m,1H),2.87-2.77(m,1H),1.64(t,J=19.1Hz,3H).LC / MS(ESI)m / z:531[M+H] + .

[0147] SFC chiral resolution was performed on 7-(4-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one to obtain Examples 1-1 and 1-2:

[0148] Example 1-1: (R)-7-(4-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Chiral separation conditions: Column: ChiralPak IG, 250×20mm ID, 5μm; Mobile phase: A=CO2 and B=MeOH (0.1% 7M NH3 in MeOH); Gradient: B 45%; Flow rate: 35mL / min; Peak 1, Rt=1.628min). 1 H NMR (400MHz, CD3OD) δ7.31–7.03(m,6H),7.03–6.96(m,1H),6.95–6.83(m,3H),6.09(s,1H),5.11 (s,2H),4.32–4.11(m,1H),3.03–2.87(m,1H),1.65(t,J=18.8Hz,3H).LC / MS(ESI)m / z:531[M+H] + .

[0149] Examples 1-2: (S)-7-(4-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Chiral separation conditions: Column: ChiralPak IG, 250×20mm ID, 5μm; Mobile phase: A=CO2 and B=MeOH (0.1% 7M NH3 in MeOH); Gradient: B 45%; Flow rate: 35mL / min; Peak 2, Rt=2.610min). 1 H NMR (400MHz, CD3OD) δ7.31–7.04(m,6H),7.03–6.97(m,1H),6.94–6.82(m,3H),6.10(s,1H),5.12 (s,2H),4.31–4.13(m,1H),3.04–2.87(m,1H),1.67(t,J=18.8Hz,3H).LC / MS(ESI)m / z:531[M+H] + .

[0150] Example 2: 7-(4-(dibenzo[b,e][1,4]dioxin-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0151]

[0152] Step 1: 3-Fluoro-4-(2-hydroxyphenoxy)benzaldehyde

[0153] Under nitrogen protection at room temperature, potassium carbonate (3.88 g, 28.2 mmol) and 3,4-difluorobenzaldehyde (2.0 g, 14.1 mmol) were added sequentially to an anhydrous N,N-dimethylformamide (30 mL) solution of catechol (3.09 g, 28.2 mmol). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (yellow solid, 2.1 g, yield 64.4%). 1 H NMR(400MHz, DMSO-d6)δ9.88(d,J=1.5Hz,1H),7.82(dd,J=11.1,1.6Hz,1H),7.70-7.67(m,1H),7.17-7 .13(m,2H),7.03(dd,J=7.9,1.2Hz,1H),6.90-6.86(m,1H),6.84-6.80(m,1H).LC / MS(ESI)m / z:231[MH] - .

[0154] Step 2: Dibenzo[b,e][1,4]dioxin-2-carboxaldehyde

[0155] Cesium carbonate (5.89 g, 18.1 mmol) was added to an anhydrous dimethyl sulfoxide (20 mL) solution of 2.1 g (9.05 mmol) of 3-fluoro-4-(2-hydroxyphenoxy)benzaldehyde at room temperature under nitrogen protection. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (white solid, 1.2 g, yield 62.5%). 1H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 7.58 (dd, J = 8.3, 1.7Hz, 1H), 7.43 (d, J = 1.7Hz, 1H), 7.19 (d, J = 8.2Hz, 1H), 7.05-7.01 (m, 4H).

[0156] Step 3: 7-(2-(dibenzo[b,e][1,4]dioxin-2-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0157] Under nitrogen protection at room temperature, 2,2-difluoropropylamine hydrochloride (309 mg, 2.36 mmol), triethylamine (1.0 g, 9.85 mmol), and dibenzo[b,e][1,4]dioxin-2-carboxaldehyde (500 mg, 2.36 mmol) were added to acetic acid (6 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (546 mg, 1.97 mmol) was added to the system, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-15% methanol) to give the title compound (yellow solid, 400 mg, yield 32.6%). LC / MS (ESI) m / z: 521 [M+H] + .

[0158] Step 4: 7-(4-(dibenzo[b,e][1,4]dioxin-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0159] Under nitrogen protection at room temperature, hydrazine hydrate (240 mg, 3.84 mmol, 80% wt) was added to a solution of 7-(2-(dibenzo[b,e][1,4]dioxin-2-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (400 mg, 0.77 mmol) in acetic acid (3 mL). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (0-95% acetonitrile in an aqueous solution containing 0.1% NH4HCO3) to give the title compound (yellow solid, 90 mg, yield 22.7%). 1H NMR(400MHz,CD3OD)δ7.26(s,1H),7.18-7.14(m,1H),7.04-7.02(m,1H),6.90-6.86(m,2H),6.82-6.79(m,4H),6 .62(s,1H),5.97(s,1H),4.28-4.15(m,1H),3.06-2.97(m,1H),1.67(t,J=18.8Hz,3H).LC / MS(ESI)m / z:517[M+H] + .

[0160] Example 3: 7-(4-(9,9-difluoro-9H-fluoren-3-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0161]

[0162] Step 1: 3-Bromospiro[fluorene-9,2'-[1,3]dithionecyclopentane]

[0163] Under nitrogen protection, 1,2-ethanedithiol (1.82 g, 19.3 mmol) and boron trifluoride diethyl ether solution (8 mL) were slowly added to a solution of 3-bromo-9H-fluorene-9-one (1.0 g, 3.86 mmol) in anhydrous dichloromethane (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, dichloromethane and water were added, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-5% ethyl acetate) to give the title compound (white solid, 800 mg, yield 61.7%).

[0164] Step 2: 3-Bromo-9,9-difluoro-9H-fluorene

[0165] Under nitrogen protection at 0°C, a solution of pyridine hydrofluoric acid (8.5 mL, 70% wt) was slowly added dropwise to a solution of N-iodosuccinimide (3.5 g, 15.6 mmol) in anhydrous dichloromethane (6 mL). The reaction mixture was stirred at 0°C for 10 min. Then, a solution of 3-bromospiro[fluorene-9,2'-[1,3]dithiacyclopentane] (750 mg, 1.90 mmol) in dichloromethane (3 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, dichloromethane and water were added, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-2% ethyl acetate) to give the title compound (white solid, 400 mg, yield 63.3%).

[0166] Step 3: Methyl 9,9-difluoro-9H-fluorene-3-carboxylic acid

[0167] Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (166 mg, 0.22 mmol) and triethylamine (347 mg, 3.43 mmol) were added to an anhydrous methanol (5 mL) solution of 3-bromo-9,9-difluoro-9H-fluorene (330 mg, 1.14 mmol). The reaction mixture was stirred overnight at 50 °C under a carbon monoxide balloon. After the reaction was complete, the mixture was concentrated under reduced pressure, and ethyl acetate and water were added to separate the ethyl acetate phase. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (white solid, 170 mg, yield 57.0%).

[0168] Step 4: 9,9-Difluoro-9H-fluorene-3-carboxylic acid

[0169] At 0 °C, lithium hydroxide monohydrate (82.6 mg, 1.96 mmol) was added to a tetrahydrofuran (3 mL) and water (1 mL) solution of methyl 9,9-difluoro-9H-fluorene-3-carboxylic acid (170 mg, 0.65 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the pH was adjusted to less than 3 with 1 N hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure to give a white solid (150 mg, 96.1% yield). LC / MS (ESI) m / z: 247 [M+H] + .

[0170] Step 5: 9,9-Difluoro-9H-fluorene-3-methanol

[0171] At 0 °C, a solution of borane dimethyl sulfide (3 mL, 2 mol / L) was slowly added dropwise to an anhydrous tetrahydrofuran (1 mL) solution of 9,9-difluoro-9H-fluorene-3-carboxylic acid (130 mg, 0.53 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction was quenched dropwise with ethanol under ice bath and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-60% ethyl acetate) to give the title compound (white solid, 90 mg, yield 73.0%).

[0172] Step 6: 9,9-Difluoro-9H-fluorene-3-carboxaldehyde

[0173] Under nitrogen protection at 0 °C, Dysmartin reagent (322 mg, 0.76 mmol) was added fractionally to a solution of 9,9-difluoro-9H-fluorene-3-methanol (90 mg, 0.38 mmol) in anhydrous dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-40% ethyl acetate) to give the title compound (white solid, 50 mg, yield 55.2%). LC / MS (ESI) m / z: 231 [M+H] + .

[0174] Step 7: 7-(2-(9,9-difluoro-9H-fluorene-3-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0175] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (20 mg, 0.2 mmol), triethylamine (100 mg, 1.0 mmol), and 9,9-difluoro-9H-fluorene-3-carboxaldehyde (50 mg, 0.21 mmol) were added to acetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (50 mg, 0.17 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-25% methanol) to give the title compound (yellow solid, 40 mg, yield 43.6%). LC / MS (ESI) m / z: 539 [M+H] + .

[0176] Step 8: 7-(5-(2,2-difluoropropyl)-4-(9-methoxy-11H-dibenzo[b,e][1,4]dioxane-heptene-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0177] Under nitrogen protection, 7-(2-(9,9-difluoro-9H-fluoren-3-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (40 mg, 0.07 mmol) was dissolved in acetic acid (1 mL), followed by the addition of hydrazine hydrate (23 mg, 0.36 mmol, 80% wt). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was purified by preparative HPLC (40-95% acetonitrile in an aqueous solution containing 0.1% NH4HCO3) to give the title compound (yellowish-white solid, 2.87 mg, yield 7.1%). 1 H NMR (400MHz, DMSO-d6) δ14.27(s,1H),11.85(s,1H),7.77(d,J=7.4Hz,1H),7.64-7.61(m,3H),7.55(t,J=7.3Hz,1H),7.45-7.31(m,2H) ,7.20-7.17(m,2H),7.02(s,1H),6.08(s,1H),4.46-3.87(m,1H),3.01-2.90(m,1H),1.66(t,J=18.8Hz,3H).LC / MS(ESI)m / z:535[M+H] + .

[0178] Examples 4 and 5: 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-11H-dibenzo[b,e][1,4]dioxane-7-nitrile (Example 4) and 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-11H-dibenzo[b,e][1,4]dioxane-8-nitrile (Example 5)

[0179]

[0180] Step 1: Methyl 3-(bromomethyl)-4-fluorobenzoate

[0181] Under nitrogen protection, benzoyl peroxide (4.2 g, 22.4 mmol) and N-bromosuccinimide (15.88 g, 89.20 mmol) were added sequentially to a solution of methyl 4-fluoro-3-methylbenzoate (15 g, 89.2 mmol) in carbon tetrachloride (250 mL). The reaction mixture was stirred at 60 °C for 6 hours. After the reaction was complete, dichloromethane and water were added, the dichloromethane phase was separated, washed with saturated brine, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-3% ethyl acetate) to give the title compound (colorless oil, 14.8 g, yield 67.2%). 1 H NMR (400MHz, CDCl3) δ8.04(dd,J=7.3,2.2Hz,1H),7.93(ddd,J=8.5,5.0,2.2Hz,1H),7.06(t,J=9.0Hz,1H),4.45(s,2H),3.85(s,3H).

[0182] Step 2: Methyl 3-((5-cyano-2-hydroxyphenoxy)methyl)-4-fluorobenzoate and methyl 3-((4-cyano-2-hydroxyphenoxy)methyl)-4-fluorobenzoate

[0183] Under nitrogen protection at 0 °C, potassium carbonate (447 mg, 6.48 mmol), potassium iodide (537 mg, 3.24 mmol), and 3,4-dihydroxybenzonitrile (437 mg, 3.24 mmol) were added sequentially to an anhydrous N,N-dimethylformamide (8 mL) solution of methyl 3-(bromomethyl)-4-fluorobenzoate (800 mg, 3.24 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (yellow oil, 740 mg, yield 75.9%). LC / MS (ESI) m / z: 302 [M+H] + .

[0184] Step 3: 7-Cyano-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid methyl ester and 8-cyano-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid methyl ester

[0185] Cesium carbonate (1.47 g, 4.51 mmol) was added to a solution of methyl 3-((5-cyano-2-hydroxyphenoxy)methyl)-4-fluorobenzoate and methyl 3-((4-cyano-2-hydroxyphenoxy)methyl)-4-fluorobenzoate (680 mg, 2.26 mmol) in anhydrous dimethyl sulfoxide (6 mL). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (white solid, 350 mg, yield 55.1%). LC / MS (ESI) m / z: 282 [M+H] + .

[0186] Step 4: 2-(hydroxymethyl)-11H-dibenzo[b,e][1,4]dioxane-7-nitrile and 2-(hydroxymethyl)-11H-dibenzo[b,e][1,4]dioxane-8-nitrile

[0187] Under nitrogen protection at 0 °C, a solution of lithium borohydride in tetrahydrofuran (1.24 mL, 4.96 mmol, 4 mol / L) was slowly added dropwise to an anhydrous tetrahydrofuran solution of methyl 7-cyano-11H-dibenzo[b,e][1,4]dioxane-2-carboxylate (350 mg, 1.24 mmol) and methyl 8-cyano-11H-dibenzo[b,e][1,4]dioxane-2-carboxylate (350 mg, 1.24 mmol). The reaction mixture was stirred at 80 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (white solid, 250 mg, yield 79.3%). LC / MS(ESI) m / z: 254 [M+H] + .

[0188] Step 5: 2-Formyl-11H-dibenzo[b,e][1,4]dioxane-7-nitrile and 2-Formyl-11H-dibenzo[b,e][1,4]dioxane-8-nitrile

[0189] Under nitrogen protection at 0 °C, fractionally add Dysmart reagent (628 mg, 1.48 mmol) to a solution of 2-(hydroxymethyl)-11H-dibenzo[b,e][1,4]dioxane-7-nitrile and 2-(hydroxymethyl)-11H-dibenzo[b,e][1,4]dioxane-8-nitrile (250 mg, 0.99 mmol) in anhydrous dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-40% ethyl acetate) to give the title compound (white solid, 220 mg, yield 88.7%). LC / MS (ESI) m / z: 252 [M+H] + .

[0190] Step 6: 2-(1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)-2,5-dihydro-1H-pyrrolo-2-yl)-11H-dibenzo[b,e][1,4]dioxacycloheptane-7-nitrile and 2-(1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)-2,5-dihydro-1H-pyrrolo-2-yl)-11H-dibenzo[b,e][1,4]dioxacycloheptane-8-nitrile

[0191] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (114 mg, 0.87 mmol), triethylamine (0.50 mL, 3.61 mmol), 2-formyl-11H-dibenzo[b,e][1,4]dioxane-7-onitrile and 2-formyl-11H-dibenzo[b,e][1,4]dioxane-8-onitrile (218 mg, 0.87 mmol) were added to acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (200 mg, 0.72 mmol) was added, and the reaction mixture was stirred at 100°C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to remove acetic acid. The residue was then subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to give the title compound (yellow solid, 100 mg, yield 24.7%). LC / MS (ESI) m / z: 560 [M+H] + .

