Benzooxycyclic derivatives, preparation methods and medical applications thereof

Abstract

The present disclosure relates to benzo-oxygen-containing ring derivatives, preparation methods thereof and their use in medicine. Specifically, the present disclosure relates to a benzo-oxygen-containing ring derivative represented by general formula (I) or (I-1) and a pharmaceutically acceptable salt thereof, a preparation method thereof and their use as MEK inhibitors, especially as cancer therapeutic agents, wherein the definition of each substituent in general formula (I) or (I-1) is the same as that in the specification. #imgabs0#

Description

Technical Field

[0001] The present disclosure relates to a novel benzooxycyclic derivative and a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the derivative, and the use of the derivative as a MEK inhibitor, especially as a cancer therapeutic agent. Background Art

[0002] Abnormalities in the MAPKs kinase pathway are closely related to the occurrence of tumors. Since they lead to uncontrolled cell proliferation and differentiation blockage, they have become the preferred target for the development of tumor drugs. Serine / threonine mitogen-activated protein kinases (MAPKs, also known as extracellular signal-regulated kinases, ERKs) are activated by tyrosine kinase receptors (such as EGF receptors) and / or cytokine receptors associated with G protein heterotrimers. They can interact with a variety of intracellular signals stimulated by different second messengers, phosphorylate and regulate the activities of various enzymes and transcription factors (such as NF-κB, Rsk 90, phospholipase A2, c-Myc, CREB, Ets-1, AP-1 and c-jun, etc.). Among the MAPK pathways involved in normal and abnormal cell growth, the Ras / Raf / MEK / Erk kinase pathway is one of the most clearly studied and important pathways. More than a decade ago, scientists discovered that the protein kinase family Erks has a proliferative effect. Subsequent studies quickly identified the upstream kinase MEK family of Erk, and then found that Raf can activate MEKs. Its upstream Ras is a G protein. Activated GTP binds to Ras and indirectly activates Raf. About 30% of patients with malignant tumors have Ras gene mutations, and in pancreatic cancer, the Ras gene mutation rate can be as high as 90%. The mutation rate of B-Raf in melanoma is as high as 50%-70%, 35% in ovarian cancer, 30% in thyroid cancer, and 10% in colon cancer. MEKs can also be activated by a kinase independent of Raf, MEK kinase (also known as MEKK).

[0003] MEKs, also known as MAP kinases (MAPKK or Erk kinases), are dual-specific kinases that can phosphorylate MAPK (p44 MAPK (Erk 1) and p42 MAPK The MEK family contains five genes: MEK1, MEK2, MEK3, MEK4 and MEK5. The N-terminus of MEKs is a negative regulatory region, and the C-terminal catalytic region has the function of binding to and activating Erks. Experiments have found that knocking out the regulatory region of MEK1 will lead to the inhibition of the intrinsic activity of MEK1 and Erk.

[0004] The molecular weight of MEK1 is about 44kDa, containing 393 amino acids. It is mainly expressed in adult tissues, especially brain tissues. Trace amounts of MEK1 expression can also be detected during embryonic development. MEK1 triggers its activity through phosphorylation at the S218 and S222 sites. Studies have found that in NIH3T3 cells, replacing these two residues with aspartic acid or glutamic acid increases its activity and colony formation. The intrinsic activity of MEK1 in primary cell culture promotes cell senescence and p53 and p16 INK4a expression of p53 or p16 in immortalized cells INK4a In cells lacking MEK1, the effect is just the opposite. MEK2 has a molecular weight of about 45 kDa and has a 79% sequence similarity to MEK1. Its activity is triggered by phosphorylation at the S222 and S226 sites. MEK1 and MEK2 have different phosphorylation catalytic activities for different MAPK subtypes, Erk1 and Erk2. MEK3, MEK4 and MEK5 do not exert their effects by acting on Erks.

[0005] Currently, there are several compounds that specifically inhibit the activity of Raf and MEK in the clinical and market stages for the MAPK signaling pathway. Among them, sorafenib (Bay 43-9006) was launched in 2006. It is a non-specific serine / threonine and tyrosine kinase inhibitor, and its targets include Raf, MEK, VEGFR2 / 3, Flt-3, PDGFR, c-Kit, etc. B-Raf specific inhibitors such as dabrafenib (GSK2118436) and vemurafenib (PLX4032) show good clinical effects, but the duration is not long. At the same time, clinical studies have found that most of the patients who received effective treatment with PLX4032 had recurrence of symptoms, indicating that long-term treatment with B-Raf inhibitors will lead to acquired drug resistance in patients and they will no longer be sensitive to B-Raf inhibitors. In order to overcome the drug resistance of patients, MEK inhibitors are often used in combination with B-Raf inhibitors in clinical practice. Trametinib (GSK-1120212), a specific inhibitor of MEK1 / 2, was developed by GSK and is now on the market. Other MEK1 / 2 inhibitors such as Selumetinib (AZD-6244), Pimasertib hydrochloride (AS-703026), and TAK-733 have entered the clinical trial stage, but these MEK inhibitors have not published their interaction data with Erk1 or Erk2.

[0006] Currently, a series of patent applications for MEK inhibitors have been disclosed, including WO2007096259, WO2010003022, WO2012162293 and CN104774188A.

[0007] In order to achieve better tumor treatment effects and better meet market demand, we hope to develop a new generation of highly effective and low-toxic inhibitors targeting MAPKs signaling pathways, especially MEK target inhibitors. The present disclosure will provide a MEK inhibitor with a novel structure, and find that compounds with such a structure have good activity and exhibit excellent anti-tumor cell proliferation effects. Summary of the invention

[0008] The object of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] Dashed lines are single or double bonds;

[0012] R 0 is halogen; preferably F;

[0013] R 1 is a hydrogen atom or a halogen;

[0014] R 2 and R 4 are the same or different and are each independently selected from a hydrogen atom, a halogen and an alkyl group;

[0015] R 3 is an alkyl group, which is optionally substituted with one or more hydroxy groups;

[0016] p is 0, 1, or 2;

[0017] q is 0, 1, or 2;

[0018] The condition is that, when the dashed line is a double bond, p and q are 0 or 1;

[0019] And when the dotted line is a single bond, R 0 Not Cl.

[0020] The present disclosure also provides a compound represented by the general formula (I-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0021]

[0022] in:

[0023] Dashed lines are single or double bonds;

[0024] R 0 is a halogen;

[0025] R 1 is a hydrogen atom or a halogen;

[0026] R 2 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group;

[0027] R 4 is selected from the group consisting of a hydrogen atom, a halogen and an alkyl group;

[0028] R 3 is an alkyl group, which is optionally substituted with one or more hydroxy groups;

[0029] p is 1 or 2;

[0030] q is 0, 1, or 2;

[0031] The condition is that at least one R 2 is halogen or alkyl.

[0032] In a preferred embodiment of the present disclosure, a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0033]

[0034] in:

[0035] R 3a and R 3b the same or different, each independently selected from a hydrogen atom, C 1-6 Alkyl and C 1-6 Hydroxyalkyl;

[0036] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (I).

[0037] In a preferred embodiment of the present disclosure, a compound represented by the general formula (I-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0038]

[0039] in:

[0040] R 3a and R 3b the same or different, each independently selected from a hydrogen atom, C 1-6 Alkyl and C 1-6 Hydroxyalkyl;

[0041] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (I-1).

[0042] In a preferred embodiment of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (II') or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0043]

[0044] in:

[0045] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (I).

[0046] In a preferred embodiment of the present disclosure, a compound represented by the general formula (I-1) or (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0047]

[0048] in:

[0049] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (I-1).

[0050] In a preferred embodiment of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0051]

[0052] in:

[0053] R 0 is a halogen;

[0054] R 3a and R 3b the same or different, each independently selected from a hydrogen atom, C 1-6 Alkyl and C 1-6 Hydroxyalkyl;

[0055] R 1 , R 2 and R 4 As defined in general formula (I).

[0056] In a preferred embodiment of the present disclosure, a compound represented by general formula (I-1) or (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0057]

[0058] in:

[0059] R 0 is a halogen;

[0060] R 3a and R 3b the same or different, each independently selected from a hydrogen atom, C 1-6 Alkyl and C 1-6 Hydroxyalkyl;

[0061] R 2 Halogen or C 1-6 alkyl;

[0062] R 1 and R 4 As defined in general formula (I-1).

[0063] In a preferred embodiment of the present disclosure, a compound represented by general formula (I), (II), (II') or (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III') or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0064]

[0065] in:

[0066] R 0 is a halogen;

[0067] R 1 , R 2 and R 4 As defined in general formula (I).

[0068] In a preferred embodiment of the present disclosure, a compound represented by general formula (I-1), (II-1), (II'-1) or (III-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0069]

[0070] in:

[0071] R 0 is a halogen;

[0072] R 2 Halogen or C 1-6 alkyl;

[0073] R 1 and R 4 As defined in general formula (I-1).

[0074] In a preferred embodiment of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0075]

[0076] in:

[0077] R 0 is selected from fluorine, bromine and iodine;

[0078] R 3a and R 3b the same or different, each independently selected from a hydrogen atom, C 1-6 Alkyl and C 1-6 Hydroxyalkyl;

[0079] R 2a , R 2b , R 4a and R 4b are the same or different and are independently selected from hydrogen atoms, halogens and C 1-6 alkyl;

[0080] R 1 As defined in general formula (I).

[0081] In a preferred embodiment of the present disclosure, a compound represented by general formula (I-1) or (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IV-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0082]

[0083] in:

[0084] R 0 is selected from fluorine, bromine and iodine;

[0085] R 3a and R 3b the same or different, each independently selected from a hydrogen atom, C 1-6 Alkyl and C 1-6 Hydroxyalkyl;

[0086] R 2a Halogen or C 1-6 alkyl;

[0087] R 2b , R 4a and R 4b are the same or different and are independently selected from hydrogen atoms, halogens and C 1-6 alkyl;

[0088] R 1 As defined in general formula (I-1).

[0089] In a preferred embodiment of the present disclosure, a compound represented by general formula (I), (II) or (II') or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IV') or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0090]

[0091] in:

[0092] R 2a , R 2b , R 4a and R 4b are the same or different and are independently selected from hydrogen atoms, halogens and C 1-6 alkyl;

[0093] R 0 and R 1 As defined in general formula (I).

[0094] In a preferred embodiment of the present disclosure, a compound represented by general formula (I-1), (II-1) or (II'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0095]

[0096] in:

[0097] R 2a Halogen or C 1-6 alkyl;

[0098] R 2b , R 4a and R 4b are the same or different and are independently selected from hydrogen atoms, halogens and C 1-6 alkyl;

[0099] R 0 and R 1 As defined in general formula (I-1).