[0192] Step 7: 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-11H-dibenzo[b,e][1,4]dioxacycloheptane-7-nitrile and 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-11H-dibenzo[b,e][1,4]dioxacycloheptane-8-nitrile

[0193] Under nitrogen protection, hydrazine hydrate (45 mg, 0.89 mmol) was added to a solution of 2-(1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)-2,5-dihydro-1H-pyrrole-2-yl)-11H-dibenzo[b,e][1,4]dioxane-7-onitrile and 2-(1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)-2,5-dihydro-1H-pyrrole-2-yl)-11H-dibenzo[b,e][1,4]dioxane-8-onitrile (100 mg, 0.18 mmol) in acetic acid (1 mL). The reaction solution was stirred at 120℃ for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% FA) to obtain 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-11H-dibenzo[b,e][1,4]dioxane-7-nitrile (white solid, 30 mg, yield 30.2%), LC / MS (ESI) m / z: 556 [M+H]. + And 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-11H-dibenzo[b,e][1,4]dioxane-8-nitrile (white solid, 30 mg, yield 30.2%), LC / MS (ESI) m / z: 556 [M+H] + .

[0194] The compounds in Table 2 were synthesized using commercially available raw materials following the synthesis steps of Example 4. Some compounds were resolved by SFC, while others were not resolved on the first attempt and underwent secondary SFC resolution. The resolution conditions are shown in the table.

[0195] Table 2:

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] Example 27: 7-(5-(2,2-difluoropropyl)-4-(10,11-dihydrodibenzo[b,f]oxetane-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0207]

[0208] Step 1: (2-Bromobenzyl)triphenylphosphonium bromide

[0209] Under nitrogen protection, triphenylphosphine (2.89 g, 11.0 mmol) was added to a solution of 1-bromo-2-(bromomethyl)benzene (2.5 g, 10.0 mmol) in N,N-dimethylformamide (7 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, toluene (20 mL) was added, and a solid precipitated. The solid was filtered. The filtered solid was dissolved in dichloromethane (12 mL), and diethyl ether (17 mL) was added. A solid precipitated again, and the solid was filtered to give the title compound (5 g, 97.6% yield).

[0210] Step 2: Methyl (E)-3-(2-bromostyryl)-4-hydroxybenzoate

[0211] Under nitrogen protection, potassium tert-butoxide (1.23 g, 10.9 mmol) was added to a tetrahydrofuran (40 mL) solution of (2-bromobenzyl)triphenylphosphonium bromide (4.0 g, 7.81 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for half an hour. Then, methyl 3-formyl-4-hydroxybenzoate (1.41 g, 7.81 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-5% ethyl acetate) to give the title compound (2.0 g, yield 76.9%). LC / MS (ESI) m / z: 333 / 335 [M+H] + .

[0212] Step 3: Methyl 3-(2-bromophenylethyl)-4-hydroxybenzoate

[0213] Under nitrogen protection, platinum dioxide (150 mg, 10% wt.) was added to a solution of methyl (E)-3-(2-bromostyryl)-4-hydroxybenzoate (1.0 g, 3.00 mmol) in ethyl acetate (40 mL). After purging the reaction system three times with nitrogen, the reaction mixture was stirred at room temperature for 5 hours under a hydrogen balloon. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-15% ethyl acetate) to give the title compound (360 mg, yield 35.8%). LC / MS (ESI) m / z: 335 / 337 [M+H] + .

[0214] Step 4: Methyl 10,11-dihydrodibenzo[b,f]oxetane-2-carboxylate

[0215] Under nitrogen protection, dimethylglycine (28 mg, 0.27 mmol), cesium carbonate (583 mg, 1.79 mmol), and cuprous iodide (17 mg, 0.09 mmol) were added to a solution of methyl 3-(2-bromophenylethyl)-4-hydroxybenzoate (300 mg, 0.89 mmol) in 1,4-dioxane (5 mL). The reaction mixture was purged with nitrogen three times and stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-30% ethyl acetate) to give the title compound (95 mg, yield 41.7%). LC / MS (ESI) m / z: 255 [M+H] + .

[0216] Step 5: (10,11-dihydrodibenzo[b,f]oxetane-2-yl)methanol

[0217] At 0 °C, lithium aluminum hydride (20 mg, 0.53 mmol) was added fractionally to an anhydrous tetrahydrofuran (2 mL) solution of methyl 10,11-dihydrodibenzo[b,f]oxetine-2-carboxylate (90 mg, 0.35 mmol). The reaction mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added to quench the reaction. The reaction mixture was diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-60% ethyl acetate) to give the title compound (70 mg, yield 87.4%). LC / MS (ESI) m / z: 209 [M-17] + .

[0218] Step 6: 10,11-Dihydrodibenzo[b,f]oxetane-2-carboxaldehyde

[0219] Under ice-water bath conditions, Dysmartin reagent (300 mg, 0.71 mmol) was added fractionally to a solution of (10,11-dihydrodibenzo[b,f]oxetine-2-yl)methanol (80 mg, 0.35 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, the dichloromethane phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-40% ethyl acetate) to give the title compound (75 mg, yield 94.6%). LC / MS (ESI) m / z: 225 [M+H] + .

[0220] Step 7: 7-(1-(2,2-difluoropropyl)-2-(10,11-dihydrodibenzo[b,f]oxetane-2-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0221] At room temperature, 2,2-difluoropropylamine hydrochloride (41 mg, 0.31 mmol), triethylamine (158 mg, 1.56 mmol), and 10,11-dihydrodibenzo[b,f]oxetane-2-carboxaldehyde (70 mg, 0.31 mmol) were added to acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (69 mg, 0.25 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-15% methanol) to give the title compound (70 mg, yield 42.1%). LC / MS (ESI) m / z: 533 [M+H] + .

[0222] Step 8: 7-(5-(2,2-difluoropropyl)-4-(10,11-dihydrodibenzo[b,f]oxetane-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0223] Under nitrogen protection, hydrazine hydrate (45 mg, 0.72 mmol, 80% wt.) was added to a 2 mL acetic acid solution of 7-(1-(2,2-difluoropropyl)-2-(10,11-dihydrodibenzo[b,f]oxetane-2-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (70 mg, 0.19 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was purified by preparative HPLC (10-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (10 mg, yield 14.4%). 1 H NMR(400MHz,CD3OD)δ7.29-7.07(m,4H),7.06-6.95(m,5H),6.94-6.88(m,1H),6.01(s,1H ),4.28-4.08(m,1H),3.05-2.87(m,5H),1.64(t,J=18.8Hz,3H).LC / MS(ESI)m / z:529[M+H] + .

[0224] Example 28: 7-(5-(2,2-difluoropropyl)-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazol-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0225]

[0226] Step 1: 5-Cyano-2-fluoro-N-(2-hydroxyphenyl)benzamide

[0227] 5-Cyano-2-fluorobenzoic acid (500 mg, 3.03 mmol) was dissolved in thionyl chloride (5 mL) at 0 °C. The reaction mixture was stirred overnight at 60 °C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (5 mL), and triethylamine (1.53 g, 15.15 mmol) and 2-aminophenol (330 mg, 3.03 mmol) were slowly added dropwise at 0 °C. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was poured into ice water. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried under reduced pressure to give the title compound (550 mg, yield 70.9%). LC / MS (ESI) m / z: 255 [MH] - .

[0228] Step 2: 11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazacycloheptane-2-nitrile

[0229] 5-Cyano-2-fluoro-N-(2-hydroxyphenyl)benzamide (500 mg, 1.95 mmol) was dissolved in anhydrous dimethyl sulfoxide (15 mL) at room temperature, and sodium hydroxide solid (78 mg, 1.95 mmol) was added. The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, water was added, and the mixture was filtered. The filter cake was dried under reduced pressure to give the title compound (400 mg, yield 86.9%). LC / MS (ESI) m / z: 237 [M+H] + .

[0230] Step 3: 10-Methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazacycloheptane-2-nitrile

[0231] Under nitrogen protection, 11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazacycloheptan-2-onitrile (300 mg, 1.27 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and sodium hydride (76.2 mg, 1.90 mmol, 60% wt) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for half an hour, and then iodomethane (183.3 mg, 1.30 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride solution at 0 °C, ethyl acetate was added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-60% ethyl acetate) to give the title compound (250 mg, yield 78.7%). LC / MS(ESI) m / z: 251 [M+H] + .

[0232] Step 4: 10-Methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazacycloheptane-2-carboxaldehyde

[0233] Under nitrogen protection, 200 mg (0.80 mmol) of 10-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazacycloheptane-2-nitrile (200 mg, 0.80 mmol) was dissolved in formic acid solution (8 mL), followed by the addition of Raney nickel (30 mg). The reaction mixture was heated to 60 °C and stirred for 5 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-70% ethyl acetate) to give the title compound (130 mg, yield 64.2%). LC / MS (ESI) m / z: 254 [M+H] + .

[0234] Step 5: (10-Methyl-10,11-dihydrodibenzo[b,f][1,4]oxazopen-2-yl)methanol

[0235] Under nitrogen protection at 0 °C, a borane tetrahydrofuran complex (5 mL, 1 M) was slowly added to an anhydrous tetrahydrofuran (5 mL) solution of 10-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazolidin-2-carboxaldehyde (253 mg, 1.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, methanol was added to quench the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-55% ethyl acetate) to give the title compound (140 mg, yield 58.3%). LC / MS (ESI) m / z: 242 [M+H] + .

[0236] Step 6: (10-Methyl-10,11-dihydrodibenzo[b,f][1,4]oxazopen-2-yl)formaldehyde

[0237] Under nitrogen protection at 0 °C, a solution of (140 mg, 0.58 mmol) of methanol in anhydrous dichloromethane (2 mL) was added fractionally to a solution of Diessmartin reagent (495 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution, and dichloromethane was added. The dichloromethane phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (95 mg, yield 67.8%). LC / MS (ESI) m / z: 240 [M+H] + .

[0238] Step 7: 7-(1-(2,2-difluoropropyl)-4-hydroxy-2-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazine-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0239] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (40 mg, 0.4 mmol), triethylamine (200 mg, 2.0 mmol), and (10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazol-2-yl)formaldehyde (95 mg, 0.40 mmol) were added to acetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (100 mg, 0.34 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the acetic acid was removed by concentration under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-15% methanol) to give the title compound (40 mg, yield 18.2%). LC / MS(ESI) m / z: 548 [M+H] + .

[0240] Step 8: 7-(5-(2,2-difluoropropyl)-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazol-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0241] Under nitrogen protection, 7-(1-(2,2-difluoropropyl)-4-hydroxy-2-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazine-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (40 mg, 0.07 mmol) was dissolved in acetic acid (1 mL), and hydrazine hydrate (23 mg, 0.36 mmol, 80% wt.) was added. The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was completed, the mixture was filtered and purified by preparative HPLC (40-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (3.05 mg, yield 7.5%). 1 H NMR (400MHz, CD3OD) δ7.24 (d, J=7.9Hz, 1H), 7.15-7.06 (m, 2H), 7.06-6.85 (m, 6H), 6.79 (t, J=7.0Hz, 1H), 6.05 (s,1H),4.29-4.12(m,3H),3.00-2.89(m,1H),2.74(s,3H),1.65(t,J=18.8Hz,3H).LC / MS(ESI)m / z:544[M+H] + .

[0242] Examples 29, 30, and 31: 7-(5-(2,2-difluoropropyl)-4-(6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Example 29) and 7-(5-(2,2-difluoropropyl)-4-( .... 5] Oxazolin-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Example 30) and 7-(5-(2,2-difluoropropyl)-4-(6-methyl-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazolin-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Example 31)

[0243]

[0244] Step 1: Methyl 4-fluoro-3-(((4-methoxybenzyl)amino)methyl)benzoate

[0245] At 0 °C, 4-methoxybenzylamine (0.75 g, 5.5 mmol) and acetic acid (0.66 g, 10.9 mmol) were added sequentially to a solution of methyl 4-fluoro-3-carboxaldehyde benzoate (1 g, 5.5 mmol) in anhydrous methanol (10 mL). The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0 °C, and sodium cyanoborohydride (0.69 g, 10.9 mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted twice with dichloromethane. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-15% ethyl acetate) to give the title compound (1.2 g, yield 72.1%).

[0246] Step 2: Methyl 4-fluoro-3-(((2-hydroxybenzyl)(4-methoxybenzyl)amino)methyl)benzoate

[0247] Under nitrogen protection at 0 °C, salicylaldehyde (0.48 g, 3.96 mmol) and acetic acid (0.48 g, 7.91 mmol) were added sequentially to a solution of methyl 4-fluoro-3-(((4-methoxybenzyl)amino)methyl)benzoate (1.2 g, 3.96 mmol) in 12 mL of anhydrous methanol. The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0 °C, and sodium cyanoborohydride (0.50 g, 7.91 mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (1.4 g, yield 86.4%). LC / MS (ESI) m / z: 410 [M+H] + .

[0248] Step 3: Methyl 6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-carboxylic acid

[0249] Cesium carbonate (2.23 g, 6.84 mmol) was added to an anhydrous N,N-dimethylformamide (15 mL) solution of methyl 4-fluoro-3-(((2-hydroxybenzyl)(4-methoxybenzyl)amino)methyl)benzoate (1.4 g, 3.42 mmol) at room temperature under nitrogen protection. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-25% ethyl acetate) to give the title compound (1.2 g, 90.1% yield). LC / MS (ESI) m / z: 390 [M+H] + .

[0250] Step 4: (6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-yl)methanol

[0251] Under nitrogen protection at 0 °C, lithium aluminum hydride (0.23 g, 6.16 mmol) was slowly added to an anhydrous tetrahydrofuran (12 mL) solution of methyl 6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-carboxylic acid ester (1.2 g, 3.08 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched by adding water (0.23 mL), sodium hydroxide aqueous solution (0.23 mL, 15% wt.), and water (0.69 mL) sequentially at 0 °C, and stirred for 30 minutes. The mixture was filtered, the filtrate was dried over sodium sulfate, filtered again, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (750 mg, yield 67.3%). LC / MS (ESI) m / z: 362 [M+H] + .

[0252] Step 5: 6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-carboxaldehyde

[0253] Under nitrogen protection at 0 °C, Desmartin reagent (1.76 g, 4.15 mmol) was added fractionally to a solution of (6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-yl)methanol (750 mg, 2.08 mmol) in 10 mL of anhydrous dichloromethane. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-25% ethyl acetate) to give the title compound (410 mg, yield 54.9%). 1 H NMR (400MHz, CD3OD) δ9.88 (s, 1H), 7.88 (dd, J = 8.4, 2.1Hz, 1H), 7.64-7.45 (m, 2H), 7.36-7.07 (m, 6H), 6.90 (d, J = 7.6Hz, 2H), 4.03-3.87 (m, 1H), 3.80 (s, 3H), 3.73-3.46 (m, 4H), 3.25-3.09 (m, 1H). LC / MS(ESI)m / z:360[M+H] + .

[0254] Step 6: 7-(1-(2,2-difluoropropyl)-4-hydroxy-2-(6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazolidine-3-yl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0255] Under nitrogen protection at room temperature, 2,2-difluoropropylamine hydrochloride (103 mg, 1.08 mmol), triethylamine (456 mg, 4.51 mmol), and 6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-carboxaldehyde (389 mg, 1.08 mmol) were added to acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazo-7-yl)butyrate (250 mg, 0.90 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the acetic acid was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-15% methanol) to give the title compound (250 mg, yield 41.5%). LC / MS(ESI) m / z: 668 [M+H] + .