[0100] In a preferred embodiment of the present disclosure, a compound represented by general formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV') or (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 0 It is F or Cl, preferably F.

[0101] In a preferred embodiment of the present disclosure, a compound represented by general formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV') and (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen, preferably F.

[0102] In a preferred embodiment of the present disclosure, a compound represented by general formula (I), (II), (II'), (III) and (III') or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogens and C 1-6 The alkyl group is preferably selected from a hydrogen atom, Cl and a methyl group, and is more preferably a hydrogen atom.

[0103] In a preferred embodiment of the present disclosure, a compound represented by general formula (I-1), (II-1) and (II'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein at least one R 2 Halogen or C 1-6 The alkyl group is preferably Cl or methyl, and more preferably methyl.

[0104] In a preferred embodiment of the present disclosure, a compound represented by general formula (III-1) and (III'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen or C 1-6 The alkyl group is preferably Cl or methyl, and more preferably methyl.

[0105] In a preferred embodiment of the present disclosure, a compound represented by general formula (IV) and (IV') or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2a Selected from hydrogen atoms, halogens and C 1-6 The alkyl group is preferably selected from a hydrogen atom, Cl and a methyl group, and is more preferably a hydrogen atom.

[0106] In a preferred embodiment of the present disclosure, a compound represented by general formula (IV-1) and (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2a It is Cl or methyl, more preferably methyl.

[0107] In a preferred embodiment of the present disclosure, a compound represented by the general formula (IV), (IV-1), (IV') and (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2b Selected from hydrogen atoms, halogens and C 1-6 The alkyl group is preferably selected from a hydrogen atom, Cl and a methyl group, and is more preferably a hydrogen atom.

[0108] In a preferred embodiment of the present disclosure, a compound represented by general formula (I) or (I-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 C is substituted with one or two hydroxyl groups 1-6 Alkyl, preferably C substituted with one or two hydroxyl groups 1-3 The alkyl group is more preferably a hydroxyethyl group.

[0109] In a preferred embodiment of the present disclosure, a compound represented by general formula (II), (III), (IV), (II-1), (III-1) and (IV-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from hydrogen atoms, C 1-6 Hydroxyalkyl and C 1-6 The alkyl group is preferably selected from a hydrogen atom, a hydroxymethyl group and a methyl group, and is more preferably a hydrogen atom.

[0110] In a preferred embodiment of the present disclosure, a compound represented by general formula (II), (III), (IV), (II-1), (III-1) and (IV-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3b Selected from hydrogen atoms, C 1-6 Hydroxyalkyl and C 1-6 The alkyl group is preferably selected from a hydrogen atom, a hydroxymethyl group and a methyl group, and is more preferably a hydrogen atom.

[0111] In a preferred embodiment of the present disclosure, a compound represented by general formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III') and (III'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is selected from the group consisting of a hydrogen atom, a halogen and a methyl group, and is preferably a hydrogen atom.

[0112] In a preferred embodiment of the present disclosure, a compound represented by the general formula (IV), (IV-1), (IV') and (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4a It is selected from the group consisting of a hydrogen atom, a halogen and a methyl group, and is preferably a hydrogen atom.

[0113] In a preferred embodiment of the present disclosure, a compound represented by the general formula (IV), (IV-1), (IV') and (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4b It is selected from the group consisting of a hydrogen atom, a halogen and a methyl group, and is preferably a hydrogen atom.

[0114] In a preferred embodiment of the present disclosure, a compound represented by general formula (II-1) and (III-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 0 For F, R 1 For F, R 2 C 1-6 Alkyl, p is 1, R 4 is a hydrogen atom, R 3a C 1-6 Hydroxyalkyl, and R 3b A hydrogen atom.

[0115] Table A Typical compounds of the present disclosure include, but are not limited to:

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] The present disclosure also provides a compound represented by general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0122]

[0123] in:

[0124] R is a hydrogen atom or an alkyl group;

[0125] Dashed line, R 0 , R 1 , R 2 , R 3a , R 3b , R 4 , p and q are as defined in the general formula (II).

[0126] The present disclosure also provides a compound represented by general formula (II'A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0127]

[0128] in:

[0129] R 5 and R 6 is an alkyl group;

[0130] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (II').

[0131] The present disclosure also provides a compound represented by general formula (IIIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0132]

[0133] in:

[0134] R is a hydrogen atom or an alkyl group;

[0135] R 0 , R 1 , R 2 , R 3a , R 3b and R 4 As defined in general formula (III).

[0136] The present disclosure also provides a compound represented by general formula (III'A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0137]

[0138] in:

[0139] R 5 and R 6 is an alkyl group;

[0140] R 0 , R 1 , R 2 and R 4 As defined in general formula (III').

[0141] The present disclosure also provides a compound represented by general formula (IVA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0142]

[0143] in:

[0144] R is a hydrogen atom or an alkyl group;

[0145] R 0 , R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b As defined in formula (IV).

[0146] The present disclosure also provides a compound represented by general formula (IV'A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0147]

[0148] in:

[0149] R 5 and R 6 is an alkyl group;

[0150] R 0 , R 1 , R 2a , R 2b , R 4a and R 4b As defined in general formula (IV').

[0151] The present disclosure also provides a compound represented by general formula (II-1A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0152]

[0153] in:

[0154] R is a hydrogen atom or an alkyl group;

[0155] Dashed line, R 0 , R 1 , R 2 , R 3a , R 3b , R 4 , p and q are as defined in the general formula (II-1).

[0156] The present disclosure also provides a compound represented by general formula (II'-1A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0157]

[0158] in:

[0159] R 5 and R 6 is an alkyl group;

[0160] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (II'-1).

[0161] The present disclosure also provides a compound represented by general formula (III-1A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0162]

[0163] in:

[0164] R is a hydrogen atom or an alkyl group;

[0165] R 0 , R 1 , R 2 , R 3a , R 3b and R 4 As defined in general formula (III-1).

[0166] The present disclosure also provides a compound represented by general formula (III'-1A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0167]

[0168] in:

[0169] R 5 and R 6 is an alkyl group;

[0170] R 0 , R 1 , R 2 and R 4 As defined in general formula (III'-1).

[0171] The present disclosure also provides a compound represented by general formula (IV-1A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0172]

[0173] in:

[0174] R is a hydrogen atom or an alkyl group;

[0175] R 0 , R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b As defined in general formula (IV-1).

[0176] The present disclosure also provides a compound represented by general formula (IV'-1A) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0177]

[0178] in:

[0179] R 5 and R 6 is an alkyl group;

[0180] R 0 , R 1 , R 2a , R 2b , R 4a and R 4b As defined in general formula (IV'-1).

[0181] Typical intermediate compounds of the present disclosure include, but are not limited to:

[0182]

[0183]

[0184]

[0185]

[0186] The present disclosure also provides a method for synthesizing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0187]

[0188] The compound of formula (IIA) is de-alkenylated to obtain the compound of formula (II);

[0189] in:

[0190] R is a hydrogen atom or an alkyl group;

[0191] Dashed line, R 0 , R 1 , R 2 , R 3a , R 3b , R 4 , p and q are as defined in the general formula (II).

[0192] The present disclosure also provides a method for synthesizing a compound represented by general formula (II') or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0193]

[0194] The compound of general formula (II'A) is subjected to a ring-opening reaction to obtain a compound of general formula (II');

[0195] in:

[0196] R 5 and R 6 is an alkyl group;

[0197] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (II').

[0198] The present disclosure also provides a method for synthesizing a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0199]

[0200] The compound of formula (IIIA) is de-alkenylated to obtain the compound of formula (III);

[0201] in:

[0202] R is a hydrogen atom or an alkyl group;

[0203] R 0 , R 1 , R 2 , R 3a , R 3b and R 4 As defined in general formula (III).

[0204] The present disclosure also provides a method for synthesizing a compound represented by general formula (III') or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0205]

[0206] The compound of general formula (III'A) is subjected to a ring-opening reaction to obtain a compound of general formula (III');

[0207] in:

[0208] R 5 and R 6 is an alkyl group;

[0209] R 0 , R 1 , R 2 and R 4 As defined in general formula (III').

[0210] The present disclosure also provides a method for preparing a compound represented by general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0211]

[0212] The compound of formula (IVA) is de-alkenylated to obtain the compound of formula (IV);

[0213] in:

[0214] R is a hydrogen atom or an alkyl group;

[0215] R 0 , R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b As defined in formula (IV).

[0216] The present disclosure also provides a method for synthesizing a compound represented by general formula (IV') or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0217]

[0218] The compound of general formula (IV'A) is subjected to a ring-opening reaction to obtain a compound of general formula (IV');

[0219] in:

[0220] R 5 and R 6 is an alkyl group;

[0221] R 0 , R 1 , R 2a , R 2b , R 4a and R 4b As defined in general formula (IV').

[0222] The present disclosure also provides a method for synthesizing a compound represented by general formula (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0223]

[0224] The compound of the general formula (II-1A) is de-alkenylated to obtain the compound of the general formula (II-1);

[0225] in:

[0226] R is a hydrogen atom or an alkyl group;

[0227] Dashed line, R 0 , R 1 , R 2 , R 3a , R 3b , R 4 , p and q are as defined in the general formula (II-1).

[0228] The present disclosure also provides a method for synthesizing a compound represented by general formula (II'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0229]

[0230] The compound of general formula (II'-1A) is subjected to a ring-opening reaction to obtain a compound of general formula (II'-1);

[0231] in:

[0232] R 5 and R 6 is an alkyl group;

[0233] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (II'-1).

[0234] The present disclosure also provides a method for synthesizing a compound represented by general formula (III-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0235]

[0236] The compound of the general formula (III-1A) is de-alkenylated to obtain the compound of the general formula (III-1);

[0237] in:

[0238] R is a hydrogen atom or an alkyl group;

[0239] R 0 , R 1 , R 2 , R 3a , R 3band R 4 As defined in general formula (III-1).

[0240] The present disclosure also provides a method for synthesizing a compound represented by general formula (III'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0241]

[0242] The compound of general formula (III'-1A) is subjected to a ring-opening reaction to obtain a compound of general formula (III'-1);

[0243] in:

[0244] R 5 and R 6 is an alkyl group;

[0245] R 0 , R 1 , R 2 and R 4 As defined in general formula (III'-1).

[0246] The present disclosure also provides a method for preparing a compound represented by general formula (IV-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0247]

[0248] The compound of the general formula (IV-1A) is de-alkenylated to obtain the compound of the general formula (IV-1);

[0249] in:

[0250] R is a hydrogen atom or an alkyl group;

[0251] R 0 , R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b As defined in general formula (IV-1).

[0252] The present disclosure also provides a method for synthesizing a compound represented by general formula (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0253]

[0254] The compound of general formula (IV'-1A) is subjected to a ring-opening reaction to obtain a compound of general formula (IV'-1);

[0255] in:

[0256] R 5 and R 6 is an alkyl group;

[0257] R 0 , R 1 , R 2a , R 2b , R 4a and R 4b As defined in general formula (IV'-1).

[0258] The present disclosure further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure of general formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A, or its tautomer, mesoform, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0259] The present disclosure further relates to the use of compounds of the general formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or their pharmaceutically acceptable salts, or pharmaceutical compositions containing the same in the preparation of drugs for inhibiting MEK.

[0260] The present disclosure further relates to the use of a compound of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or as shown in Table A, or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for treating an inflammatory disorder, an autoimmune disease, a cardiovascular disorder, a proliferative disease or a nociceptive disorder, wherein the proliferative disease is preferably cancer (as defined below) or polycythemia vera.

[0261] The present disclosure further relates to the use of compounds of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A or their tautomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for treating cancer, wherein the cancer is selected from melanoma, brain tumor (glioma with malignant astroglial and oligodendroglioma components, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, breast cancer, ovarian cancer, Ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteoma, seminoma, testicular tumor, uterine cancer (cervical cancer, endometrial cancer, etc.), head and neck tumor (maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, oral cancer, etc.), multiple myeloma, malignant lymphoma (reticular cell sarcoma, lymphosarcoma, Hodgkin's lymphoma, etc.), leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma or pediatric tumor (Ewing's familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.), etc.; preferably colorectal cancer or lung cancer; wherein the sarcoma is preferably osteosarcoma; and the osteoma is preferably osteochondroma.

[0262] The present disclosure further relates to the use of a compound of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or as shown in Table A, or its tautomer, mesoform, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for treating cancer, wherein the cancer is preferably colorectal cancer or lung cancer.

[0263] The present disclosure further relates to the use of compounds of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A or their tautomers, mesomorphs, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for treating cancer, wherein the drugs are further used in combination with one or more other anticancer agents selected from alkylating agents (cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, etc.), , fulvestrant, pemetrexed, etc.), plant alkaloids (vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), hormonal anticancer agents (leuprorelin, goserelin, exemestane, letrozole, anastrozole, dutasteride, etc.), antibody drugs (trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, bevacizumab, etc.), VEGFR or EG FR inhibitors (sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (vemurafenib, GSK-2118436, etc.) or AKT inhibitors (perifosine, MK-2206, etc.), etc.

[0264] The present disclosure also relates to a method for inhibiting MEK activity, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the general formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0265] The present disclosure relates to a method for treating an inflammatory disorder, an autoimmune disease, a cardiovascular disorder, a proliferative disease or a nociceptive disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or as shown in Table A, or a tautomer, mesoform, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the proliferative disease is preferably cancer (as defined below) or polycythemia vera.

[0266] The present disclosure further relates to a method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or a compound shown in Table A or its tautomer, mesoform, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from melanoma, brain tumor (glioma with malignant astroglial and oligodendroglioma components, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), renal cancer , breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteoma, seminoma, testicular tumor, uterine cancer (cervical cancer, endometrial cancer, etc.), head and neck tumors (maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, oral cancer, etc.), multiple myeloma, malignant lymphoma (reticular cell sarcoma, lymphosarcoma, Hodgkin's lymphoma, etc.), leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma or pediatric tumor (Ewing family sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.), etc.; preferably colorectal cancer or lung cancer; wherein the sarcoma is preferably osteosarcoma; the osteoma is preferably osteochondroma.

[0267] The present disclosure also relates to a method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or a compound shown in Table A or its tautomer, mesomorph, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and one or more other anticancer agents selected from alkylating agents (cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fluorouracil, etc.), Vestrant, pemetrexed, etc.), plant alkaloids (vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), hormonal anticancer agents (leuprorelin, goserelin, exemestane, letrozole, anastrozole, dutasteride, etc.), antibody drugs (trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, bevacizumab, etc.), VEGFR or EGF R inhibitors (sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (vemurafenib, GSK-2118436, etc.) or AKT inhibitors (perifosine, MK-2206, etc.), etc.

[0268] The present disclosure also relates to compounds of the general formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, as drugs for inhibiting MEK activity.

[0269] The present disclosure also relates to compounds of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A or their tautomers, mesomers, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same as drugs for treating inflammatory disorders, autoimmune diseases, cardiovascular disorders, proliferative diseases or nociceptive disorders, wherein the proliferative disease is preferably cancer (as defined below) or polycythemia vera.

[0270] The present disclosure further relates to compounds of the general formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A or their tautomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same as drugs for treating cancer, wherein the cancer is selected from melanoma, brain tumor (glioma with malignant astroglial and oligodendroglioma components, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, breast cancer, ovarian cancer , prostate cancer, skin cancer, neuroblastoma, sarcoma, osteoma, seminoma, testicular tumor, uterine cancer (cervical cancer, endometrial cancer, etc.), head and neck tumors (maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, oral cancer, etc.), multiple myeloma, malignant lymphoma (reticular cell sarcoma, lymphosarcoma, Hodgkin's lymphoma, etc.), leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma or pediatric tumor (Ewing family sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms' tumor, etc.), etc.; preferably colorectal cancer or lung cancer; wherein the sarcoma is preferably osteosarcoma; the osteoma is preferably osteochondroma.

[0271] The present disclosure also relates to compounds of formula (I), (I-1), (II), (II-1), (II'), (II'-1), (III), (III-1), (III'), (III'-1), (IV), (IV-1), (IV'), (IV'-1) or shown in Table A or their tautomers, mesomorphs, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, and one or more other anticancer agents selected from alkylating agents (cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed ), plant alkaloids (vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), hormonal anticancer agents (leuprorelin, goserelin, exemestane, letrozole, anastrozole, dutasteride, etc.), antibody drugs (trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, bevacizumab, etc.), VEGFR or EGFR inhibitors agents (sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (vemurafenib, GSK-2118436, etc.) or AKT inhibitors (perifosine, MK-2206, etc.), etc.

[0272] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compound of the present disclosure can also be formulated into a sustained release dosage form, such as a tablet, a hard or soft capsule, an aqueous or oily suspension, an emulsion, an injection, a dispersible powder or granules, a suppository, a lozenge or a syrup.

[0273] As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0274] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0275] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0276] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0277] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0278] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0279] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0280] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0281] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0282] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0283] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0284] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the severity of the disease, the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0285] Terminology

[0286] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0287] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred is a lower alkyl group containing 1 to 6 carbon atoms, and further preferred is a lower alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from one or more of H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0288] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0289] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0290] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the alkyl group is as defined above. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from one or more substituents of hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0291] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed, and bridged rings.

[0292] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0293]

[0294] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan). According to the number of the composition ring, dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan of dicycloalkyl. The limiting examples of condensed cycloalkyl include:

[0295]

[0296] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0297]

[0298] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferably

[0299] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0300] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0301] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms being carbon. Preferably, it contains 3 to 12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g. 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (e.g. 1, 2 and 3); more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

[0302] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. It is more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0303]

[0304] The term "fused heterocyclic radical" refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system. The polycyclic heterocyclic group, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radical. Non-limiting examples of fused heterocyclic radicals include:

[0305]

[0306] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0307]

[0308] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0309] wait.

[0310] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl, and heteroaryl.

[0311] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0312]

[0313] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituent is preferably selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0314] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0315]

[0316]

[0317] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituent is preferably selected from one or more of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0318] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from the removal of one hydrogen atom from a parent ring atom, or two residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0319] The term "amino protecting group" is a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule are reacted. Non-limiting examples include, but are not limited to, (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

[0320] The term "hydroxy protecting group" refers to suitable groups for protecting the hydroxy group known in the art, and non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

[0321] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined above.

[0322] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0323] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0324] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0325] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0326] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0327] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0328] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0329] The term "hydroxy" refers to -OH.

[0330] The term "thiol" refers to -SH.

[0331] The term "amino" refers to -NH2.

[0332] The term "cyano" refers to -CN.

[0333] The term "nitro" refers to -NO2.

[0334] The term "oxo" refers to "=0".

[0335] The term "carbonyl" refers to C=O.

[0336] The term "carboxy" refers to -C(O)OH.

[0337] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0338] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form. Optically pure forms may be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0339] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and In the chemical structure of the compounds disclosed in the present invention, the bond The configuration is not specified, i.e., it can be Z, E, or both. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0340] Compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. Lactam-lactim equilibrium examples are between A and B as shown below.

[0341]

[0342] All compounds in the present disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0343] The compounds of the present disclosure include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure, with "deuterium" or "tritium" replacing hydrogen, or with 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a deuterium atom (C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. The various deuterated forms of the compounds of formula (I) disclosed herein refer to compounds in which each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds of formula (I), or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0344] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0345] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0346] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0347] "Pharmaceutically acceptable salts" refer to salts of the disclosed compounds that are safe and effective for use in mammals and have the desired biological activity. Salts can be prepared during the final isolation and purification of the compounds, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0348] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0349] The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0350] "Prodrug" refers to a compound that can be transformed in vivo under physiological conditions, for example, by hydrolysis in the blood, to yield the active prodrug.

[0351] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0352] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0353] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0354] Synthesis method disclosed herein

[0355] In order to achieve the synthesis purpose of the present disclosure, the present disclosure adopts the following synthesis technology scheme:

[0356] Solution 1

[0357] The method for preparing the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, comprises the following steps:

[0358]

[0359] The compound of general formula (IIA) is subjected to acidic conditions to remove the alkenyl substituent to obtain the compound of general formula (II);

[0360] in:

[0361] R is a hydrogen atom or an alkyl group;

[0362] Dashed line, R 0 , R 1 , R 2 , R 3a , R 3b , R 4 , p and q are as defined in the general formula (II).

[0363] Solution 2

[0364] The method for preparing the compound represented by the general formula (II') of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt comprises the following steps:

[0365]

[0366] The compound of general formula (II'A) is subjected to a ring-opening reaction under acidic conditions to obtain a compound of general formula (II');

[0367] in:

[0368] R 5 and R 6 is an alkyl group;

[0369] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (II').

[0370] Option 3

[0371] The method for preparing the compound represented by the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, comprises the following steps:

[0372]

[0373] The compound of general formula (IIIA) is subjected to acidic conditions to remove the alkenyl substituent to obtain the compound of general formula (III);

[0374] in:

[0375] R is a hydrogen atom or an alkyl group;

[0376] R 0 , R 1 , R 2 , R 3a , R 3b and R 4 As defined in general formula (III).