[0256] Step 7: 7-(5-(2,2-difluoropropyl)-4-(6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Example 29)

[0257] Under nitrogen protection at room temperature, hydrazine hydrate (117 mg, 1.87 mmol, 80% wt.) was added to a solution of 7-(1-(2,2-difluoropropyl)-4-hydroxy-2-(6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazolidine-3-yl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (250 mg, 0.37 mmol) in acetic acid (2 mL). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (130 mg, yield 52%). 1 H NMR (400MHz, CD3OD) δ7.46–7.40(m,1H),7.28–7.26(m,2H),7.19–6.86(m,9H),6.74–6.44(m,2H),6.04(s,1H),4.64–4.38(m,1H ),4.28–4.13(m,1H),3.87–3.81(m,3H),3.57–3.37(m,4H),3.06–2.85(m,2H),1.66(t,J=18.7Hz,3H).LC / MS(ESI)m / z:664[M+H] + .

[0258] Step 8: 7-(5-(2,2-difluoropropyl)-4-(6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Example 30)

[0259] Under nitrogen protection at room temperature, 1-chloroethyl chloroformate (52 mg, 0.36 mmol) was added to a solution of 7-(5-(2,2-difluoropropyl)-4-(6-(4-methoxybenzyl)-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (120 mg, 0.18 mmol) in anhydrous dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure to remove the solvent. The residue was then added to methanol (2 mL) and heated to reflux with stirring for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (20-90% acetonitrile in H2O solution and 0.1% NH4HCO3) to obtain the title compound (16 mg, yield 16.3%). 1 HNMR(400MHz,CD3OD)δ7.26-7.24(m,4H),7.16-7.05(m,5H),7.00-6.98(m,1H),6.05(s ,1H),4.23-4.11(m,1H),3.98-3.79(m,4H),2.97-2.88(m,1H),1.64(t,J=18.8Hz,3H). LC / MS(ESI)m / z:544[M+H] + .

[0260] Step 9: 7-(5-(2,2-difluoropropyl)-4-(6-methyl-6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Example 31)

[0261] Under nitrogen protection at room temperature, acetic acid (0.05 mL), 38% formaldehyde aqueous solution (0.05 mL), and sodium cyanoborohydride (2.3 mg, 0.036 mmol) were added sequentially to a methanol (1 mL) solution of 7-(5-(2,2-difluoropropyl)-4-(6,7-dihydro-5H-dibenzo[b,g][1,5]oxazoline-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (10 mg, 0.018 mmol) in sequence. The reaction mixture was stirred at room temperature for 15 minutes. After the reaction was completed, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (10-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (1.6 mg, yield 16%). 1H NMR(400MHz,CD3OD)δ7.48-6.93(m,10H),6.05(s,1H),4.58(s,3H),4.25-4.13(m,1 H), 3.76-3.65 (m, 1H), 3.52-3.41 (m, 3H), 3.01-2.86 (m, 1H), 1.65 (t, J = 18.8Hz, 3H). LC / MS(ESI)m / z:558[M+H] + .

[0262] Example 32: 7-(5-(2,2-difluoropropyl)-4-(6,7-dihydrodibenzo[b,e][1,4]dioxane-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0263]

[0264] Step 1: Methyl 2-(2-(methoxymethoxy)phenyl)acetate

[0265] At 0 °C, N,N-diisopropylethylamine (3 mL, 18.2 mmol) and chloromethyl methyl ether (1 mL, 13.2 mmol) were added sequentially to a solution of methyl 2-(2-hydroxyphenyl)acetate (1 g, 6.02 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, dichloromethane and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (910 mg, yield 71.9%).

[0266] Step 2: 2-(2-(methoxymethoxy)phenyl)ethanol-1-ol

[0267] Under nitrogen protection at 0°C, lithium aluminum hydride (246 mg, 6.48 mmol) was slowly added in portions to anhydrous tetrahydrofuran (10 mL) containing methyl 2-(2-(methoxymethoxy)phenyl)acetate (910 mg, 4.33 mmol). After the reaction was complete, the reaction mixture was quenched by adding water (0.24 mL), sodium hydroxide aqueous solution (0.48 mL, 15% wt.), and water (0.74 mL) sequentially at 0°C, and the mixture was stirred for 30 minutes. The mixture was filtered, the filter cake was washed twice with ethyl acetate, the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-40% ethyl acetate) to give the title compound (660 mg, yield 83.7%).

[0268] Step 3: 4-Fluoro-3-(2-(methoxymethoxy)phenethoxy)benzylnitrile

[0269] Under nitrogen protection at 0 °C, diisopropyl azodicarboxylate (1.4 mL, 7.11 mmol) was added dropwise to anhydrous tetrahydrofuran (20 mL) of 2-(2-(methoxymethoxy)phenyl)ethanol-1-ol (660 mg, 3.62 mmol), 4-fluoro-3-hydroxybenzonitrile (497 mg, 3.62 mmol), and triphenylphosphine (1900 mg, 7.24 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-5% ethyl acetate) to give the title compound (600 mg, yield 55.0%).

[0270] Step 4: 4-Fluoro-3-(2-hydroxyphenethoxy)benzonitrile

[0271] At room temperature, trifluoroacetic acid (2 mL, 26.1 mmol) was added to a solution of 600 mg (1.99 mmol) of 4-fluoro-3-(2-(methoxymethoxy)phenethoxy)benzyl nitrile in dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution and extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (250 mg, yield 48.8%). LC / MS (ESI) m / z: 513 [2M-H] - .

[0272] Step 5: 6,7-Dihydrodibenzo[b,e][1,4]dioxane-3-nitrile

[0273] At room temperature, cesium carbonate (633 mg, 1.94 mmol) was added to an anhydrous dimethyl sulfoxide (3 mL) solution of 250 mg (0.97 mmol) of 4-fluoro-3-(2-hydroxyphenethoxy)benzonitrile. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (55 mg, yield 23.9%).

[0274] Step 6: 6,7-Dihydrodibenzo[b,e][1,4]dioxane-3-carboxaldehyde

[0275] Under nitrogen protection at room temperature, Raney nickel (6 mg) was added to a mixture of acetic acid (3 mL) and water (1 mL) containing 55 mg (0.23 mmol) of 6,7-dihydrodibenzo[b,e][1,4]dioxane-3-onitrile. The reaction mixture was purged with nitrogen three times and stirred at 80 °C for 1 hour under hydrogen atmosphere at 1 atm. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (44 mg, yield 79.0%).

[0276] Step 7: 7-(1-(2,2-difluoropropyl)-2-(6,7-dihydrodibenzo[b,e][1,4]dioxane-3-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0277] At room temperature, 2,2-difluoropropylamine hydrochloride (25 mg, 0.19 mmol), triethylamine (0.08 mL, 0.61 mmol), and 6,7-dihydrodibenzo[b,e][1,4]dioxane-3-carboxaldehyde (44 mg, 0.18 mmol) were added to acetic acid (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (42 mg, 0.15 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to give the title compound (25 mg, yield 30.1%). LC / MS (ESI) m / z: 549 [M+H] + .

[0278] Step 8: 7-(5-(2,2-difluoropropyl)-4-(6,7-dihydrodibenzo[b,e][1,4]dioxane-3-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0279] At room temperature, hydrazine hydrate (19 mg, 0.24 mmol, 80% wt.) was added to a 2 mL acetic acid solution of 7-(1-(2,2-difluoropropyl)-2-(6,7-dihydrodibenzo[b,e][1,4]dioxane-3-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (25 mg, 0.05 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (11.31 mg, yield 45.6%). 1 H NMR (400MHz, DMSO-d6) δ14.22(s,1H),7.27(d,J=7.9Hz,1H),7.23-7.17(m,3H),7.15-7.07(m,3H),7.02(d,J=7.3Hz,1H),6.79-6.72(m,2H) ,5.90(s,1H),4.22-4.15(m,2H),4.15-4.08(m,1H),3.01-2.94(m,2H),2.90-2.81(m,1H),1.63(t,J=19.2Hz,3H).LC / MS(ESI)m / z:545[M+H] + .

[0280] Example 33: 7-(4-(7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0281]

[0282] Step 1: 4,5-Difluoro-2-methoxyphenol

[0283] Under nitrogen protection at 0 °C, aluminum trichloride (3.06 g, 22.98 mmol) was slowly added to a solution of 1,2-difluoro-4,5-dimethoxybenzene (1 g, 5.74 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched in ice water and extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-30% ethyl acetate) to give the title compound (900 mg, yield 97.8%). LC / MS (ESI) m / z: 161 [M+H] + .

[0284] Step 2: Methyl 5-cyano-2-(4,5-difluoro-2-methoxyphenoxy)benzoate

[0285] At room temperature, cesium carbonate (2182 mg, 6.71 mmol) and 4,5-difluoro-2-methoxyphenol (715 mg, 4.47 mmol) were added sequentially to an anhydrous N,N-dimethylformamide (8 mL) solution of methyl 5-cyano-2-fluorobenzoate (800 mg, 4.47 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (800 mg, yield 56.1%). LC / MS (ESI) m / z: 320 [M+H] + .

[0286] Step 3: Methyl 5-cyano-2-(4,5-difluoro-2-hydroxyphenoxy)benzoate

[0287] Under nitrogen protection at -70°C, boron tribromide (1.25 g, 5.01 mmol) was slowly added dropwise to a solution of methyl 5-cyano-2-(4,5-difluoro-2-methoxyphenoxy)benzoate (800 mg, 2.51 mmol) in anhydrous dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution at 0°C and extracted twice with dichloromethane. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (420 mg, yield 54.9%). LC / MS (ESI) m / z: 306 [M+H] + .

[0288] Step 4: 4-(4,5-difluoro-2-hydroxyphenoxy)-3-(hydroxymethyl)benzonitrile

[0289] Under nitrogen protection at 0 °C, a solution of lithium borohydride tetrahydrofuran (0.68 mL, 2.75 mmol, 4 M) was slowly added dropwise to an anhydrous tetrahydrofuran (4 mL) solution of methyl 5-cyano-2-(4,5-difluoro-2-hydroxyphenoxy)benzoate (420 mg, 1.38 mmol). The reaction mixture was stirred at 80 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-35% ethyl acetate) to give the title compound (200 mg, yield 52.4%). LC / MS (ESI) m / z: 278 [M+H] + .

[0290] Step 5: 3-(chloromethyl)-4-(4,5-difluoro-2-hydroxyphenoxy)benzonitrile

[0291] Under nitrogen protection at 0 °C, pyridine (0.01 mL, 0.09 mmol) and sulfoxide (56 mg, 0.47 mmol) were slowly added dropwise to an anhydrous toluene (2 mL) solution of 4-(4,5-difluoro-2-hydroxyphenoxy)-3-(hydroxymethyl)benzonitrile (130 mg, 0.47 mmol). The reaction mixture was stirred at 80 °C for 1 hour under nitrogen protection. After the reaction was complete, ethyl acetate and water were added, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-30% ethyl acetate) to give the title compound (130 mg, 93.7% yield). LC / MS (ESI) m / z: 296 [M+H] + .

[0292] Step 6: 7,8-Difluoro-11H-dibenzo[b,e][1,4]dioxane-2-nitrile

[0293] At room temperature, cesium carbonate (198 mg, 0.61 mmol) was added to an anhydrous N,N-dimethylformamide (2 mL) solution of 120 mg (120 mg, 0.41 mmol) of 3-(chloromethyl)-4-(4,5-difluoro-2-hydroxyphenoxy)benzonitrile. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-15% ethyl acetate) to give the title compound (70 mg, yield 66.5%). LC / MS (ESI) m / z: 260 [M+H] + .

[0294] Step 7: 7,8-Difluoro-11H-dibenzo[b,e][1,4]dioxane-2-carboxaldehyde

[0295] At room temperature, Raney nickel (7 mg) was added to a solution of 7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-nitrile (70 mg, 0.27 mmol) in formic acid (2 mL) and water (0.7 mL). The reaction mixture was purged three times with nitrogen and stirred at 80 °C for 30 min under hydrogen atmosphere at 1 atm. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (45 mg, yield 63.5%). LC / MS (ESI) m / z: 263 [M+H] + .

[0296] Step 8: 7-(2-(7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0297] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (23 mg, 0.17 mmol), triethylamine (0.10 mL, 0.72 mmol), and 7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-carboxaldehyde (45 mg, 0.17 mmol) were added to acetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (40 mg, 0.14 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to give the title compound (40 mg, yield 48.6%). LC / MS(ESI) m / z: 571 [M+H] + .

[0298] Step 9: 7-(4-(7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Example 33)

[0299] Under nitrogen protection, hydrazine hydrate (5 mg, 0.07 mmol, 80% wt.) was added to a 1 mL acetic acid solution of 7-(2-(7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (40 mg, 0.07 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% FA) to give the title compound (3.5 mg, yield 8.8%). 1 H NMR (400MHz, CD3OD) δ7.27-7.15(m,3H),7.14-7.09(m,2H),7.07-6.97(m,2H),6.82-6.74(m,1H),6.08(s, 1H),5.11(s,2H),4.30-4.10(m,1H),3.00-2.86(m,1H),1.65(t,J=18.8Hz,3H).LC / MS(ESI)m / z:567[M+H] + .

[0300] SFC chiral resolution was performed on 7-(4-(7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one to obtain Examples 33-1 and 33-2:

[0301] Example 33-1: (S)-7-(4-(7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Chiral separation conditions: Column: ChiralCel OD, 250×30mm I.D., 5μm; Mobile phase: A=CO2 and B=MeOH (0.1% 7M NH3 in MeOH); Gradient: B 50%; Flow rate: 60mL / min; Peak 1, Rt=1.363min) 1 H NMR (400MHz, CD3OD) δ7.34–7.16(m,3H),7.14–7.07(m,2H),7.06–6.96(m,2H),6.80–6.72(m,1H),6.09(s, 1H),5.11(s,2H),4.29–4.14(m,1H),3.01–2.86(m,1H),1.65(t,J=18.8Hz,3H).LC / MS(ESI)m / z:567[M+H] + .

[0302] Example 33-2: (R)-7-(4-(7,8-difluoro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one (Chiral separation conditions: Column: ChiralCel OD, 250×30mm I.D., 5μm; Mobile phase: A=CO2 and B=MeOH (0.1% 7M NH3 in MeOH); Gradient: B 50%; Flow rate: 60mL / min; Peak 2, Rt=1.881min)1 H NMR (400MHz, CD3OD) δ7.30–7.16(m,3H),7.14–7.08(m,2H),7.07–6.97(m,2H),6.81–6.72(m,1H),6.09(s, 1H),5.11(s,2H),4.29–4.13(m,1H),3.02–2.86(m,1H),1.65(t,J=18.8Hz,3H).LC / MS(ESI)m / z:567[M+H] + .