[0377] Option 4

[0378] The method for preparing the compound represented by the general formula (III') of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt comprises the following steps:

[0379]

[0380] The compound of general formula (III'A) is subjected to a ring-opening reaction under acidic conditions to obtain a compound of general formula (III');

[0381] in:

[0382] R 5 and R 6 is an alkyl group;

[0383] R 0 , R 1 , R 2 and R 4 As defined in general formula (III').

[0384] Option 5

[0385] The method for preparing the compound represented by the general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, comprises the following steps:

[0386]

[0387] The compound of general formula (IVA) is subjected to acidic conditions to remove the alkenyl substituent to obtain the compound of general formula (IV);

[0388] in:

[0389] R is a hydrogen atom or an alkyl group;

[0390] R 0 , R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b As defined in formula (IV).

[0391] Option 6

[0392] The method for preparing the compound represented by the general formula (IV') of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt comprises the following steps:

[0393]

[0394] The compound of general formula (IV'A) is subjected to a ring-opening reaction under acidic conditions to obtain a compound of general formula (IV');

[0395] in:

[0396] R 5 and R 6 is an alkyl group;

[0397] R 0 , R 1 , R 2a , R 2b , R 4a and R 4b As defined in general formula (IV').

[0398] Option 7

[0399] The present invention discloses a method for preparing a compound represented by general formula (II-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0400]

[0401] The compound of the general formula (II-1A) is subjected to acidic conditions to remove the alkenyl substituent to obtain the compound of the general formula (II-1);

[0402] in:

[0403] R is a hydrogen atom or an alkyl group;

[0404] Dashed line, R 0 , R 1 , R 2 , R 3a , R 3b , R 4 , p and q are as defined in the general formula (II-1).

[0405] Option 8

[0406] The method for preparing the compound represented by the general formula (II'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, comprises the following steps:

[0407]

[0408] The compound of general formula (II'-1A) is subjected to a ring-opening reaction under acidic conditions to obtain a compound of general formula (II'-1);

[0409] in:

[0410] R 5 and R 6 is an alkyl group;

[0411] Dashed line, R 0 , R 1 , R 2 , R 4 , p and q are as defined in the general formula (II'-1).

[0412] Option 9

[0413] The present invention discloses a method for preparing a compound represented by general formula (III-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0414]

[0415] The compound of the general formula (III-1A) is subjected to acidic conditions to remove the alkenyl substituent to obtain the compound of the general formula (III-1);

[0416] in:

[0417] R is a hydrogen atom or an alkyl group;

[0418] R 0 , R 1 , R 2 , R 3a , R 3b and R 4 As defined in general formula (III-1).

[0419] Plan 10

[0420] The present invention discloses a method for preparing a compound represented by the general formula (III'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0421]

[0422] The compound of general formula (III'-1A) is subjected to a ring-opening reaction under acidic conditions to obtain a compound of general formula (III'-1);

[0423] in:

[0424] R 5 and R 6 is an alkyl group;

[0425] R 0 , R 1 , R 2 and R 4 As defined in general formula (III'-1).

[0426] Plan 11

[0427] The present invention discloses a method for preparing a compound represented by the general formula (IV-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0428]

[0429] The compound of the general formula (IV-1A) is subjected to acidic conditions to remove the alkenyl substituent to obtain the compound of the general formula (IV-1);

[0430] in:

[0431] R is a hydrogen atom or an alkyl group;

[0432] R 0 , R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b As defined in general formula (IV-1).

[0433] Plan 12

[0434] The present invention discloses a method for preparing a compound represented by the general formula (IV'-1) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0435]

[0436] The compound of the general formula (IV'-1A) is subjected to a ring-opening reaction under acidic conditions to obtain the compound of the general formula (IV'-1);

[0437] in:

[0438] R 5 and R 6 is an alkyl group;

[0439] R 0 , R 1 , R 2a , R 2b , R 4a and R 4b As defined in general formula (IV'-1).

[0440] The reagents providing acidic conditions in the above reaction include but are not limited to ammonium chloride, trifluoroacetic acid, hydrochloric acid, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid and p-toluenesulfonic acid; preferably hydrochloric acid.

[0441] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, toluene, xylene, pyridine, dioxane, N,N-dimethylacetamide or N,N-dimethylformamide and mixtures thereof. DETAILED DESCRIPTION

[0442] The present disclosure is further described below in conjunction with embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0443] The experimental methods without specific conditions in the examples disclosed herein are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0444] Example

[0445] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0446] MS was measured using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0447] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489.

[0448] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0449] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0450] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0451] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0452] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0453] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0454] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0455] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0456] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0457] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0458] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0459] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0460] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0461] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0462] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0463] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0464] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: n-hexane / dichloromethane system, D: ethyl acetate:methanol, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0465] Example 1

[0466] 6-((4-bromo-2-fluorophenyl)amino)-3-chloro-N-(2,3-dihydroxypropoxy)-7-fluorobenzofuran-5-carboxamide 1

[0467]

[0468] first step

[0469] 1-Bromo-2-(2-bromoethoxy)-3,4-difluorobenzene 1b

[0470] 6-Bromo-2,3-difluorophenol 1a (9.10 g, 43.50 mmol, prepared by the known method "Journal of Organic Chemistry, 2016, 81 (20), 9765-9774") and 1,2-dibromoethane (8.20 g, 43.60 mmol) were dissolved in 100 mL of acetonitrile, anhydrous potassium carbonate (8.00 g, 57.90 mmol) was added, and the mixture was heated to 80°C for 5 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 1b (5.85 g, yield: 42.5%).

[0471] 1 H NMR (500MHz, CD3Cl) δ7.31-7.26(m,1H),6.90-6.82(m,1H),4.43(t,2H),3.67(t,2H).

[0472] Step 2

[0473] 6,7-Difluoro-2,3-dihydrobenzofuran 1c

[0474] Compound 1b (9.20 g, 29.12 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran, cooled to -78 ° C under nitrogen atmosphere, and 2.5 M n-butyl lithium in n-hexane solution (12.5 mL) was added dropwise, stirred at -78 ° C for 30 minutes, and slowly returned to room temperature. 300 mL of water was added to the reaction solution to quench the reaction, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 1c (4.32 g, yield: 95.0%).

[0475] 1 H NMR (500MHz, CD3Cl) δ6.87-6.79(m,1H),6.66-6.55(m,1H),4.71(t,2H),3.22(t,2H).

[0476] Step 3

[0477] 6,7-Difluoro-2,3-dihydrobenzofuran-5-carboxylic acid 1d

[0478] Compound 1c (4.32 g, 27.67 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran, cooled to -78 °C under nitrogen atmosphere, and 2.5 M n-butyl lithium in n-hexane solution (11.73 mL) was added dropwise, stirred at -78 °C for 60 minutes, and dry ice was carefully added to slowly return to room temperature. 300 mL of water was added to the reaction solution to quench the reaction, 1 M hydrochloric acid was added dropwise until the pH of the reaction solution was 5-6, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title product 1d (4.00 g, yield: 72.2%).

[0479] 1 H NMR (500MHz, DMSO-d6) δ13.11(s,1H),7.55(d,1H),4.79(t,2H),3.26(t,2H).

[0480] Step 4

[0481] 6,7-Difluoro-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester 1e

[0482] Compound 1d (4.00 g, 19.98 mmol) was dissolved in 50 mL of methanol, 1 mL of concentrated sulfuric acid was carefully added dropwise, and the mixture was heated to 60°C for 18 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1e (3.28 g, yield: 76.7%).

[0483] 1 H NMR (500MHz, CD3Cl) δ7.55(d,1H),4.78(t,2H),3.90(s,3H),3.26(t,1.4Hz,2H).

[0484] Step 5

[0485] 6,7-Difluorobenzofuran-5-carboxylic acid methyl ester 1f

[0486] Compound 1e (3.28 g, 15.33 mmol) was dissolved in 30 mL of chlorobenzene, N-bromosuccinimide (2.70 g, 15.17 mmol) and azobisisobutyronitrile (120 mg, 0.73 mmol) were added, and the mixture was heated at 85°C for 2 hours. The organic solvent was concentrated, 200 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 1f (2.50 g, yield: 76.8%).

[0487] 1 H NMR (500MHz, DMSO-d6) δ7.97-7.92(m,1H),7.70(d,1H),6.82(t,1H),3.94(s,3H).

[0488] Step 6

[0489] 2,3-Dichloro-6,7-difluoro-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester 1g

[0490] Compound 1f (950 mg, 4.48 mmol) was dissolved in 10 mL of dichloromethane, and sulfuryl chloride (2.6 g, 19.26 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 1g (419 mg, yield 33.05%).

[0491] 1H NMR (500MHz, CD3Cl) δ7.90(dd,1H),6.57(s,1H),5.46(s,1H),3.94(s,3H).

[0492] Step 7

[0493] 3-Chloro-6,7-difluorobenzofuran-5-carboxylic acid ethyl ester 1h

[0494] Compound 1g (419 mg, 1.48 mmol) was dissolved in 6 mL of ethanol solution, potassium carbonate (600 mg, 4.34 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 1h (292 mg, yield: 75.6%).

[0495] 1 H NMR (500MHz, CD3Cl) δ7.97(dd,1H),7.75(s,1H),4.44(q,2H),1.43(t,3H).

[0496] Step 8

[0497] 3-Chloro-6,7-difluorobenzofuran-5-carboxylic acid 1i

[0498] Compound 1h (300 mg, 1.15 mmol) was dissolved in 10 mL of tetrahydrofuran, and sodium hydroxide aqueous solution (2.5 M, 2.0 mL) was added, and the mixture was heated at 60°C for 2 hours. 1 M hydrochloric acid was added dropwise until the pH of the reaction solution was 5-6, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1i (320 mg, crude product), which was directly used for the next step without purification.

[0499] MS m / z(ESI):230.9[M-1].

[0500] Step 9

[0501] 6-((4-Bromo-2-fluorophenyl)amino)-3-chloro-7-fluorobenzofuran-5-carboxylic acid 1j

[0502] Compound 1i (100 mg, 0.43 mmol), 4-bromo-2-fluoroaniline (85 mg, 0.45 mmol, Shaoyuan), lithium amide (45 mg, 1.96 mmol) were dissolved in 8 mL of tetrahydrofuran and heated at 85°C with stirring for 2 hours. The pH was adjusted to 5-6 with a 3M saline solution, the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a CombiFlash rapid preparation instrument using an eluent system A to obtain the title product 1j (165 mg, yield: 95%).

[0503] MS m / z(ESI):401.8[M+1].