[0303] Example 34: 7-(5-(2,2-difluoropropyl)-4-(5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0304]

[0305] Step 1: Methyl 4-fluoro-3-hydroxymethylbenzoate

[0306] Under nitrogen protection, sodium borohydride (0.25 g, 6.59 mmol) was added in portions to a methanol (20 mL) solution of methyl 4-fluoro-3-carboxaldehyde benzoate (1 g, 5.49 mmol) at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with a saturated ammonium chloride solution at 0 °C, concentrated under reduced pressure to remove methanol, and then ethyl acetate and water were added. The mixture was separated, and the aqueous phase was extracted once with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-15% ethyl acetate) to give the title compound (900 mg, yield 89%). 1 H NMR (400MHz, CDCl3) δ8.16 (dd, J=7.1, 2.0Hz, 1H), 8.02-7.91 (m, 1H), 7.09 (t, J=9.1Hz, 1H), 4.79 (s, 2H), 3.91 (s, 3H).

[0307] Step 2: Methyl 4-fluoro-3-((2-oxocyclohexyl)oxy)methyl)benzoate

[0308] Under nitrogen protection at room temperature, 4A molecular sieve (2.5 g), silica gel powder (2.5 g), and silver oxide (3.46 g, 14.9 mmol) were added sequentially to a solution of methyl 4-fluoro-3-hydroxymethylbenzoate (2.5 g, 13.6 mmol) and 2-bromocyclohexanone (2.40 g, 13.6 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (500 mg, yield 13%). 1 H NMR (400MHz, CDCl3) δ8.19(dd,J=7.0,2.1Hz,1H),8.05-7.95(m,1H),7.09(t,J=9.0Hz,1H),4.82(d,J=12.3Hz,1H),4.57(d,J=12.3Hz,1H), 3.97-3.92(m,1H),3.91(s,3H),2.61-2.51(m,1H),2.28–2.24(m,2H) ,1.98–1.94(m,2H),1.85(dt,J=13.1,10.4Hz,1H),1.79-1.64(m,2H).

[0309] Step 3: Methyl 4-fluoro-3-((2-hydroxycyclohexyl)oxy)methyl)benzoate

[0310] Under nitrogen protection at 0°C, sodium borohydride (101 mg, 2.68 mmol) was added in portions to a methanol (10 mL) solution of methyl 4-fluoro-3-((2-oxocyclohexyl)oxy)methyl)benzoate (500 mg, 1.78 mmol). After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted twice with ethyl acetate, and the organic phase was washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (290 mg, yield 58%). 1 H NMR (400MHz, CDCl3) δ8.13(dd,J=7.0,2.0Hz,1H),8.02-7.96(m,1H),7.10(t,J=9.0Hz,1H),4.64(q,J=12.1Hz,2H),3.92 (s,3H),3.88(s,1H),3.57-3.50(m,1H),2.25(d,J=5.1Hz,1H),1.94-1.76(m,2H),1.69-1.47(m,4H),1.35-1.25(m,2H).

[0311] Step 4: 5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid methyl ester

[0312] Cesium carbonate (669 mg, 2.05 mmol) was added to an anhydrous dimethyl sulfoxide (20 mL) solution of methyl 4-fluoro-3-((2-hydroxycyclohexyl)oxy)methyl)benzoate (290 mg, 1.03 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-5% ethyl acetate) to give the title compound (100 mg, yield 37%). LC / MS (ESI) m / z: 263.0 [M+H] + .

[0313] Step 5: 5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid

[0314] At room temperature, a solution of methyl 5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid (100 mg, 0.38 mmol) in tetrahydrofuran (6 mL) was added to a solution of lithium hydroxide monohydrate (48 mg, 1.14 mmol) in water (2 mL). The reaction mixture was stirred at 50 °C for 8 hours. The tetrahydrofuran was removed by concentration under reduced pressure. The aqueous phase was adjusted to pH 3–4 with 2N hydrochloric acid, extracted twice with ethyl acetate, and the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0–30% ethyl acetate) to give the title compound (60 mg, yield 63%). LC / MS (ESI) m / z: 249.3 [M+H] + .

[0315] Step 6: (5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-yl)methanol

[0316] Under nitrogen protection at 0 °C, boranetetrahydrofuran (1.21 mL, 1.21 mmol) was added dropwise to an anhydrous tetrahydrofuran (2 mL) solution of 5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-heptane-2-carboxylic acid (60 mg, 0.24 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with aqueous sodium bicarbonate solution, extracted twice with ethyl acetate, and the combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (55 mg, 97% yield). LC / MS (ESI) m / z: 217.3 [M+H-18] + .

[0317] Step 7: 5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-carboxaldehyde

[0318] At room temperature, Dysmart reagent (149 mg, 0.35 mmol) was added fractionally to a solution of (5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-yl)methanol (55 mg, 0.23 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (40 mg, 73% yield). LC / MS (ESI) m / z: 233.0 [M+H] + .

[0319] Step 8: 7-(1-(2,2-difluoropropyl)-2-(5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0320] At room temperature, triethylamine (0.13 mL, 0.97 mmol) was added dropwise to a solution of 2,2-difluoropropylamine hydrochloride (25 mg, 0.19 mmol) and 5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-carboxaldehyde (45 mg, 0.19 mmol) in acetic acid (5 mL). The reaction solution was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (43 mg, 0.15 mmol) was added, and the reaction solution was stirred at 100 °C for another 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to give the title compound (18 mg, yield 17%). LC / MS (ESI) m / z: 541.3 [M+H] + .

[0321] Step 9: 7-(5-(2,2-difluoropropyl)-4-(5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0322] At room temperature, hydrazine hydrate (10.5 mg, 0.17 mmol, 80% wt.) was added to a 3 mL acetic acid solution of 7-(1-(2,2-difluoropropyl)-2-(5a,6,7,8,9,9a-hexahydro-11H-dibenzo[b,e][1,4]dioxane-2-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (18 mg, 0.03 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was directly purified by preparative HPLC (0.1% ammonium bicarbonate aqueous solution of 20-95% acetonitrile) to give the title compound (1.33 mg, yield 7.4%). 1H NMR (400MHz, CD3OD) δ7.16 (d, J=7.8Hz, 1H), 7.09 (td, J=7.9, 2.2Hz, 1H), 7. 02-6.91(m,3H),6.82(t,J=7.8Hz,1H),6.00(s,1H),4.59-4.57(m,1H),4.52 -4.46(m,1H),4.36-4.34(m,1H),4.22-4.11(m,1H),3.91-3.87(m,1H),2.9 8-2.90(m,3H),1.90-1.87(m,1H),1.70-1.61(m,5H),1.21(t,J=7.3Hz,3H). LC / MS (ESI) m / z: 537.3 [M+H] + .

[0323] Example 35: 7-(4-(11H-dibenzo[b,e][1,4]dioxane-3-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0324]

[0325] Step 1: Methyl 3-fluoro-4-((2-hydroxyphenoxy)methyl)benzoate

[0326] Potassium carbonate (1.3 g, 9.72 mmol) was added to a solution of methyl 4-(bromomethyl)-3-fluorobenzoate (1.2 g, 4.86 mmol) and o-diphenol (530 mg, 4.86 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-15% ethyl acetate) to give the title compound (900 mg, yield 67.1%). 1 H NMR (400MHz, CDCl3) δ7.86 (dd, J=8.0, 1.3Hz, 1H), 7.77 (dd, J=10.4, 1.4Hz, 1H), 7.53 (t, J=7.5Hz, 1H), 6.98-6.90 (m, 4H), 5.24 (s, 2H), 3.94 (s, 3H).

[0327] Step 2: 11H-dibenzo[b,e][1,4]dioxane-3-carboxylic acid methyl ester

[0328] At room temperature, cesium carbonate (2.1 g, 6.52 mmol) was added to an anhydrous dimethyl sulfoxide (18 mL) solution of methyl 3-fluoro-4-((2-hydroxyphenoxy)methyl)benzoate (900 mg, 3.26 mmol). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (300 mg, yield 35.9%). 1 H NMR (400MHz, CDCl3) δ7.91-7.70(m,2H),7.42-7.28(m,1H),7.21-7.14(m,1H),6.93(dd,J=5.6,4.0Hz,3H),5.27(s,2H),3.93(s,3H).

[0329] Step 3: (11H-dibenzo[b,e][1,4]dioxane-3-yl)methanol

[0330] Under nitrogen protection at 0 °C, a solution of lithium borohydride in tetrahydrofuran (1.2 mL, 4.68 mmol, 4 M) was slowly added dropwise to an anhydrous tetrahydrofuran (5 mL) solution of methyl 11H-dibenzo[b,e][1,4]dioxane-3-carboxylic acid (300 mg, 1.17 mmol). The reaction mixture was stirred at 80 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (240 mg, yield 89.8%). The crude product was used directly in the next reaction. LC / MS (ESI) m / z: 211 [M+H-18] + .

[0331] Step 4: 11H-Dibenzo[b,e][1,4]dioxane-3-carboxaldehyde

[0332] Under nitrogen protection at 0 °C, Dysmart reagent (669 mg, 1.58 mmol) was added fractionally to a solution of (11H-dibenzo[b,e][1,4]dioxane-3-yl)methanol (240 mg, 1.05 mmol) in anhydrous dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-8% ethyl acetate) to give the title compound (210 mg, 88.3%). 1 H NMR (400MHz, CDCl3) δ10.01(s,1H),7.70(s,1H),7.62(d,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),7.19(d,J=7.3Hz,1H),7.03-6.88(m,3H),5.28(s,2H).

[0333] Step 5: 5-(11H-dibenzo[b,e][1,4]dioxane-3-yl)-1-(2,2-difluoropropyl)-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)pyrrolidine-2,3-dione

[0334] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (114 mg, 0.87 mmol), triethylamine (364 mg, 3.61 mmol), and 11H-dibenzo[b,e][1,4]dioxane-3-carboxaldehyde (197 mg, 0.87 mmol) were added to acetic acid (3 mL), and the reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (200 mg, 0.72 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to give the title compound (220 mg, yield 50.7%). LC / MS (ESI) m / z: 535 [M+H] + .

[0335] Step 6: 7-(4-(11H-dibenzo[b,e][1,4]dioxane-3-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0336] At room temperature, hydrazine hydrate (129 mg, 2.06 mmol, 80% wt.) was added to a acetic acid (3 mL) solution of 5-(11H-dibenzo[b,e][1,4]dioxane-3-yl)-1-(2,2-difluoropropyl)-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)pyrrolidine-2,3-dione (220 mg, 0.41 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was directly purified by preparative HPLC (20-95% acetonitrile aqueous solution containing 0.1% FA) to give the title compound (102 mg, yield 46.7%). 1 H NMR (400MHz, CD3OD) δ7.30-7.13(m,2H),7.12-7.06(m,2H),7.02-6.95(m,3H),6.94-6.87(m,2H),6.85-6.81(m,1H),6.09(s ,1H),5.13(dd,J=33.8,13.0Hz,2H),4.32-4.16(m,1H),3.02-2.91(m,1H),1.67(t,J=18.8Hz,3H).LC / MS(ESI)m / z:531[M+H] + .

[0337] Example 36: 7-(4-(11H-dibenzo[b,e][1,4]dioxane-8-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0338]

[0339] Step 1: Methyl 2-(4-bromo-2-methoxyphenoxy)benzoate

[0340] At room temperature, cesium carbonate (32 g, 0.099 mol) was added to a solution of 4-bromo-2-methoxyphenol (10 g, 0.049 mol) and methyl o-fluorobenzoate (7.6 g, 0.049 mol) in dimethyl sulfoxide (100 mL). The reaction mixture was stirred at 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The ethyl acetate phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the crude compound (10 g, yield 60.2%).

[0341] Step 2: 2-(4-bromo-2-methoxyphenoxy)phenyl)methanol

[0342] Under nitrogen protection, lithium aluminum hydride (1.24 g, 32.6 mmol) was added in portions to an anhydrous tetrahydrofuran (100 mL) solution of methyl 2-(4-bromo-2-methoxyphenoxy)benzoate (11 g, 32.6 mmol) at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched by adding water (1.24 mL), sodium hydroxide aqueous solution (1.24 mL, 15% wt.), and water (3.72 mL) sequentially at 0 °C, and the mixture was stirred for 30 minutes. The mixture was filtered, the filter cake was washed twice with ethyl acetate, the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (2.2 g, yield 21.8%). 1 H NMR (400MHz, CDCl3) δ7.39 (dd, J=7.4, 1.3Hz, 1H), 7.19 (td, J=8.0, 1.7Hz, 1H), 7.11 (d, J=2.2Hz, 1H) ,7.09-7.04(m,2H),6.88(d,J=8.4Hz,1H),6.69(d,J=8.2Hz,1H),4.78(d,J=5.6Hz,2H),3.79(s,3H).

[0343] Step 3: 5-Bromo-2-(2-(bromomethyl)phenoxy)phenol

[0344] Under nitrogen protection, a solution of boron tribromide (5.35 g, 21.4 mmol) in dichloromethane (5 mL) was added dropwise to a solution of 2-(4-bromo-2-methoxyphenoxy)phenyl)methanol (2.2 g, 7.1 mmol) in 40 mL of anhydrous dichloromethane at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was quenched with an aqueous sodium bicarbonate solution. Dichloromethane and water were added to the mixture, and the dichloromethane phase was separated. The aqueous phase was extracted with dichloromethane, and the organic phases were combined, washed with water, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (1.6 g, yield 62.8%). 1 H NMR (400MHz, CDCl3) δ7.42(d,J=7.5Hz,1H),7.29-7.23(m,2H),7.09(t,J=7.1Hz,1H),7.04-6.97(m ,1H),6.85(dd,J=8.6,2.0Hz,1H),6.79(d,J=8.1Hz,1H),5.96(d,J=1.9Hz,1H),4.67-4.60(m,2H).

[0345] Step 4: 8-Bromo-11H-dibenzo[b,e][1,4]dioxane

[0346] Potassium carbonate (1.24 g, 8.94 mmol) was added to an anhydrous N,N-dimethylformamide (30 mL) solution of 5-bromo-2-(2-(bromomethyl)phenoxy)phenol (1.6 g, 4.47 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the ethyl acetate phase was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with water and saturated brine respectively, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-3% ethyl acetate) to give the title compound (550 mg, yield 44.4%). 1 H NMR(400MHz, CDCl3)δ7.33(td,J=7.9,1.6Hz,1H),7.30-7.26(m,1H),7.17(d,J=7.6H z, 1H), 7.12 (td, J=7.4, 0.9Hz, 1H), 7.01 (ddd, J=10.9, 6.5, 2.2Hz, 3H), 5.24 (s, 2H).

[0347] Step 5: 11H-dibenzo[b,e][1,4]dioxane-8-carboxylic acid methyl ester

[0348] Under nitrogen protection at room temperature, 1,1-bis(diphenylphosphine)diphenylferric palladium dichloride (145.22 mg, 0.20 mmol) was added to a solution of 8-bromo-11H-dibenzo[b,e][1,4]dioxane (550 mg, 1.98 mmol) in anhydrous methanol (60 mL) and triethylamine (20 mL). The reaction mixture was purged with nitrogen three times and stirred at 90 °C for 24 hours under carbon monoxide balloon protection. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-2% ethyl acetate) to give the title compound (50 mg, yield 9.8%). 1 H NMR (400MHz, CDCl3) δ7.58-7.49(m,2H),7.29-7.25(m,1H),7.21(s,1H),7.12(dd,J=8.0,4.1Hz,2H),7.05(t,J=7.4Hz,1H),5.17(s,2H),3.81(s,3H).

[0349] Step 6: (11H-dibenzo[b,e][1,4]dioxane-8-yl)methanol

[0350] Under nitrogen protection, lithium aluminum hydride (59.2 mg, 1.56 mmol) was added in portions to an anhydrous tetrahydrofuran (5 mL) solution of methyl 11H-dibenzo[b,e][1,4]dioxane-8-carboxylic acid (50 mg, 0.20 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour after the addition was complete. The reaction mixture was quenched with sodium sulfate decahydrate and stirred until a white solid appeared. The mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (44 mg, 98.8% yield). LC / MS (ESI) m / z: 211.0 [M+H-18] + .

[0351] Step 7: 11H-dibenzo[b,e][1,4]dioxane-8-carboxaldehyde

[0352] At room temperature, Dys-Martin oxidant (149 mg, 0.35 mmol) was added fractionally to a solution of (11H-dibenzo[b,e][1,4]dioxane-8-yl)methanol (45 mg, 0.20 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. Diatomaceous earth was added to the reaction mixture, and the mixture was filtered. The filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (33 mg, 74% yield). LC / MS (ESI) m / z: 226.9 [M+H] + .

[0353] Step 8: 7-(2-(11H-dibenzo[b,e][1,4]dioxane-8-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0354] Under nitrogen protection, triethylamine (0.10 mL, 0.73 mmol) was added dropwise to a solution of 2,2-difluoropropylamine hydrochloride (19.2 mg, 0.15 mmol), 11H-dibenzo[b,e][1,4]dioxane-8-carboxaldehyde (33 mg, 0.15 mmol) in acetic acid (3 mL). The reaction mixture was stirred overnight at room temperature. Subsequently, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (32.4 mg, 0.12 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to remove acetic acid. The residue was dissolved in ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to give the title compound (25 mg, yield 32%). LC / MS (ESI) m / z: 535.0 [M+H] + .

[0355] Step 9: 7-(4-(11H-dibenzo[b,e][1,4]dioxane-8-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0356] At room temperature, hydrazine hydrate (14.6 mg, 0.23 mmol, 80% wt.) was added to a acetic acid (3 mL) solution of 7-(2-(11H-dibenzo[b,e][1,4]dioxane-8-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (25 mg, 0.05 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was directly purified by preparative HPLC (0.1% ammonium bicarbonate aqueous solution of 20-95% acetonitrile) to give the title compound (5 mg, yield 20.2%). 1H NMR (400MHz, DMSO-d6) δ7.40(d,J=7.4Hz,1H),7.36(t,J=7.8Hz,1H),7.31(d,J=7.9Hz,1H),7.19-7.11(m,3H),7.09(d,J=8.7Hz,1H),7.02(d ,J=7.7Hz,1H),6.66-6.64(m,2H),5.89(s,1H),5.27-5.16(m,2H),4.14(dd,J=32.9,17.0Hz,1H),2.87-2.75(m,1H),1.64(t,J=19.2Hz,3H). LC / MS(ESI)m / z:531.0[M+H] + .

[0357] Example 37: 7-(5-(2,2-difluoropropyl)-6-oxo-4-(7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0358]

[0359] Step 1: Methyl 3-formyl-4-(2-methoxy-5-(trifluoromethoxy)phenoxy)benzoate

[0360] At room temperature, cesium carbonate (3.13 g, 9.61 mmol) and methyl 4-fluoro-3-carboxybenzoate (880 mg, 4.80 mmol) were added to an anhydrous dimethyl sulfoxide (15 mL) solution of 2-methoxy-5-(trifluoromethoxy)phenol (1 g, 4.81 mmol). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-30% ethyl acetate) to give the title compound (1.7 g, 95.6% yield). LC / MS (ESI) m / z: 371 [M+H] + .

[0361] Step 2: Methyl 3-(hydroxymethyl)-4-(2-methoxy-5-(trifluoromethoxy)phenoxy)benzoate

[0362] Under nitrogen protection, sodium borohydride (260 mg, 6.89 mmol) was slowly added to an anhydrous methanol (20 mL) solution of methyl 3-formyl-4-(2-methoxy-5-(trifluoromethoxy)phenoxy)benzoate (1.7 g, 4.59 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, methanol was removed by concentration under reduced pressure, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (1.2 g, yield 70.2%). LC / MS (ESI) m / z: 373 [M+H] + .

[0363] Step 3: Methyl 3-(bromomethyl)-4-(2-hydroxy-5-(trifluoromethoxy)phenoxy)benzoate

[0364] Under nitrogen protection, boron tribromide (3.7 g, 14.8 mmol) was slowly added to a solution of methyl 3-(hydroxymethyl)-4-(2-methoxy-5-(trifluoromethoxy)phenoxy)benzoate (1.1 g, 2.95 mmol) in anhydrous dichloromethane (15 mL) at -70 °C. The reaction mixture was slowly heated to room temperature and stirred for 3 hours. After the reaction was complete, the reaction was quenched with methanol at -70 °C, and the reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (310 mg, yield 25.0%). LC / MS (ESI) m / z: 421 / 423 [M+H] + .

[0365] Step 4: 7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid methyl ester

[0366] Potassium carbonate (720 mg, 5.22 mmol) was added to an anhydrous N,N-dimethylformamide (25 mL) solution of methyl 3-(bromomethyl)-4-(2-hydroxy-5-(trifluoromethoxy)phenoxy)benzoate (1.1 g, 2.61 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (310 mg, yield 34.9%).

[0367] Step 5: (7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-yl)methanol

[0368] Under nitrogen protection at 0 °C, lithium aluminum hydride (50 mg, 1.32 mmol) was slowly added to an anhydrous tetrahydrofuran (5 mL) solution of methyl 7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-carboxylate (300 mg, 0.88 mmol). The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (220 mg, yield 79.9%). LC / MS (ESI) m / z: 295 [M+H-18] + .

[0369] Step 6: 7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-carboxaldehyde

[0370] Under ice-water bath conditions, Dysmart reagent (598 mg, 1.41 mmol) was added fractionally to a solution of (7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-yl)methanol (220 mg, 0.70 mmol) in anhydrous dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-20% methanol) to give the title compound (550 mg, yield 91.2%). LC / MS (ESI) m / z: 311 [M+H] + .

[0371] Step 7: 7-(1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2-(7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-yl)-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0372] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (43 mg, 0.33 mmol), triethylamine (163 mg, 1.61 mmol), and 4-(dimethylphosphoryl)benzaldehyde (100 mg, 0.32 mmol) were added to acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (72 mg, 0.26 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-20% methanol) to give the title compound (100 mg, yield 50.2%). LC / MS (ESI) m / z: 619 [M+H] + .

[0373] Step 8: 7-(5-(2,2-difluoropropyl)-6-oxo-4-(7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0374] Under nitrogen protection, hydrazine hydrate (45 mg, 0.72 mmol, 80% wt.) was added to a 2 mL acetic acid solution of 7-(1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2-(7-(trifluoromethoxy)-11H-dibenzo[b,e][1,4]dioxane-2-yl)-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (100 mg, 0.16 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was purified by preparative HPLC (10-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (15 mg, yield 15.2%). 1 H NMR (400MHz, CD3OD) δ7.34-7.16(m,3H),7.15-7.09(m,2H),7.04(d,J=2.3Hz,1H),6.99(d,J=7.9Hz,1H),6.92(d,J=9.0Hz,1H),6.88- 6.82(m,1H),6.09(s,1H),5.18-5.08(m,2H),4.31-4.12(m,1H),3.04-2.82(m,1H),1.66(t,J=18.8Hz,3H).LC / MS(ESI)m / z:615[M+H] + .

[0375] Example 38: 7-(5-(2,2-difluoropropyl)-4-(6,11-dihydrodibenzo[b,e]oxetane-8-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0376]

[0377] Step 1: 4-Bromo-2-(phenoxymethyl)benzoic acid

[0378] At room temperature, a 30% sodium methoxide methanol solution (6.6 mL, 35.6 mmol) was added to a solution of 5-bromophthalide (5 g, 23.5 mmol) and phenol (3.31 g, 35.2 mmol) in N-methylpyrrolidone (50 mL). The reaction mixture was stirred at 120 °C for 3 hours. After the reaction was complete and cooled to room temperature, the reaction solution was poured into a mixed solution of water (50 mL) and methanol (100 mL), and the pH was adjusted to 4–5 by adding 4 M hydrochloric acid. The mixture was filtered, and the filter cake was washed with a water / methanol mixture of 3:2. The crude product was dried under reduced pressure to obtain the crude product. The crude product was subjected to reversed-phase column chromatography (C10). 18 The title compound (1.45 g, 20.11% yield) was purified using water / acetonitrile (elution: 0-60% acetonitrile) as an eluent. LC / MS (ESI) m / z: 305 [MH] - .

[0379] Step 2: 8-Bromodibenzo[b,e]oxetane-11(6H)-one

[0380] Under nitrogen protection at 0 °C, trifluoroacetic anhydride (1.2 mL, 8.63 mmol) and boron trifluoride diethyl ether (0.1 mL, 0.79 mmol) were slowly added sequentially to a solution of 4-bromo-2-(phenoxymethyl)benzoic acid (1.45 g, 4.72 mmol) in n-heptane (30 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the mixture was quenched with ice water and extracted twice with ethyl acetate. The separated organic phase was washed sequentially with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-15% ethyl acetate) to give the title compound (1.18 g, 86.5% yield). LC / MS (ESI) m / z: 289 [M+H] + .

[0381] Step 3: 8-Bromo-6,11-dihydrodibenzo[b,e]oxetane

[0382] Under nitrogen protection, triethylsilane (12 mL, 75.1 mmol) and boron trifluoride diethyl ether (4 mL, 31.7 mmol) were added dropwise to anhydrous dichloromethane (10 mL) containing 930 mg, 3.22 mmol of 8-bromodibenzo[b,e]oxetane-11(6H)-one. The reaction mixture was stirred at 40 °C for 16 h. After the reaction was complete, the mixture was quenched with water and extracted twice with ethyl acetate. The separated organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-5% ethyl acetate) to give the title compound (780 mg, yield 88.1%).

[0383] Step 4: Methyl 6,11-dihydrodibenzo[b,e]oxetane-8-carboxylic acid

[0384] Under nitrogen protection, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (207 mg, 0.28 mmol) was added to a mixed solution of 8-bromo-6,11-dihydrodibenzo[b,e]oxetane (780 mg, 2.83 mmol) in methanol (60 mL) and triethylamine (20 mL). The reaction mixture was purged with nitrogen three times and stirred at 90 °C for 16 hours under carbon monoxide at 1 atm. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (90 mg, yield 12.7%).

[0385] Step 5: (6,11-dihydrodibenzo[b,e]oxetane-8-yl)methanol

[0386] Under nitrogen protection at 0 °C, lithium aluminum hydride (40 mg, 1.05 mmol) was slowly added in portions to anhydrous tetrahydrofuran (10 mL) of methyl 6,11-dihydrodibenzo[b,e]oxetane-8-carboxylate (90 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added to quench the reaction, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (70 mg, yield 87.4%). The crude product was used directly in the next step without purification. LC / MS (ESI) m / z: 209 [M+H-18] + .

[0387] Step 6: 6,11-Dihydrodibenzo[b,e]oxetane-8-carboxaldehyde

[0388] Under nitrogen protection at 0 °C, Desmartin reagent (197 mg, 0.46 mmol) was added in portions to a solution of (6,11-dihydrodibenzo[b,e]oxetane-8-yl)methanol (70 mg, 0.31 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (50 mg, yield 72.1%).

[0389] Step 7: 7-(1-(2,2-difluoropropyl)-2-(6,11-dihydrodibenzo[b,e]oxetane-8-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0390] At room temperature, 2,2-difluoropropylamine hydrochloride (29 mg, 0.22 mmol), triethylamine (0.10 mL, 0.75 mmol), and 6,11-dihydrodibenzo[b,e]oxetane-8-carboxaldehyde (50 mg, 0.22 mmol) were added to a solution of acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (52 mg, 0.19 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-15% methanol) to give the title compound (27 mg, yield 27.0%). LC / MS (ESI) m / z: 533 [M+H] + .

[0391] Step 8: 7-(5-(2,2-difluoropropyl)-4-(6,11-dihydrodibenzo[b,e]oxetane-8-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0392] To a solution of 7-(1-(2,2-difluoropropyl)-2-(6,11-dihydrodibenzo[b,e]oxetane-8-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (27 mg, 0.05 mmol) in acetic acid (2 mL), hydrazine hydrate (20 mg, 0.26 mmol, 80% wt.) was added. The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (6.29 mg, yield 23.5%). 1 H NMR (400MHz, DMSO-d6) δ14.20 (s, 1H), 7.27 (dd, J = 15.2, 7.8Hz, 2H), 7.17- 7.12(m,1H),7.12-7.07(m,2H),7.07-7.02(m,2H),7.01-6.96(m,1H),6.8 3-6.77(m,1H),6.70-6.66(m,1H),5.98(s,1H),5.18(s,2H),4.24-4.08(m ,3H),2.81-2.72(m,1H),1.63(t,J=19.2Hz,3H).LC / MS(ESI)m / z:529[M+H] + .

[0393] Example 39: 7-(4-(11H-dibenzo[b,f][1,4]oxothiophene-2-yl)-5-(2,2-difluoro)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0394]

[0395] Step 1: Methyl 4-fluoro-3-((2-hydroxyphenyl)thio)methyl)benzoate

[0396] Under nitrogen protection at room temperature, potassium bicarbonate (506 mg, 5.05 mmol) was added to an anhydrous N,N-dimethylformamide (5 mL) solution of 2-hydroxythiophenol (607 mg, 4.81 mmol), followed by the slow dropwise addition of an anhydrous N,N-dimethylformamide (5 mL) solution of methyl 3-(bromomethyl)-4-fluorobenzoate (1.2 g, 4.86 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (1.3 g, yield 92.4%). LC / MS (ESI) m / z: 293 [M+H] + .

[0397] Step 2: 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxylic acid methyl ester

[0398] At room temperature, cesium carbonate (2.17 g, 6.67 mmol) was added to an anhydrous dimethyl sulfoxide (20 mL) solution of methyl 4-fluoro-3-((2-hydroxyphenyl)thio)methyl)benzoate (1.3 g, 4.45 mmol). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (990 mg, yield 81.8%).

[0399] Step 3: (11H-dibenzo[b,f][1,4]oxathiophen-2-yl)methanol

[0400] Under nitrogen protection at 0 °C, lithium aluminum hydride (56 mg, 1.48 mmol) was slowly added in portions to anhydrous tetrahydrofuran (5 mL) containing methyl 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxylate (200 mg, 0.73 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added to quench the reaction, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (150 mg, yield 83.6%). The product was used directly in the next reaction without purification. LC / MS (ESI) m / z: 227 [M+H-18] + .