[0504] Step 10 and 11

[0505] 6-((4-bromo-2-fluorophenyl)amino)-3-chloro-N-(2,3-dihydroxypropoxy)-7-fluorobenzofuran-5-carboxamide 1

[0506] Compound 1j (50 mg, 0.12 mmol) was dissolved in 5 mL of tetrahydrofuran, triethylamine (18 mg, 0.18 mmol) was added, triphosgene (15 mg, 0.05 mmol) was added under ice bath cooling, and O-(2,2-dimethyl-1,3-dioxane-5-yl)hydroxylamine 1k (20 mg, 0.14 mmol, prepared by the method disclosed in "Example 33 on page 43 of the specification of patent application US20046245" was added after stirring for 18 hours at room temperature. Dilute hydrochloric acid (2M, 0.2 mL) was then added to the reaction solution, and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 6-7. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 1 (18 mg, yield 29.2%).

[0507] MS m / z(ESI):490.9[M+H].

[0508] 1 H NMR(500MHz,DMSO-d6)δ11.93(s,1H),8.51(s,1H),8.37(s,1H),7.70(s,1H),7.49(d d,1H),7.22-7.14(m,1H),6.77-6.67(m,1H),4.66(s,2H),3.81(s,1H),3.53(m,4H).

[0509] Example 2

[0510] 6-((4-bromo-2-fluorophenyl)amino)-N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluorobenzofuran-5-carboxamide

[0511]

[0512] first step

[0513] 6,7-Difluoro-2,3-dihydrobenzofuran-5-carbaldehyde 2a

[0514] Compound 1c (1.9 g, 12.17 mmol) and 20 mL of dichloromethane were added to the reaction flask. Titanium tetrachloride (3.7 g, 19.55 mmol, Sinopharm) was added at 0°C and stirred for 5 minutes. 1,1-dichloromethyl ether (2.1 g, 18.26 mmol, Sinopharm) was slowly added dropwise and stirred at room temperature for 12 hours. 100 mL of ice water was added, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 2a (1.6 g, yield: 72.2%).

[0515] MS m / z(ESI):184.9[M+1].

[0516] Step 2

[0517] 6,7-Difluoro-2,3-dihydrobenzofuran-5-carboxylic acid 2b

[0518] Compound 2a (1.6 g, 8.79 mmol) and 40 mL of a mixed solution of tert-butyl alcohol and water (V / V=3:1) were added to a reaction flask. Isoamylene (5.5 g, 79.28 mmol, Chinese medicine), sodium dihydrogen phosphate (4.7 g, 39.58 mmol, Chinese medicine) and sodium chlorite (1.6 g, 17.69 mmol, Chinese medicine) were added in sequence. The reaction was stirred at room temperature for 16 hours. 100 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2b (1.7 g, yield: 96.5%). The product was directly used for the next step without purification.

[0519] MS m / z(ESI):198.9[M-1].

[0520] Step 3

[0521] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-2,3-dihydrobenzofuran-5-carboxylic acid 2c

[0522] Crude compound 2b (1.8 g, 8.99 mmol), 2-fluoro-4-iodoaniline (1.8 g, 9.89 mmol, Shaoyuan), lithium amide (0.83 g, 35.97 mmol, Alfa) and 30 mL of tetrahydrofuran were added to the reaction flask. Nitrogen was replaced three times and the reaction was carried out at 95 ° C for 2 hours. The reaction solution was cooled to room temperature, poured into 100 mL of water, and 2N hydrochloric acid solution was added dropwise to adjust the pH to <7. It was extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 2c (3.0 g, yield: 90.1%)

[0523] MS m / z(ESI):369.8[M+1].

[0524] Step 4

[0525] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester 2d

[0526] Compound 2c (1 g, 2.70 mmol) and 30 mL of methanol were added to a reaction flask, and 1.5 mL of concentrated sulfuric acid was added. The temperature was raised to reflux and the reaction was stirred for 48 hours. The reaction solution was cooled to room temperature and distilled under reduced pressure. 75 mL of ethyl acetate was added to the residue, which was washed with water (75 mL × 1) and saturated sodium chloride solution (75 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 2d (0.76 g, yield: 73.2%).

[0527] MS m / z(ESI):383.9[M+1].

[0528] Step 5

[0529] 6-((4-bromo-2-fluorophenyl)amino)-7-fluorobenzofuran-5-carboxylic acid methyl ester 2e

[0530] Compound 2d (320 mg, 0.74 mmol) and 30 mL of toluene were added to a reaction flask, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.67 g, 2.96 mmol) was added, and the mixture was heated to 110°C for 2 hours. The reaction solution was cooled to room temperature, 70 mL of ethyl acetate was added, washed with water (60 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 2e (0.46 g, yield: 60.5%).

[0531] MS m / z(ESI):381.9[M+1].

[0532] Step 6

[0533] 6-((4-Bromo-2-fluorophenyl)amino)-7-fluorobenzofuran-5-carboxylic acid 2f

[0534] Compound 2e (0.2 g, 523.34 mmol) and 40 mL of tetrahydrofuran were added to a reaction flask, and 2N sodium hydroxide solution (2.0 mL) was added. The reaction solution was heated to 45°C and stirred for 16 hours. The reaction solution was cooled to room temperature and distilled under reduced pressure to remove most of the methanol. 10 mL of water was added and the pH was adjusted to <7 with 2N hydrochloric acid solution. The reaction solution was concentrated under reduced pressure to obtain a crude title product 2f (400 mg, content 50%), which was directly used for the next step without purification.

[0535] MS m / z(ESI):365.9[M-1].

[0536] Step 7

[0537] 6-((4-bromo-2-fluorophenyl)amino)-N-((2,2-dimethyl-1,3-dioxane-5-yl)oxy)-7-fluorobenzofuran-5-carboxamide 2 g

[0538] The crude compound 2f (0.1 g, 271.64 mmol), 1k (48 mg, 326.01 mmol) and 10 mL of N,N-dimethylformamide were added to a reaction flask, and N,N-diisopropylethylamine (175 mg, 1.36 mmol, Ademas) and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (191 mg, 814.9 μmol, Shaoyuan) were added in sequence, and stirred at room temperature for 16 hours. 40 mL of water was added, and the mixture was extracted with ethyl acetate (35 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 2g (0.1 g, yield: 74.0%).

[0539] MS m / z(ESI):496.9[M+1].

[0540] Step 8

[0541] 6-((4-bromo-2-fluorophenyl)amino)-N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluorobenzofuran-5-carboxamide

[0542] Compound 2g (100 mg, 0.22 mmol) and 5 mL of methanol were added to a reaction flask, and 1 mL of 1N hydrochloric acid solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was distilled under reduced pressure, and the resulting residue was purified using a CombiFlash rapid preparation instrument with eluent system A to obtain the title product 2 (32 mg, yield: 31.2%).

[0543] MS m / z(ESI):457.0[M+1].

[0544] 1 HNMR(400MHz,DMSO-d6)δ11.74(s,1H),8.16(d,1H),7.72(s,1H),7.48-7.45(m,1H),7. 16-7.14(m,2H),6.62-6.58(m,1H),4.65(s,2H),3.78-3.74(m,1H),3.53-3.49(m,4H).

[0545] Example 3

[0546] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-N-(2-hydroxyethoxy)benzofuran-5-carboxamide

[0547]

[0548]

[0549] first step

[0550] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-N-(2-(vinyloxy)ethoxy)benzofuran-5-carboxamide 3a

[0551] Compound 2f (0.1 g, 271.64 μmol), 1-[2-(aminooxy)ethoxy]ethylene (33.6 mg, 326.02 μmol, Shaoyuan) and 10 mL of N,N-dimethylformamide were added to a reaction flask, followed by N,N-diisopropylethylamine (175.23 mg, 1.36 mmol, Ademas) and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (191.73 mg, 814.95 μmol, Shaoyuan), and stirred at room temperature for 16 hours. 40 mL of water was added, extracted with ethyl acetate (35 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 3a (0.1 g, yield: 81.2%).

[0552] MS m / z(ESI):452.9[M+1].

[0553] Step 2

[0554] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-N-(2-hydroxyethoxy)benzofuran-5-carboxamide

[0555] Compound 3a (100 mg, 0.22 mmol) and 5 mL of methanol were added to a reaction flask, and 1 mL of 1N hydrochloric acid solution was added, and stirred at room temperature for 2 hours. The reaction solution was distilled under reduced pressure, and the resulting residue was purified using a CombiFlash rapid preparation instrument with eluent system A to obtain the title product 3 (32 mg, yield: 34.0%).

[0556] MS m / z(ESI):427.0[M+1].

[0557] 1 HNMR(400MHz,DMSO-d6)δ11.75(s,1H),8.23(s,1H),8.16(d,1H),7.70(s,1H),7.47( t,1H),7.16-7.13(m,2H),6.64-6.51(m,1H),4.70(s,1H),3.83(t,2H),3.55(t,2H).

[0558] Example 4

[0559] 6-((4-bromo-2-fluorophenyl)amino)-N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-3-methylbenzofuran-5-carboxamide

[0560]

[0561]

[0562] first step

[0563] 2-(Allyloxy)-1-bromo-3,4-difluorobenzene 4b

[0564] Compound 6-bromo-2,3-difluorophenol 4a (3.0 g, 14.35 mmol, prepared by the known method "Journal of Organic Chemistry, 2018, 83 (15), 7907-7918") was dissolved in 50 mL of acetone, and anhydrous potassium carbonate (3.969 g, 28.71 mmol) and allyl bromide (1.911 g, 15.79 mmol, 1.36 mL, Admas) were added, and the reaction solution was heated to 70 ° C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to obtain the target compound 4b (2.838 g, yield: 79.3%)

[0565] Step 2

[0566] 6,7-Difluoro-3-methyl-2,3-dihydrobenzofuran 4c

[0567] Under nitrogen atmosphere, compound 4b (1.838 g, 7.38 mmol) was dissolved in 120 mL of toluene, tributyltin hydride (2.578 g, 8.85 mmol, 2.3 mL) and azobisisobutyronitrile (122 mg, 742.9 μmol) were added, and the reaction solution was heated to 90°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the target compound 4c (1.148 g, yield: 91.4%).

[0568] Step 3

[0569] 6,7-Difluoro-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid 4d

[0570] Under nitrogen atmosphere, compound 4c (1.148 g, 6.74 mmol) was dissolved in 50 mL of tetrahydrofuran, cooled to -78 °C, and n-butyl lithium (3 mL, 7.41 mmol, 2.5 M) was added dropwise. The mixture was stirred for 2 hours. Dry ice was then added and the mixture was naturally heated to room temperature. Water was added to the reaction solution, and the pH of the reaction solution was adjusted to less than 7 with concentrated hydrochloric acid. The aqueous phase was extracted with ethyl acetate (80 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 4d (686 mg, yield: 47.4%).