[0401] Step 4: 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxaldehyde

[0402] Under nitrogen protection at 0 °C, Dysmartin reagent (391 mg, 0.92 mmol) was added fractionally to a solution of (11H-dibenzo[b,f][1,4]oxathiophene-2-yl)methanol (150 mg, 0.61 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, the filtrate was quenched with saturated sodium bicarbonate solution, and extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-30% ethyl acetate) to give the title compound (80 mg, yield 53.8%). LC / MS (ESI) m / z: 243 [M+H] + .

[0403] Step 5: 7-(2-(11H-dibenzo[b,f][1,4]oxothiophene-2-yl)-1-(2,2-difluoro)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0404] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (43 mg, 0.33 mmol), triethylamine (0.20 mL, 1.44 mmol), and 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxaldehyde (80 mg, 0.33 mmol) were added to acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (75 mg, 0.27 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-15% methanol) to give the title compound (27 mg, yield 18.1%). LC / MS (ESI) m / z: 551 [M+H] + .

[0405] Step 6: 7-(4-(11H-dibenzo[b,f][1,4]oxothiophene-2-yl)-5-(2,2-difluoro)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0406] At room temperature, hydrazine hydrate (20 mg, 0.26 mmol, 80% wt.) was added to a 2 mL acetic acid solution of 7-(2-(11H-dibenzo[b,f][1,4]oxothiophene-2-yl)-1-(2,2-difluoro)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (27 mg, 0.05 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (11.20 mg, yield 41.8%). 1 H NMR (400MHz, DMSO-d6) δ14.21(s,1H),11.68(s,1H),7.26(d,J=7.9Hz,1H),7.23-7.18(m,2H),7.15(d,J=12.2Hz,2H),7.12-7.04(m,2H),7.0 3-6.95(m,3H),5.97(s,1H),4.35(d,J=13.6Hz,1H),4.24-4.10(m,2H),2.87-2.76(m,1H),1.64(t,J=19.2Hz,3H).LC / MS(ESI)m / z:547[M+H] + .

[0407] Example 40: 7-(5-(2,2-difluoropropyl)-4-(10,10-dioxa-11H-dibenzo[b,f][1,4]oxothiophene-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0408]

[0409] Step 1: 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxylic acid methyl ester 10,10-dioxide

[0410] To a solution of methyl 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxylate (300 mg, 1.10 mmol) in acetic acid (6 mL), 30% hydrogen peroxide (2 mL, 1.10 mmol) was added. The reaction mixture was stirred at 110 °C for 1 hour. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-40% ethyl acetate) to give the title compound (310 mg, 92.5% yield).

[0411] Step 2: 2-(hydroxymethyl)-11H-dibenzo[b,f][1,4]oxathiophene 10,10-dioxide

[0412] Under nitrogen protection at 0 °C, lithium aluminum hydride (58 mg, 1.53 mmol) was slowly added in portions to an anhydrous tetrahydrofuran (5 mL) solution of methyl 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxylate 10,10-dioxide (310 mg, 1.02 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added to quench the reaction, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (250 mg, 88.8% yield). The product was directly used for the next step without purification. LC / MS (ESI) m / z: 259 [M+H-18] + .

[0413] Step 3: 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxaldehyde 10,10-dioxide

[0414] Under nitrogen protection at 0 °C, Dysmartin reagent (576 mg, 1.36 mmol) was added fractionally to a solution of 2-(hydroxymethyl)-11H-dibenzo[b,f][1,4]oxathiophene 10,10-dioxide (250 mg, 0.90 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, the filtrate was quenched with saturated sodium bicarbonate solution, and extracted twice with dichloromethane. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-40% ethyl acetate) to give the title compound (160 mg, yield 64.5%). LC / MS (ESI) m / z: 275 [M+H] + .

[0415] Step 4: 7-(1-(2,2-difluoropropyl)-2-(10,10-dioxa-11H-dibenzo[b,f][1,4]oxothiophene-2-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0416] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (49 mg, 0.37 mmol), triethylamine (0.20 mL, 1.44 mmol), and 11H-dibenzo[b,f][1,4]oxathiophene-2-carboxaldehyde 10,10-dioxide (100 mg, 0.36 mmol) were added to acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (84 mg, 0.30 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-15% methanol) to give the title compound (53 mg, yield 30.0%). LC / MS (ESI) m / z: 581 [MH] - .

[0417] Step 5: 7-(5-(2,2-difluoropropyl)-4-(10,10-dioxa-11H-dibenzo[b,f][1,4]oxothiophene-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0418] At room temperature, hydrazine hydrate (36 mg, 0.46 mmol, 80% wt.) was added to a 2 mL acetic acid solution of 7-(1-(2,2-difluoropropyl)-2-(10,10-dioxa-11H-dibenzo[b,f][1,4]oxothiophene-2-yl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (53 mg, 0.09 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (29.62 mg, yield 56.3%). 1H NMR (400MHz, DMSO-d6) δ14.25 (s, 1H), 11.68 (s, 1H), 7.76 (dd, J = 8.0, 1.3Hz, 1H), 7.67- 7.61(m,1H),7.47(d,J=8.2Hz,1H),7.42-7.34(m,3H),7.30-7.22(m,2H),7.13-7.06(m, 1H),7.00(d,J=7.7Hz,1H),6.01(s,1H),5.12(d,J=14.6Hz,1H),4.95(d,J=14.6Hz,1H), 4.26-4.10(m,1H),2.84-2.72(m,1H),1.63(t,J=19.2Hz,3H).LC / MS(ESI)m / z:579[M+H] + .

[0419] Example 41: 7-(4-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-fluorobenzo[d]oxazol-2(3H)-one

[0420]

[0421] Step 1: 1-(4-fluoro-2-hydroxy-3-nitrophenyl)ethyl-1-one

[0422] At 0 °C, concentrated nitric acid (1.8 mL, 32.44 mmol) was slowly added dropwise to a solution of 1-(4-fluoro-2-hydroxyphenyl)ethyl-1-one (5 g, 32.44 mmol) in 25 mL of concentrated sulfuric acid. The reaction mixture was stirred at 0 °C for 0.5 h. After the reaction was complete, the reaction mixture was poured into ice water and extracted twice with ethyl acetate. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (1.7 g, yield 26.3%). LC / MS (ESI) m / z: 200 [M+H] + .

[0423] Step 2: 1-(3-amino-4-fluoro-2-hydroxyphenyl)ethyl-1-one

[0424] Under nitrogen protection at 0 °C, acetic acid (35 mL) and zinc powder (2.2 g, 33.6 mmol) were added to a solution of 1-(4-fluoro-2-hydroxy-3-nitrophenyl)ethyl-1-one (1.7 g, 8.54 mmol) in anhydrous methanol (137 mL). The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, ethyl acetate and water were added, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (1.1 g, yield 76.2%). LC / MS (ESI) m / z: 170 [M+H] + .

[0425] Step 3: 7-Acetyl-4-fluorobenzo[d]oxazol-2(3H)-one

[0426] Under nitrogen protection at room temperature, N,N'-carbonyldiimidazole (1.48 g, 9.10 mmol) was added to an anhydrous tetrahydrofuran (11 mL) solution of 1-(3-amino-4-fluoro-2-hydroxyphenyl)ethyl-1-one (1.1 g, 6.50 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, ice water was slowly added to the reaction mixture, and the mixture was filtered. The filter cake was washed twice with acetonitrile and dried under reduced pressure to give the title compound (750 mg, yield 59.1%). LC / MS (ESI) m / z: 196 [M+H] + .

[0427] Step 4: Ethyl 4-(4-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-2,4-dioxobutyrate

[0428] Under nitrogen protection, a 1M solution of potassium tert-butoxide in tetrahydrofuran (2 mL, 2 mmol) was added dropwise to anhydrous tetrahydrofuran (4 mL) containing 200 mg (1.02 mmol) of 7-acetyl-4-fluorobenzo[d]oxazol-2(3H)-one and diethyl oxalate (180 mg, 1.23 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into 10 mL of 1M dilute hydrochloric acid at 0 °C and extracted twice with tetrahydrofuran. The separated organic phase was concentrated under reduced pressure until a small amount of solid precipitated, heated at 65 °C until the solid was completely dissolved, cooled, and water was added to the mixture until the solid precipitated. The mixture was filtered, the filter cake was washed with a mixture of tetrahydrofuran and water (2:1), and dried under reduced pressure to give the title compound (200 mg, yield 66.1%). LC / MS (ESI) m / z: 296 [M+H] + .

[0429] Step 5: 7-(2-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-4-fluorobenzo[d]oxazol-2(3H)-one

[0430] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (37 mg, 0.28 mmol), triethylamine (0.16 mL, 1.19 mmol), and 11H-dibenzo[b,e][1,4]dioxane-8-carboxaldehyde (64 mg, 0.28 mmol) were added to acetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, ethyl 4-(4-fluoro-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-2,4-dioxobutyrate (70 mg, 0.24 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to give the title compound (60 mg, yield 45.8%). LC / MS (ESI) m / z: 553 [M+H] + .

[0431] Step 6: 7-(4-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-fluorobenzo[d]oxazol-2(3H)-one

[0432] Under nitrogen protection, hydrazine hydrate (20 mg, 0.33 mmol, 80% wt.) was added to a 1 mL acetic acid solution of 7-(2-(11H-dibenzo[b,e][1,4]dioxane-2-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-4-fluorobenzo[d]oxazol-2(3H)-one (60 mg, 0.11 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% FA) to give the title compound (11.6 mg, yield 19.5%). 1H NMR (400MHz, DMSO-d6) δ14.18(s,1H),12.38(s,1H),7.31-7.18(m,2H),7.17-7.09(m,3H),7.05(t,J=9.3Hz,1H),6.97-6.8 6(m,3H),5.98(s,1H),5.14(s,2H),4.28-4.04(m,1H),2.91-2.75(m,1H),1.64(t,J=19.2Hz,3H).LC / MS(ESI)m / z:549[M+H] + .

[0433] Example 42: 7-(5-(2,2-difluoropropyl)-4-(9-(dimethylphosphoryl)-11H-dibenzo[b,e][1,4]dioxane-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0434]

[0435] Step 1: Methyl 3-((2-bromo-6-hydroxyphenoxy)methyl)-4-fluorobenzoate

[0436] At room temperature, potassium carbonate (2.52 g, 18.21 mmol) and methyl 3-(bromomethyl)-4-fluorobenzoate (3 g, 12.14 mmol) in anhydrous N,N-dimethylformamide (30 mL) were added to a solution of 3-bromocatechol (2.30 g, 12.14 mmol) in anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture, and the ethyl acetate phase was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, respectively, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-10% ethyl acetate) to give the title compound (2.4 g, 56% yield). LC / MS (ESI) m / z: 353.1 [MH] - .

[0437] Step 2: 9-Bromo-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid methyl ester

[0438] At room temperature, cesium carbonate (4.40 g, 13.52 mmol) was added to a solution of methyl 3-((2-bromo-6-hydroxyphenoxy)methyl)-4-fluorobenzoate (2.4 g, 6.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The ethyl acetate phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, respectively, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-3% ethyl acetate) to give the title compound (1.9 g, 84% yield). 1 H NMR (400MHz, CDCl3) δ8.02 (dd, J=8.4, 2.1Hz, 1H), 7.96 (d, J=1.9Hz, 1H), 7.29-7.2 2(m,2H),7.15(dd,J=8.2,1.5Hz,1H),6.85-6.80(m,1H),5.33(s,2H),3.92(s,3H).

[0439] Step 3: 9-(dimethylphosphoryl)-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid methyl ester

[0440] Under nitrogen protection at room temperature, dimethylphosphine oxide (205 mg, 2.63 mmol), tris(dibenzylacetone)dipalladium (120 mg, 0.13 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (76 mg, 0.13 mmol), and triethylamine (0.9 mL, 6.56 mmol) were added sequentially to an anhydrous N,N-dimethylformamide (5 mL) solution of methyl 9-bromo-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid ester (440 mg, 1.31 mmol) and triethylamine (0.9 mL, 6.56 mmol). The reaction solution was purged with nitrogen three times, and the reaction was stirred at 100 °C for 10 hours under nitrogen protection. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol gradient: 0-10% methanol) to give the title compound (300 mg, yield 68.8%). LC / MS (ESI) m / z: 333 [M+H] + .

[0441] Step 4: (2-(hydroxymethyl)-11H-dibenzo[b,e][1,4]dioxane-9-yl)dimethylphosphine oxide

[0442] Under nitrogen protection at 0 °C, a solution of lithium borohydride in tetrahydrofuran (0.9 mL, 3.61 mmol, 4 M) was slowly added dropwise to an anhydrous tetrahydrofuran solution of methyl 9-(dimethylphosphoryl)-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid ester (300 mg, 0.90 mmol) in 5 mL. The reaction mixture was stirred at 80 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (240 mg, 87.4% yield). The crude product was used directly in the next reaction. LC / MS (ESI) m / z: 287 [M+H-18] + .

[0443] Step 5: 9-(dimethylphosphoryl)-11H-dibenzo[b,e][1,4]dioxane-2-carboxaldehyde

[0444] Under nitrogen protection at 0 °C, Dysmart reagent (502 mg, 1.18 mmol) was added fractionally to a solution of (2-(hydroxymethyl)-11H-dibenzo[b,e][1,4]dioxane-9-yl)dimethylphosphine oxide (240 mg, 0.79 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol gradient: 0-8% methanol) to give the title compound (200 mg, 83.9% yield). LC / MS (ESI) m / z: 303 [M+H] + .

[0445] Step 6: 1-(2,2-difluoropropyl)-5-(8-(dimethylphosphoryl)-11H-dibenzo[b,e][1,4]dioxane-2-yl)-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)pyrrolidine-2,3-dione

[0446] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (48 mg, 0.36 mmol), triethylamine (184 mg, 1.82 mmol), and 9-(dimethylphosphoryl)-11H-dibenzo[b,e][1,4]dioxane-2-carboxaldehyde (110 mg, 0.36 mmol) were added to acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (81 mg, 0.29 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the acetic acid was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-20% methanol) to give the title compound (100 mg, yield 44.9%). LC / MS(ESI) m / z: 611 [M+H] + .

[0447] Step 7: 7-(5-(2,2-difluoropropyl)-4-(9-(dimethylphosphoryl)-11H-dibenzo[b,e][1,4]dioxane-2-yl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0448] At room temperature, hydrazine hydrate (51 mg, 0.82 mmol, 80% wt.) was added to acetic acid (2 mL) containing 1-(2,2-difluoropropyl)-5-(8-(dimethylphosphoryl)-11H-dibenzo[b,e][1,4]dioxane-2-yl)-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)pyrrolidine-2,3-dione (100 mg, 0.16 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile aqueous solution containing 0.1% FA) to give the title compound (15 mg, yield 15.1%). 1 H NMR (400MHz, CD3OD) δ7.49-7.43(m,1H),7.41-7.35(m,1H),7.33-6.93(m,7H),6.12(s,1H),5.30(dd,J=37.8,12.8Hz,2H ),4.36-4.13(m,1H),3.04-2.90(m,1H),1.76(dd,J=13.9,7.0Hz,6H),1.68(t,J=18.8Hz,3H).LC / MS(ESI)m / z:607[M+H] + .

[0449] The compounds in the examples in Table 3 were synthesized using commercially available raw materials following the synthesis steps of Example 42.

[0450] Table 3:

[0451]

[0452] Example 44: 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-7-nitrile

[0453]

[0454] Step 1: 7-Cyano-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid methyl ester

[0455] Under nitrogen protection, 1,3-bis-(2,6-diisopropylphenyl)imidazoline chloride (213 mg, 0.5 mmol), palladium acetate (112 mg, 0.5 mmol), sodium carbonate (530 mg, 5.0 mmol), and tetrapotassium hexacyanoferrate trihydrate (528 mg, 1.25 mmol) were added sequentially to an anhydrous N,N-dimethylacetamide (5 mL) solution of methyl 7-bromo-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-2-carboxylic acid ester (350 mg, 1.0 mmol) and ferric hexacyanocyanate trihydrate (528 mg, 1.25 mmol) to the reaction mixture. After purging the reaction system three times with nitrogen, the reaction mixture was heated to 120 °C and stirred overnight under nitrogen protection. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to give the title compound (153 mg, yield 50.6%). LC / MS (ESI) m / z: 300 [M+H] + .

[0456] Step 2: 6-Fluoro-2-(hydroxymethyl)-11H-dibenzo[b,e][1,4]dioxane-7-nitrile

[0457] Under nitrogen protection, lithium aluminum hydride (124 mg, 3.28 mmol) was slowly added at 0°C to an anhydrous tetrahydrofuran (3 mL) solution of methyl 7-cyano-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-2-carboxylate (150 mg, 0.5 mmol) of methyl 7-cyano-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-2-carboxylate (150 mg, 0.5 mmol). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, water was added sequentially, followed by quenching with an aqueous sodium hydroxide solution. Ethyl acetate was added, and the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-60% ethyl acetate) to give the title compound (120 mg, 88.8% yield). LC / MS (ESI) m / z: 272 [M+H] + .

[0458] Step 3: 6-Fluoro-2-formyl-11H-dibenzo[b,e][1,4]dioxane-7-nitrile

[0459] Under nitrogen protection, Dysmart reagent (424 mg, 1.0 mmol) was added in portions to a solution of 6-fluoro-2-(hydroxymethyl)-11H-dibenzo[b,e][1,4]dioxane-7-nitrile (120 mg, 0.44 mmol) in anhydrous dichloromethane (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate solution, and dichloromethane was added. The dichloromethane phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-45% ethyl acetate) to give the title compound (105 mg, yield 87.5%).

[0460] Step 4: 2-(1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)-2,5-dihydro-1H-pyrrole-2-yl)-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-7-nitrile

[0461] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (136 mg, 1.14 mmol), triethylamine (418 mg, 4.1 mmol), and 6-fluoro-2-formyl-11H-dibenzo[b,e][1,4]dioxane-7-nitrile (105 mg, 0.38 mmol) were added to a reaction flask containing acetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (111 mg, 0.4 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-15% methanol) to give the title compound (100 mg, yield 54.5%). LC / MS(ESI) m / z: 577 [M+H] + .

[0462] Step 5: 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-7-nitrile

[0463] Under nitrogen protection, hydrazine hydrate (45 mg, 0.72 mmol, 80% wt) was added to a acetic acid (1 mL) solution of 2-(1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-carbonyl)-2,5-dihydro-1H-pyrrole-2-yl)-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-7-nitrile (40 mg, 0.07 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (4.54 mg, yield 11.3%). 1 H NMR (400MHz, CD3OD) δ7.37-7.16(m,5H),7.12(t,J=7.9Hz,1H),6.99(d,J=7.8Hz,1H),6.76(dd,J=8.9,1.7Hz,1H),6.11( s,1H),5.31(s,2H),4.21(dd,J=33.0,15.3Hz,1H),2.99-2.87(m,1H),1.65(t,J=18.8Hz,3H).LC / MS(ESI)m / z:574[M+H] + .

[0464] Example 45: 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-7-carboxamide

[0465]

[0466] Step 1: 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-7-carboxamide

[0467] At room temperature, potassium carbonate (67.5 mg, 0.5 mmol) and hydrogen peroxide (0.2 mL, 30%) were added sequentially to an anhydrous N,N-dimethylformamide (2 mL) solution of 2-(5-(2,2-difluoropropyl)-6-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)-6-fluoro-11H-dibenzo[b,e][1,4]dioxane-7-onitrile (80 mg, 0.14 mmol) and 2 mL of hydrogen peroxide. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC (20-95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the title compound (4.54 mg, yield 11.3%). 1 H NMR (400MHz, CD3OD) δ7.37-7.32(m,1H),7.31-7.14(m,4H),7.11(t,J=7.7Hz,1H),6.99(s,1H),6.68(dd,J=9.0,1.7Hz, 1H),6.10(s,1H),5.25(s,2H),4.34-4.08(m,1H),3.02-2.85(m,1H),1.65(t,J=18.8Hz,3H).LC / MS(ESI)m / z:592[M+H] + .

[0468] Example 46: 7-(4-(6H-benzo[6,7][1,4]dioxaneheptano[2,3-b]pyridin-8-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0469]

[0470] Step 1: Methyl 4-hydroxy-3-hydroxymethylbenzoate

[0471] Under nitrogen protection, sodium borohydride (2.5 g, 65.8 mmol) was slowly added to methyl 3-formyl-4-hydroxybenzoate (6 g, 33.3 mmol) in methanol (60 mL) at 0 °C. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (4.1 g, yield 67.6%). LC / MS (ESI) m / z: 183 [M+H] + .

[0472] Step 2: Methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxybenzoate

[0473] Under nitrogen protection, imidazole (1.49 g, 22.0 mmol) and tert-butyldimethylchlorosilane (3.31 g, 22.0 mmol) were slowly added to a solution of methyl 4-hydroxy-3-hydroxymethylbenzoate (4 g, 22.0 mmol) in dichloromethane (100 mL) at 0 °C. The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-100% ethyl acetate) to give the title compound (2.2 g, yield 33.8%). LC / MS (ESI) m / z: 295 [MH] - .

[0474] Step 3: Methyl 4-((3-bromopyridin-2-yl)oxy)-3-((tert-butyldimethylsilyl)oxy)methyl)benzoate

[0475] Under nitrogen protection, 3-bromo-2-iodopyridine (1.92 g, 6.75 mmol), N,N-dimethylglycine (210 mg, 2.02 mmol), cesium carbonate (4.4 g, 13.5 mmol), and cuprous iodide (130 mg, 0.67 mmol) were added to a solution of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxybenzoate (2 g, 6.75 mmol) in 1,4-dioxane (30 mL). The reaction mixture was purged with nitrogen three times, and the mixture was stirred overnight at 90 °C under nitrogen protection. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (1.2 g, yield 39.3%). LC / MS(ESI) m / z: 452 [M+H] + .

[0476] Step 4: Methyl 4-((3-bromopyridin-2-yl)oxy)-3-(hydroxymethyl)benzoate

[0477] At room temperature, water (5 mL) and acetic acid (5 mL) were slowly added to a tetrahydrofuran (10 mL) solution of methyl 4-((3-bromopyridin-2-yl)oxy)-3-((tert-butyldimethylsilyl)oxy)methyl)benzoate (1.2 g, 2.65 mmol) at 0 °C. The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-100% ethyl acetate) to give the title compound (450 mg, yield 50.2%). LC / MS (ESI) m / z: 338 [M+H] + .

[0478] Step 5: 6H-benzo[6,7][1,4]dioxane-heptano[2,3-b]pyridine-8-carboxylic acid methyl ester

[0479] Under nitrogen protection, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (120 mg, 0.21 mmol), cesium carbonate (674 mg, 2.07 mmol), and palladium acetate (23 mg, 0.10 mmol) were added to a solution of methyl 4-((3-bromopyridin-2-yl)oxy)-3-(hydroxymethyl)benzoate (350 mg, 1.04 mmol) in 1,4-dioxane (15 mL). The reaction mixture was purged with nitrogen three times, and the mixture was stirred overnight at 100 °C under nitrogen protection. After the reaction was complete, ethyl acetate and water were added, the ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (100 mg, yield 37.6%). LC / MS (ESI) m / z: 258 [M+H] + .

[0480] Step 6: (6H-benzo[6,7][1,4]dioxane-heptano[2,3-b]pyridin-8-yl)methanol

[0481] Under nitrogen protection, lithium aluminum hydride (30 mg, 0.78 mmol) was slowly added to an anhydrous tetrahydrofuran (3 mL) solution of methyl 6H-benzo[6,7][1,4]dioxane-heptano[2,3-b]pyridine-8-carboxylate (100 mg, 0.39 mmol) at 0 °C. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, water was added sequentially, the mixture was quenched with an aqueous sodium hydroxide solution, and ethyl acetate was added. The ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (80 mg, 89.8% yield). LC / MS (ESI) m / z: 230 [M+H] + .

[0482] Step 7: 6H-benzo[6,7][1,4]dioxane-heptano[2,3-b]pyridine-8-carboxaldehyde

[0483] Under nitrogen protection, a solution of (6H-benzo[6,7][1,4]dioxane-heptano[2,3-b]pyridin-8-yl)methanol (80 mg, 0.35 mmol) in anhydrous dichloromethane (3 mL) was added at 0 °C with Dysmartin reagent (296 mg, 0.70 mmol). The reaction was carried out at room temperature for 1 hour. After the reaction was complete, the solution was quenched with saturated sodium bicarbonate solution, and dichloromethane was added. The dichloromethane phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (65 mg, yield 82.0%). LC / MS (ESI) m / z: 228 [M+H] + .

[0484] Step 8: 7-(2-(6H-benzo[6,7][1,4]dioxane-heptano[2,3-b]pyridin-8-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one

[0485] Under nitrogen protection, 2,2-difluoropropylamine hydrochloride (35 mg, 0.26 mmol), triethylamine (133 mg, 1.32 mmol), and 2-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxaldehyde (60 mg, 0.26 mmol) were added to a reaction flask containing acetic acid (2 mL), and the reaction was carried out at room temperature for 1 hour. Then, ethyl 2,4-dioxo-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)butyrate (73 mg, 0.26 mmol) was added, and the reaction was carried out at 100 °C for 1 hour. After the reaction was complete, the acetic acid was removed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-20% methanol) to give the title compound (80 mg, yield 56.6%). LC / MS (ESI) m / z: 536 [M+H] + .

[0486] Step 9: 7-(4-(6H-benzo[6,7][1,4]dioxaneheptano[2,3-b]pyridin-8-yl)-5-(2,2-difluoropropyl)-6-oxo-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)benzo[d]oxazol-2(3H)-one

[0487] Under nitrogen protection, hydrazine hydrate (45 mg, 0.72 mmol, 80% wt) was added to a 2 mL acetic acid solution of 7-(2-(6H-benzo[6,7][1,4]dioxane-heptano[2,3-b]pyridin-8-yl)-1-(2,2-difluoropropyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)benzo[d]oxazol-2(3H)-one (80 mg, 0.15 mmol). The reaction mixture was stirred at 120 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was purified by preparative HPLC (10-95% acetonitrile in H2O solution and 0.1% FA) to give the title compound (12 mg, yield 15.1%). 1 H NMR (400MHz, CD3OD) δ7.82 (dd, J=4.7, 1.6Hz, 1H), 7.37 (dd, J=7.9, 1.6Hz, 1H), 7.31-7.16 (m, 4H), 7.15-7.06 (m, 2H), 7.04-6.95 (m,1H),6.11(s,1H),5.21-5.10(m,2H),4.32-4.12(m,1H),3.02-2.86(m,1H),1.66(t,J=18.8Hz,3H).LC / MS(ESI)m / z:532[M+H] + .

[0488] Effect Example

[0489] Experimental methods:

[0490] 1. Biochemical experiments: Detecting the inhibitory effect of compounds on the biochemical activity of PTDSS1 protein.

[0491] The PTDSS1 protein catalyzes the exchange of L-serine using PC as a substrate to generate PS, while simultaneously releasing choline. Choline, catalyzed by choline oxidase, produces hydrogen peroxide, which reacts 1:1 with Amplex Red dye to produce a strong red fluorescent substance that can be quantitatively detected by a microplate reader (excitation wavelength 540 nm, absorption wavelength 590 nM). A PTDSS1 plasmid with an N-terminal Flag and His tag and a C-terminal HA tag was constructed. PTDSS1 protein was expressed using an insect expression system. Membrane fractions were collected to obtain a stock solution (20 mM Tris / HCl, 20% Glycerol, 1 mM TCEP, pH 7.8) with a protein concentration of 34.520 mg / mL for detection.

[0492] The specific testing methods are as follows:

[0493] 1) The reaction buffer contains 50 mM HEPES / NaOH (pH = 7.5) and 5 mM CaCl2;

[0494] 2) Add 25 μL of PTDSS1 membrane fraction diluted with reaction buffer to a 384-well plate, bringing the final protein concentration to 0.05 mg / mL; 2) Add the test compound solution using an autopilot and incubate at room temperature for 2 h; 3) Add 5 μL of 6× choline oxidase solution (0.1 U / mL) to each well of the 384-well plate and incubate at room temperature for 2 h; 4) After the reaction, add 20 μL of 2.5× HRP / Amplex Red reagent (0.2 U / mL and 100 μM, respectively) and incubate at room temperature for 10 min; 5) Analyze the data obtained from the microplate reader to explore the inhibitory effect of the compound on the enzyme activity of PTDSS1 protein.

[0495] Data analysis was performed on the measurement results: the CV% of the control group should be less than 10%, and the z' value should be greater than 0.5. Using data meeting the above quality control requirements, the inhibition rate of the compound on the biochemical activity of PTDSS1 protein was calculated (inhibition rate (%) = 100 × (control group average - experimental group) / (control group average - blank group average). A nonlinear regression was used to fit the inhibition rate curve of the compound and the IC50 was obtained. 50 value.

[0496] 2. DLD1wt (DLD1 wild type) and DLD1-PTDSS2- / - Cell proliferation inhibition experiment (for colon cancer cell lines with PTDSS2 deficiency)

[0497] The in vitro efficacy of the inhibitor was assessed using a cell viability assay, specifically the commonly used CTG assay, with CellTiter Glo reagent (Promega, G7573). The specific assay method is as follows:

[0498] 1) Cultivate DLD1wt, DLD1-PTDSS2 - / - Cells were digested with trypsin (0.025% Trypsin-EDTA, Hyclone) one day before the assay, centrifuged at 1000 rpm for 3 min, and collected. Cells were counted using a cell counter (Shanghai Mengwei Biomedical Technology Co., Ltd., SmartCell600A.SC1006) and seeded into 384-well cell culture plates (UniVision, 6007680) at an appropriate seeding ratio.