[0571] Step 4

[0572] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid 4e

[0573] 4-Bromo-2-fluoroaniline (670 mg, 3.52 mmol, Bidex Pharmaceuticals), compound 4d (686 mg, 3.20 mmol), and lithium amide (370 mg, 16.11 mmol) were added to 30 mL of tetrahydrofuran and heated to 80°C for 2 hours. The reaction solution was cooled to room temperature, and the pH of the reaction solution was adjusted to 2-3 with 1N hydrochloric acid, and then ethyl acetate was added for extraction (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 4e (1.12 g, yield: 91.0%).

[0574] Step 5

[0575] Methyl 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-3-methyl-2,3-dihydrobenzofuran-5-carboxylate 4f

[0576] Compound 4e (650 mg, 1.69 mmol) was dissolved in 30 mL of tetrahydrofuran, cooled to 0°C, triethylamine (364 mg, 3.59 mmol, 0.5 mL) and triphosgene (225 mg, 758.2 μmol) were added, stirred for 1 hour, and then 30 mL of methanol was added, stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 4f (193 mg, yield: 28.6%).

[0577] Step 6

[0578] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-3-methylbenzofuran-5-carboxylic acid methyl ester 4g

[0579] Compound 4f (193 mg, 484.6 μmol) was dissolved in 30 mL of toluene, 2,3-dichloro-5,6-dicyano-p-benzoquinone (165 mg, 726.8 μmol) was added, and the mixture was heated to 110°C for 1.5 hours. The reaction solution was concentrated under reduced pressure, 30 mL of water and 30 mL of ethyl acetate were added to the residue, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, passed through anhydrous sodium sulfate column, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 4g (183 mg, yield: 95.3%).

[0580] Step 7

[0581] 6-((4-Bromo-2-fluorophenyl)amino)-7-fluoro-3-methylbenzofuran-5-carboxylic acid 4h

[0582] Compound 4g (183 mg, 461.9 μmol) was dissolved in a mixed solvent of 30 mL methanol and tetrahydrofuran (V / V=1:1), sodium hydroxide (1 M, 2.5 mL) was added, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to 2-3 with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 4h (196 mg, crude product), which was directly used for the next step without purification.

[0583] Step 8

[0584] 6-((4-bromo-2-fluorophenyl)amino)-N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-3-methylbenzofuran-5-carboxamide

[0585] Compound 4h (100 mg, 261.6 μmol) was dissolved in 30 mL of tetrahydrofuran, cooled to 0°C, triethylamine (40 mg, 395.2 μmol, 55 μL) and triphosgene (31 mg, 104.4 μmol) were added, stirred for 1 hour, and compound 1k (46 mg, 312.5 μmol) was added, stirred at room temperature for overnight. 30 mL of saturated sodium bicarbonate aqueous solution was added to quench, the liquids were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system D to obtain the target compound 4 (40 mg, yield: 32.4%).

[0586] MS m / z(ESI):472.9[M+1].

[0587] 1 H NMR (400MHz, DMSO-d6): δ11.78(s,1H),8.20(s,1H),7.96(s,1H),7.72(s,1H),7.48(dd,1H),7.15-7 .17(m,1H),6.59-6.63(m,1H),4.66-4.68(m,2H),3.77-3.79(m,1H),3.49-3.56(m,4H),2.26(s,3H).

[0588] Example 5

[0589] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzofuran-5-carboxamide

[0590]

[0591] The synthetic route of compound 4 in Example 4 was adopted, and the raw material compound 1k in the eighth step was replaced by the raw material 1-[2-(aminooxy)ethoxy]ethylene (Shaoyuan) to obtain the title compound 5 (40 mg).

[0592] MS m / z(ESI):442.9[M+1].

[0593] 1 H NMR (400MHz, DMSO-d6): δ11.78(s,1H),8.28(s,1H),7.96(s,1H),7.69(s,1H),7.48(dd,1H),7.15 -7.17(m,1H),6.60-6.65(m,1H),4.72(t,1H),3.86-3.88(m,2H),3.55-3.59(m,2H),2.25(s,3H).

[0594] Example 6

[0595] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

[0596]

[0597] first step

[0598] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-N-(2-(vinyl)ethoxy)-2,3-dihydrobenzofuran-5-carboxamide 6a

[0599] Compound 2c (0.1 g, 270.16 μmol), 1-[2-(aminooxy)ethoxy]ethylene (33 mg, 324.28 μmol, Shaoyuan) and 10 mL of N,N-dimethylformamide were added to a reaction flask, followed by N,N-diisopropylethylamine (174 mg, 1.36 mmol, Ademas) and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (190 mg, 810.53 μmol, Shaoyuan), and stirred at room temperature for 16 hours. 40 mL of water was added, extracted with ethyl acetate (35 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 6a (0.12 g, yield: 97.5%).

[0600] MS m / z(ESI):455.0[M+1].

[0601] Step 2

[0602] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-N-(2-hydroxyethoxy)-2,3-dihydrobenzofuran-5-carboxamide

[0603] Compound 6a (120 mg, 263.59 μmol) and 5 mL of methanol were added to a reaction flask, and 1 mL of 1N hydrochloric acid solution was added. The reaction solution was distilled under reduced pressure, and the resulting residue was purified using a CombiFlash rapid preparation instrument with eluent system A to obtain the title product 6 (40 mg, yield: 35.3%).

[0604] MS m / z(ESI):428.9[M+1].

[0605] 1 HNMR(400MHz,DMSO-d6)δ11.64(s,1H),8.65(s,1H),7.49-7.46(m,1H),7.31(s,1H),7.21-7. 18(m,1H),6.65-6.61(m,1H),4.75-4.69(m,3H),3.83(t,2H),3.55(t,2H),3.29-3.24(m,2H).

[0606] Example 7

[0607] 6-((4-bromo-2-fluorophenyl)amino)-N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-2,3-dihydrobenzofuran-5-carboxamide 7

[0608]

[0609]

[0610] first step

[0611] 6-((4-bromo-2-fluorophenyl)amino)-N-((2,2-dimethyl-1,3-dioxan-5-yl)oxy)-7-fluoro-2,3-dihydrobenzofuran-5-carboxamide 7a

[0612] Compound 2c (50 mg, 135.08 μmol), 1k (26 mg, 175.64 μmol) and 10 mL of N,N-dimethylformamide were added to a reaction flask, followed by N,N-diisopropylethylamine (87 mg, 675.42 μmol, Ademas) and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (154 mg, 405.25 μmol, Shaoyuan), and stirred at room temperature for 16 hours. 40 mL of water was added, extracted with ethyl acetate (35 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 7a (30 mg, yield: 44.5%).

[0613] MS m / z(ESI):496.9[M+1].

[0614] Step 2

[0615] 6-((4-bromo-2-fluorophenyl)amino)-N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-2,3-dihydrobenzofuran-5-carboxamide 7

[0616] Compound 7a (30 mg, 60.12 μmol) and 5 mL of methanol were added to a reaction flask, and 1 mL of 1N hydrochloric acid solution was added. The reaction solution was distilled under reduced pressure, and the resulting residue was purified using a CombiFlash rapid preparation instrument with eluent system A to obtain the title product 7 (15 mg, yield: 54.5%).

[0617] MS m / z(ESI):460.9[M+1].

[0618] 1 HNMR(400MHz,DMSO-d6)δ7.47-7.45(m,1H),7.39(s,1H),7.20-7.18(m,1H),6.6 4-6.59(m,1H),4.72(t,2H),3.70-3.68(m,1H),3.49-3.47(m,4H),3.25(t,2H).

[0619] Example 8

[0620] 6-((4-bromo-2-fluorophenyl)amino)-7-fluoro-N-((1-hydroxy-2-methylprop-2-yl)oxy)benzofuran-5-carboxamide 8

[0621]

[0622]

[0623] Compound 2f (35 mg, 95.07 μmol), 2-(aminooxy)-2-methylpropan-1-ol 8a (20 mg, 190.15 μmol, prepared by the method disclosed in Example 63 on page 48 of the specification of the well-known synthesis method "US200454172A1") and 5 mL N,N-dimethylformamide was added to the reaction flask, followed by N,N-diisopropylethylamine (37 mg, 286.28 μmol) and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (55 mg, 144.65 μmol), and stirred at room temperature for 16 hours. 40 mL of water was added, extracted with ethyl acetate (35 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 8 (12 mg, yield: 27.7%).

[0624] MS m / z(ESI):454.8[M+1].

[0625] 1 HNMR(400MHz,DMSO-d6)δ11.25(s,1H),8.19(s,1H),8.01(s,1H),7.74(s,1H),7.47(d, 1H),7.19(s,1H),7.15(d,1H),6.56(dt,1H),4.66(brs,1H),3.20(s,2H),1.12(s,6H).

[0626] Example 9

[0627] N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-3-methylbenzofuran-5-carboxamide 9

[0628]

[0629]

[0630] first step

[0631] 7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid 9a

[0632] 4d (8.3 g, 39.98 mmol, Bidex Pharmaceuticals), compound 4-iodo-2-fluoroaniline (9.5 g, 40.16 mmol), lithium amide (3.6 g, 156.33 mmol) were added to 100 mL of tetrahydrofuran and heated to 90°C for 2 hours. The reaction solution was cooled to room temperature, the pH of the reaction solution was adjusted to 2-3 with 1N hydrochloric acid, and then ethyl acetate was added for extraction (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 9a (16 g, yield: 95.1%).

[0633] MS m / z(ESI):431.9[M+1].

[0634] Step 2

[0635] 7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester 9b

[0636] Compound 9a (3 g, 6.95 mmol) and 60 mL of methanol were added to a reaction flask, and 2 mL of concentrated sulfuric acid was added. The temperature was raised to reflux and the reaction was stirred for 48 hours. The reaction solution was cooled to room temperature and distilled under reduced pressure. 75 mL of ethyl acetate was added to the residue, which was washed with water (75 mL × 1) and saturated sodium chloride solution (75 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 9b (2.45 g, yield: 79.1%).

[0637] MS m / z(ESI):445.9[M+1].

[0638] Step 3

[0639] 7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-3-methylbenzofuran-5-carboxylic acid methyl ester 9c

[0640] Compound 9b (2.45 g, 5.50 mmol) was dissolved in 60 mL of toluene, 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.88 g, 8.28 mmol) was added, and the mixture was heated to 100°C for 1.5 hours. The reaction solution was concentrated under reduced pressure, 60 mL of water and 60 mL of ethyl acetate were added to the residue, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (60 mL×3), the organic phases were combined, passed through anhydrous sodium sulfate column, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 9c (1.2 g, yield: 49.2%).

[0641] Step 4

[0642] 7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-3-methylbenzofuran-5-carboxylic acid 9d

[0643] Compound 9c (1.2 g, 2.70 mmol) was dissolved in a mixed solvent of 30 mL methanol and tetrahydrofuran (V / V=1:1), sodium hydroxide (1 M, 2.5 mL) was added, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to 2-3 with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 9d (196 mg, crude product), which was directly used for the next step without purification.

[0644] MS m / z(ESI):429.8[M+1].

[0645] Step 5

[0646] N-((2,2-dimethyl-1,3-dioxan-5-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-3-methylbenzofuran-5-carboxamide 9e

[0647] Compound 9d (0.22 g, 512.63 μmol), 1k (90.5 mg, 619.20 mmol) and 10 mL of N,N-dimethylformamide were added to a reaction flask, followed by N,N-diisopropylethylamine (330.6 mg, 2.56 mmol, Ademas) and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (390 mg, 1.02 mmol, Shaoyuan), and stirred at room temperature for 16 hours. 40 mL of water was added, extracted with ethyl acetate (35 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 9e (0.2 g, yield: 69.8%).

[0648] MS m / z(ESI):557.4[M-1].

[0649] Step 6

[0650] N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-3-methylbenzofuran-5-carboxamide 9

[0651] Compound 9e (200 mg, 308.22 μmol) and 10 mL of methanol were added to a reaction flask, and 2 mL of 1N hydrochloric acid solution was added. The reaction solution was distilled under reduced pressure, and the resulting residue was purified using a CombiFlash rapid preparation instrument with eluent system A to obtain the title product 9 (100 mg, yield: 53.8%).

[0652] MS m / z(ESI):518.9[M+1].

[0653] 1 H NMR (500MHz, DMSO-d6): δ11.79(s,1H),8.23(s,1H),7.95(s,1H),7.71(s,1H),7.55(dd,1H),7. 29(dd,1H),6.47-6.43(m,1H),4.70(s,2H),3.77-3.75(m,1H),3.54-3.50(m,4H),2.24(s,3H).

[0654] Example 10

[0655] 7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-3-methylbenzofuran-5-carboxamide 10

[0656]

[0657] first step

[0658] 7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-3-methyl-N-(2-(vinyloxy)ethoxy)benzofuran-5-carboxamide 10a

[0659] Compound 9d (0.7 g, 709.53 μmol), 1-[2-(aminooxy)ethoxy]ethylene (80 mg, 780.55 μmol, Shaoyuan) and 10 mL of N,N-dimethylformamide were added to a reaction flask, followed by N,N-diisopropylethylamine (457.6 mg, 3.55 mmol, Ademas) and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (500 mg, 2.13 mmol, Shaoyuan), and stirred at room temperature for 16 hours. 40 mL of water was added, extracted with ethyl acetate (35 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system B to obtain the title product 10a (0.3 g, yield: 41.1%).

[0660] MS m / z(ESI):512.9[M-1].

[0661] Step 2

[0662] 7-Fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-3-methylbenzofuran-5-carboxamide 10

[0663] Compound 10a (300 mg, 583.36 μmol) and 10 mL of methanol were added to a reaction flask, and 2 mL of 1N hydrochloric acid solution was added. The reaction solution was distilled under reduced pressure, and the resulting residue was purified using a CombiFlash rapid preparation instrument with eluent system A to obtain the title product 10 (120 mg, yield: 42.1%).

[0664] MS m / z(ESI):488.9[M+1].

[0665] 1 H NMR (500MHz, DMSO-d6): δ11.76(s,1H),8.29(s,1H),7.94(s,1H),7.68(s,1H),7.54(dd,1H) ,7.29(dd,1H),6.49-6.44(m,1H),4.71(s,1H),3.86-3.82(m,2H),3.56(t,2H),2.24(s,3H).

[0666] Embodiment 11

[0667] 3-Chloro-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzofuran-5-carboxamide 11

[0668]

[0669] first step

[0670] 3-Chloro-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxylic acid 11a

[0671] Compound 1i (110 mg, 0.47 mmol), 4-iodo-2-fluoroaniline (115 mg, 0.48 mmol, Shaoyuan), lithium amide (50 mg, 2.18 mmol, Adamas) were dissolved in 8 mL of tetrahydrofuran and heated at 85°C with stirring for 2 hours. The pH was adjusted to 5-6 with a 3M saline solution, the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a CombiFlash rapid preparation instrument using an eluent system A to obtain the title product 11a (217 mg, yield: 102%).

[0672] MS m / z(ESI):449.8[M+1].

[0673] Step 2

[0674] 3-Chloro-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzofuran-5-carboxamide 11

[0675] Compound 11a (100 mg, 0.22 mmol) was dissolved in 5 mL of tetrahydrofuran, triethylamine (35 mg, 0.35 mmol, Sinopharm) was added, triphosgene (30 mg, 0.10 mmol, Adamas) was added under ice-bath cooling, 1-[2-(aminooxy)ethoxy]ethylene (25 mg, 0.24 mmol, Shaoyuan) was added after stirring for 1 hour, and the mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was added dropwise until the pH of the reaction solution was 6-7, the liquid was separated, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 11 (16 mg, yield 14.2%). MS m / z (ESI): 508.8 [M+H].

[0676] 1 H NMR(500MHz,DMSO-d6)δ11.91(s,1H),8.49(s,2H),7.67(s,1H),7.56(d,1 H),7.32(d,1H),6.65-6.50(m,1H),4.72(s,1H),3.86(s,2H),3.57(s,2H).

[0677] Example 12

[0678] 3-Chloro-N-((1,3-dihydroxypropan-2-yl)oxy)-7-fluoro-6-((2-fluoro-4-iodophenyl)amino)benzofuran-5-carboxamide 12

[0679]

[0680] Compound 11a (100 mg, 0.22 mmol) was dissolved in 5 mL of tetrahydrofuran, triethylamine (35 mg, 0.35 mmol, Chinese medicine) was added, triphosgene (30 mg, 0.10 mmol, Adamas) was added under ice bath cooling, 1k (36 mg, 0.24 mmol) was added after stirring for 1 hour, and stirred at room temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was added dropwise until the pH of the reaction solution was 6-7, the liquids were separated, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 12 (30 mg, yield 25.0%).

[0681] MS m / z(ESI):538.8[M+H].

[0682] 1 H NMR(500MHz,DMSO-d6)δ11.91(s,1H),8.50(s,1H),8.38(s,1H),7.70(s,1H),7.56(d,1H) ,7.35-7.28(m,1H),6.62-6.52(m,1H),4.66(s,2H),3.86-3.75(m,1H),3.61-3.47(m,4H).

[0683] Embodiment 13

[0684] 6-((4-bromo-2-fluorophenyl)amino)-3-chloro-7-fluoro-N-(2-hydroxyethoxy)benzofuran-5-carboxamide 13

[0685]

[0686]

[0687] Compound 1j (50 mg, 0.12 mmol) was dissolved in 5 mL of tetrahydrofuran, triethylamine (18 mg, 0.17 mmol, Sinopharm) was added, triphosgene (15 mg, 0.05 mmol, Adamas) was added under ice-bath cooling, and 1-[2-(aminooxy)ethoxy]ethylene (15 mg, 0.14 mmol, Shaoyuan) was added after stirring for 1 hour, and stirred at room temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was added dropwise until the pH of the reaction solution was 6-7, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with eluent system A to obtain the title compound 13 (32 mg, yield 55.8%).

[0688] MS m / z(ESI):460.8[M+H].

[0689] 1 H NMR(500MHz,DMSO-d6)δ11.92(s,1H),8.50(s,1H),8.44(s,1H),7.67(s,1H),7.49 (dd,1H),7.21-7.13(m,1H),6.72(td,1H),4.72(s,1H),3.87(s,2H),3.58(s,2H).

[0690] Comparative Example A and Comparative Example B

[0691]

[0692] The compounds of Comparative Examples A and B were prepared with reference to Examples 3 and 2 of CN104774188A.

[0693] Test example:

[0694] Biological evaluation

[0695] Test Example 1: Determination of the proliferation inhibition of COLO205 by the disclosed compounds

[0696] The in vitro cell experiment described below can determine the proliferation inhibitory activity of the test compound on human colon cancer cell lines. Its activity can be measured by IC 50 Values ​​are used to represent. On the first day of the experiment, COLO205 cells (ATCC, CRL-222) were seeded in a 96-well plate at a density of 5000 cells / well using RPMI medium containing 2% FBS, with 90 μL of cell suspension in each well, and the plates were cultured overnight in a 37°C, 5% CO2 cell culture incubator. On the second day, 10 μL of gradient dilutions of the compound to be tested prepared with plating medium were added to each well. The final concentration of the compound was 9 concentration points with a 4-fold gradient dilution starting from 1 μM. Blank control cell wells and cell-free control wells containing 0.5% DMSO were set, and the well plates were cultured in a 37°C, 5% CO2 cell culture incubator for 72 hours. On the fifth day, the 96-well cell culture plate was taken out, and 50 μL of the compound to be tested was added to each well. Luminescent Cell Viability Assay (Promega, G7573), after standing at room temperature for 10 minutes, the luminescent signal value was read using a multifunctional microplate reader (PerkinElmer, VICTOR 3). The inhibition rate of each concentration of the compound was calculated by the control well, and the curve was fitted and the IC was calculated based on the logarithmic concentration and inhibition rate of the compound using GraphPad Prism. 50 value.

[0697] The biological activity of the disclosed compounds was determined by the above analysis, and the calculated IC 50 The values ​​are shown in Table 1:

[0698] Table 1 Proliferation inhibition activity of the disclosed compounds on COLO205 cells

[0699] Example No. <![CDATA[COLO205 IC 50 (nM)]]> 2 28.0 3 14.1 4 111.2 6 74.8 7 79.8 9 7.8 10 8.3 11 24.5 12 9.3 13 86.1

[0700] Conclusion: The disclosed compounds have significant proliferation inhibitory activity on COLO205 cells.

[0701] Test Example 2: Biological evaluation of the inhibition of ERK phosphorylation in COLO205 cells by the disclosed compounds I. Test purpose

[0702] This experiment detects the inhibitory effect of compounds on cell ERK phosphorylation. 50 The inhibitory effect of the disclosed compounds on the MEK target was evaluated.