[0499] 2) Drug treatment was performed 24 hours after cell seeding, which was recorded as Day 0. The compound was added using an automated pipette (Thermo, Multidrop 8). The plate was set as a 384-well plate, with initial concentrations of 10 μM and 3 μM, diluted by 1 / 3 ratio, and a total of 9 detection points were set, with 2 replicates per group. The cells were incubated at 37℃ in a 5% CO2 incubator.

[0500] 3) On Day 3, remove the cell culture plate and add an equal volume of CTG reagent (the CTG reagent needs to be brought back to temperature and premixed according to the reagent instructions). Gently mix for 10 minutes (speed 300) on a constant temperature mixer (Hangzhou Aosheng Instrument Co., Ltd., MSC-100). Perform chemiluminescence detection using an ELISA reader (Thermo, Varioskan LUX).

[0501] 4) Data analysis of the measurement results: The CV% of the control group should be less than 30%, and the z' value should be greater than 0.5. Data meeting the above quality control results were used to calculate cell viability (inhibition rate (%) = 100 × (control group average - experimental group) / (control group average - culture medium control group average). GraphPad Prism8 was used to perform nonlinear regression fitting of the compound's inhibition rate curve and derive the IC50. 50 value.

[0502] Testing showed that the compounds in the embodiments of this application are effective against DLD1-PTDSS2. - / - The cells showed strong inhibitory effects on proliferation, but very weak inhibitory effects on DLD1 wild-type cells, indicating that the compounds in the examples of this application have good selectivity in inhibiting the proliferation of the two cell types.

[0503] Data list:

[0504] NT = Not detected;

[0505] Table 3: Specific data from biochemical experiments and cell viability detection experiments:

[0506]

[0507]

Claims

1. A compound as shown in Formula I or a pharmaceutically acceptable salt thereof: in, X 1 X 2 X 3 X 4 X 5 and X 6 Independently CH, CR RR Or N; R 1 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 replace; Each R 1-1 Independently, H, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein C 3-6 The cycloalkyl group, the 3-6 membered heterocycloalkyl group, the phenyl group, and the 5-6 membered heteroaryl group may independently and optionally be surrounded by 1, 2, or 3 R groups. RR replace; L 1 and L 2 Independently, it can be a connecting key or -(CH2). m -, m is 1, 2, 3, 4 or 5, -(CH2) m Any one or two -CH2- can be optionally replaced by -O-, -S-, -S(=O)2-, or -NR. 3 -、-CR 4 R 5 One or two substitutions in - and -C(=O)-; R 3 R 4 and R 5 Independently H, deuterium, halogen or C 1-6 Alkyl, and R 4 and R 5 Not both H or R 4 and R 5 Together with the C connected to it, they form C 3-6 cycloalkanes; the C 1-6 Alkyl groups and the C 3-6 Cycloalkanes can be optionally surrounded by 1, 2, or 3 R groups. RR replace; Ring A is C 6-10 Aromatic rings, benzene rings, and fused carbon rings 3-6 Cycloalkanes, 5-6 membered heterocycles of benzene rings, 5-6 membered heteroene rings of benzene rings, 5-10 membered heteroaromatic rings, C 3-10 Cycloalkanes or 5-10 membered heterocycles; n is 0, 1, 2, 3 or 4; Each R 2 Independently, it can be deuterium, halogen, cyano, oxo, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, -C(=O)OC 1-6 Alkyl, trifluoromethoxy, -NR 2-1 R 2-2 , -C(=O)NR 2-3 R 2-4 C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; the C 1-6 Alkyl group, the aforementioned C 1-6 Alkoxy, the aforementioned C 6-10 Aryl, the 5-10 membered heteroaryl, the C 3-10 The cycloalkyl group and the 3-10 membered heterocyclic alkyl group may optionally be associated with 1, 2 or 3 R groups. RR replace; R 2-1 R 2-2 R 2-3 and R 2-4 Independent of H, deuterium, and C 1-6 Alkyl or C 3-6 cycloalkyl, or R 2-1 and R 2-2 Together with the atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups; Each R RR Independently deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 6-10 Aryl, the C 6-10 The aryl group may optionally be substituted by one or more of the following groups: halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy; The heteroatoms in the 3-6 membered heterocyclic alkyl group, the 5-6 membered heteroaryl group, the benzo[a] 5-6 membered heterocyclic ring, the benzo[a] 5-6 membered heteroene ring, the 5-10 membered heteroaryl group, and the 5-10 membered heterocyclic ring are independently one or more of P, N, S, and O, and the number is 1, 2, or 3.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, X 1 X 2 X 3 X 4 X 5 and X 6 Independently CH, CR RR Or N; R 1 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 replace; Each R 1-1 Independently, H, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein C 3-6 The cycloalkyl group, the 3-6 membered heterocycloalkyl group, the phenyl group, and the 5-6 membered heteroaryl group may independently and optionally be surrounded by 1, 2, or 3 R groups. RR replace; L 1 and L 2 Independently, it can be a connecting key or -(CH2). m -, m is 1, 2, 3, 4 or 5, -(CH2) m Any one or two -CH2- can be optionally replaced by -O-, -S-, -S(=O)2-, or -NR. 3 -、-CR 4 R 5 One or two substitutions in - and -C(=O)-; R 3 R 4 and R 5 Independently H, deuterium, halogen or C 1-6 Alkyl, and R 4 and R 5 Not both H or R 4 and R 5 Together with the C connected to it, they form C 3-6 cycloalkanes; the C 1-6 Alkyl groups and the C 3-6 Cycloalkanes can be optionally surrounded by 1, 2, or 3 R groups. RR replace; Ring A is C 6-10 Aromatic rings, benzene rings, and fused carbon rings 3-6 Cycloalkanes, 5-6 membered heterocycles of benzene rings, 5-6 membered heteroene rings of benzene rings, 5-10 membered heteroaromatic rings, C 3-10 Cycloalkanes or 5-10 membered heterocycles; n is 0, 1, 2, 3 or 4; Each R 2 Independently, it can be deuterium, halogen, cyano, oxo, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, -C(=O)OC 1-6 Alkyl, trifluoromethoxy, -NR 2-1 R 2-2 , -C(=O)NR 2-3 R 2-4 C 6-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl; the C 1-6 Alkyl group, the aforementioned C 1-6 Alkoxy, the aforementioned C 6-10 Aryl, the 5-10 membered heteroaryl, the C 3-10 The cycloalkyl group and the 3-10 membered heterocyclic alkyl group may optionally be associated with 1, 2 or 3 R groups. RR replace; R 2-1 R 2-2 R 2-3 and R 2-4 Independent of H, deuterium, and C 1-6 Alkyl or C 3-6 cycloalkyl, or R 2-1 and R 2-2 Together with the atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups; Each R RR Independently deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; The heteroatoms in the 3-6 membered heterocyclic alkyl group, the 5-6 membered heteroaryl group, the benzo[a] 5-6 membered heterocyclic ring, the benzo[a] 5-6 membered heteroene ring, the 5-10 membered heteroaryl group, and the 5-10 membered heterocyclic ring are independently one or more of P, N, S, and O, and the number is 1, 2, or 3.

3. The compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is a compound represented by Formula I-1a, I-2a, I-3a, I-1b, I-2b or I-3b:

4. The compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula I is a compound represented by any of the general formulas Ia to Io: In formulas Ia to Io, "*" marks the carbon atom as either an S-configuration chiral carbon atom or an R-configuration chiral carbon atom.

5. The compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 Each R 2 R 3 R 4 R 5 Each R 1-1 R 2-1 R 2-2 R 2-3 R 2-4 and each R RR In the context, C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, n-propyl, isopropyl, or tert-butyl; (2)R 1 Each R 2 Each R 1-1 and each R RR In the context, C 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyl or tert-butoxy, for example, methoxy; (3)R 1 Each R 1-1 R 2-1 R 2-2 R 2-3 and R 2-4 and each R RR In the context, C 3-6 Cycloalkyl groups are monocyclic C 3-6 C of cycloalkyl, bispiro, or bibridged rings 5-6 The cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl or spiro[2.3]hexyl; (4)R 1 and each R 1-1 In this context, the 3-6 membered heterocyclic alkyl group is a monocyclic 3-6 membered heterocyclic alkyl group, with heteroatoms being N and / or O, and the number being 1 or 2, which can be tetrahydrofuranyl, oxocyclic butyl or azircyclic butyl; (5) Each R 2 R 3 R 4 R 5 Each R 1-1 and each R RR In this context, the halogen is F, Cl, Br, or I, for example, F; (6) When R 4 and R 5 Together with the C connected to it, they form C 3-6 In the case of cycloalkanes, the C 3-6 Cycloalkanes are cyclopropane, cyclobutane, cyclopentane, or cyclohexane, such as cyclopropane; (7) In ring A, the C 6-10 The aromatic ring is a benzene ring or a naphthalene ring; (8) In ring A, the benzo[a]C 3-6 C in cycloalkanes 3-6 Cycloalkanes are monocyclic C1666 compounds. 3-6 Cycloalkanes, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane; (9) In ring A, the 5-6 membered heterocyclic ring of the 5-6 membered heterocyclic ring of the benzo[a] 5-6 membered heterocyclic ring has N and / or O heteroatoms, and the number of heteroatoms is 1 or 2, and it can be pyrrolidine; (10) Ring A and each R 2 In the above, the 5-6 membered heteroene ring in the benzo[5-6] fused heteroene ring is a 5-6 membered monocyclic heteroene ring, the heteroatom is N and / or O, the number is 1 or 2, and it can be 3,6-dihydro-2H-pyran; (11) In ring A, the 5-10 membered heteroaromatic ring is a 5-6 membered monocyclic heteroaromatic ring, the heteroatom is N and / or O, the number is 1 or 2, and it can be a pyridine ring, pyrimidine ring, pyrazine ring or oxazole ring; (12) In ring A, the C 3-10 Cycloalkanes are C16-365 ... 3-6 Monocyclic cycloalkanes can be cyclopropyl, cyclobutane, cyclopentane, or cyclohexane, such as cyclobutane or cyclohexane; (13) In ring A, the 3-10 membered heterocycle is a 5-6 membered monocyclic heterocycle, the heteroatom is N and / or O, the number is 1 or 2, and it can be an oxocyclic butane ring, a tetrahydrofuran ring, a pyrrole ring or a 1,4-dioxane ring; (14) Each R 2 In the context, C 2-6 The alkenyl group is vinyl; (15) Each R 2 In this context, the 5-10 member heteroaryl group is a 5-6 member monocyclic heteroaryl group; (16) Each R 2 In the context, C 3-10 Cycloalkyl group is C 3-8 The monocyclic cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclopropyl; (17) Each R 2 In this context, the 3-10 membered heterocyclic alkyl group is a 5-10 membered monocyclic heterocyclic alkyl group, with heteroatoms being N and / or O, and the number being 1 or 2, and may be an oxocyclic butyl group; (18) Each R RR In the context, C 6-10 The aromatic ring is a benzene ring or a naphthalene ring.

6. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 Replace; each R 1-1 Independently, it is H, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl group and the aforementioned 3-6 membered heterocycloalkyl group may independently and optionally be surrounded by 1, 2, or 3 R groups. RR replace; R 1 It can also be C 1-6 Alkyl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 Replace; each R 1-1 Halogens are independent of each other; (2)L 1 and L 2 Independently, it can be a connecting key or -(CH2). m -, m can be 1, 2, or 3, -(CH2) m -Any one of -CH2- can be optionally replaced by -O- or -NR 3 -or-CR 4 R 5 - Replace, or any two -CH2- can optionally be replaced by "-NR 3 -and-C(=O)-” or "-O-and-CR 4 R 5 -"Replace; R 3 H, halogen or C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be surrounded by 1, 2, or 3 R groups. RR Replace, R 4 and R 5 Together with the C connected to it, they form C 3-6 Cycloalkanes; (3) Each R 2 Independently halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl, -NR 2-1 R 2 -2 -C(=O)NR 2-3 R 2-4 C 6-10 Aryl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl, wherein C 1-6 alkyl groups and the C 1-6 The alkoxy group may optionally be replaced by one, two, or three halogens; (4) for (5)X 4 X 5 and X 6 For CH; (6) Ring A is a benzene ring, naphthalene ring, pyridine ring, pyrimidine ring, pyrazine ring, oxazole ring, cyclobutane ring, cyclohexane ring, oxacyclobutane ring, tetrahydrofuran ring, pyrrole ring, 1,4-dioxane ring, benzocyclopentane ring, benzocyclopyrrole or benzocyclo3,6-dihydro-2H-pyran.

7. The compound of formula I as claimed in claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 It is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or spiron[2.3]hexyl, R 1 Can be optionally bounded by 1, 2 or 3 R 1-1 Replace; each R 1-1 Independently, F, methyl, ethyl, Preferred, R 1 It is n-propyl, R 1 It can be optionally replaced by 1, 2 or 3 F; (2)L 1 and L 2 Independently for connection keys, For example (3) Each R 2 Independently, it can be F, Cl, Br, cyano, amino, oxo, methyl, isopropyl, tert-butyl, or -CF3. -OCH3, -OCF3, Or -P(=O)(CH3)2.

8. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 for It can also be used for (2) It can be any of the following structures:

9. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any one of the following compounds: Its stereoisomers or mixtures of the two in any proportion.

10. A method for preparing a compound of formula I as described in any one of claims 1-9, or a pharmaceutically acceptable salt thereof, characterized in that, It includes the following steps: subjecting compound II and compound III to a cyclization reaction to obtain the compound shown in Formula I; Among them, X 1 X 2 X 3 X 4 X 5 X 6 L 1 L 2 n, ring A, R 1 and R 2 The definitions are as described in any one of claims 1-9.

11. A pharmaceutical composition, characterized in that, It includes compounds of Formula I as described in any one of claims 1-9, or pharmaceutically acceptable salts thereof, and pharmaceutical excipients.

12. The use of a compound of Formula I as described in any one of claims 1-9, or a pharmaceutically acceptable salt thereof, in the preparation of a PTDSS1 inhibitor or in the preparation of a medicament for the treatment or prevention of diseases related to PTDSS1; The PTDSS1-related diseases mentioned above may be tumors associated with PTDSS2 deficiency; The PTDSS2 deficiency may be a mutation of PTDSS2, loss of heterozygosity, low expression, or no expression of PTDSS2. The tumors mentioned may be testicular germ cell tumors, ovarian cancer, bladder cancer, lung cancer, breast cancer, esophageal cancer, colon cancer, prostate cancer, stomach cancer, cervical cancer, endometrial cancer, uterine body cancer, kidney cancer, thyroid cancer, squamous cell carcinoma, osteosarcoma, melanoma, glioblastoma, neuroblastoma, head and neck cancer, testicular cancer, colorectal cancer, hematologic malignancies, retinoblastoma, or pancreatic cancer.

13. A compound as shown in Formula II: in, X 1 X 2 X 3 X 4 X 5 X 6 L 1 L 2 n, ring A, R 1 and R 2 The definitions are all as described in any one of claims 1-9; The compound represented by Formula III is preferably any of the following compounds:

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