[0703] 2. Experimental Methods

[0704] COLO205 cells (ATCC, CCL-222) were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, COLO205 was seeded in a 96-well plate at a density of 63,000 cells / well using complete medium, with 90 μL of cell suspension per well, and cultured overnight in a 37°C, 5% CO2 cell culture incubator. On the second day, 10 μL of the compound to be tested prepared in complete medium was added to each well, and the final concentration of the compound was 9 concentration points of 4-fold gradient dilution starting from 1 μM, and a blank control containing 0.5% DMSO was set up. The well plate was placed in a 37°C, 5% CO2 cell culture incubator for 4 hours. After 4 hours, the 96-well cell culture plate was removed, the medium was aspirated, and 200 μL PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well to wash once. PBS was removed, and 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well. The well plate was placed on a shaker for 40 minutes at room temperature for lysis. After lysis, the well was mixed by pipetting, and 16 μL of lysis solution was transferred to each well into two HTRF 96-well detection plates (Cisbio, 66PL96100), and then 4 μL of premixed phospho-ERK1 / 2 antibody solution (Cisbio, 64AERPEG) or 4 μL of premixed total-ERK1 / 2 antibody solution (Cisbio, 64NRKPEG) was added to the two plates. The microplate was sealed with a sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark. On the third day, the fluorescence values ​​of 337 nm excitation and 665 nm and 620 nm emission wavelengths were read using a PHERAstar multifunctional microplate reader (BMG Labtech, S / N 471-0361). 665nm / Signal value 620nm The ratio of pERK to total ERK corresponding to each concentration of the compound was calculated using the formula.

[0705] 3. Data Analysis

[0706] Graphpad Prism software was used to calculate the IC of the inhibitory activity of the compound based on the compound concentration and the ratio of pERK / total ERK. 50 The results are shown in Table 2 below.

[0707] Table 2 Inhibitory activity data of the disclosed compounds on ERK phosphorylation in COLO205 cells

[0708] Example No. <![CDATA[IC 50 (nM) <!-- 61 -->]]> 1 112.7 2 12.7 3 4.9 4 43.7 5 42.8 6 33.5 7 38.1 8 83.6 9 12.6 10 11.4 11 33.1 12 26.6 13 129.7

[0709] Conclusion: The disclosed compounds have a good inhibitory effect on ERK phosphorylation in COLO205 cells.

[0710] Test Example 3: Inhibitory effect of the disclosed compounds on the enzyme activity of the CYP3A4 testosterone metabolic site in human liver microsomes

[0711] The enzyme activity of the disclosed compounds on the testosterone metabolism site of human liver microsome CYP3A4 was determined by the following experimental method:

[0712] 1. Experimental Materials and Instruments

[0713] 1. Phosphate buffer (20×PBS, purchased from Bioscientific),

[0714] 2. NADPH (ACROS, A2646-71-1),

[0715] 3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 905002, Donor 35),

[0716] 4. ABI QTrap 4000 LC / MS instrument (AB Sciex),

[0717] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA),

[0718] 6. CYP probe substrate (testosterone, Wokai, CAS No. [58-22-0]), and positive control inhibitor (ketoconazole, SIGMA, Cat No. K1003-100MG).

[0719] 2. Experimental steps

[0720] Prepare 100mM PBS buffer, use the buffer to prepare 7.5mM MgCl2 and 5mM NADPH solution, then use the 7.5mM MgCl2 to prepare 0.25mg / mL microsome solution, dilute the 30mM stock solution with DMSO to a series of solutions I with concentrations of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, 0mM, and 0mM, and then use phosphate buffer (PBS) to dilute the above series of solutions I 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0μM). Dilute the testosterone working solution to a concentration of 375μM with PBS.

[0721] Take 40 μL of 0.25 mg / mL microsomal solution prepared in 7.5 mM Mgcl2, and then take 20 μL of 375 μM testosterone working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM) respectively, and mix well. The positive control group uses the same concentration of ketoconazole instead of the compound. At the same time, pre-incubate 5 mM NADPH solution at 37 ° C for 5 minutes. After 5 minutes, add 20 μL NADPH to each well, start the reaction, and incubate for 30 minutes. After 30 minutes, add 250 μL of acetonitrile containing internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of supernatant and mix with 80 μL ultrapure water, and transfer to LC-MS / MS analysis.

[0722] The values ​​were calculated by Graphpad Prism to obtain the IC of the drug for the CYP3A4 testosterone metabolism site. 50 See Table 3 for values.

[0723] Table 3 IC values ​​of the disclosed compounds for the testosterone metabolism site of human liver microsomal CYP3A4 50 value

[0724] Example No. <![CDATA[IC 50 (μM)]]> 3 >30 9 >30 Comparative Example A 1.5 Comparative Example B 2.3

[0725] Conclusion: The disclosed compounds have weaker inhibition on the testosterone metabolic site of human liver microsomal CYP3A4, showing better safety, suggesting that metabolic drug interactions based on the CYP3A4 testosterone metabolic site will not occur; and the effect is significant compared with comparative examples A and B.

[0726] Test Example 4: Inhibitory effect of the disclosed compounds on the enzyme activity of the CYP2C9 diclofenac metabolic site in human liver microsomes

[0727] The enzyme activity of the disclosed compounds on the diclofenac metabolic site of human liver microsome CYP2C9 was determined using the following experimental method:

[0728] 1. Experimental Materials and Instruments

[0729] 1. Phosphate buffer (20×PBS, purchased from Bioscientific),

[0730] 2. NADPH (ACROS, A2646-71-1),

[0731] 3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 9050002, Donor, 35)

[0732] 4. ABI QTrap 4000 LC / MS instrument (AB Sciex),

[0733] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA),

[0734] 6. CYP probe substrate (diclofenac, SIGMA, Cat No. D6899-10G) and positive control inhibitor (sulfaphenazole, SIGMA, Cat No. 526-08-9).

[0735] 2. Experimental steps

[0736] Prepare 100mM PBS buffer, use the buffer to prepare 7.5mM MgCl2 and 5mM NADPH solution, then use the 7.5mM MgCl2 to prepare 0.25mg / mL microsome solution, dilute the 30mM stock solution with DMSO to a series of solutions I with concentrations of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, 0mM, and 0mM, and then use phosphate buffer (PBS) to dilute the above series of solutions I 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0μM). Dilute the diclofenac working solution to a concentration of 20μM with PBS.

[0737] Take 40 μL of 0.25 mg / mL microsomal solution prepared in 7.5 mM MgCl2, and then take 20 μL of 15 μM diclofenac working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM) respectively, and mix them evenly. The positive control group used sulfaphenazole of the same concentration instead of the compound. At the same time, pre-incubate the 5 mM NADPH solution at 37 ° C for 5 minutes. After 5 minutes, add 20 μL NADPH to each well to start the reaction and incubate for 30 minutes. All incubation samples are set as double samples. After 30 minutes, add 250 μL of acetonitrile containing internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of supernatant and mix with 80 μL ultrapure water, and transfer to LC-MS / MS analysis.

[0738] The values ​​were calculated by Graphpad Prism to obtain the IC of the drug for the CYP2C9 diclofenac metabolic site. 50 See Table 4 for values.

[0739] Table 4 IC values ​​of the compounds disclosed herein for the diclofenac metabolic site of human liver microsome CYP2C9 50 value

[0740] Example No. <![CDATA[IC 50 (μM)]]> 3 >30 Comparative Example A <1 Comparative Example B 4.4

[0741] Conclusion: The disclosed compounds have weak inhibitory effects on the diclofenac metabolic site of human liver microsome CYP2C9, showing better safety, suggesting that metabolic drug interactions based on the diclofenac metabolic site of CYP2C9 will not occur; and the effects are significant compared with comparative examples A and B.

[0742] Test Example 5: Inhibitory effect of the disclosed compounds on the enzyme activity of the dextromethorphan metabolic site of CYP2D6 in human liver microsomes

[0743] The enzyme activity of the disclosed compounds on the dextromethorphan metabolic site of human liver microsome CYP2D6 was determined using the following experimental method:

[0744] 1. Experimental Materials and Instruments

[0745] 1. Phosphate buffer (20×PBS, purchased from Bioscientific),

[0746] 2. NADPH (ACROS, A2646-71-1),

[0747] 3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 9050002, Donor, 35)

[0748] 4. ABI QTrap 4000 LC / MS instrument (AB Sciex),

[0749] 5. ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent Technologies, USA),

[0750] 6. CYP probe substrate (dextromethorphan, Sigma, Cat No. D9684-5G) and positive control inhibitor (quinidine, SIGMA, Q0750-5G).

[0751] 2. Experimental steps

[0752] Prepare 100mM PBS buffer, use the buffer to prepare 7.5mM MgCl2 and 5mM NADPH solution, then use the 7.5mM MgCl2 to prepare 0.25mg / mL microsome solution, dilute the 30mM stock solution with DMSO to a series of solutions I with concentrations of 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, 0mM, and 0mM, and then use phosphate buffer (PBS) to dilute the above series of solutions I 200 times to obtain a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0μM). Dilute the dextromethorphan working solution to a concentration of 20μM with PBS.

[0753] Take 40 μL of 0.25 mg / mL microsomal solution prepared in 7.5 mM MgCl2, and then take 20 μL of 15 μM dextromethorphan working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0 μM) respectively, and mix them evenly. The positive control group uses quinidine at the same concentration instead of compound. At the same time, pre-incubate 5 mM NADPH solution at 37 ° C for 5 minutes. After 5 minutes, add 20 μL NADPH to each well, start the reaction, and incubate for 30 minutes. All incubation samples are set as double samples. After 30 minutes, add 250 μL acetonitrile containing internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, and then centrifuge at 3700 rpm for 10 minutes. Take 100 μL of supernatant and mix with 80 μL ultrapure water, and transfer to LC-MS / MS analysis.

[0754] The values ​​were calculated by Graphpad Prism to obtain the IC of the drug for the CYP2D6 dextromethorphan metabolic site. 50 See Table 5 for values.

[0755] Table 5 IC values ​​of the compounds disclosed herein for the dextromethorphan metabolic site of human liver microsome CYP2D6 50 value

[0756] Example No. <![CDATA[IC 50 (μM)]]> 3 >30 9 20.9 Comparative Example A 2.2 Comparative Example B 6.8

[0757] Conclusion: The disclosed compounds have weak inhibitory effects on the dextromethorphan metabolic site of human liver microsome CYP2D6, showing better safety, suggesting that metabolic drug interactions based on the CYP2D6 dextromethorphan metabolic site will not occur; and the effects are significant compared with comparative examples A and B.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following structures:

2. A compound selected from the following structures:

3. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 3, in the preparation of a drug for inhibiting MEK.

5. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 3, in the preparation of a medicament for treating an inflammatory disorder, an autoimmune disease, a cardiovascular disorder, a proliferative disease or a nociceptive disorder.

6. The use according to claim 5, wherein the proliferative disease is cancer or polycythemia vera.

7. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3 in the preparation of a medicament for treating cancer, wherein the cancer is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteoma, seminoma, testicular tumor, endometrial cancer, cervical cancer, head and neck tumor, multiple myeloma, malignant lymphoma, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma or pediatric tumor.

8. The use according to claim 7, wherein the cancer is colorectal cancer or lung cancer; the sarcoma is osteosarcoma; and the bone tumor is osteochondroma.

9. The use according to claim 7, wherein the drug is further used in combination with one or more other anticancer agents.

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